INHIBITORS OF GLYCOGEN SYNTHASE 1 (GYS1) AND METHODS OF USE THEREOF

20230104740 · 2023-04-06

Inventors

Cpc classification

International classification

Abstract

Provided herein are compounds of formula (I′):

##STR00001##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y.sup.2, Y.sup.3, L.sup.1, L.sup.2, X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, Q.sup.1, R.sup.1, R.sup.2, R.sup.k, R.sup.m, and R.sup.n are as defined elsewhere herein. Also provided herein are methods of preparing compounds of formula (I′). Also provided herein are methods of inhibiting GYS1 and methods of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

Claims

1: A compound of formula (I-A): ##STR01896## or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Y.sup.1 is CH or N; R.sup.x and R.sup.z are independently H, halo, C.sub.1-6alkyl, or —NH.sub.2, wherein, when Y.sup.1 is CH, the C.sub.1-6alkyl of R.sup.x or R.sup.z may be optionally substituted with one or more halo; R.sup.y is (i) C.sub.1-6alkyl, or (ii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl; R.sup.k is H, halo, —OH, —NH.sub.2, or —NH—C(O)C.sub.1-6alkyl; R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b; and R.sup.b is halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, C.sub.3-10cycloalkyl, 3-15 membered heterocyclyl, or —C(O)—C.sub.1-6alkoxy, wherein the C.sub.1-6alkyl of R.sup.b is optionally substituted with one or more halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, and the 3-15-membered heterocyclyl of R.sup.b is optionally substituted with one or more halo or —C(O)—C.sub.1-6alkoxy.

2: The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the moiety represented by ##STR01897## has a stereochemical configuration of the formula: ##STR01898##

3.-5. (canceled)

6: The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the moiety represented by ##STR01899## is selected from the group consisting of ##STR01900##

7: The compound of claim 6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the moiety represented by ##STR01901## is selected from the group consisting of ##STR01902##

8.-36. (canceled)

37: The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.x is H, fluoro, or methyl, and R.sup.y is (i) isopropyl, or (ii) C.sub.3-4cycloalkyl, wherein the C.sub.3-4cycloalkyl is optionally substituted with one or more fluoro or methyl.

38: The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.k is H or halo.

39.-41. (canceled)

42: The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is selected from the group consisting of ##STR01903## ##STR01904## ##STR01905##

43: The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is ##STR01906##

44.-53. (canceled)

54: The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from the group consisting of ##STR01907## ##STR01908## ##STR01909## ##STR01910## ##STR01911## ##STR01912## ##STR01913## ##STR01914## ##STR01915## ##STR01916## ##STR01917## ##STR01918## ##STR01919## ##STR01920## ##STR01921## ##STR01922## ##STR01923## ##STR01924## ##STR01925## ##STR01926## ##STR01927## ##STR01928## ##STR01929## ##STR01930## ##STR01931## ##STR01932## ##STR01933## ##STR01934## ##STR01935## ##STR01936## ##STR01937## ##STR01938## ##STR01939## ##STR01940## ##STR01941## ##STR01942## ##STR01943## ##STR01944## ##STR01945## ##STR01946## ##STR01947## ##STR01948## ##STR01949## ##STR01950## ##STR01951## ##STR01952## ##STR01953## ##STR01954## ##STR01955## ##STR01956## ##STR01957## ##STR01958## ##STR01959## ##STR01960## ##STR01961## ##STR01962## ##STR01963## ##STR01964## ##STR01965## ##STR01966## ##STR01967## ##STR01968## ##STR01969## ##STR01970## ##STR01971## ##STR01972## ##STR01973## ##STR01974## ##STR01975## ##STR01976## ##STR01977## ##STR01978## ##STR01979## ##STR01980## ##STR01981## ##STR01982## ##STR01983## ##STR01984## ##STR01985## ##STR01986## ##STR01987## ##STR01988## ##STR01989## ##STR01990## ##STR01991## ##STR01992## ##STR01993## ##STR01994## ##STR01995## ##STR01996## ##STR01997## ##STR01998## ##STR01999## ##STR02000## ##STR02001## ##STR02002## ##STR02003## ##STR02004## ##STR02005## ##STR02006## ##STR02007## ##STR02008## ##STR02009## ##STR02010## ##STR02011## ##STR02012## ##STR02013## ##STR02014## ##STR02015## ##STR02016## ##STR02017## ##STR02018## ##STR02019## ##STR02020## ##STR02021## ##STR02022## ##STR02023## ##STR02024## ##STR02025## ##STR02026## ##STR02027## ##STR02028## ##STR02029## ##STR02030## ##STR02031## ##STR02032## ##STR02033##

55. (canceled)

56: A pharmaceutical composition comprising (i) a compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

57: A method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 56.

58.-64. (canceled)

65: A kit, comprising (i) a compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 56, and (ii) instructions for use in treating an GYS1-mediated disease, disorder, or condition in an individual in need thereof.

66.-72. (canceled)

73: A method of modulating GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a GYS1 modulator, or a pharmaceutical composition comprising a GYS1 modulator.

74: A method of inhibiting GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a GYS1 inhibitor, or a pharmaceutical composition comprising a GYS1 inhibitor.

75: A method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual an effective amount of a GYS1 inhibitor, or a pharmaceutical composition comprising a GYS1 inhibitor.

76: A method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising subjecting the individual to glycogen substrate reduction therapy.

77.-90. (canceled)

91: The compound of claim 1, wherein the compound is a compound of formula (I-A3): ##STR02034## or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.x is H, halo, C.sub.1-6alkyl, or —NH.sub.2, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo.

92: The compound of claim 1, wherein the compound is (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoro-N—((S)-(4-isopropylphenyl)(phenyl)methyl)pyrrolidine-2-carboxamide having the structure ##STR02035## or a pharmaceutically acceptable salt thereof.

93: The compound of claim 92, wherein the compound is (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoro-N—((S)-(4-isopropylphenyl)(phenyl)methyl)pyrrolidine-2-carboxamide having the structure ##STR02036##

94: The compound of claim 1, wherein the compound is (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoro-N—((S)-(5-isopropylpyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide having the structure ##STR02037## or a pharmaceutically acceptable salt thereof.

95: The compound of claim 94, wherein the compound is (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoro-N—((S)-(5-isopropylpyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide having the structure ##STR02038##

96: The compound of claim 1, wherein the compound is (2S,4R)—N—((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-1-(2-(5-(difluoromethyl)-1H-tetrazol-1-yl)acetyl)-4-fluoropyrrolidine-2-carboxamide having the structure ##STR02039## or a pharmaceutically acceptable salt thereof.

97: The compound of claim 96, wherein the compound is (2S,4R)—N—((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-1-(2-(5-(difluoromethyl)-1H-tetrazol-1-yl)acetyl)-4-fluoropyrrolidine-2-carboxamide having the structure ##STR02040##

98: The compound of claim 1, wherein the compound is (2S,4R)-4-fluoro-N—((S)-(3-fluoro-4-isopropylphenyl)(phenyl)methyl)-1-(2-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)acetyl)pyrrolidine-2-carboxamide having the structure ##STR02041## or a pharmaceutically acceptable salt thereof.

99: The compound of claim 98, wherein the compound is (2S,4R)-4-fluoro-N—((S)-(3-fluoro-4-isopropylphenyl)(phenyl)methyl)-1-(2-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)acetyl)pyrrolidine-2-carboxamide having the structure ##STR02042##

100: The compound of claim 1, wherein the compound is (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoro-N—((S)-(6-fluoro-5-isopropylpyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide having the structure ##STR02043## or a pharmaceutically acceptable salt thereof.

101: The compound of claim 100, wherein the compound is (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoro-N—((S)-(6-fluoro-5-isopropylpyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide having the structure ##STR02044##

102: The compound of claim 1, wherein the compound is (2S,4R)-1-(2-(1H-benzo[d]imidazol-1-yl)acetyl)-N—((S)-(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide having the structure ##STR02045## or a pharmaceutically acceptable salt thereof.

103: The compound of claim 102, wherein the compound is (2S,4R)-1-(2-(1H-benzo[d]imidazol-1-yl)acetyl)-N—((S)-(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide having the structure ##STR02046##

104: The compound of claim 1, wherein the compound is (2S,4R)—N—[(S)-[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide having the structure ##STR02047## or a pharmaceutically acceptable salt thereof.

105: The compound of claim 104, wherein the compound is (2S,4R)—N—[(S)-[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide having the structure ##STR02048##

106: The compound of claim 1, wherein the compound is (2S,4R)—N—[(S)-[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide having the structure ##STR02049## or a pharmaceutically acceptable salt thereof.

107: The compound of claim 106, wherein the compound is (2S,4R)—N—[(S)-[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl]-4-fluoro-1l-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide having the structure ##STR02050##

108: The compound of claim 1, wherein the compound is (2S,4R)—N—[(S)-[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide having the structure ##STR02051## or a pharmaceutically acceptable salt thereof.

109: The compound of claim 108, wherein the compound is (2S,4R)—N—[(S)-[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide having the structure ##STR02052##

110: The compound of claim 1, wherein the compound is (2S,4R)-4-fluoro-N—[(S)-[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl]-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide having the structure ##STR02053## or a pharmaceutically acceptable salt thereof.

111: The compound of claim 110, wherein the compound is (2S,4R)-4-fluoro-N—[(S)-[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl]-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide having the structure ##STR02054##

112: The compound of claim 1, wherein the compound is (2S,4R)-1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-4-fluoro-N—[(S)-[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl]pyrrolidine-2-carboxamide having the structure ##STR02055## or a pharmaceutically acceptable salt thereof.

113: The compound of claim 112, wherein the compound is (2S,4R)-1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-4-fluoro-N—[(S)-[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl]pyrrolidine-2-carboxamide having the structure ##STR02056##

114: The compound of claim 1, wherein the compound is (2S,4R)-1-(2-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)acetyl)-4-fluoro-N—((S)-(5-isopropyl-4-methylpyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide having the structure ##STR02057## or a pharmaceutically acceptable salt thereof.

115: The compound of claim 114, wherein the compound is (2S,4R)-1-(2-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)acetyl)-4-fluoro-N—((S)-(5-isopropyl-4-methylpyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide having the structure ##STR02058##

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0136] FIG. 1 depicts the pathway in which PPP1R3A Loss of Function (LoF) leads to reduction in muscle glycogen.

[0137] FIGS. 2A and 2B depict the association between PPP1R3A protein truncating variant (PTV) and left ventricular ejection (LVEF) (%) and left ventricle wall thickness (mm) in UK Biobank.

[0138] FIGS. 2C and 2D depict the association between PPP1R3A protein truncating variant (PTV) and exercise output (watts) and max heart rate (HR) exercise (bpm) in UK Biobank.

[0139] FIGS. 2E and 2F depict the association between PPP1R3A protein truncating variant (PTV) and PQ interval (ms) and QRS duration (ms) in UK Biobank.

[0140] FIGS. 2G and 2H depict the association between PPP1R3A protein truncating variant (PTV) and QT interval (ms) and serum glucose (mmol/L) in UK Biobank.

DETAILED DESCRIPTION OF THE INVENTION

[0141] “Individual” refers to mammals and includes humans and non-human mammals. Examples of individuals include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, individual refers to a human.

[0142] As used herein, “about” a parameter or value includes and describes that parameter or value per se. For example, “about X” includes and describes X per se.

[0143] As used herein, an “at risk” individual is an individual who is at risk of developing a disease or condition. An individual “at risk” may or may not have a detectable disease or condition, and may or may not have displayed detectable disease prior to the treatment methods described herein. “At risk” denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art. An individual having one or more of these risk factors has a higher probability of developing the disease or condition than an individual without these risk factor(s).

[0144] “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired results may include one or more of the following: decreasing one or more symptom resulting from the disease or condition; diminishing the extent of the disease or condition; slowing or arresting the development of one or more symptom associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition); and relieving the disease, such as by causing the regression of clinical symptoms (e.g., ameliorating the disease state, enhancing the effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival).

[0145] As used herein, “delaying” development of a disease or condition means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition.

[0146] As used herein, the term “therapeutically effective amount” or “effective amount” intends such amount of a compound of the disclosure or a pharmaceutically salt thereof sufficient to effect treatment when administered to an individual. As is understood in the art, an effective amount may be in one or more doses, e.g., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.

[0147] As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient, or compound, which may be in a pharmaceutically acceptable carrier.

[0148] As used herein, by “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing significant undesirable biological effects.

[0149] The term “alkyl”, as used herein, refers to an unbranched or branched saturated univalent hydrocarbon chain. As used herein, alkyl has 1-20 carbons (i.e., C.sub.1-20alkyl), 1-16 carbons (i.e., C.sub.1-16alkyl), 1-12 carbons (i.e., C.sub.1-12alkyl), 1-10 carbons (i.e., C.sub.1-10alkyl), 1-8 carbons (i.e., C.sub.1-8alkyl), 1-6 carbons (i.e., C.sub.1-6alkyl), 1-4 carbons (i.e., C.sub.1-4alkyl), or 1-3 carbons (i.e., C.sub.1-3alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, iso-pentyl, neo-pentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “butyl” includes n-butyl, sec-butyl, iso-butyl, and tert-butyl; and “propyl” includes n-propyl and iso-propyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkyl” group, may be referred to as an “alkylene”.

[0150] The term “alkenyl”, as used herein, refers to a branched or unbranched univalent hydrocarbon chain comprising at least one carbon-carbon double bond. As used herein, alkenyl has 2-20 carbons (i.e., C.sub.2-20alkenyl), 2-16 carbons (i.e., C.sub.2-16alkenyl), 2-12 carbons (i.e., C.sub.2-12alkenyl), 2-10 carbons (i.e., C.sub.2-10alkenyl), 2-8 carbons (i.e., C.sub.2-6alkenyl), 2-6 carbons (i.e., C.sub.2-6alkenyl), 2-4 carbons (i.e., C.sub.2-4alkenyl), or 2-3 carbons (i.e., C.sub.2-3alkenyl). Examples of alkenyl include, but are not limited to, ethenyl, prop-1-enyl, prop-2-enyl 1,2-butadienyl, and 1,3-butadienyl. When an alkenyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “propenyl” includes prop-1-enyl and prop-2-enyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkenyl” group, may be referred to as an “alkenylene”.

[0151] The term “alkynyl”, as used herein, refers to a branched or unbranched univalent hydrocarbon chain comprising at least one carbon-carbon triple bond. As used herein, alkynyl has 2-20 carbons (i.e., C.sub.2-20alkynyl), 2-16 carbons (i.e., C.sub.2-16alkynyl), 2-12 carbons (i.e., C.sub.2-12alkynyl), 2-10 carbons (i.e., C.sub.2-10alkynyl), 2-8 carbons (i.e., C.sub.2-6alkynyl), 2-6 carbons (i.e., C.sub.2-6alkynyl), 2-4 carbons (i.e., C.sub.2-4alkynyl), or 2-3 carbons (i.e., C.sub.2-3alkynyl). Examples of alkynyl include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, and but-3-ynyl. When an alkynyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “propynyl” includes prop-1-ynyl and prop-2-ynyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkynyl” group, may be referred to as an “alkynylene”.

[0152] The term “alkoxy”, as used herein, refers to an —O-alkyl moiety. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0153] The term “aryl”, as used herein, refers to a fully unsaturated carbocyclic ring moiety. The term “aryl” encompasses monocyclic and polycyclic fused-ring moieties. As used herein, aryl encompasses ring moieties comprising, for example, 6 to 20 annular carbon atoms (i.e., C.sub.6-20aryl), 6 to 16 annular carbon atoms (i.e., C.sub.6-16aryl), 6 to 12 annular carbon atoms (i.e., C.sub.6-12aryl), or 6 to 10 annular carbon atoms (i.e., C.sub.6-10aryl). Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl.

[0154] The term “cycloalkyl”, as used herein, refers to a saturated or partially unsaturated carbocyclic ring moiety. The term “cycloalkyl” encompasses monocyclic and polycyclic ring moieties, wherein the polycyclic moieties may be fused, branched, or spiro. Cycloalkyl includes cycloalkenyl groups, wherein the ring moiety comprises at least one annular double bond. Cycloalkyl includes any polycyclic carbocyclic ring moiety comprising at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule. As used herein, cycloalkyl includes rings comprising, for example, 3 to 20 annular carbon atoms (i.e., a C.sub.3-20cycloalkyl), 3 to 16 annular carbon atoms (i.e., a C.sub.3-16cycloalkyl), 3 to 12 annular carbon atoms (i.e., a C.sub.3-12cycloalkyl), 3 to 10 annular carbon atoms (i.e., a C.sub.3-10cycloalkyl), 3 to 8 annular carbon atoms (i.e., a C.sub.3-6cycloalkyl), 3 to 6 annular carbon atoms (i.e., a C.sub.3-6cycloalkyl), or 3 to 5 annular carbon atoms (i.e., a C.sub.3-5cycloalkyl). Monocyclic cycloalkyl ring moieties include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbonyl, decalinyl, 7,7-dimethyl-bicyclo [2.2.1]heptanyl, and the like. Still further, cycloalkyl also includes spiro cycloalkyl ring moieties, for example, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro [5.5]undecanyl.

[0155] The term “halo”, as used herein, refers to atoms occupying groups VIIA of The Periodic Table and includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo).

[0156] The term “heteroaryl”, as used herein, refers to an aromatic (fully unsaturated) ring moiety that comprises one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term “heteroaryl” includes both monocyclic and polycyclic fused-ring moieties. As used herein, a heteroaryl comprises, for example, 5 to 20 annular atoms (i.e., a 5-20 membered heteroaryl), 5 to 16 annular atoms (i.e., a 5-16 membered heteroaryl), 5 to 12 annular atoms (i.e., a 5-12 membered heteroaryl), 5 to 10 annular atoms (i.e., a 5-10 membered heteroaryl), 5 to 8 annular atoms (i.e., a 5-8 membered heteroaryl), or 5 to 6 annular atoms (i.e., a 5-6 membered heteroaryl). Any monocyclic or polycyclic aromatic ring moiety comprising one or more annular heteroatoms is considered a heteroaryl, regardless of the point of attachment to the remainder of the molecule (i.e., the heteroaryl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heteroaryl moiety). Examples of heteroaryl groups include, but are not limited to, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl can be bound via either ring of the fused system.

[0157] The term “heterocyclyl”, as used herein, refers to a saturated or partially unsaturated cyclic moiety that encompasses one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term “heterocyclyl” includes both monocyclic and polycyclic ring moieties, wherein the polycyclic ring moieties may be fused, bridged, or spiro. Any non-aromatic monocyclic or polycyclic ring moiety comprising at least one annular heteroatom is considered a heterocyclyl, regardless of the point of attachment to the remainder of the molecule (i.e., the heterocyclyl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heterocyclyl moiety). Further, the term heterocyclyl is intended to encompass any polycyclic ring moiety comprising at least one annular heteroatom wherein the polycyclic ring moiety comprises at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule. As used herein, a heterocyclyl comprises, for example, 3 to 20 annular atoms (i.e., a 3-20 membered heterocyclyl), 3 to 16 annular atoms (i.e., a 3-16 membered heterocyclyl), 3 to 12 annular atoms (i.e., a 3-12 membered heterocyclyl), 3 to 10 annular atoms (i.e., a 3-10 membered heterocyclyl), 3 to 8 annular atoms (i.e., a 3-8 membered heterocyclyl), 3 to 6 annular atoms (i.e., a 3-6 membered heterocyclyl), 3 to 5 annular atoms (i.e., a 3-5 membered heterocyclyl), 5 to 8 annular atoms (i.e., a 5-8 membered heterocyclyl), or 5 to 6 annular atoms (i.e., a 5-6 membered heterocyclyl). Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Examples of spiro heterocyclyl rings include, but are not limited to, bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.

[0158] The term “oxo”, as used herein, refers to a ═O moiety.

[0159] The terms “optional” and “optionally”, as used herein, mean that the subsequently described event or circumstance may or may not occur and that the description includes instances where the event or circumstance occurs and instances where it does not. Accordingly, the term “optionally substituted” infers that any one or more (e.g., 1, 2, 1 to 5, 1 to 3, 1 to 2, etc.) hydrogen atoms on the designated atom or moiety or group may be replaced or not replaced by an atom or moiety or group other than hydrogen. By way of illustration and not limitation, the phrase “methyl optionally substituted with one or more chloro” encompasses —CH.sub.3, —CH.sub.2Cl, —CHCl.sub.2, and —CCl.sub.3 moieties.

[0160] It is understood that aspects and embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments.

[0161] The term “pharmaceutically acceptable salt”, as used herein, of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” include, for example, salts with inorganic acids, and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. See, e.g., Handbook of Pharmaceutical Salts Properties, Selection, and Use, International Union of Pure and Applied Chemistry, John Wiley & Sons (2008), which is incorporated herein by reference. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, trifluoroacetic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0162] Isotopically labeled forms of the compounds depicted herein may be prepared. Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as .sup.2H, .sup.3H .sup.11C, .sup.13C, .sup.14C, .sup.13N, .sup.15N, .sup.15O, .sup.17O, .sup.18O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, .sup.36Cl, .sup.123I, and .sup.125I, respectively. In some embodiments, a compound of formula (A) is provided wherein one or more hydrogen is replaced by deuterium or tritium.

[0163] Some of the compounds provided herein may exist as tautomers. Tautomers are in equilibrium with one another. By way of illustration, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds of this disclosure are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, for example, amide-containing compounds are understood to include their imidic acid tautomers. Likewise, imidic-acid containing compounds are understood to include their amide tautomers.

[0164] Also provided herein are prodrugs of the compounds depicted herein, or a pharmaceutically acceptable salt thereof. Prodrugs are compounds that may be administered to an individual and release, in vivo, a compound depicted herein as the parent drug compound. It is understood that prodrugs may be prepared by modifying a functional group on a parent drug compound in such a way that the modification is cleaved in vitro or in vivo to release the parent drug compound. See, e.g., Rautio, J., Kumpulainen, H., Heimbach, T. et al. Prodrugs: design and clinical applications. Nat Rev Drug Discov 7, 255-270 (2008), which is incorporated herein by reference.

[0165] The compounds of the present disclosure, or their pharmaceutically acceptable salts, may include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- (or as (D)- or (L)- for amino acids). The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms and mixtures thereof in any ratio. Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or may be resolved using conventional techniques, for example, chromatography and/or fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or the resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC), and chiral supercritical fluid chromatography (SFC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless specified otherwise, it is intended that the present disclosure includes both E and Z geometric isomers. Likewise, cis- and trans- are used in their conventional sense to describe relative spatial relationships.

[0166] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds, but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose structures are non-superimposable mirror images of one another. “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

[0167] Where enantiomeric and/or diastereomeric forms exist of a given structure, flat bonds indicate that all stereoisomeric forms of the depicted structure may be present, e.g.,

##STR00014##

[0168] Where enantiomeric and/or diastereomeric forms exist of a given structure, flat bonds and the presence of a “*” symbol indicate that the composition is made up of at least 90%, by weight, of a single isomer with unknown stereochemistry, e.g.,

##STR00015##

[0169] Where enantiomeric and/or diastereomeric forms exist of a given structure, wedged or hashed bonds indicate the composition is made up of at least 90%, by weight, of a single enantiomer or diastereomer with known stereochemistry, e.g.,

##STR00016##

[0170] Where relevant, combinations of the above notation may be used. Exemplified species may contain stereogenic centers with known stereochemistry and stereogenic centers with unknown stereochemistry, stereochemistry, e.g.,

##STR00017##

[0171] Where relevant, combinations of the above notation may be used. Exemplified species may contain stereogenic centers with known stereochemistry and stereogenic centers bearing a mixture of isomers, e.g.,

##STR00018##

Compounds

[0172] In one aspect, provided herein is a compound of formula (I′):

##STR00019##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: [0173] Y.sup.2 and Y.sup.3 are each C, or [0174] one of Y.sup.2 and Y.sup.3 is N and the other of Y.sup.2 and Y.sup.3 is C; [0175] X.sup.1 and X.sup.2 are each independently H, C.sub.1-6alkyl, or C.sub.1-6alkoxy; [0176] X.sup.3 and X.sup.4 are each independently H, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, or 5-20 membered heteroaryl, wherein the C.sub.1-6alkyl of X.sup.3 and X.sup.4 is optionally substituted with one of more halo; [0177] X.sup.5 is H, C.sub.1-6alkyl, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl; either [0178] (1) L.sup.1 is absent; and [0179] Q.sup.1 is selected from (i) to (iv): [0180] (i) phenyl, wherein the phenyl of Q.sup.1 is substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), —NH—C(O)-(3-15 membered heterocyclyl), C.sub.3-10cycloalkyl, or 5-20 membered heteroaryl, wherein [0181] the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH—C(O)—NH(C.sub.1-6alkyl), —NH—C(O)—C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, [0182] the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl, and [0183] the 5-20 membered heteroaryl is optionally substituted with one or more C.sub.1-6alkyl, [0184] (ii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo, or C.sub.1-6alkyl, [0185] (iii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein, [0186] the C.sub.1-6alkyl is optionally substituted with one or more halo, and [0187] the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl, and [0188] (iv) C.sub.3-10cycloalkyl; [0189] or [0190] (2) L.sup.1 is —CH.sub.2—; and [0191] Q.sup.1 is C.sub.3-10cycloalkyl; [0192] L.sup.2 is —C(O)— or —S(O).sub.2— [0193] R.sup.1 is H or C.sub.1-6alkyl; [0194] R.sup.k is H, halo, —OH, —NH.sub.2, or —NH—C(O)C.sub.1-6alkyl; [0195] R.sup.m is H, —OH, or C.sub.1-6alkyl; [0196] R.sup.n is H, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl or R.sup.n taken together with the carbon atom to which it is attached forms C.sub.3-5 cycloalkyl; [0197] or R.sup.k is taken together with either R.sup.m or R.sup.n, and the atoms to which they are attached, to form cyclopropyl; and [0198] R.sup.2 is selected from (i) to (vii): [0199] (i) C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is optionally substituted with one or more R.sup.a, wherein R.sup.a is: [0200] (a) —OH, [0201] (b) cyano, [0202] (c) C.sub.2-6alkynyl, [0203] (d) C.sub.6-20aryl, wherein the C.sub.6-20aryl of R.sup.a is optionally substituted with one or more halo, cyano, C.sub.1-6alkoxy, or —NH—C(O)—C.sub.1-6alkyl, [0204] (e) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c, wherein [0205] R.sup.c is halo, oxo, C.sub.1-6alkyl, C.sub.1-6alkoxy, —C(O)—C.sub.1-6alkyl, or —C(O)—C.sub.1-6alkoxy, wherein [0206] the C.sub.1-6alkyl of R.sup.c is optionally substituted with one or more halo or C.sub.2-6alkynyl, and [0207] the —C(O)—C.sub.1-6alkoxy of R.sup.c is optionally substituted with one or more halo, [0208] (f) —N(R.sup.c)(R.sup.d), wherein R.sup.c and R.sup.d of N(R.sup.c)(R.sup.d) are, independently of each other, H, C.sub.1-6alkyl, —C(O)—C.sub.1-6alkyl, —C(O)—C.sub.1-6alkoxy, —C(O)—NH.sub.2, —C(O)—NH(C.sub.1-6alkyl), —C(O)—N(C.sub.1-6alkyl).sub.2, —C(O)-(3-15 membered heterocyclyl), —CH.sub.2—C(O)—NH.sub.2, 3-15 membered heterocyclyl, or 5-20 membered heteroaryl, wherein [0209] the C.sub.1-6alkyl of R.sup.c or R.sup.d is optionally substituted with one or more —C(O)—NH.sub.2, [0210] the —C(O)—C.sub.1-6alkyl of R.sup.c or R.sup.d is optionally substituted with one or more halo, [0211] the 3-15 membered heterocyclyl and the 5-20 membered heteroaryl of R.sup.c or R.sup.d are independently optionally substituted with one or more C.sub.1-6alkyl, [0212] the —C(O)-(3-15 membered heterocyclyl) of R.sup.c or R.sup.d is optionally substituted with one or more halo, —C(O)—C.sub.1-6alkoxy, or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and [0213] the C.sub.1-6alkyl of the —C(O)—N(C.sub.1-6alkyl).sub.2 of R.sup.c or R.sup.d are, independently of each other, optionally substituted with one or more halo or C.sub.6-20aryl, [0214] (g) —O—R.sup.e, wherein R.sup.e is C.sub.1-6alkyl, C.sub.6-20aryl, —C(O)-(3-15 membered heterocyclyl), —C(O)—N—(C.sub.1-6alkyl).sub.2, or 5-20 membered heteroaryl, wherein [0215] the C.sub.1-6alkyl of R.sup.e is optionally substituted with one or more C.sub.1-6alkoxy, wherein the C.sub.1-6alkoxy is optionally substituted with one or more C.sub.2-6alkynyl, [0216] the C.sub.6-20aryl of R.sup.e is optionally substituted with one or more C.sub.1-6alkyl, and [0217] the —C(O)-(3-15 membered heterocyclyl) of R.sup.e is optionally substituted with one or more C.sub.1-6alkyl, C.sub.1-6alkoxy, or —C(O)—C.sub.1-6alkoxy, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, [0218] (h) —C(O)—R.sup.e, wherein R.sup.e of —C(O)—R.sup.e is —NH.sub.2, —OH, or 3-15 membered heterocyclyl, or [0219] (i) —S(O).sub.2—R.sup.f, wherein R.sup.f is C.sub.1-6alkyl or 3-15 membered heterocyclyl, provided that, when R.sup.2 is unsubstituted methyl, then either [0220] (1) Q.sup.1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, C.sub.3-10cycloalkyl, or —OH, and wherein Q.sup.1 is not unsubstituted pyridyl, or [0221] (2) Q.sup.1 is phenyl, wherein the phenyl of Q.sup.1 is substituted with [0222] (i) at least one C.sub.3-6alkyl, wherein the at least one C.sub.3-6alkyl is optionally substituted with one or more halo, or [0223] (ii) at least one C.sub.3-10cycloalkyl, wherein the at least one C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl, or [0224] (iii) at least one 5-20 membered heteroaryl, wherein the at least one 5-20 membered heteroaryl is optionally substituted with one or more C.sub.1-6alkyl, [0225] (ii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl of R.sup.2 is optionally substituted with one or more R.sup.q, wherein R.sup.q is 5-20 membered heteroaryl or C.sub.6-20aryl, wherein the C.sub.6-20aryl of R.sup.q is optionally substituted with one or more C.sub.1-6alkoxy, [0226] (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.2 is optionally substituted with one or more halo, oxo, C.sub.1-6alkyl, —C(O)—C.sub.1-6alkyl, or 5-20 membered heteroaryl, [0227] (iv) 5-20 membered heteroaryl or —(C.sub.1-4alkyl)(5-20 membered heteroaryl), wherein the C.sub.1-4 alkyl is optionally substituted with one or more or more —OH, halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, and wherein the 5-20 membered heteroaryl is optionally substituted with one or more R.sup.s, wherein [0228] R.sup.s is halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)—C.sub.1-6alkyl, C.sub.6-20aryl, C.sub.3-10cycloalkyl, 3-15 membered heterocyclyl, 5-20 membered heteroaryl, or —C(O)—C.sub.1-6alkoxy, wherein [0229] the C.sub.1-6alkyl of R.sup.s is optionally substituted with one or more halo, C.sub.1-6alkoxy, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, and [0230] the 3-15-membered heterocyclyl of R.sup.s is optionally substituted with one or more halo or —C(O)—C.sub.1-6alkoxy, [0231] (v) —N(R.sup.g)(R.sup.h), wherein R.sup.g and R.sup.h are independently H or C.sub.1-6alkyl, [0232] (vi) —C(O)—R.sup.j, wherein R.sup.j is C.sub.3-10cycloalkyl, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, or —NH (5-20 membered heteroaryl), and [0233] (vii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of R.sup.2 is optionally substituted with one or more 5-20 membered heteroaryl or —O—R.sup.p, wherein R.sup.p is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.p is optionally substituted with one or more —C(O)—C.sub.1-6alkyl.

[0234] In one aspect, provided is a compound of formula (I):

##STR00020##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: [0235] X.sup.1 and X.sup.2 are each independently H, C.sub.1-6alkyl, or C.sub.1-6alkoxy; [0236] X.sup.3 and X.sup.4 are each independently H, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, or 5-20 membered heteroaryl; [0237] X.sup.5 is H, C.sub.1-6alkyl, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl; [0238] Q.sup.1 is selected from (i) to (iii): [0239] (i) phenyl, wherein the phenyl of Q.sup.1 is substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), —NH—C(O)-(3-15 membered heterocyclyl), or C.sub.3-10cycloalkyl, wherein [0240] the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl, [0241] (ii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo, and [0242] (iii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein [0243] the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl; [0244] R.sup.1 is H or C.sub.1-6alkyl; [0245] R.sup.k is H, halo, —OH, —NH.sub.2, or —NH—C(O)C.sub.1-6alkyl; [0246] R.sup.m is H, —OH, or C.sub.1-6alkyl; [0247] R.sup.n is H, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl; [0248] or R.sup.k is taken together with either R.sup.m or R.sup.n, and the atoms to which they are attached, to form [0249] cyclopropyl; and [0250] R.sup.2 is selected from (i) to (vii): [0251] (i) C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is optionally substituted with one or more R.sup.a, wherein R.sup.a is: [0252] (a) —OH, [0253] (b) cyano, [0254] (c) C.sub.2-6alkynyl, [0255] (d) C.sub.6-20aryl, wherein the C.sub.6-20aryl of R.sup.a is optionally substituted with one or more halo, cyano, C.sub.1-6alkoxy, or —NH—C(O)—C.sub.1-6alkyl, [0256] (e) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b, wherein [0257] R.sup.b is halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, C.sub.3-10cycloalkyl, 3-15 membered heterocyclyl, or —C(O)—C.sub.1-6alkoxy, wherein [0258] the C.sub.1-6alkyl of R.sup.b is optionally substituted with one or more halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, and [0259] the 3-15-membered heterocyclyl of R.sup.b is optionally substituted with one or more halo or —C(O)—C.sub.1-6alkoxy, [0260] (f) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c, wherein [0261] R.sup.c is halo, oxo, C.sub.1-6alkyl, C.sub.1-6alkoxy, —C(O)—C.sub.1-6alkyl, or —C(O)—C.sub.1-6alkoxy, wherein [0262] the C.sub.1-6alkyl of R.sup.c is optionally substituted with one or more halo or C.sub.2-6alkynyl, and [0263] the —C(O)—C.sub.1-6alkoxy of R.sup.c is optionally substituted with one or more halo, [0264] (g) —N(R.sup.c)(R.sup.d), wherein R.sup.c and R.sup.d are, independently of each other, H, C.sub.1-6alkyl, —C(O)—C.sub.1-6alkyl, —C(O)—C.sub.1-6alkoxy, —C(O)—NH.sub.2, —C(O)—NH(C.sub.1-6alkyl), —C(O)—N(C.sub.1-6alkyl).sub.2, —C(O)-(3-15 membered heterocyclyl), —CH.sub.2—C(O)—NH.sub.2, 3-15 membered heterocyclyl, or 5-20 membered heteroaryl, wherein [0265] the —C(O)—C.sub.1-6alkyl of R.sup.c or R.sup.d is optionally substituted with one or more halo, [0266] the 3-15 membered heterocyclyl and the 5-20 membered heteroaryl of R.sup.c or R.sup.d are independently optionally substituted with one or more C.sub.1-6alkyl, and [0267] the —C(O)-(3-15 membered heterocyclyl) of R.sup.c or R.sup.d is optionally substituted with one or more halo, —C(O)—C.sub.1-6alkoxy, or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, [0268] (h) —O—R.sup.e, wherein R.sup.e is C.sub.1-6alkyl, C.sub.6-20aryl, —C(O)-(3-15 membered heterocyclyl), —C(O)—N—(C.sub.1-6alkyl).sub.2, or 5-20 membered heteroaryl, wherein [0269] the C.sub.1-6alkyl of R.sup.e is optionally substituted with one or more C.sub.1-6alkoxy, wherein the C.sub.1-6alkoxy is optionally substituted with one or more C.sub.2-6alkynyl, [0270] the C.sub.6-20aryl of R.sup.e is optionally substituted with one or more C.sub.1-6alkyl, and [0271] the —C(O)-(3-15 membered heterocyclyl) of R.sup.e is optionally substituted with one or more C.sub.1-6alkyl, C.sub.1-6alkoxy, or —C(O)—C.sub.1-6alkoxy, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, [0272] (i) —C(O)—R.sup.e, wherein R.sup.e is —NH.sub.2, —OH, or 3-15 membered heterocyclyl, or [0273] (j) —S(O).sub.2—R.sup.f, wherein R.sup.f is C.sub.1-6alkyl or 3-15 membered heterocyclyl, provided that, when R.sup.2 is unsubstituted methyl, then either [0274] (1) Q.sup.1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, C.sub.3-10cycloalkyl, or —OH, or [0275] (2) Q.sup.1 is phenyl, wherein the phenyl of Q.sup.1 is substituted with at least one C.sub.3-6alkyl or at least one C.sub.3-10cycloalkyl, wherein the at least one C.sub.3-6alkyl is optionally substituted with one or more halo, and the at least one C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl, [0276] (ii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl of R.sup.2 is optionally substituted with one or more R.sup.q, wherein R.sup.q is 5-20 membered heteroaryl or C.sub.6-20aryl, wherein the C.sub.6-20aryl of R.sup.q is optionally substituted with one or more C.sub.1-6alkoxy, [0277] (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.2 is optionally substituted with one or more halo, oxo, C.sub.1-6alkyl, —C(O)—C.sub.1-6alkyl, or 5-20 membered heteroaryl, [0278] (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.2 is optionally substituted with one or more R.sup.s, wherein R.sup.s is C.sub.1-6alkyl, C.sub.1-6alkoxy, —NH—C(O)—C.sub.1-6alkyl, C.sub.6-20aryl, or 5-20 membered heteroaryl, wherein the C.sub.1-6alkyl of R.sup.s is optionally substituted with one or more C.sub.1-6alkoxy, [0279] (v) —N(R.sup.g)(R.sup.h), wherein R.sup.g and R.sup.h are independently H or C.sub.1-6alkyl, [0280] (vi) —C(O)—R.sup.j, wherein R.sup.j is C.sub.3-10cycloalkyl, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, or —NH (5-20 membered heteroaryl), and [0281] (vii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of R.sup.2 is optionally substituted with one or more 5-20 membered heteroaryl or —O—R.sup.p, wherein R.sup.p is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.p is optionally substituted with one or more —C(O)—C.sub.1-6alkyl.

[0282] Any embodiments provided herein of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, are also, where applicable, embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0283] In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L.sup.2 is —C(O) or —S(O).sub.2—. In some embodiments, L.sup.2 is —C(O)—. In some embodiments, L.sup.2 is —S(O).sub.2—.

[0284] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q.sup.1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more C.sub.1-6alkyl or halo. In some embodiments, Q.sup.1 is 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more C.sub.1-6alkyl or halo. In some embodiments, Q.sup.1 is pyridinyl, wherein the pyridinyl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more C.sub.1-6alkyl or halo. In some embodiments, Q.sup.1 is 2-pyridinyl or 3-pyridinyl, wherein the 2-pyridinyl or 3-pyridinyl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more C.sub.1-6alkyl or halo. In some embodiments, Q.sup.1 is 2-pyridinyl, wherein the 2-pyridinyl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more C.sub.1-6alkyl or halo. In some embodiments Q.sup.1 is 2-pyridinyl, wherein the 2-pyridinyl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more C.sub.1-6alkyl or halo. In some embodiments, Q.sup.1 is 2-pyridinyl, wherein the 2-pyridinyl of Q.sup.1 is optionally substituted with one or more fluoro, chloro, methyl, iso-propyl, tert-butyl, cyclopropyl, or cyclobutyl, wherein the cyclopropyl and cyclobutyl are independently optionally substituted with one or more methyl or fluoro.

[0285] In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q.sup.1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more C.sub.1-6alkyl or halo. In some embodiments, Q.sup.1 is 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more C.sub.1-6alkyl or halo. In some embodiments, Q.sup.1 is pyridinyl, wherein the pyridinyl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more C.sub.1-6alkyl or halo. In some embodiments, Q.sup.1 is 2-pyridinyl or 3-pyridinyl, wherein the 2-pyridinyl or 3-pyridinyl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more C.sub.1-6alkyl or halo. In some embodiments, Q.sup.1 is 2-pyridinyl, wherein the 2-pyridinyl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more C.sub.1-6alkyl or halo. In some embodiments Q.sup.1 is 2-pyridinyl, wherein the 2-pyridinyl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more C.sub.1-6alkyl or halo. In some embodiments, Q.sup.1 is 2-pyridinyl, wherein the 2-pyridinyl of Q.sup.1 is optionally substituted with one or more fluoro, chloro, methyl, iso-propyl, tert-butyl, cyclopropyl, cyclobutyl, or methoxy, wherein the methyl is optionally substituted with one or more fluoro and the cyclopropyl and cyclobutyl are independently optionally substituted with one or more methyl or fluoro.

[0286] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q.sup.1 is selected from the group consisting of

##STR00021##

[0287] In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q.sup.1 is selected from the group consisting of

##STR00022##

[0288] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q.sup.1 is selected from the group consisting of

##STR00023##

[0289] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q.sup.1 is phenyl, wherein the phenyl of Q.sup.1 is substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6 alkenyl, —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), —NH—C(O)-(3-15 membered heterocyclyl), or C.sub.3-10cycloalkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments, Q.sup.1 is phenyl, wherein the phenyl of Q.sup.1 is substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6 alkenyl, or C.sub.3-10cycloalkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments, Q.sup.1 is phenyl, wherein the phenyl of Q.sup.1 is substituted with one or more fluoro, chloro, methyl, iso-propyl, sec-butyl, tert-butyl, prop-1-en-2-yl, cyclopropyl, or cyclobutyl, wherein the methyl, iso-propyl, sec-butyl, and tert-butyl are independently optionally substituted with one or more halo, and the cyclopropyl and cyclobutyl are independently optionally substituted with one or more fluoro or methyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0290] In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q.sup.1 is phenyl, wherein the phenyl of Q.sup.1 is substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), —NH—C(O)-(3-15 membered heterocyclyl), C.sub.3-10cycloalkyl, or 5-20 membered heteroaryl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH—C(O)—NH(C.sub.1-6alkyl), —NH—C(O)—C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl, and the 5-20 membered heteroaryl is optionally substituted with one or more C.sub.1-6alkyl.

[0291] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q is selected from the group consisting of

##STR00024##

[0292] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q.sup.1 is selected from the group consisting of

##STR00025##

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q.sup.1 is selected from the group consisting of

##STR00026##

[0293] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q.sup.1 is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo. In some embodiments, Q.sup.1 is

##STR00027##

[0294] In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q.sup.1 is (i) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo, or C.sub.1-6alkyl, (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein, the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl, or (iii) C.sub.3-10cycloalkyl.

[0295] In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q.sup.1 is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo, or C.sub.1-6alkyl. In some embodiments Q.sup.1 is selected from the group consisting of

##STR00028##

[0296] In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q.sup.1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein, the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments Q.sup.1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more C.sub.1-6alkyl. In some embodiments, is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 comprises one or more annular N. In some embodiments, is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 comprises two annular N. In some embodiments, is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Qi is monocyclic of bicyclic. In some embodiments, is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is monocyclic. In some embodiments, is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q is bicyclic. In some embodiments Q.sup.1 is selected from the group consisting of

##STR00029##

[0297] In some embodiments of a compound of formula (I′), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q.sup.1 is C.sub.3-10cycloalkyl. In some embodiments, Q.sup.1 is C.sub.3-6cycloalkyl. In some embodiments Q.sup.1 is cyclopropyl.

[0298] In some embodiments of a compound of formula (I′), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L.sup.1 is absent or is —CH.sub.2—. In some embodiments, L.sup.1 is absent. In some embodiments, L.sup.1 is —CH.sub.2—. In some embodiments, L.sup.1 is absent and Q.sup.1 is C.sub.3-10cycloalkyl. In some embodiments, L.sup.1 is absent and Q.sup.1 is C.sub.3-6cycloalkyl. In some embodiments L.sup.1 is absent and Q.sup.1 is cyclopropyl. In some embodiments, Li is —CH.sub.2— and Q.sup.1 is C.sub.3-10cycloalkyl. In some embodiments, L.sup.1 is —CH.sub.2— and Q.sup.1 is C.sub.3-6cycloalkyl. In some embodiments L.sup.1 is —CH.sub.2— and Q.sup.1 is cyclopropyl.

[0299] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.1, X.sup.2, X.sup.3, X.sup.4, and X.sup.5 are each H. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0300] In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.1 is H or C.sub.1-6alkyl. In some embodiments R.sup.1 is H. In some embodiments, R.sup.1 is C.sub.1-3alkyl. In some embodiments, R.sup.1 is methyl.

[0301] In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is H, halo, —OH, —NH.sub.2, or —NH—C(O)C.sub.1-6alkyl. In some embodiments, R.sup.k is H. In some embodiments, R.sup.k is halo. In some embodiments, R.sup.k is F.

[0302] In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.m is H, —OH, or C.sub.1-6alkyl. In some embodiments R.sup.m is H.

[0303] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.n is H, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl. In some embodiments R.sup.n is H.

[0304] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.m is H, R.sup.n is H, and R.sup.k is H, halo, —OH, —NH.sub.2, or —NH—C(O)C.sub.1-6alkyl. In some embodiments, R.sup.m is H, R.sup.n is H, and R.sup.k is halo, —OH, or —NH.sub.2. In some embodiments, R.sup.m is H, R.sup.n is H, and R.sup.k is halo. In some embodiments, R.sup.m is H, R.sup.n is H, and R.sup.k is fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0305] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is taken together with either R.sup.m or R.sup.n, and the atoms to which they are attached, to form cyclopropyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0306] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.n taken together with the carbon atom to which it is attached forms C.sub.3-5 cycloalkyl. In some embodiments, R.sup.n taken together with the carbon atom to which it is attached forms cyclopropyl.

[0307] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.1 is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0308] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is optionally substituted with one or more R.sup.a. In some embodiments, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro.

[0309] In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is 5-20 membered heteroaryl or —(C.sub.1-4alkyl)(5-20 membered heteroaryl), wherein the C.sub.1-4 alkyl is optionally substituted with one or more or more —OH, halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, and wherein the 5-20 membered heteroaryl is optionally substituted with one or more R.sup.s. In some embodiments, R.sup.2 is 5-20 membered heteroaryl, wherein the C.sub.1-4 alkyl is optionally substituted with one or more or more —OH, halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, and wherein the 5-20 membered heteroaryl is optionally substituted with one or more R.sup.s. In some embodiments, R.sup.2 is (methyl)(5-20 membered heteroaryl), wherein the methyl is optionally substituted with one or more or more —OH, halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, and wherein the 5-20 membered heteroaryl is optionally substituted with one or more R.sup.s. In some embodiments, R.sup.s is halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)—C.sub.1-6alkyl, C.sub.6-20aryl, C.sub.3-10cycloalkyl, 3-15 membered heterocyclyl, 5-20 membered heteroaryl, or —C(O)—C.sub.1-6alkoxy. In some embodiments, the C.sub.1-6alkyl of R.sup.s is optionally substituted with one or more halo, C.sub.1-6alkoxy, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, and the 3-15-membered heterocyclyl of R.sup.s is optionally substituted with one or more halo or —C(O)—C.sub.1-6alkoxy.

[0310] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is selected from the group consisting of

##STR00030##

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is

##STR00031##

[0311] In some embodiments of a compound of formula (I′), (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is selected from the group consisting of

##STR00032##

[0312] In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is selected from the group consisting of

##STR00033## ##STR00034## ##STR00035##

In some embodiments, R.sup.2 is

##STR00036##

[0313] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c.

[0314] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more oxo or C.sub.1-6alkyl. In some embodiments, R.sup.2 is

##STR00037##

[0315] In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c, wherein R.sup.c is oxo, C.sub.1-6alkyl, or —C(O)—C.sub.1-6alkoxy, wherein the C.sub.1-6alkyl of R.sup.c is optionally substituted with one or more halo, and the —C(O)—C.sub.1-6alkoxy of R.sup.c is optionally substituted with one or more halo. In some embodiments, R.sup.2 is selected from the group consisting of

##STR00038## ##STR00039##

[0316] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e, wherein R.sup.e is —C(O)-(3-15 membered heterocyclyl). In some embodiments, R.sup.2 is

##STR00040##

[0317] In some embodiments of a compound of formula (I′), (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e, wherein R.sup.e is —C(O)-(3-15 membered heterocyclyl) wherein the —C(O)-(3-15 membered heterocyclyl) of R.sup.e is optionally substituted with one or more C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl. In some embodiments, R.sup.2 is selected from the group consisting of

##STR00041##

[0318] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d is —C(O)—N(C.sub.1-6alkyl).sub.2. In some embodiments, R.sup.2 is

##STR00042##

[0319] In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d, —C(O)—C.sub.1-6alkyl, —C(O)—N(C.sub.1-6alkyl).sub.2, or —C(O)-(3-15 membered heterocyclyl). In some embodiments, R.sup.2 is selected from the group consisting of

##STR00043##

[0320] In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is ethyl, wherein the ethyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d is —C(O)—C.sub.1-6alkyl. In some embodiments, R.sup.2 is

##STR00044##

[0321] In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.1 and X.sup.2 are each independently H, C.sub.1-6alkyl, or C.sub.1-6alkoxy. In some embodiments, X.sup.1 and X.sup.2 are each H.

[0322] In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.3 and X.sup.4 are each independently H, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, or 5-20 membered heteroaryl, wherein the C.sub.1-6alkyl of X.sup.3 and X.sup.4 is optionally substituted with one of more halo.

[0323] In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.5 is H, C.sub.1-6alkyl, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl. In some embodiments, X.sup.5 is H, C.sub.1-4alkyl, C.sub.1-3alkoxy, or C.sub.3-6cycloalkyl. In some embodiments, X.sup.5 is H. In some embodiments, X.sup.5 is isopropyl, n-butyl, iso-butyl or t-butyl.

[0324] In some embodiments of a compound of formula (I), X.sup.1-X.sup.5 are each H, and Q.sup.1 is a 5-20 membered heteroaryl optionally substituted with one or more halo, C.sub.1-6alkyl, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments, X.sup.1-X.sup.5 are each H, and Q.sup.1 is a 5-6 membered heteroaryl optionally substituted with one or more halo, C.sub.1-6alkyl, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments, X.sup.1-X.sup.5 are each H, and Q.sup.1 is a pyridinyl optionally substituted with one or more halo, C.sub.1-6alkyl, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments, X.sup.1-X.sup.5 are each H, and Q.sup.1 is a pyridinyl optionally substituted with one or more halo, C.sub.1-4alkyl, —NH.sub.2, or C.sub.3-4cycloalkyl, wherein the C.sub.3-4cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments of the foregoing, R.sup.m is H and R.sup.n is H. In some embodiments of the foregoing, R.sup.1 is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0325] In some embodiments of a compound of formula (I), X.sup.1-X.sup.5 are each H, and Q.sup.1 is phenyl substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6 alkenyl, —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), —NH—C(O)-(3-15 membered heterocyclyl), or C.sub.3-10cycloalkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments, X.sup.1-X.sup.5 are each H, and Q.sup.1 is phenyl substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6 alkenyl, —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), —NH—C(O)-(3-10 membered heterocyclyl), or C.sub.3-10cycloalkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments, X.sup.1-X.sup.5 are each H, and Q.sup.1 is phenyl substituted with one or more halo, C.sub.1-4alkyl, C.sub.2-4 alkenyl, —NH.sub.2, —NH—C(O)—(C.sub.1-4alkyl), —NH—C(O)-(3-10 membered heterocyclyl), or C.sub.3-4cycloalkyl, wherein the C.sub.1-4alkyl is optionally substituted with one or more halo, and the C.sub.3-4cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0326] In some embodiments of the foregoing, R.sup.1 is H. In some embodiments of the foregoing, R.sup.m is H and R.sup.n is H. In some embodiments of the foregoing, R.sup.k is taken together with either R.sup.m or R.sup.n, and the atoms to which they are attached, to form cyclopropyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0327] In some embodiments of a compound of formula (I′) or (I), or any embodiment or variation thereof, such as a compound of formula (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-C), (I-D), (I-D1), (I-D2), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented by

##STR00045##

with carbon atoms bearing moieties

##STR00046##

R.sup.k, R.sup.m, R.sup.n, and R.sup.1, has a stereochemical configuration of the formula

##STR00047##

wherein X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, Y.sup.2, Y.sup.3, R.sup.1, R.sup.k, R.sup.m and R.sup.n are as defined elsewhere herein.

[0328] In some embodiments of a compound of formula (I′) or (I), or any embodiment or variation thereof, such as a compound of formula (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-C), (I-D), (I-D1), (I-D2), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented by

##STR00048##

with carbon atoms bearing moieties

##STR00049##

R.sup.k, R.sup.m, R.sup.n, and R.sup.1, has a stereochemical configuration of the formula

##STR00050##

wherein R.sup.1 and R.sup.m are both H, and X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, Y.sup.2, Y.sup.3, R.sup.k, and R.sup.n are as defined elsewhere herein.

[0329] In some embodiments of a compound of formula (I′) or (I), or any embodiment or variation thereof, such as a compound of formula (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-C), (I-D), (I-D1), (I-D2), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented by

##STR00051##

with carbon atoms bearing moieties

##STR00052##

R.sup.k, R.sup.m, R.sup.n, and R.sup.1, has a stereochemical configuration of the formula

##STR00053##

wherein R.sup.1, R.sup.m, and R.sup.n are each H, and X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, Y.sup.2, Y.sup.3, and R.sup.k are as defined elsewhere herein.

[0330] In some embodiments of a compound of formula (I′) or (I), or any embodiment or variation thereof, such as a compound of formula (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-C), (I-D), (I-D1), (I-D2), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented by

##STR00054##

with carbon atoms bearing moieties

##STR00055##

R.sup.k, R.sup.m, R.sup.n, and R.sup.1, has a stereochemical configuration of the formula

##STR00056##

wherein R.sup.1, R.sup.m, and R.sup.n are each H, R.sup.k is halo or H, and X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, Y.sup.2, and Y.sup.3 are as defined elsewhere herein. In some embodiments, the moiety R.sup.k is fluoro.

[0331] In some embodiments of a compound of formula (I′) or (I), or any embodiment or variation thereof, such as a compound of formula (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-C), (I-D), (I-D1), (I-D2), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented by

##STR00057##

with carbon atoms bearing moieties

##STR00058##

R.sup.k, R.sup.m, R.sup.n, and R.sup.1, has a stereochemical configuration of the formula

##STR00059##

wherein R.sup.1, R.sup.m, and R.sup.n are each H, R.sup.k is fluoro, and X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, Y.sup.2, and Y.sup.3 are as defined elsewhere herein. In some embodiments Y.sup.2 and Y.sup.3 are each C. In some embodiments one Y.sup.2 and Y.sup.3 is C and the other of Y.sup.2 and Y.sup.3 is N.

[0332] In some embodiments, provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-A):

##STR00060##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y.sup.1 is CH or N; R.sup.x and R.sup.z are independently H, halo, C.sub.1-6alkyl, or —NH.sub.2, wherein, when Y.sup.1 is CH, the C.sub.1-6alkyl of R.sup.x or R.sup.z may be optionally substituted with one or more halo; and R.sup.y is (i) C.sub.1-6alkyl, (ii), C.sub.2-6alkenyl, or (iii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some variations, R.sup.2, R.sup.k, R.sup.x, R.sup.y, and R.sup.z of formula (I-A1) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein Y.sup.1 is CR.sup.x or N; wherein, when the ring bearing R.sup.x, R.sup.y and R.sup.z is phenyl, R.sup.x, R.sup.y and R.sup.z is H, halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), —NH—C(O)-(3-15 membered heterocyclyl), C.sub.3-10cycloalkyl, or 5-20 membered heteroaryl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH—C(O)—NH(C.sub.1-6alkyl), —NH—C(O)—C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl, and the 5-20 membered heteroaryl is optionally substituted with one or more C.sub.1-6alkyl; and wherein when the ring bearing R.sup.x, R.sup.y and R.sup.z is pyridyl, R.sup.x, R.sup.y and R.sup.z are each independently H, halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein, the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl.

[0333] In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.x and R.sup.z are independently H, fluoro, chloro, or methyl; and R.sup.y is (i) isopropyl, (ii) isopropenyl, or (iii) C.sub.3-4cycloalkyl, wherein the C.sub.3-4cycloalkyl is optionally substituted with one or more fluoro or methyl. In some embodiments, R.sup.x and R.sup.z are independently H, fluoro, chloro, or methyl; and R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl, wherein the C.sub.3-4cycloalkyl is optionally substituted with one or more fluoro or methyl. In some embodiments, R.sup.x is H, fluoro, chloro, or methyl; R.sup.z is H; and R.sup.y is (i) isopropyl, or (ii) C.sub.3-4cycloalkyl, wherein the C.sub.3-4cycloalkyl is optionally substituted with one or more fluoro or methyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0334] In some embodiments of a compound of formula (I′), (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.x is fluoro or methyl optionally substituted with one or more fluoro; R.sup.y is (i) isopropyl (ii) isopropenyl or (iii) C.sub.3-4cycloalkyl optionally substituted with one or more halo or C.sub.1-6alkyl or (iv) butyl; and R.sup.z is fluoro or methyl; provided that at least one of R.sup.x and R.sup.z is halo, CF.sub.2 or CF.sub.3.

[0335] In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is H or halo. In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is H or fluoro. In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0336] In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is optionally substituted with one or more R.sup.a. In some embodiments, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro.

[0337] In some embodiments of a compound of formula (I′), (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is 5-20 membered heteroaryl or —(C.sub.1-4alkyl)(5-20 membered heteroaryl), wherein the C.sub.1-4 alkyl is optionally substituted with one or more or more —OH, halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, and wherein the 5-20 membered heteroaryl is optionally substituted with one or more R.sup.s. In some embodiments, R.sup.s is halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)—C.sub.1-6alkyl, C.sub.6-20aryl, C.sub.3-10cycloalkyl, 3-15 membered heterocyclyl, 5-20 membered heteroaryl, or —C(O)—C.sub.1-6alkoxy. In some embodiments, the C.sub.1-6alkyl of R.sup.s is optionally substituted with one or more halo, C.sub.1-6alkoxy, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, and the 3-15-membered heterocyclyl of R.sup.s is optionally substituted with one or more halo or —C(O)—C.sub.1-6alkoxy.

[0338] In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is selected from the group consisting of

##STR00061##

In some embodiments, R.sup.2 is

##STR00062##

[0339] In some embodiments of a compound of formula (I′), (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is selected from the group consisting of

##STR00063## ##STR00064## ##STR00065##

In some embodiments, R.sup.2 is

##STR00066##

[0340] In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more oxo or C.sub.1-6alkyl. In some embodiments, R.sup.2 is

##STR00067##

[0341] In some embodiments of a compound of formula (I′), (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c, wherein R.sup.c is oxo, C.sub.1-6alkyl, or —C(O)—C.sub.1-6alkoxy, wherein the C.sub.1-6alkyl of R.sup.c is optionally substituted with one or more halo, and the —C(O)—C.sub.1-6alkoxy of R.sup.c is optionally substituted with one or more halo. In some embodiments, R.sup.2 is selected from the group consisting of

##STR00068## ##STR00069##

[0342] In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e, wherein R.sup.e is —C(O)-(3-15 membered heterocyclyl). In some embodiments, R.sup.2 is

##STR00070##

[0343] In some embodiments of a compound of formula (I′), (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e, wherein R.sup.e is —C(O)-(3-15 membered heterocyclyl) wherein the —C(O)-(3-15 membered heterocyclyl) of R.sup.e is optionally substituted with one or more C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl. In some embodiments, R.sup.2 is selected from the group consisting of

##STR00071##

[0344] In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d is —C(O)—N(C.sub.1-6alkyl).sub.2. In some embodiments, R.sup.2 is

##STR00072##

[0345] In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d, —C(O)—C.sub.1-6alkyl, —C(O)—N(C.sub.1-6alkyl).sub.2, or —C(O)-(3-15 membered heterocyclyl). In some embodiments, R.sup.2 is selected from the group consisting of

##STR00073##

[0346] In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is ethyl, wherein the ethyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d, is —C(O)—C.sub.1-6alkyl. In some embodiments, R.sup.2 is

##STR00074##

[0347] In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y.sup.1 is CH or N; R.sup.x and R.sup.z are independently H or halo; R.sup.y is C.sub.1-6alkyl or C.sub.3-10cycloalkyl; R.sup.k is H or halo; and R.sup.2 is selected from (i) to (iii): [0348] (i) C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is [0349] (a) —OH, [0350] (b) C.sub.6-20aryl, wherein the C.sub.6-20aryl of R.sup.a is optionally substituted with one or more halo, cyano, C.sub.1-6alkoxy, or —NH—C(O)—C.sub.1-6alkyl, [0351] (c) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c, wherein [0352] R.sup.c is halo, oxo, C.sub.1-6alkyl, C.sub.1-6alkoxy, —C(O)—C.sub.1-6alkyl, or —C(O)—C.sub.1-6alkoxy, wherein [0353] the C.sub.1-6alkyl of R.sup.c is optionally substituted with one or more halo or C.sub.2-6alkynyl, and [0354] the —C(O)—C.sub.1-6alkoxy of R.sup.c is optionally substituted with one or more halo, [0355] (d) —N(R.sup.c)(R.sup.d), wherein R.sup.c and R.sup.d of N(R.sup.c)(R.sup.d) are, independently of each other, H, C.sub.1-6alkyl, —C(O)—C.sub.1-6alkyl, —C(O)—C.sub.1-6alkoxy, —C(O)—NH.sub.2, —C(O)—NH(C.sub.1-6alkyl), —C(O)—N(C.sub.1-6alkyl).sub.2, —C(O)-(3-15 membered heterocyclyl), —CH.sub.2—C(O)—NH.sub.2, 3-15 membered heterocyclyl, or 5-20 membered heteroaryl, wherein [0356] the C.sub.1-6alkyl of R.sup.c or R.sup.d is optionally substituted with one or more —C(O)—NH.sub.2, [0357] the —C(O)—C.sub.1-6alkyl of R.sup.c or R.sup.d is optionally substituted with one or more halo, [0358] the 3-15 membered heterocyclyl and the 5-20 membered heteroaryl of R.sup.c or R.sup.d are independently optionally substituted with one or more C.sub.1-6alkyl, [0359] the —C(O)-(3-15 membered heterocyclyl) of R.sup.c or R.sup.d is optionally substituted with one or more halo, —C(O)—C.sub.1-6alkoxy, or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, and [0360] the C.sub.1-6alkyl of the —C(O)—N(C.sub.1-6alkyl).sub.2 of R.sup.c or R.sup.d are, independently of each other, optionally substituted with one or more halo or C.sub.6-20aryl, [0361] (e) —O—R.sup.e, wherein R.sup.e is C.sub.1-6alkyl, C.sub.6-20aryl, —C(O)-(3-15 membered heterocyclyl), —C(O)—N—(C.sub.1-6alkyl).sub.2, or 5-20 membered heteroaryl, wherein [0362] the C.sub.1-6alkyl of R.sup.e is optionally substituted with one or more C.sub.1-6alkoxy, wherein the C.sub.1-6alkoxy is optionally substituted with one or more C.sub.2-6alkynyl, [0363] the C.sub.6-20aryl of R.sup.e is optionally substituted with one or more C.sub.1-6alkyl, and [0364] the —C(O)-(3-15 membered heterocyclyl) of R.sup.e is optionally substituted with one or more C.sub.1-6alkyl, C.sub.1-6alkoxy, or —C(O)—C.sub.1-6alkoxy, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, or [0365] (f) —C(O)—R.sup.e, wherein R.sup.e of —C(O)—R.sup.e is —NH.sub.2, —OH, or 3-15 membered heterocyclyl, [0366] (ii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.2 is optionally substituted with one or more halo, oxo, C.sub.1-6alkyl, —C(O)—C.sub.1-6alkyl, or 5-20 membered heteroaryl, [0367] (iii) 5-20 membered heteroaryl or —(C.sub.1-4alkyl)(5-20 membered heteroaryl), wherein the C.sub.1-4 alkyl is optionally substituted with one or more or more —OH, halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, and wherein the 5-20 membered heteroaryl is optionally substituted with one or more R.sup.s, wherein [0368] R.sup.s is halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)—C.sub.1-6alkyl, C.sub.6-20aryl, C.sub.3-10cycloalkyl, 3-15 membered heterocyclyl, 5-20 membered heteroaryl, or —C(O)—C.sub.1-6alkoxy, wherein [0369] the C.sub.1-6alkyl of R.sup.s is optionally substituted with one or more halo, C.sub.1-6alkoxy, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, and [0370] the 3-15-membered heterocyclyl of R.sup.s is optionally substituted with one or more halo or —C(O)—C.sub.1-6alkoxy.

[0371] In some embodiments of formula (I-A), Y.sup.1 is CH or N; R.sup.x and R.sup.z are independently H or halo; R.sup.y is C.sub.1-6alkyl or C.sub.3-10cycloalkyl; R.sup.k is H or halo; R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a; R.sup.a is [0372] (a) —OH, [0373] (b) C.sub.6-10aryl optionally substituted with one or more halo, cyano, C.sub.1-3alkoxy, or —NH—C(O)—C.sub.1-3alkyl, or [0374] (c) 3-15 membered heterocyclyl optionally substituted with one or more halo, oxo, C.sub.1-6alkyl, C.sub.1-6alkoxy, —C(O)—C.sub.1-6alkyl, or —C(O)—C.sub.1-6alkoxy.

[0375] In some embodiments of formula (I-A), Y.sup.1 is CH or N; R.sup.x and R.sup.z are independently H or halo; R.sup.y is C.sub.1-3alkyl or C.sub.3-5cycloalkyl; R.sup.k is halo; R.sup.2 is C.sub.1-4alkyl substituted with one or more R.sup.a; R.sup.a is [0376] (a) —OH, [0377] (b) C.sub.6-10aryl optionally substituted with one or more halo, cyano, C.sub.1-3alkoxy, or —NH—C(O)—C.sub.1-3alkyl, or [0378] (c) C.sub.3-8heteroaryl optionally substituted with one or more halo, oxo, C.sub.1-6alkyl, C.sub.1-6alkoxy, —C(O)—C.sub.1-6alkyl, or —C(O)—C.sub.1-6alkoxy.

[0379] In some embodiments, provided herein is a compound of formula (I) or formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-A1):

##STR00075##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.x and R.sup.z are independently H, halo, C.sub.1-6alkyl, or —NH.sub.2, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo. In some embodiments, R.sup.x is H, halo, or C.sub.1-6alkyl; R.sup.y is (i) C.sub.1-6alkyl, (ii) C.sub.2-6alkenyl, or (ii) C.sub.3-10cycloalkyl; and R.sup.z is H, halo or C.sub.1-6alkyl. In some embodiments, R.sup.z is H. In some embodiments, at least one of R.sup.x and R.sup.z is halo. In some variations, R.sup.2, R.sup.k, R.sup.x, R.sup.y, and R.sup.z of formula (I-A1) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein R.sup.x, R.sup.y and R.sup.z are independently H, halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), —NH—C(O)-(3-15 membered heterocyclyl), C.sub.3-10cycloalkyl, or 5-20 membered heteroaryl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH—C(O)—NH(C.sub.1-6alkyl), —NH—C(O)—C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl, and the 5-20 membered heteroaryl is optionally substituted with one or more C.sub.1-6alkyl. In some embodiments, R.sup.x is H, halo, or C.sub.1-6alkyl optionally substituted with one or more halo; R.sup.y is (i) C.sub.1-6alkyl, (ii) C.sub.2-6alkenyl, (iii) C.sub.3-10cycloalkyl optionally substituted with one or more halo or C.sub.1-6alkyl or (iv) butyl; and R.sup.z is H, halo or C.sub.1-6alkyl. In some embodiments, R.sup.z is H. In some embodiments, at least one of R.sup.x and R.sup.z is halo or C.sub.1-6alkyl optionally substituted with one or more halo.

[0380] In some embodiments of a compound of formula (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.x is fluoro or methyl; R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl; and R.sup.z is fluoro or methyl; provided that at least one of R.sup.x and R.sup.z is halo. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0381] In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.x is fluoro or methyl optionally substituted with one or more fluoro; R.sup.y is (i) isopropyl (ii) C.sub.3-4cycloalkyl optionally substituted with one or more halo or C.sub.1-6alkyl or (iii) butyl; and R.sup.z is fluoro or methyl; provided that at least one of R.sup.x and R.sup.z is halo, CF.sub.2 or CF.sub.3.

[0382] In some embodiments of a compound of formula (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is H or halo. In some embodiments of a compound of formula (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is H or fluoro. In some embodiments of a compound of formula (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0383] In some embodiments of a compound of formula (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is optionally substituted with one or more R.sup.a. In some embodiments, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro.

[0384] In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is 5-20 membered heteroaryl or —(C.sub.1-4alkyl)(5-20 membered heteroaryl), wherein the C.sub.1-4 alkyl is optionally substituted with one or more or more —OH, halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, and wherein the 5-20 membered heteroaryl is optionally substituted with one or more R.sup.s. In some embodiments, R.sup.s is halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)—C.sub.1-6alkyl, C.sub.6-20aryl, C.sub.3-10cycloalkyl, 3-15 membered heterocyclyl, 5-20 membered heteroaryl, or —C(O)—C.sub.1-6alkoxy. In some embodiments, the C.sub.1-6alkyl of R.sup.s is optionally substituted with one or more halo, C.sub.1-6alkoxy, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, and the 3-15-membered heterocyclyl of R.sup.s is optionally substituted with one or more halo or —C(O)—C.sub.1-6alkoxy.

[0385] In some embodiments of a compound of formula (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is selected from the group consisting of

##STR00076##

In some embodiments, R.sup.2 is

##STR00077##

[0386] In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is selected from the group consisting of

##STR00078##

In some embodiments, R.sup.2 is

##STR00079##

[0387] In some embodiments of a compound of formula (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more oxo or C.sub.1-6alkyl. In some embodiments, R.sup.2 is

##STR00080##

[0388] In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c, wherein R.sup.c is oxo, C.sub.1-6alkyl, or —C(O)—C.sub.1-6alkoxy, wherein the C.sub.1-6alkyl of R.sup.c is optionally substituted with one or more halo, and the —C(O)—C.sub.1-6alkoxy of R.sup.c is optionally substituted with one or more halo. In some embodiments, R.sup.2 is

##STR00081##

[0389] In some embodiments of a compound of formula (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e, wherein R.sup.e is —C(O)-(3-15 membered heterocyclyl). In some embodiments, R.sup.2 is

##STR00082##

[0390] In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e, wherein R.sup.e is —C(O)-(3-15 membered heterocyclyl) wherein the —C(O)-(3-15 membered heterocyclyl) of R.sup.e is optionally substituted with one or more C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl. In some embodiments, R.sup.2 is

##STR00083##

[0391] In some embodiments of a compound of formula (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d is —C(O)—N(C.sub.1-6alkyl).sub.2. In some embodiments, R.sup.2 is

##STR00084##

[0392] In some embodiments of a compound of formula (I′) (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d, —C(O)—C.sub.1-6alkyl, —C(O)—N(C.sub.1-6alkyl).sub.2, or —C(O)-(3-15 membered heterocyclyl). In some embodiments, R.sup.2 is

##STR00085##

[0393] In some embodiments of a compound of formula (I′) (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is ethyl, wherein the ethyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d, is —C(O)—C.sub.1-6alkyl. In some embodiments, R.sup.2 is

##STR00086##

[0394] In some embodiments, provided is a compound of formula (I) or formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-A2):

##STR00087##

[0395] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.x is H, halo, C.sub.1-6alkyl, or —NH.sub.2, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo; and R.sup.y is (i) C.sub.1-6alkyl, (ii), C.sub.2-6alkenyl, or (iii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments, R.sup.x is H, halo, or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo; and R.sup.y is (i), C.sub.1-6alkyl, (ii) C.sub.2-6alkenyl, or (iii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments, R.sup.x is H, halo, or C.sub.1-6alkyl; and R.sup.y is (i) C.sub.1-6alkyl, (ii) C.sub.2-6alkenyl, or (iii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some variations, R.sup.2, R.sup.k, R.sup.x, and R.sup.y of formula (I-A2) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein R.sup.x and R.sup.y are each independently H, halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), —NH—C(O)-(3-15 membered heterocyclyl), C.sub.3-10cycloalkyl, or 5-20 membered heteroaryl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH—C(O)—NH(C.sub.1-6alkyl), —NH—C(O)—C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl, and the 5-20 membered heteroaryl is optionally substituted with one or more C.sub.1-6alkyl. In some embodiments, R.sup.x is H, halo, or C.sub.1-6alkyl optionally substituted with one or more halo; and R.sup.y is (i) C.sub.1-6alkyl, (ii) C.sub.3-10cycloalkyl optionally substituted with one or more halo or C.sub.1-6alkyl or (iii) butyl.

[0396] In some embodiments of a compound of formula (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.x is H, fluoro, chloro, or methyl, wherein the methyl is optionally substituted with one or more fluoro; and R.sup.y is (i) isopropyl, (ii) isopropenyl, (iii) sec-butyl, (iv) tert-butyl, or (v) C.sub.3-4cycloalkyl, wherein the C.sub.3-4cycloalkyl is optionally substituted with one or more fluoro or methyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0397] In some embodiments of a compound of formula (I′), (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.x is fluoro or methyl optionally substituted with one or more fluoro; and R.sup.y is (i) isopropyl (ii) C.sub.3-4cycloalkyl optionally substituted with one or more halo or C.sub.1-6alkyl or (iii) butyl.

[0398] In some embodiments of a compound of formula (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is H or halo. In some embodiments of a compound of formula (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is H or fluoro. In some embodiments of a compound of formula (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0399] In some embodiments of a compound of formula (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is optionally substituted with one or more R.sup.a. In some embodiments, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro.

[0400] In some embodiments of a compound of formula (I′), (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is —(C.sub.1-4alkyl)(5-20 membered heteroaryl), wherein the C.sub.1-4 alkyl is optionally substituted with one or more or more —OH, and wherein the 5-20 membered heteroaryl is optionally substituted with one or more R.sup.s. In some embodiments, R.sup.s is halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)—C.sub.1-6alkyl, C.sub.6-20aryl, C.sub.3-10cycloalkyl, 3-15 membered heterocyclyl, 5-20 membered heteroaryl, or —C(O)—C.sub.1-6alkoxy. In some embodiments, the C.sub.1-6alkyl of R.sup.s is optionally substituted with one or more halo, C.sub.1-6alkoxy, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, and the 3-15-membered heterocyclyl of R.sup.s is optionally substituted with one or more halo or —C(O)—C.sub.1-6alkoxy.

[0401] In some embodiments of a compound of formula (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is selected from the group consisting of

##STR00088##

In some embodiments, R.sup.2 is

##STR00089##

[0402] In some embodiments of a compound of formula (I′), (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is selected from the group consisting of

##STR00090##

In some embodiments, R.sup.2 is

##STR00091##

[0403] In some embodiments of a compound of formula (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more oxo or C.sub.1-6alkyl. In some embodiments, R.sup.2 is

##STR00092##

In some variations, the embodiments provided herein also apply to a compound of formula (I) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0404] In some embodiments of a compound of formula (I′), (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c, wherein R.sup.c is oxo, C.sub.1-6alkyl, or —C(O)—C.sub.1-6alkoxy, wherein the C.sub.1-6alkyl of R.sup.c is optionally substituted with one or more halo, and the —C(O)—C.sub.1-6alkoxy of R.sup.c is optionally substituted with one or more halo. In some embodiments, R.sup.2 is selected from the group consisting of

##STR00093##

In some embodiments of a compound of formula (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e wherein R.sup.e is —C(O)-(3-15 membered heterocyclyl). In some embodiments, R.sup.2 is

##STR00094##

In some embodiments of a compound of formula (I), (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e, wherein R.sup.e is —C(O)-(3-15 membered heterocyclyl) wherein the —C(O)-(3-15 membered heterocyclyl) of R.sup.e is optionally substituted with one or more C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl. In some embodiments, R.sup.2 is selected from the group consisting of

##STR00095##

[0405] In some embodiments of a compound of formula (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d is —C(O)—N(C.sub.1-6alkyl).sub.2. In some embodiments, R.sup.2 is

##STR00096##

In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some embodiments of a compound of formula (I), (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d, —C(O)—C.sub.1-6alkyl, —C(O)—N(C.sub.1-6alkyl).sub.2, or —C(O)-(3-15 membered heterocyclyl). In some embodiments, R.sup.2 is selected from the group consisting of

##STR00097##

[0406] In some embodiments of a compound of formula (I′) (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is ethyl, wherein the ethyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d, is —C(O)—C.sub.1-6alkyl. In some embodiments, R.sup.2 is

##STR00098##

[0407] In some embodiments, provided herein is a compound of formula (I) or formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-A3):

##STR00099##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.x is H, halo, C.sub.1-6alkyl, or —NH.sub.2, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo; and R.sup.y is (i) C.sub.1-6alkyl, (ii), C.sub.2-6alkenyl, or (iii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments, R.sup.x is H, halo, C.sub.1-6alkyl, or —NH.sub.2; and R.sup.y is (i) C.sub.1-6alkyl or (ii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some variations, R.sup.2, R.sup.k, R.sup.x, and R.sup.y of formula (I-A3) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein R.sup.x and R.sup.y are each independently H, halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein, the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments, R.sup.x is H, halo, C.sub.1-6alkyl, or —NH.sub.2; and R.sup.y is (i) C.sub.1-6alkyl or (ii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl.

[0408] In some embodiments of a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.x is H, fluoro, or methyl; and R.sup.y is (i) H, (ii) isopropyl, (iii) tert-butyl, or (iv) C.sub.3-4cycloalkyl, wherein the C.sub.3-4cycloalkyl is optionally substituted with one or more fluoro or methyl. In some embodiments, R.sup.x is H, fluoro, or methyl; and R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl, wherein the C.sub.3-4cycloalkyl is optionally substituted with one or more fluoro or methyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0409] In some embodiments of a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is H or halo. In some embodiments of a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is H or fluoro. In some embodiments of a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0410] In some embodiments of a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is optionally substituted with one or more R.sup.a. In some embodiments, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0411] In some embodiments of a compound of formula (I′), (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is —(C.sub.1-4alkyl)(5-20 membered heteroaryl), wherein the 5-20 membered heteroaryl is optionally substituted with one or more R.sup.s. In some embodiments, R.sup.s is halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)—C.sub.1-6alkyl, C.sub.6-20aryl, C.sub.3-10cycloalkyl, 3-15 membered heterocyclyl, 5-20 membered heteroaryl, or —C(O)—C.sub.1-6alkoxy. In some embodiments, the C.sub.1-6alkyl of R.sup.s is optionally substituted with one or more halo, C.sub.1-6alkoxy, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, and the 3-15-membered heterocyclyl of R.sup.s is optionally substituted with one or more halo or —C(O)—C.sub.1-6alkoxy.

[0412] In some embodiments of a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is selected from the group consisting of

##STR00100##

In some embodiments, R.sup.2 is

##STR00101##

[0413] In some embodiments of a compound of formula (I′), (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is selected from the group consisting of

##STR00102## ##STR00103## ##STR00104##

In some embodiments, R.sup.2 is

##STR00105##

In some embodiments, R.sup.2 is

##STR00106##

[0414] In some embodiments of a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more oxo or C.sub.1-6alkyl. In some embodiments, R.sup.2 is

##STR00107##

In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0415] In some embodiments of a compound of formula (I′), (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c, wherein R.sup.c is oxo, C.sub.1-6alkyl, or —C(O)—C.sub.1-6alkoxy, wherein the C.sub.1-6alkyl of R.sup.c is optionally substituted with one or more halo, and the —C(O)—C.sub.1-6alkoxy of R.sup.c is optionally substituted with one or more halo. In some embodiments, R.sup.2 is

##STR00108##

[0416] In some embodiments of a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e, wherein R.sup.e is —C(O)-(3-15 membered heterocyclyl). In some embodiments, R.sup.2 is

##STR00109##

In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some embodiments of a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d is —C(O)—N(C.sub.1-6alkyl).sub.2. In some embodiments, R.sup.2 is

##STR00110##

[0417] In some embodiments of a compound of formula (I′), (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d, —C(O)—C.sub.1-6alkyl, —C(O)—N(C.sub.1-6alkyl).sub.2, or —C(O)-(3-15 membered heterocyclyl), wherein the —C(O)-(3-15 membered heterocyclyl) of R.sup.c or R.sup.d is optionally substituted with one or more halo, —C(O)—C.sub.1-6alkoxy, or C.sub.1-6alkyl, and the C.sub.1-6alkyl of the —C(O)—N(C.sub.1-6alkyl).sub.2 of R.sup.c or R.sup.d are, independently of each other, optionally substituted with one or more halo or C.sub.6-20aryl. In some embodiments, R.sup.2 is

##STR00111##

[0418] In some embodiments of a compound of formula (I′), (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.c or R.sup.d are independently optionally substituted with one or more C.sub.1-6alkyl. In some embodiments, R.sup.2 is

##STR00112##

[0419] In some embodiments, provided herein is a compound of formula (I) or formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-A4):

##STR00113##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.z is H, halo, C.sub.1-6alkyl, or —NH.sub.2 and R.sup.y is (i) C.sub.1-6alkyl, (ii), C.sub.2-6alkenyl, or (iii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments, R.sup.z is H, halo, or C.sub.1-6alkyl; and R.sup.y is (i) C.sub.1-6alkyl, (ii), C.sub.2-6alkenyl, or (iii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments, R.sup.z is H or C.sub.1-6alkyl; and R.sup.y is (i) C.sub.1-6alkyl or (ii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments of a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.z is H or methyl; and R.sup.y is (i) isopropyl, or (ii) C.sub.3-4cycloalkyl. In some variations, R.sup.2, R.sup.k, R.sup.y, and R.sup.z of formula (I-A4) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein R.sup.y and R.sup.z are each independently H, halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein, the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments, R.sup.z is H, halo, or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.z is optionally substituted with one or more halo; and R.sup.y is (i) C.sub.1-6alkyl, (ii), or (ii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments of a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.z is H or methyl, wherein the methyl of R.sup.z is optionally substituted with one or more halo; and R.sup.y is (i) isopropyl, or (ii) C.sub.3-4cycloalkyl.

[0420] In some embodiments of a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is H or halo. In some embodiments of a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is H or fluoro. In some embodiments of a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0421] In some embodiments of a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is optionally substituted with one or more R.sup.a. In some embodiments, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro.

[0422] In some embodiments of a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is selected from the group consisting of

##STR00114##

In some embodiments, R.sup.2 is

##STR00115##

[0423] In some embodiments of a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more oxo or C.sub.1-6alkyl. In some embodiments, R.sup.2 is

##STR00116##

[0424] In some embodiments of a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e, wherein R.sup.e is —C(O)-(3-15 membered heterocyclyl). In some embodiments, R.sup.2 is

##STR00117##

[0425] In some embodiments of a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d is —C(O)—N(C.sub.1-6alkyl).sub.2. In some embodiments, R.sup.2 is

##STR00118##

[0426] In some embodiments, provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-B):

##STR00119##

[0427] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y.sup.1 is CH or N; R.sup.x is H, halo, C.sub.1-6alkyl, or —NH.sub.2, wherein, when Y.sup.1 is CH, the C.sub.1-6alkyl of Rx may be optionally substituted with one or more halo; R.sup.y is (i) C.sub.1-6alkyl, (ii), C.sub.2-6alkenyl, or (iii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl; and Rk is taken together with either Rm or Rn, and the atoms to which they are attached, to form cyclopropyl. In some variations, Y.sup.1, R.sup.2, R.sup.k, R.sup.m, R.sup.n, R.sup.x, R.sup.y, and R.sup.z of formula (I-B) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein Y1 is CR.sup.x or N; wherein, when the ring bearing R.sup.x, and R.sup.y is phenyl, R.sup.x, and R.sup.y are each independently H, halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), —NH—C(O)-(3-15 membered heterocyclyl), C.sub.3-10cycloalkyl, or 5-20 membered heteroaryl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH—C(O)—NH(C.sub.1-6alkyl), —NH—C(O)—C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl, and the 5-20 membered heteroaryl is optionally substituted with one or more C.sub.1-6alkyl; and wherein when the ring bearing R.sup.x, and R.sup.y is pyridyl, R.sup.x, and R.sup.y are each independently H, halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein, the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl.

[0428] In some embodiments of a compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y.sup.1 is CH or N; R.sup.x is H, halo, C.sub.1-6alkyl, or NH.sub.2, wherein, when Y.sup.1 is CH, the C.sub.1-6alkyl of R.sup.x may be optionally substituted with one or more halo; and R.sup.y is (i) C.sub.1-6alkyl, (ii), C.sub.2-6alkenyl, or (iii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments, Y.sup.1 is CH or N; R.sup.x is H or halo; R.sup.y is C.sub.1-6alkyl or C.sub.3-10cycloalkyl; and R.sup.k is taken together with either R.sup.m or R.sup.n, and the atoms to which they are attached, to form cyclopropyl. In some embodiments, Y.sup.1 is CH or N; R.sup.x is H or fluoro; R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl; and R.sup.k is taken together with either R.sup.m or R.sup.n, and the atoms to which they are attached, to form cyclopropyl. In some embodiments, Y.sup.1 is CH or N; R.sup.x is H or fluoro; R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl; and R.sup.k is taken together with R.sup.m and the atoms to which they are attached to form cyclopropyl. In some embodiments, Y.sup.1 is CH or N; R.sup.x is H or fluoro; R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl; and R.sup.k is taken together with R.sup.n and the atoms to which they are attached to form cyclopropyl. In some embodiments, Y.sup.1 is CH; R.sup.x is H or fluoro; R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl; and R.sup.k is taken together with R.sup.n or R.sup.n and the atoms to which they are attached to form cyclopropyl. In some embodiments, Y.sup.1 is N; R.sup.x is H or fluoro; R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl; and R.sup.k is taken together with R.sup.n or R.sup.n and the atoms to which they are attached to form cyclopropyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0429] In some embodiments of a compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is optionally substituted with one or more R.sup.a. In some embodiments, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0430] In some embodiments of a compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is selected from the group consisting of

##STR00120##

In some embodiments, R.sup.2 is

##STR00121##

[0431] In some embodiments of a compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more oxo or C.sub.1-6alkyl. In some embodiments, R.sup.2 is

##STR00122##

[0432] In some embodiments of a compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e, wherein R.sup.e is —C(O)-(3-15 membered heterocyclyl). In some embodiments, R.sup.2 is

##STR00123##

[0433] In some embodiments of a compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d is —C(O)—N(C.sub.1-6alkyl).sub.2. In some embodiments, R.sup.2 is

##STR00124##

[0434] In some embodiments, provided here is a compound of formula (I) or formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-B1):

##STR00125##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y.sup.1 is CH or N; R.sup.x is H or halo; and R.sup.y is C.sub.1-6alkyl or C.sub.3-10cycloalkyl. In some embodiments, Y.sup.1 is CH or N; R.sup.x is H or fluoro; and R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl. In some embodiments, Y.sup.1 is CH; R.sup.x is H or fluoro; and R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl. In some embodiments, Y.sup.1 is N; R.sup.x is H or fluoro; and R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl. In some variations, Y.sup.1, R.sup.2, R.sup.x, and R.sup.y of formula (I-B1) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein Y.sup.1 is CR.sup.x or N; wherein, when the ring bearing R.sup.x, and R.sup.y is phenyl, R.sup.x, and R.sup.y are each independently H, halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), —NH—C(O)-(3-15 membered heterocyclyl), C.sub.3-10cycloalkyl, or 5-20 membered heteroaryl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH—C(O)—NH(C.sub.1-6alkyl), —NH—C(O)—C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl, and the 5-20 membered heteroaryl is optionally substituted with one or more C.sub.1-6alkyl; and wherein when the ring bearing R.sup.x, and R.sup.y is pyridyl, R.sup.x, and R.sup.y are each independently H, halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein, the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments, Y.sup.1 is CH or N; R.sup.x is H or fluoro; and R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl. In some embodiments, Y.sup.1 is CH; R.sup.x is H or fluoro; and R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl. In some embodiments, Y.sup.1 is N; R.sup.x is H or fluoro; and R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl.

[0435] In some embodiments of a compound of formula (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is optionally substituted with one or more R.sup.a. In some embodiments, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0436] In some embodiments of a compound of formula (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is selected from the group consisting of

##STR00126##

In some embodiments, R.sup.2 is

##STR00127##

[0437] In some embodiments of a compound of formula (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more oxo or C.sub.1-6alkyl. In some embodiments, R.sup.2 is

##STR00128##

[0438] In some embodiments of a compound of formula (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e, wherein R.sup.e is —C(O)-(3-15 membered heterocyclyl). In some embodiments, R.sup.2 is

##STR00129##

[0439] In some embodiments of a compound of formula (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d is —C(O)—N(C.sub.1-6alkyl).sub.2. In some embodiments, R.sup.2 is

##STR00130##

[0440] In some embodiments, provided herein is a compound of formula (I) or formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-B2):

##STR00131##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y.sup.1 is CH or N; R.sup.x is H or halo; and R.sup.y is C.sub.1-6alkyl or C.sub.3-10cycloalkyl. In some embodiments, Y.sup.1 is CH or N; R.sup.x is H or fluoro; and R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl. In some embodiments, Y.sup.1 is CH; R.sup.x is H or fluoro; and R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl. In some embodiments, Y.sup.1 is N; R.sup.x is H or fluoro; and R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl. In some variations, Y.sup.1, R.sup.2, R.sup.x, and R.sup.y of formula (I-B2) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein Y.sup.1 is is CR.sup.x or N; wherein, when the ring bearing R.sup.x, and R.sup.y is phenyl, R.sup.x, and R.sup.y are each independently H, halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), —NH—C(O)-(3-15 membered heterocyclyl), C.sub.3-10cycloalkyl, or 5-20 membered heteroaryl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH—C(O)—NH(C.sub.1-6alkyl), —NH—C(O)—C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl, and the 5-20 membered heteroaryl is optionally substituted with one or more C.sub.1-6alkyl; and wherein when the ring bearing R.sup.x, and R.sup.y is pyridyl, R.sup.x, and R.sup.y are each independently H, halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein, the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments, Y.sup.1 is CH or N; R.sup.x is H or fluoro; and R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl. In some embodiments, Y.sup.1 is CH; R.sup.x is H or fluoro; and R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl. In some embodiments, Y.sup.1 is N; R.sup.x is H or fluoro; and R.sup.y is (i) isopropyl or (ii) C.sub.3-4cycloalkyl.

[0441] In some embodiments of a compound of formula (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is optionally substituted with one or more R.sup.a. In some embodiments, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0442] In some embodiments of a compound of formula (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is selected from the group consisting of

##STR00132##

In some embodiments, R.sup.2 is

##STR00133##

[0443] In some embodiments of a compound of formula (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more oxo or C.sub.1-6alkyl. In some embodiments, R.sup.2 is

##STR00134##

[0444] In some embodiments of a compound of formula (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e, wherein R.sup.e is —C(O)-(3-15 membered heterocyclyl). In some embodiments, R.sup.2 is

##STR00135##

[0445] In some embodiments of a compound of formula (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d is —C(O)—N(C.sub.1-6alkyl).sub.2. In some embodiments, R.sup.2 is

##STR00136##

[0446] In some embodiments, provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-C):

##STR00137##

wherein X.sup.5 is H, C.sub.1-6alkyl, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl; X.sup.4 is H, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, or 5-20 membered heteroaryl; R.sup.v is —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), or —NH—C(O)-(3-15 membered heterocyclyl); and R.sup.w is H, —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), or —NH—C(O)-(3-15 membered heterocyclyl). In some embodiments, X.sup.5 is H or C.sub.1-6alkyl; X.sup.4 is H; R.sup.v is —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), or —NH—C(O)-(3-15 membered heterocyclyl); and R.sup.w is H, —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), or —NH—C(O)-(3-15 membered heterocyclyl). In some embodiments, R.sup.w is H and R.sup.v is —NH—C(O)C.sub.1-6alkyl. In some embodiments, R.sup.w is H and R.sup.v is —NH—C(O)CH.sub.3. In some variations, R.sup.2, R.sup.k, R.sup.w, R.sup.v, X.sup.4 and X.sup.5 of formula (I-C) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein X.sup.5 is H, C.sub.1-6alkyl, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl; X.sup.4 is H, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, or 5-20 membered heteroaryl; R.sup.v is —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), or —NH—C(O)-(3-15 membered heterocyclyl); and R.sup.w is H, —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), or —NH—C(O)-(3-15 membered heterocyclyl). In some embodiments, X.sup.5 is H or C.sub.1-6alkyl; X.sup.4 is H; R.sup.v is —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), or —NH—C(O)-(3-15 membered heterocyclyl); and R.sup.w is H, —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), or —NH—C(O)-(3-15 membered heterocyclyl). In some embodiments, R.sup.w is H and R.sup.v is —NH—C(O)C.sub.1-6alkyl. In some embodiments, R.sup.w is H and R.sup.v is —NH—C(O)CH.sub.3.

[0447] In some embodiments, provided is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-D):

##STR00138##

wherein X.sup.5 is H, C.sub.1-6alkyl, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl; X.sup.4 is H, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, or 5-20 membered heteroaryl; and R.sup.t and R.sup.u are independently H, C.sub.1-6alkoxy, or —NH.sub.2. In some embodiments, X.sup.5 is C.sub.1-6alkyl; X.sup.4 is H, halo, or C.sub.1-6alkyl; and R.sup.t and R.sup.u are independently H or —NH.sub.2. In some embodiments, at least one of R.sup.t and R.sup.u is —NH.sub.2. In some embodiments, R.sup.t is H and R.sup.u is —NH.sub.2. In some embodiments, R.sup.t is —NH.sub.2 and R.sup.u is H. In some variations, R.sup.2, R.sup.k, R.sup.t, R.sup.u, X.sup.4 and X.sup.5 of formula (I-D) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein X.sup.5 is H, C.sub.1-6alkyl, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl; X.sup.4 is H, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, or 5-20 membered heteroaryl; and R.sup.t and R.sup.u are independently H, C.sub.1-6alkoxy, or —NH.sub.2. In some embodiments, X.sup.5 is C.sub.1-6alkyl; X.sup.4 is H, halo, or C.sub.1-6alkyl; and R.sup.t and R.sup.u are independently H or —NH.sub.2. In some embodiments, at least one of R.sup.t and R.sup.u is —NH.sub.2. In some embodiments, R.sup.t is H and R.sup.u is —NH.sub.2. In some embodiments, R.sup.t is —NH.sub.2 and R.sup.u is H.

[0448] In some embodiments of a compound of formula (I-C) or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is H or halo. In some embodiments of a compound of formula (I-C) or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is H or fluoro. In some embodiments of a compound of formula (I-C) or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0449] In some embodiments, provided is a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-D1):

##STR00139##

[0450] In some embodiments, provided is a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-D2):

##STR00140##

wherein X.sup.5 is H, C.sub.1-6alkyl, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl; X.sup.4 is H, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, or 5-20 membered heteroaryl, wherein the C.sub.1-6alkyl of X.sup.4 is optionally substituted with one of more halo; and R.sup.t and R.sup.u are independently H, C.sub.1-6alkoxy, or —NH.sub.2. In some embodiments, X.sup.5 is C.sub.1-6alkyl; X.sup.4 is H, halo, or C.sub.1-6alkyl; and R.sup.u and R.sup.z are independently H, halo or —NH.sub.2. In some embodiments, at least one of R.sup.u and R.sup.z is —NH.sub.2. In some embodiments, R.sup.u is H and R.sup.z is —NH.sub.2. In some embodiments, R.sup.u is —NH.sub.2 and R.sup.z is H. In some embodiments, at least one of R.sup.u and R.sup.z is halo. In some embodiments, R.sup.u is H and R.sup.z is fluoro. In some embodiments, R.sup.u is fluoro and R.sup.z is H.

[0451] In some embodiments, provided is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-E):

##STR00141##

wherein R.sup.k and R.sup.m are independently H, OH, —NH.sub.2, or —NH—C(O)C.sub.1-6alkyl. In some embodiments, R.sup.k is H and R.sup.m is H, OH, —NH.sub.2, or —NH—C(O)C.sub.1-6alkyl. In some embodiments, R.sup.k is H and R.sup.m is OH. In some embodiments, R.sup.k is H, OH, —NH.sub.2, or —NH—C(O)C.sub.1-6alkyl, and R.sup.m is H. In some embodiments, R.sup.k is OH, —NH.sub.2, or —NH—C(O)C.sub.1-6alkyl, and R.sup.m is H. In some embodiments, R.sup.k is OH, —NH.sub.2, or —NH—C(O)CH.sub.3, and R.sup.m is H. In some variations, R.sup.2, R.sup.k, and R.sup.m of formula (I-E) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein R.sup.k and R.sup.m are independently H, OH, —NH.sub.2, or —NH—C(O)C.sub.1-6alkyl. In some embodiments, R.sup.k is H and R.sup.m is H, OH, —NH.sub.2, or —NH—C(O)C.sub.1-6alkyl. In some embodiments, R.sup.k is H and R.sup.m is OH. In some embodiments, R.sup.k is H, OH, —NH.sub.2, or —NH—C(O)C.sub.1-6alkyl, and R.sup.m is H. In some embodiments, R.sup.k is OH, —NH.sub.2, or —NH—C(O)C.sub.1-6alkyl, and R.sup.m is H. In some embodiments, R.sup.k is OH, —NH.sub.2, or —NH—C(O)CH.sub.3, and R.sup.m is H.

[0452] In some embodiments, provided is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-F):

##STR00142##

wherein Y.sup.1 is CH or N; R.sup.x is H, halo, C.sub.1-6alkyl, or —NH.sub.2, wherein, when Y.sup.1 is CH, the C.sub.1-6alkyl of R.sup.x may be optionally substituted with one or more halo; R.sup.y is (i) C.sub.1-6alkyl, (ii), C.sub.2-6alkenyl, or (iii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl; R.sup.k is H, halo, —OH, —NH.sub.2, or —NH—C(O)C.sub.1-6alkyl; and R.sup.n is H, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl. In some embodiments, Y.sup.1 is CH or N; R.sup.x is H, halo, or C.sub.1-6alkyl; R.sup.y is (i) C.sub.1-6alkyl, (ii), C.sub.2-6alkenyl, or (iii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl; R.sup.k is H, halo, —OH, —NH.sub.2, or —NH—C(O)C.sub.1-6alkyl; and R.sup.n is H, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl. In some variations, R.sup.2, R.sup.k, R.sup.x, R.sup.y, and R.sup.z of formula (I-F) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein Y.sup.1 is CH or N; R.sup.x is H, halo, C.sub.1-6alkyl, or —NH.sub.2, wherein, when Y.sup.1 is CH, the C.sub.1-6alkyl of R.sup.x may be optionally substituted with one or more halo; R.sup.y is (i) C.sub.1-6alkyl, (ii), C.sub.2-6alkenyl or (iii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl; R.sup.k is H, halo, —OH, —NH.sub.2, or —NH—C(O)C.sub.1-6alkyl; and R.sup.n is H, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl. In some embodiments, Y.sup.1 is CH or N; R.sup.x is H, halo, or C.sub.1-6alkyl; R.sup.y is (i) C.sub.1-6alkyl, or (ii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl; R.sup.k is H, halo, —OH, —NH.sub.2, or —NH—C(O)C.sub.1-6alkyl; and R.sup.n is H, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl.

[0453] In some embodiments of a compound of formula (I-F), Y.sup.1 is CH or N; R.sup.x is H, halo, or C.sub.1-6alkyl; R.sup.y is (i) C.sub.1-6alkyl, (ii), C.sub.2-6alkenyl, or (iii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10 cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl; R.sup.k is H or halo; and R.sup.n is H, C.sub.1-6alkyl, or C.sub.3-6cycloalkyl. In some embodiments, Y.sup.1 is N or CH, R.sup.x is H or halo, R.sup.y is C.sub.1-6alkyl or C.sub.3-6cycloalkyl, R.sup.k is H or halo, and R.sup.n is C.sub.1-6alkyl or C.sub.3-6cycloalkyl. In some embodiments, Y.sup.1 is N or CH, R.sup.x is H or fluoro, R.sup.y is C.sub.1-6alkyl or C.sub.3-6cycloalkyl, R.sup.k is H or fluoro, and R.sup.n is C.sub.1-6alkyl or C.sub.3-6cycloalkyl. In some embodiments, Y.sup.1 is N or CH, R.sup.x is H or fluoro, R.sup.y is C.sub.1-6alkyl or C.sub.3-6cycloalkyl, R.sup.k is H or fluoro, and R.sup.n is C.sub.1-6alkyl or C.sub.3-6cycloalkyl. In some embodiments, Y.sup.1 is N or CH, R.sup.x is H or fluoro, R.sup.y is C.sub.1-6alkyl or C.sub.3-6cycloalkyl, R.sup.k is H, and R.sup.n is C.sub.1-6alkyl or C.sub.3-6cycloalkyl. In some embodiments, Y.sup.1 is N or CH, R.sup.x is H or fluoro, R.sup.y is C.sub.1-3alkyl or C.sub.3-6cycloalkyl, R.sup.k is H, and R.sup.n is C.sub.1-3lkyl or C.sub.3-6cycloalkyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0454] In some embodiments of a compound of formula (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is optionally substituted with one or more R.sup.a. In some embodiments, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[0455] In some embodiments of a compound of formula (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is selected from the group consisting of

##STR00143##

In some embodiments, R.sup.2 is

##STR00144##

[0456] In some embodiments of a compound of formula (I′), (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is selected from the group consisting of

##STR00145##

[0457] In some embodiments of a compound of formula (I′), (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is selected from the group consisting of

##STR00146## ##STR00147##

In some embodiments, R.sup.2 is

##STR00148##

[0458] In some embodiments of a compound of formula (I), (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is

##STR00149##

[0459] In some embodiments of a compound of formula (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more oxo or C.sub.1-6alkyl. In some embodiments, R.sup.2 is

##STR00150##

[0460] In some embodiments of a compound of formula (I′) (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c, wherein R.sup.c is oxo, C.sub.1-6alkyl, or —C(O)—C.sub.1-6alkoxy, wherein the C.sub.1-6alkyl of R.sup.c is optionally substituted with one or more halo, and the —C(O)—C.sub.1-6alkoxy of R.sup.c is optionally substituted with one or more halo. In some embodiments, R.sup.2 is selected from the group consisting of

##STR00151##

[0461] In some embodiments of a compound of formula (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e. In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e, wherein R.sup.e is —C(O)-(3-15 membered heterocyclyl). In some embodiments, R.sup.2 is

##STR00152##

[0462] In some embodiments of a compound of formula (I′), (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e, wherein R.sup.e is —C(O)-(3-15 membered heterocyclyl) wherein the —C(O)-(3-15 membered heterocyclyl) of R.sup.e is optionally substituted with one or more C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl. In some embodiments, R.sup.2 is selected from the group consisting of

##STR00153##

[0463] In some embodiments of a compound of formula (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d). In some embodiments, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d is —C(O)—N(C.sub.1-6alkyl).sub.2. In some embodiments, R.sup.2 is

##STR00154##

[0464] In some embodiments of a compound of formula (I′), (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d, —C(O)—C.sub.1-6alkyl, —C(O)—N(C.sub.1-6alkyl).sub.2, or —C(O)-(3-15 membered heterocyclyl). In some embodiments, R.sup.2 is

##STR00155##

[0465] In some embodiments, provided herein is a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-G):

##STR00156##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is (i) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of ring A is optionally substituted with one or more oxo, (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of ring A is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein, the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl, or (iii) C.sub.3-10cycloalkyl.

[0466] In some embodiments of a compound of formula (I′), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X.sup.3 is H, fluoro or methyl optionally substituted with one or more fluoro; X.sup.4 is (i) isopropyl (ii) C.sub.3-4cycloalkyl optionally substituted with one or more halo or C.sub.1-6alkyl or (iii) butyl; and R.sup.z is fluoro or methyl; provided that at least one of X.sup.3 and X.sup.4 is halo, CF.sub.2 or CF.sub.3.

[0467] In some embodiments of a compound of formula (I′), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is H or halo. In some embodiments of a compound of formula (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is H or fluoro. In some embodiments of a compound of formula (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.k is fluoro.

[0468] In some embodiments of a compound of formula (I′), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is 5-20 membered heteroaryl or —(C.sub.1-4alkyl)(5-20 membered heteroaryl), wherein the C.sub.1-4 alkyl is optionally substituted with one or more or more —OH, halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, and wherein the 5-20 membered heteroaryl is optionally substituted with one or more R.sup.s. In some embodiments, R.sup.s is halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)—C.sub.1-6alkyl, C.sub.6-20aryl, C.sub.3-10cycloalkyl, 3-15 membered heterocyclyl, 5-20 membered heteroaryl, or —C(O)—C.sub.1-6alkoxy. In some embodiments, the C.sub.1-6alkyl of R.sup.s is optionally substituted with one or more halo, C.sub.1-6alkoxy, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, and the 3-15-membered heterocyclyl of R.sup.s is optionally substituted with one or more halo or —C(O)—C.sub.1-6alkoxy.

[0469] In some embodiments of a compound of formula (I′), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is selected from the group consisting of

##STR00157##

[0470] In some embodiments of a compound of formula (I′) (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d, —C(O)—C.sub.1-6alkyl, —C(O)—N(C.sub.1-6alkyl).sub.2, or —C(O)-(3-15 membered heterocyclyl). In some embodiments, R.sup.2 is

##STR00158##

[0471] In some embodiments of a compound of formula (I′) (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is (i) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of ring A is optionally substituted with one or more oxo, or C.sub.1-6alkyl, (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of ring A is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein, the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl, or (iii) C.sub.3-10cycloalkyl.

[0472] In some embodiments of a compound of formula (I′), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of ring A is optionally substituted with one or more oxo, or C.sub.1-6alkyl. In some embodiments ring A is selected from the group consisting of

##STR00159##

[0473] In some embodiments of a compound of formula (I′), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of ring A is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein, the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl. In some embodiments ring A is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of ring A is optionally substituted with one or more C.sub.1-6alkyl. In some embodiments ring A is selected from the group consisting of

##STR00160##

[0474] In some embodiments of a compound of formula (I′), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is C.sub.3-10cycloalkyl. In some embodiments, ring A is C.sub.3-6cycloalkyl. In some embodiments ring A is cyclopropyl.

[0475] In some embodiments, provided herein is a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-H):

##STR00161##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y.sup.1 is CR.sup.x or N; wherein, when the ring bearing R.sup.x, R.sup.y and R.sup.z is phenyl, R.sup.x, R.sup.y and R.sup.z is H, halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), —NH—C(O)-(3-15 membered heterocyclyl), C.sub.3-10cycloalkyl, or 5-20 membered heteroaryl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH—C(O)—NH(C.sub.1-6alkyl), —NH—C(O)—C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl, and the 5-20 membered heteroaryl is optionally substituted with one or more C.sub.1-6alkyl; and wherein when the ring bearing R.sup.x, R.sup.y and R.sup.z is pyridyl, R.sup.x, R.sup.y and R.sup.z are each independently H, halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein, the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl.

[0476] In some embodiments, provided herein is a compound of formula (I), such as a compound of formula (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is optionally substituted with one or more R.sup.a. In some embodiments, R.sup.2 is C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl of R.sup.2 is optionally substituted with one or more R.sup.q. In other embodiments, R.sup.2 is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.2 is optionally substituted with one or more halo, oxo, C.sub.1-6alkyl, —C(O)—C.sub.1-6alkyl, or 5-20 membered heteroaryl. In some embodiments, R.sup.2 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.2 is optionally substituted with one or more R.sup.s. In some embodiments, R.sup.2 is —N(R.sup.g)(R.sup.h), wherein R.sup.g and R.sup.h are independently H or C.sub.1-6alkyl. In some embodiments, R.sup.2 is —C(O)—R.sup.j, wherein R.sup.j is C.sub.3-10cycloalkyl, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, or —NH (5-20 membered heteroaryl). In some embodiments, R.sup.2 is C.sub.6-20aryl, wherein the C.sub.6-20aryl of R.sup.2 is optionally substituted with one or more 5-20 membered heteroaryl or —O(R.sup.p), wherein R.sup.p is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.p is optionally substituted with one or more —C(O)—C.sub.1-6alkyl.

[0477] In some embodiments, provided herein is a compound of formula (I′), such as a compound of formula (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-C), (I-D), (I-D1), (I-D2), (I-E), (I-F), (I-G), or (I-H) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is optionally substituted with one or more R.sup.a. In some embodiments, R.sup.2 is C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl of R.sup.2 is optionally substituted with one or more R.sup.q. In other embodiments, R.sup.2 is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.2 is optionally substituted with one or more halo, oxo, C.sub.1-6alkyl, —C(O)—C.sub.1-6alkyl, or 5-20 membered heteroaryl. In some embodiments, R.sup.2 is 5-20 membered heteroaryl, or —(C.sub.1-4alkyl)(5-20 membered heteroaryl), wherein the C.sub.1-4 alkyl is optionally substituted with one or more or more —OH, halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, and wherein the 5-20 membered heteroaryl is optionally substituted with one or more R.sup.s. In some embodiments, R.sup.2 is —N(R.sup.g)(R.sup.h), wherein R.sup.g and R.sup.h are independently H or C.sub.1-6alkyl. In some embodiments, R.sup.2 is —C(O)—R.sup.j, wherein R.sup.j is C.sub.3-10cycloalkyl, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, or —NH (5-20 membered heteroaryl). In some embodiments, R.sup.2 is C.sub.6-20aryl, wherein the C.sub.6-20aryl of R.sup.2 is optionally substituted with one or more 5-20 membered heteroaryl or —O(R.sup.p), wherein R.sup.p is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.p is optionally substituted with one or more —C(O)—C.sub.1-6alkyl.

[0478] In some embodiments of a compound of formula (I), or formula (I′), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from Table 1.

[0479] Compound Names included in Table 1 and for all intermediates and compounds were generated using ChemDraw© Professional software version 17.1.1.0 or Collaborative Drug Discovery Inc. (CDD) CDD Vault update #3.

[0480] A Knime workflow was created to retrieve structures from an internal ChemAxon Compound Registry, generate the canonical smiles using RDKit Canon SMILES node, remove the stereochemistry using ChemAxon/Infocom MolConverter node, and name the structure using ChemAxon/Infocom Naming node. The following denotes the version of the Knime Analytics Platform and extensions utilized in the workflow: [0481] Knime Analytics Platform 4.2.2 [0482] RDKit Knime Integration 4.0.1.v202006261025 (this extension includes the RDKit Canon SMILES node) [0483] ChemAxon/Infocom Marvin Extensions Feature 4.3.0v202100 (this extension includes the MolConverter node) [0484] ChemAxon/Infocom JChem Extensions Feature 4.3.0v202100 (this extension includes the Naming node)

TABLE-US-00001 TABLE 1 Compound No. Structure IUPAC 1 [00162] embedded image (2S,4R)-1-(2-(1H-1,2,3-triazol-5- yl)acetyl)-4-fluoro-N-((S)-(4- isopropylphenyl)(phenyl)methyl) pyrrolidine-2-carboxamide 2 [00163] (2S,4R)-4-fluoro-1-{3-[N-(1- methyl-1H-pyrazol-3- yl)acetamido)propanoyl}-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 3 [00164] embedded image (2S,4R)-1-[(3aS,6aS)-5-acetyl- hexahydro-1H-furo[3,4-c]pyrrole- 3a-carbonyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 4 [00165] (2S,4R)-{7-acetyl-1-oxa-2,7- diazaspiro[4.4]non-2-ene-3- carbonyl}-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 5 [00166] embedded image (2S,4R)-4-fluoro-1-[(2S,3R)-3- methoxy-2-(N- methylacetamido)butanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 6 [00167] (2S,4R)-1-[(4S,5R)-7-acetyl-7-oxo- 2,7-diazaspiro[4.4]nonane-4- carbonyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 7 [00168] embedded image (2S,4R)-1-(2-{2-acetyl-2- azaspiro[3.4]octan-5-yl}acetyl)-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 8 [00169] (2S,4R)-4-fluoro-1-[(5S)-2-oxo- 1,3-oxazolidine-5-carbonyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 9 [00170] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (1H-1,2,3-tetrazol-1- yl)acetyl]pyrrolidine-2- carboxamide 10 [00171] (2S,4R)-4-fluoro-1-[2-(5-methyl- 1,3,4-oxadiazol-2-yl)acetyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 11 [00172] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[3- (1H-1,2,3-triazol-1- yl)propanoyl]pyrrolidine-2- carboxamide 12 [00173] embedded image (2S,4R)-4-fluoro-1-(1,3-oxazole-5- carbonyl)-N-[(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]pyrrolidine-2- carboxamide 13 [00174] (2S,4R)-1-(3-cyanopropanoyl)-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 14 [00175] (2S,4R)-4-fluoro-1-(2- methanesulfonylacetyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 15 [00176] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (1,3-thiazol-4-yl)acetyl]pyrrolidine- 2-carboxamide 16 [00177] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (1H-1,2,4-triazol-1- yl)acetyl]pyrrolidine-2- carboxamide 17 [00178] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (2H-1,2,3-triazol-2- yl)acetyl]pyrrolidine-2- carboxamide 18 [00179] embedded image (2S,4R)-4-fluoro-1-[2-(1H- imidazol-4-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 19 [00180] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (1H-pyrazol-5- yl)acetyl]pyrrolidine-2- carboxamide 20 [00181] (2S,4R)-1-[2-(4-chloro-1H-pyrazol- 1-yl)acetyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 21 [00182] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (pyridazin-3- yloxy)acetyl]pyrrolidine-2- carboxamide 22 [00183] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (1H-pyrazol-1- yl)acetyl]pyrrolidine-2- carboxamide 23 [00184] (2S,4R)-4-fluoro-1-[2-(1H- imidazol-1-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 24 [00185] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (1H-1,2,3,4-tetrazol-1- yl)propanoyl]pyrrolidine-2- carboxamide 25 [00186] (2S,4R)-4-fluoro-1-(3- methyloxetane-3-carbonyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 26 [00187] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (pyrazin-2-yl)acetyl]pyrrolidine-2- carboxamide 27 [00188] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (pyrimidin-5-yl)acetyl]pyrrolidine- 2-carboxamide 28 [00189] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (pyrimidin-2-yl)acetyl]pyrrolidine- 2-carboxamide 29 [00190] (2S,4R)-4-fluoro-1-[2-(5-methyl- 1,2,4-oxadiazol-3-yl)acetyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 30 [00191] embedded image (2S,4R)-4-fluoro-1-(4- methylpyrimidine-5-carbonyl)-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 31 [00192] (2S,4R)-4-fluoro-1-[2-(3-methyl- 1,2,4-oxadiazol-5-yl)acetyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 32 [00193] (2S,4R)-4-fluoro-1-[2-(2-oxo-1,2- dihydropyrazin-1-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 33 [00194] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (1H-1,2,3-triazol-1- yl)propanoyl]pyrrolidine-2- carboxamide 34 [00195] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (1H-1,2,4-triazol-1- yl)propanoyl]pyrrolidine-2- carboxamide 35 [00196] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[3- (1H-1,2,4-triazol-1- yl)propanoyl]pyrrolidine-2- carboxamide 36 [00197] embedded image (2S,4R)-4-fluoro-1-[2-(5- fluoropyridin-2-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 37 [00198] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (pyridin-2-yl)acetyl]pyrrolidine-2- carboxamide 38 [00199] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (pyridin-3-yl)acetyl]pyrrolidine-2- carboxamide 39 [00200] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (pyridin-4-yl)acetyl]pyrrolidine-2- carboxamide 40 [00201] (2S,4R)-4-fluoro-1-[2-(3-methyl- 1,2-oxazol-5-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 41 [00202] (2S,4R)-4-fluoro-1-[2-(2-methyl- 1,3-thiazol-5-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 42 [00203] embedded image (2S,4R)-1-(2-ethyl-1,3-oxazole-4- carbonyl)-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 43 [00204] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (1H-pyrazol-1- yl)propanoyl]pyrrolidine-2- carboxamide 44 [00205] (2S,4R)-4-fluoro-1-[2-(1H- imidazol-1-yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 45 [00206] embedded image (2S,4R)-4-fluoro-1-[3-(1H- imidazol-5-yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 46 [00207] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[3- (1H-pyrazol-4- yl)propanoyl]pyrrolidine-2- carboxamide 47 [00208] (2S,4R)-4-fluoro-1-[3-(1H- imidazol-2-yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 48 [00209] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (pyridin-3- yloxy)acetyl]pyrrolidine-2- carboxamide 49 [00210] (2S,4R)-4-fluoro-1-[2-(1-methyl- 1H-pyrazol-3-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 50 [00211] (2S,4R)-4-fluoro-1-[2-(1-methyl- 1H-pyrazol-4-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 51 [00212] embedded image (2S,4R)-4-fluoro-1-[2-(2-oxo-1,2- dihydropyridin-1-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 52 [00213] (2S,4R)-4-fluoro-1-[2-(2-methyl- 1,3-thiazol-4-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 53 [00214] embedded image (2S,4R)-1-(1-ethyl-1H-pyrazole-5- carbonyl)-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 54 [00215] (2S,4R)-4-fluoro-1-[2-(3-methyl- 1H-pyrazol-5-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 55 [00216] (2S,4R)-4-fluoro-1-[2-(3-methyl- 1H-pyrazol-1-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 56 [00217] embedded image (2S,4R)-4-fluoro-1-[2-(4-methyl- 1H-pyrazol-1-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 57 [00218] (2S,4R)-4-fluoro-1-[(2S)-1-methyl- 5-oxopyrrolidine-2-carbonyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 58 [00219] embedded image (2S,4R)-4-fluoro-1-(6- oxopiperidine-3-carbonyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 59 [00220] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[3- (pyrazin-2- yl)propanoyl]pyrrolidine-2- carboxamide 60 [00221] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[3- (pyrimidin-5- yl)propanoyl]pyrrolidine-2- carboxamide 61 [00222] embedded image (2S,4R)-4-fluoro-1-(3-methoxy-1- methyl-1H-pyrazole-4-carbonyl)- N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 62 [00223] (2S,4R)-4-fluoro-1-[3-(5-methyl- 1,3,4-thiadiazol-2-yl)propanoyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 63 [00224] embedded image (2S,4R)-1-[2-(2-chloro-5- fluorophenyl]acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 64 [00225] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (pyridin-2- yl)propanoyl]pyrrolidine-2- carboxamide 65 [00226] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[3- (pyridin-2- yl)propanoyl]pyrrolidine-2- carboxamide 66 [00227] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[3- (pyridin-3- yl)propanoyl]pyrrolidine-2- carboxamide 67 [00228] (2S,4R)-1-{2- [(dimethylcarbamoyl)amino]acetyl}- 4-fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 68 [00229] (2S,4R)-1-[2-(1H-1,2,3- benzotriazol-1-yl)acetyl]-4-fluoro- N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 69 [00230] embedded image (2S,4R)-1-[2-(2,5-dimethyl-1,3- thiazol-4-yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 70 [00231] (2S,4R)-1-[2-(3,5-dimethyl-1,2- oxazol-4-yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 71 [00232] embedded image (2S,4R)-4-fluoro-1-[2-(N- methylacetamido)propanoyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 72 [00233] (2S,4R)-1-(2-acetamidopyridine-4- carbonyl)-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 73 [00234] (2S,4R)-4-fluoro-1-[2-(2-oxo-1,2- dihydropyridin-1-yl)propanoyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 74 [00235] embedded image (2S,4R)-4-fluoro-1-{3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyridine-8- carbonyl}-N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 75 [00236] (2S,4R)-4-fluoro-1-[4-(1H- imidazol-1-yl)butanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 76 [00237] embedded image (2S,4R)-4-fluoro-1-[3-(1-methyl- 1H-pyrazol-4-yl)propanoyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 77 [00238] (2S,4R)-1-[2-(1H-1,3-benzodiazol- 1-yl)acetyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 78 [00239] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[5- (pyridin-4-yl)-1H-pyrazole-3- carbonyl]pyrrolidine-2- carboxamide 79 [00240] embedded image (2S,4R)-4-fluoro-1-[3-(1H- imidazol-1-yl)-2-methylpropanoyl]- N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 80 [00241] (2S,4R)-4-fluoro-1-[2-methyl-3- (1H-pyrazol-1-yl)propanoyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 81 [00242] embedded image (2S,4R)-4-fluoro-1-[2-(6- methoxypyridin-2-yl)acetyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 82 [00243] (2S,4R)-4-fluoro-1-[5- (methoxymethyl)-1,2-oxazole-4- carbonyl]-N-[(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]pyrrolidine-2- carboxamide 83 [00244] (2S,4R)-1-[2-(1,5-dimethyl-1H- pyrazol-3-yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 84 [00245] embedded image (2S,4R)-1-[2-(3,5-dimethyl-1H- pyrazol-4-yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 85 [00246] (2S,4R)-4-fluoro-1-[2-(2- oxopiperidin-1-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 86 [00247] (2S,4R)-4-fluoro-1-[2-(1H-indol-3- yl)acetyl]-N-[(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]pyrrolidine-2- carboxamide 87 [00248] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-{2- [5-(propan-2-yl)-1,2,4-oxadiazol-3- yl]acetyl}pyrrolidine-2- carboxamide 88 [00249] (2S,4R)-4-fluoro-1-[2-(4- methoxyphenyl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 89 [00250] (2S,4R)-4-fluoro-1-[2-(3-fluoro-4- methoxyphenyl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 90 [00251] embedded image (2S,4R)-4-fluoro-1-[2-(5-fluoro-2- methoxyphenyl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 91 [00252] (2S,4R)-4-fluoro-1-[2-(2- methylphenoxy)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 92 [00253] (2S,4R)-4-fluoro-1-[2-methyl-2- (pyridin-2-yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 93 [00254] embedded image (2S,4R)-4-fluoro-1-(2- oxopiperidin-4-carbonyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 94 [00255] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[4- (pyridin-3-yl)butanoyl]pyrrolidine- 2-carboxamide 95 [00256] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[4- (pyridin-4-yl)butanoyl]pyrrolidine- 2-carboxamide 96 [00257] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (quinolin-6-yl)acetyl]pyrrolidine-2- carboxamide 97 [00258] (2S,4R)-4-fluoro-1-(2-oxo-1,2,3,4- tetrahydroquinoline-7-carbonyl)-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 98 [00259] (2S,4R)-4-fluoro-1-[2-methyl-3- (pyridin-4-yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 99 [00260] embedded image (2S,4R)-4-fluoro-1-[3-(2- methylpyridin-4-yl)propanoyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 100 [00261] (2S,4R)-4-fluoro-1-[3-(6- methylpyridin-3-yl)propanoyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 101 [00262] (2S,4R)-4-fluoro-1-[3-(5- methylpyridin-2-yl)propanoyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 102 [00263] embedded image (2S,4R)-4-fluoro-1-[3-(2- methylpyridin-3-yl)propanoyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 103 [00264] (2S,4R)-1-[3-(3,5-dimethyl-1,2- oxazol-4-yl)propanoyl]-4-fluoro-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 104 [00265] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-(3- {1H-pyrrolo[2,3-b]pyridin-3- yl}propanoyl)pyrrolidine-2- carboxamide 105 [00266] (2S,4R)-4-fluoro-1-[4-(2-methyl- 1H-imidazol-1-yl)butanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 106 [00267] embedded image (2S,4R)-1-[3-(3,5-dimethyl-1H- pyrazol-1-yl)propanoyl]-4-fluoro- N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 107 [00268] (2S,4R)-1-[2-(4- acetamidophenyl)acetyl]-4-fluoro- N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 108 [00269] (2S,4R)-4-fluoro-1-[4-oxo-4- (pyrrolidin-1-yl)butanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 109 [00270] embedded image (2S,4R)-4-fluoro-1-[3-(1H-indol-3- yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 110 [00271] (2S,4R)-1-[3-(2,6-dimethylpyridin- 3-yl)propanoyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 111 [00272] (2S,4R)-4-fluoro-1-{[(2- methylpropyl)carbamoyl]carbonyl}- N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 112 [00273] embedded image (2S,4R)-1-{4-[(1-acetylazetidin-3- yl)oxy]benzoyl}-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 113 [00274] (2S,4R)-1-(2-cyclopropyl-2- oxoacetyl)-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 114 [00275] (2S,4R)-4-fluoro-1-[3-(6-oxo-1,6- dihydropyridazin-3-yl)propanoyl]- N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 115 [00276] embedded image (2S,4R)-1- [(dimethylcarbamoyl)carbonyl]-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 116 [00277] (2S,4R)-1-[2-(4-acetyl-3,5-dihydro- 2H-1,4-benzoxazin-2-yl)acetyl]-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 117 [00278] embedded image (2S,4R)-1-[2-(2,5- dioxoimidazolidin-1-yl)acetyl]-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 118 [00279] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-(2- {[1,2,4]triazolo[1,5-a]pyridin-6- yl}acetyl)pyrrolidine-2- carboxamide 119 [00280] embedded image (2S,4R)-1-[2-(1,2-benzoxazol-3- yl)acetyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 120 [00281] (2S,4R)-4-fluoro-1-[2-methyl-3- (1H-1,2,4-triazol-1-yl)propanoyl]- N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 121 [00282] embedded image (2S,4R)-4-fluoro-1-(2- {imidazo[1,2-a]pyridin-3- yl}acetyl-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 122 [00283] (2S,4R)-4-fluoro-1-(3-oxo-3,4- dihydro-2H-1,4-benzoxazine-6- carbonyl)-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 123 [00284] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[3- (1H-1,2,4-triazol-1- yl)benzoyl]pyrrolidine-2- carboxamide 124 [00285] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (pyridin-3- yloxy)propanoyl]pyrrolidine-2- carboxamide 125 [00286] (2S,4R)-1-[2-(3,5-dimethyl-1H- pyrazol-1-yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 126 [00287] embedded image (2S,4R)-4-fluoro-1-[2-(5-methyl- 2,4-dioxo-1,2,3,4- tetrahydropyrimidin-1-yl)acetyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 127 [00288] (2S,4R)-4-fluoro-1-[2-(4-methyl- 1H-pyrazol-1-yl)propanoyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 128 [00289] embedded image (2S,4R)-4-fluoro-1-[2-(4-fluoro- 1H-indol-1-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 129 [00290] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (pyrrolidine-1- sulfonyl)acety]pyrrolidine-2- carboxamide 130 [00291] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (quinolin-5-yl)acetyl]pyrrolidine-2- carboxamide 131 [00292] embedded image (2S,4R)-4-fluoro-1-{4-oxo- 4H,5H,6H,7H,8H-pyrazolo[1,5- a][1,4]diazepine-2-carbonyl}-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 132 [00293] (2S,4R)-4-fluoro-1-[2-methyl-3- (pyridin-2-yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 133 [00294] embedded image (2S,4R)-1-[2-(2-cyano-4- methoxyphenyl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 134 [00295] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-(3- {1H-pyrrolo[2,3-b]pyridin-5- yl}propanoyl)pyrrolidine-2- carboxamide 135 [00296] embedded image (2S,4R)-4-fluoro-1-[3-(3- methoxypyridin-2-yl)propanoyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 136 [00297] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (1,3,5-trimethyl-1H-pyrazol-4- yl)acetyl]pyrrolidine-2- carboxamide 137 [00298] embedded image (2S,4R)-4-fluoro-1-[2-(1-methyl- 1H-indol-2-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 138 [00299] (2S,4R)-4-fluoro-1-[2-(5-methyl- 1H-indol-3-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 139 [00300] (2S,4R)-4-fluoro-1-(3-oxo- octahydroindolizine-6-carbonyl)-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 140 [00301] embedded image (2S,4R)-1-[(2R,3R)-1-acetyl-2- (pyridin-3-yl)pyrrolidine-3- carbonyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 141 [00302] (2S,4R)-1-(4-acetylmorpholine-2- carbonyl)-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 142 [00303] embedded image (2S,4R)-4-fluoro-1-[2-(N- methylacetamido)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 143 [00304] (2S,4R)-1-(1-acetyl-3- fluoroazetidine-3-carbonyl)-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 144 [00305] (2S,4R)-1-(1-acetylpiperidine-4- carbonyl)-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 145 [00306] embedded image (2S,4R)-4-fluoro-1-[(2R)-2-(N- methylacetamido)propanoyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 146 [00307] (2S,4R)-1-(1-acetyl-3- methylazetidine-3-carbonyl)-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 147 [00308] embedded image (2S,4R)-1-(1-acetylpyrrolidine-3- carbonyl)-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 148 [00309] (2S,4R)-1-[(1S,5S)-3-acetyl-3- azabicyclo[3.1.0]hexane-1- carbonyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 149 [00310] embedded image (2S,4R)-1-(4-acetylmorpholine-3- carbonyl)-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 150 [00311] (2S,4R)-1-[(1S)-5-acetyl-2-oxa-5- azabicyclo[2.2.1]heptane-1- carbonyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 151 [00312] embedded image (2S,4R)-1-{2-acetyl-5-oxa-2,6- diazaspiro[3.4]oct-6-ene-7- carbonyl}-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 152 [00313] (2S,4R)-1-(1-acetyl-3- methylpyrrolidine-3-carbonyl)-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 153 [00314] embedded image (2S,4R)-1-[(3S)-1-acetylpiperidine- 3-carbonyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 154 [00315] (2S,4R)-1-[2-(1-acetyl-3- methylazetidin-3-yl)acetyl]-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 155 [00316] embedded image (2S,4R)-1-{2-[(2R)-1- acetylpyrrolidin-2-yl]acetyl}-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 156 [00317] (2S,4R)-1-{5-acetyl-5- azaspiro[2.4]heptane-1-carbonyl}- 4-fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 157 [00318] embedded image (2S,4R)-1-[(2S)-7-acetyl-7- azabicyclo[2.2.1]heptane-2- carbonyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 158 [00319] (2S,4R)-1-[(2R)-4-acetyl-1,4- oxazepane-2-carbonyl]-4-fluoro- N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 159 [00320] embedded image (2S,4R)-1-[(2S,3R)-4-acetyl-2- methylmorpholine-3-carbonyl]-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 160 [00321] (2S,4R)-1-[2-(4-acetyl-2- oxopiperazin-1-yl)acetyl]-4-fluoro- N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 161 [00322] embedded image (2S,4R)-1-[2-(1-acetyl-3- methoxyazetidin-3-yl)acetyl]-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 162 [00323] (2S,4R)-1-[(2R,3aR,6aR)-5-acetyl- hexahydro-2H-furo[2,3-c]pyrrole- 2-carbonyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 163 [00324] embedded image (2S,4R)-1-{2-acetyl-5-oxa-2- azaspiro[3.4]octane-6-carbonyl}-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 164 [00325] (2S,4R)-1-{2-acetyl-5-oxa-2- azaspiro[3.4]octane-7-carbonyl}-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 165 [00326] embedded image (2S,4R)-1-[(3R,3aS,6aS)-5-acetyl- hexahydro-2H-furo[2,3-c]pyrrole- 3-carbonyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 166 [00327] (2S,4R)-1-[(3aR,6S,6aR)-4-acetyl- hexahydro-2H-furo[3,2-b]pyrrole- 6-carbonyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 167 [00328] embedded image (2S,4R)-1-{acetyl-5H,6H,7H,8H- pyrido[3,4-b]pyrazine-7-carbonyl}- 4-fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 168 [00329] (2S,4R)-1-(1-acetyl-3- methylpiperidine-3-carbonyl)-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 169 [00330] embedded image (2S,4R)-1-(1-acetylazepane-4- carbonyl)-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 170 [00331] (2S,4R)-1-[(3S,4R)-1-acetyl-4- methylpiperidine-3-carbonyl]-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 171 [00332] embedded image (2S,4R)-1-{2-[(3S)-1- acetylpiperidin-3-yl]acetyl}-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 172 [00333] (2S,4R)-1-[3-(1-acetylpyrrolidin-2- yl)propanoyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 173 [00334] embedded image (2S,4R)-1-[(1R,5S,8S)-3-acetyl-3- azabicyclo[3.2.1]octane-8- carbonyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 174 [00335] (2S,4R)-1-{6-acetyl-6- azaspiro[2.5]octane-1-carbonyl}-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 175 [00336] embedded image (2S,4R)-1-{8-acetyl-8- azabicyclo[3.2.1]octane-3- carbonyl}-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 176 [00337] (2S,4R)-1-[(1S,4R)-2-acetyl-2- azabicyclo[2.2.2]octane-6- carbonyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 177 [00338] embedded image (2S,4R)-1-[(3aS,4S,6aS)-2-acetyl- octahydrocyclopenta[c]pyrrole-4- carbonyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 178 [00339] (2S,4R)-1-(1-acetyl-2- methylpiperidine-3-carbonyl)-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 179 [00340] embedded image (2S,4R)-1-[(3R,4S)-1-acetyl-4- ethylpyrrolidine-3-carbonyl]-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 180 [00341] (2S,4R)-1-[2-(1-acetylpiperidin-4- yl)propanoyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 181 [00342] embedded image (2S,4R)-1-(1-acetyl-4- methylazepane-4-carbonyl)-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 182 [00343] (2S,4R)-1-{2-acetyl-2- azaspiro[4.4]nonane-6-carbonyl}-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 183 [00344] embedded image (2S,4R)-1-[(3aS,4R,7aS)-2-acetyl- octahydro-1H-isoindole-4- carbonyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 184 [00345] (2S,4R)-1-{8-acetyl-8- azaspiro[4.5]decane-2-carbonyl}-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 185 [00346] embedded image (2S,4R)-4-fluoro-1-(2-hydroxy-3- methylbutanoyl)-N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 186 [00347] (2S,4R)-1-(2,3- dihydroxypropanoyl)-4-fluoro-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 187 [00348] (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (2,2,2- trifluoroacetamido)acetyl] pyrrolidine-2-carboxamide 188 [00349] embedded image (2S,4R)-1-(2-cyanoacetyl)-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 189 [00350] (2S,4R)-1-{2-[N- (carbamoylmethyl)acetamido] acetyl}-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 190 [00351] (2S,4R)-1-(3-acetamidopropanoyl)- 4-fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 191 [00352] embedded image (2S,4R)-1-(4-acetamidobutanoyl)- 4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 192 [00353] (2S,4R)-4-fluoro-1-[2-(2- oxopyrrolidin-1-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 193 [00354] (2S,4R)-4-fluoro-1-{2-[(3- methyloxetan-3-yl)amino]acetyl}- N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 194 [00355] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (4H-1,2,4-triazol-3- yl)acetyl]pyrrolidine-2- carboxamide 195 [00356] (2S,4R)-4-fluoro-1-[2-(1,3-oxazol- 5-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 196 [00357] (4S)-4-acetamido-5-[(2S,4R)-4- fluoro-2-{[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]carbamoyl} pyrrolidin-1-yl]-5-oxopentanoic acid 197 [00358] embedded image (4R)-4-acetamido-5-[(2S,4R)-4- fluoro-2-{[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]carbamoyl} pyrrolidin-1-yl]-5-oxopentanoic acid 198 [00359] (2S,4R)-4-fluoro-1-{2-[(1,3- oxazol-2-yl)amino]acetyl}-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 199 [00360] (1S,3S,5S)-2-acetyl-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]-2- azabicyclo[3.1.0]hexane-3- carboxamide 200 [00361] embedded image (1R,3S,5R)-2-acetyl-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]-2- azabicyclo[3.1.0]hexane-3- carboxamide 201 [00362] (1S,2S,5R)-3-acetyl-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]-3- azabicycl[3.1.0]hexane-2- carboxamide 202 [00363] (2S,4R)-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]-1-[2-(4H-1,2,4- triazol-4-yl)acetyl]pyrrolidine-2- carboxamide 203 [00364] embedded image (2S)-1-cyclopropanecarbonyl-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 204 [00365] (2S,4S)-1-acetyl-4-hydroxy-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 205 [00366] (2S,4R)-1-acetyl-4-hydroxy-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 206 [00367] embedded image (2S,3S)-1-acetyl-3-hydroxy-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 207 [00368] (2S,4R)-1-acetyl-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 208 [00369] (2S,4R)-1-[(2S)-3-carbamoyl-2- acetamidopropanoyl]-4-fluoro-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 209 [00370] embedded image (2S,4R)-1-[(2R)-3-carbamoyl-2- acetamidopropanoyl]-4-fluoro-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 210 [00371] tert-butyl N-{2-oxo-2-[(2S)-2- {[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]carbamoyl} pyrrolidin-1-yl]ethyl}carbamate 211 [00372] (2S)-1-(2-hydroxyacetyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 212 [00373] embedded image (2S)-1-(2-acetamidoacetyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 213 [00374] (2S)-1-(3-carbamoylpropanoyl)-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 214 [00375] (2S,5S)-1-acetyl-5-methyl-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 215 [00376] embedded image (2S,5R)-1-acetyl-5-methyl-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 216 [00377] (2S)-1-[2-(1,3-oxazol-2-yl)acetyl]- N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 217 [00378] (2S,4R)-4-fluoro-1-[2-(2-oxo-1,3- oxazolidin-3-yl)acetyl-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 218 [00379] embedded image (2S,4R)-4-fluoro-1-[2-(oxetan-3- yl)acetyl]-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 219 [00380] (2S,4R)-4-fluoro-1-[2-(3- oxomorpholin-4-yl)acethyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 220 [00381] (2S,4RS)-4-fluoro-1-[2-(1-methyl- 1H-pyrazol-5-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 221 [00382] embedded image (2S,4RS)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (1H-pyrazol-1- yl)acetyl]pyrrolidine-2- carboxamide 222 [00383] (2RS,4R)-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]-1-[2-(1H-1,2,3- triazol-1-yl)acetyl]pyrrolidine-2- carboxamide 223 [00384] (2RS,4R)-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]-1-[2-(2H- 1,2,3,4-tetrazol-5- yl)acetyl]pyrrolidine-2- carboxamide 224 [00385] embedded image (2RS,4R)-4-fluoro-1-[2-(1,3,4- oxadiazol-2-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 225 [00386] (2RS,4R)-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]-1-[2-(1H- pyrazol-3-yl)acetyl]pyrrolidine-2- carboxamide 226 [00387] (2RS,4R)-4-fluoro-1-[2-(5-methyl- 1H-1,2,3-tetrazol-1-yl)acetyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 227 [00388] embedded image (2RS,4R)-4-fluoro-1-[2-(4-methyl- 4H-1,2,4-triazol-3-yl)acetyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 228 [00389] (2RS,4R)-4-fluoro-1-[2-(1-methyl- 1H-1,2,3-triazol-5-yl)acetyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 229 [00390] embedded image (2RS,4R)-4-fluoro-1-[2-(1-methyl- 1H-1,2,3-triazol-4-yl)acetyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 230 [00391] (2S,4R)-4-fluoro-1-[2-(1,2-oxazol- 4-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 231 [00392] (2S,4R)-4-fluoro-1-[2-(1,2-oxazol- 3-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 232 [00393] embedded image (2S,4R)-4-fluoro-1-[2-(3-methyl- 1H-1,2,4-triazol-5-yl)acetyl]-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 233 [00394] (2S,4R)-4-fluoro-1-[2-methyl-2- (1H-1,2,4-triazol-5-yl)propanoyl]- N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 234 [00395] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1-[2- (piperazin-1-yl)acetyl]pyrrolidine- 2-carboxamide 235 [00396] (2S,4R)-1-[2-(4-acetylpiperazin-1- yl)acetyl]-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 236 [00397] (2S,4R)-4-fluoro-1-[2-(5-methyl-2- oxo-2,3-dihydro-1,3,4-oxadiazol-3- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 237 [00398] embedded image tert-butyl N-[(5-{2-[(2S,4R)-4- fluoro-2-{[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]carbamoyl} pyrrolidin-1-yl]-2-oxoethyl}-1,3,4- oxadiazol-2-yl)methyl]carbamate 238 [00399] (2S,4R)-1-{2-[5-(aminomethyl)- 1,3,4-oxadiazol-2-yl]acetyl}-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 239 [00400] embedded image (2S,4R)-1-{2-[5- (acetamidomethyl)-1,3,4-oxadiazol- 2-yl]acetyl}-4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 240 [00401] (2S,4R)-1-{2-[5-(aminomethyl)- 1H-1,2,3-triazol-1-yl]acetyl}-4- fluoro-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 241 [00402] embedded image (2S,4R)-1-(2-{5- [(dimethylamino)methyl]-1H-1,2,3- triazol-1-yl}acetyl)-4-fluoro-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 242 [00403] (2S,4R)-1-(2-{5- [(dimethylamino)methyl]-1,3,4- oxadiazol-2-yl}acetyl)-4-fluoro-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 243 [00404] embedded image (2S,4R)-1-{2-[5- (acetamidomethyl)-1H-1,2,3- triazol-1-yl]acetyl}-4-fluoro-N- [(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 244 [00405] (2S,4R)-1-(2-(1H-1,2,3-triazol-5- yl)acetyl)-4-fluoro-N-((S)-(5- isopropylpyridin-2- yl)(phenyl)methyl)pyrrolidine-2- carboxamide 245 [00406] embedded image (2S)-1-acetyl-N-[(S)-phenyl[5- (propan-2-yl)pyridin-2- yl]methyl]pyrrolidine-2- carboxamide 246 [00407] (2S,4R)-1-[2-(3,5-dimethyl-1H- pyrazol-4-yl)acetyl]-4-fluoro-N- [(S)-phenyl[5-(propan-2-yl)pyridin- 2-yl]methyl]pyrrolidine-2- carboxamide 247 [00408] (2S,4R)-4-fluoro-N-[(S)-phenyl[5- (propan-2-yl)pyridin-2-yl]methyl]- 1-[2-(quinolin-5- yl)acetyl]pyrrolidine-2- carboxamide 248 [00409] embedded image (2S,4R)-1-[2-(1H-1,3-benzodiazol- 1-yl)acetyl]-4-fluoro-N-[(S)- phenyl[5-(propan-2-yl)pyridin-2- yl]methy]pyrrolidine-2- carboxamide 249 [00410] (2S,4R)-4-fluoro-1-[2-(5-methyl- 2,4-dioxo-1,2,3,4- tetrahydropyrimidin-1-yl)acetyl]-N- [(S)-phenyl[5-(propan-2-yl)pyridin- 2-yl]methyl]pyrrolidine-2- carboxamide 250 [00411] embedded image (2S,4R)-1-{2- [(dimethylcarbamoyl)amino]acetyl}- 4-fluoro-N-[(S)-phenyl[5-(propan- 2-yl)pyridin-2- yl]methyl]pyrrolidine-2- carboxamide 251 [00412] 2-[(2S,4R)-4-fluoro-2-{[(S)- phenyl[5-(propan-2-yl)pyridin-2- yl]methyl]carbamoyl}pyrrolidin- 1-yl]-2-oxoethyl-N,N- dimethylcarbamate 252 [00413] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[5- (propan-2-yl)pyridin-2-yl]methyl}- 1-[2-(1H-1,2,3-tetrazol-1- yl)acetyl]pyrrolidine-2- carboxamide 253 [00414] (2S,4R)-1-{2-[5-(difluoromethyl)- 1,3,4-oxadiazol-2-yl]acetyl}-4- flouro-N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 254 [00415] embedded image (2S,4R)-1-{2-[5-(difluoromethyl)- 1H-1,2,3-tetrazol-1-yl]acetyl}-4- fluoro-N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 255 [00416] (2S,4R)-4-fluoro-N-[(S)-phenyl[5- (propan-2-yl)pyridin-2-yl]methyl]- 1-{2-[5-(trifluoromethyl)-2H- 1,2,3,4-tetrazol-2- yl]acetyl}pyrrolidine-2- carboxamide 256 [00417] embedded image (2S,4R)-1-{2-[5-(difluoromethyl)- 2H-1,2,3,4-tetrazol-2-yl]acetyl}-4- fluoro-N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 257 [00418] (2S,4R)-4-fluoro-1-[2-(2- methylquinolin-5-yl)acetyl]- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 258 [00419] embedded image (2S,4R)-4-fluoro-1-(2-{3-oxo- 2H,3H-[1,2,4]triazolo[4,3- a]pyridin-8-yl}acetyl)- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 259 [00420] (2S,4R)-1-{2-[4-(dimethylamino)- 2H-1,2,3-triazol-2-yl]acety}-4- fluoro-N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 260 [00421] embedded image (2S,4R)-1-{2-[4-(dimethylamino)- 1H-1,2,3-triazol-1-yl]acetyl}-4- fluoro-N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 261 [00422] (2S,4R)-4-fluoro-1-{2- [(methylcarbamoyl)amino]acetyl}- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 262 [00423] embedded image (2S,4R)-1-[2- (carbamoylamino)acetyl]-4-fluoro- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 263 [00424] (2S,4R)-4-fluoro-1-[2-(1-methyl-5- oxo-4,5-dihydro-1H-1,2,4-triazol-3- yl)acetyl]- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 264 [00425] embedded image (2S,4R)-4-fluoro-1-[2-(4-methyl-5- oxo-4,5-dihydro-1H-1,2,4-triazol-3- yl)acetyl]- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 265 [00426] (2S,4R)-1-{2-[(azetidine-1- carbonyl)amino]acetyl}-4-fluoro- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 266 [00427] embedded image (2S,4R)-4-fluoro-1-[2-(4-methyl-5- oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)acetyl]- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 267 [00428] (2S,4R)-4-fluoro-1-[2-(4-methyl-5- oxo-4,5-dihydro-1,2,4-oxadiazol-3- yl)acetyl]- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 268 [00429] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[5- (propan-2-yl)pyridin-2-yl]methyl]- 1-{2-[4-(trifluoromethyl)-1H-1,2,3- triazol-5-yl]acetyl}pyrrolidine-2- carboxamide 269 [00430] (2S,4R)-4-fluoro-1-{2-[(2- methylpyrimidin-4- yl)amino]acetyl}- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 270 [00431] embedded image (2S,4R)-4-fluoro-1-[2-(1,3-oxazol- 2-yl)acetyl]- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 271 [00432] (2S,4R)-4-fluoro-1-[2-(5-methyl- 1,3-oxazol-2-yl)acetyl]- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 272 [00433] (2S,4R)-4-fluoro-1-[2-(5-methyl- 1,3-oxazol-2-yl)methyl]- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 273 [00434] embedded image (2S,4R)-1-[(2S)-2- [(dimethylcarbamoyl)amino] propanoyl]-4-fluoro- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 274 [00435] (2S,4R)-1-[(2R)-2- [(dimethylcarbamoyl)amino] propanoyl]-4-fluoro- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 275 [00436] embedded image (2S,4R)-4-fluoro-1-[2-(5-methyl-2- oxo-2,3-dihydro-1,3,4-oxadiazol-3- yl)acetyl]-N- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 276 [00437] (2S,4R)-1-{2-[4-(azetidin-1-yl)-2H- 1,2,3-triazol-2-yl]acetyl}-4-fluoro- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 277 [00438] embedded image (2S,4R)-1-{2-[4-(3,3- difluoroazetidin-1-yl)-2H-1,2,3- triazol-2-yl]acetyl}-4-fluoro- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 278 [00439] (2S,4R)-1-{2-[4-(diethylamino)- 2H-1,2,3-triazol-2-yl]acety}-4- fluoro-N- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 279 [00440] embedded image (1S,2S,5R)-N-[(S)-phenyl[5- (propan-2-yl)pyridin-2-yl]methyl]- 3-[2-(1H-1,2,3-triazol-5-yl)acetyl]- 3-azabicyclo[3.1.0]hexane-2- carboxamide 280 [00441] (2S,5S)-5-methyl-N-[(S)-phenyl[5- (propan-2-yl)pyridin-2-yl]methyl]- 1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 281 [00442] embedded image N-{2-[(2S,4R)-4-fluoro-2-{[(S)- phenyl[5-(propan-2-yl)pyridin-2- yl]methyl]carbamoyl}pyrrolidin-1- yl]-2-oxoethyl}-4-(2,2,2- trifluoroethyl)piperazine-1- carboxamide 282 [00443] 4-(cyclopropylmethyl)-N-{2- [(2S,4R)-4-fluoro-2-{[(S)- phenyl[5-(propan-2-yl)pyridin-2- yl]methyl]carbamoyl}pyrrolidin-1- yl]-2-oxoethyl}piperazine-1- carboxamide 283 [00444] embedded image N-{2-[(2S,4R)-4-fluoro-2-{[(S)- phenyl[5-(propan-2-yl)pyridin-2- yl]methyl]carbamoyl}pyrrolidin-1- yl]-2-oxoethyl}-4- methylpiperazine-1-carboxamide 284 [00445] (2S,4R)-4-fluoro-1-[2-(5-oxo-4,5- dihydro-1H-1,2,4-triazol-3- yl)acetyl]-N-[(S)-phenyl[5-(propan- 2-yl)pyridin-2- yl]methyl]pyrrolidine-2- carboxamide 285 [00446] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[5- (propan-2-yl)pyridin-2-yl]methyl]- 1-[2-(4H-1,2,4-triazol-4- yl)acetyl]pyrrolidine-2- carboxamide 286 [00447] (2S,4R)-4-fluoro-1-[2-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3- yl)acetyl]- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 287 [00448] embedded image (2S,4R)-4-fluoro-1-[3-(5-oxo-4,5- dihydro-1H-1,2,4-triazol-3- yl)propanoyl]- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 288 [00449] (2S,4R)-4-fluoro-1-[2-(5-oxo-4,5- dihydro-1H-1,2,4-triazol-4- yl)acetyl]- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 289 [00450] embedded image (2S,4R)-4-fluoro-1-(3-{3-oxo- 2H,3H-[1,2,4]triazolo[4,3- a]pyridin-2-yl}propanoyl)- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 290 [00451] (2S,4R)-1-{2-[(3,3- difluoroazetidine-1- carbonyl]amino]acetyl}-4-fluoro- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 291 [00452] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[5- (propan-2-yl)pyridin-2-yl]methyl]- 1-(2-{[3-(trifluoromethyl)azetidin- 1-carbonyl]amino}acetyl) pyrrolidine-2- carboxamide 292 [00453] (2S,4R)-4-fluoro-N-[(S)-phenyl[5- (propan-2-yl)pyridin-2-yl]methyl]- 1-[2-(1H-pyrazol-1- yl)acetyl]pyrrolidine-2- carboxamide 293 [00454] embedded image (2S,4R)-N-((S)-(5-cyclopropl-6- fluoropyridin-2-yl)(phenyl)methyl)- 1-(2-(5-(difluoromethyl)-1H- tetrazol-1-yl)acetyl)-4- fluoropyrrolidine-2-carboxamide 294 [00455] (2S,4R)-1-[2-(1H-1,3-benzodiazol- 1-yl)acetyl]-N-[(S)-(5-cyclopropyl- 6-fluoropyridin-2- yl)(phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide 295 [00456] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-[2-(5-methyl-2,4-dioxo- 1,2,3,4-tetrahydropyrimidin-1- yl)acetyl]pyrrolidine-2- carboxamide 296 [00457] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-[2-(4H-1,2,4-triazol-4- yl)acetyl]pyrrolidine-2- carboxamide 297 [00458] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-(2-{3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyridin-8- yl}acetyl)pyrrolidine-2- carboxamide 298 [00459] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-{2-[5-(dimethylamino)-1H-1,2,3- triazol-1-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 299 [00460] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-{2-[4-(dimethylamino)-1H-1,2,3- triazol-1-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 300 [00461] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-{2- [(dimethylcarbamoyl)amino]acetyl}- 4-fluoropyrrolidine-2-carboxamide 301 [00462] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-{2- [(methylcarbamoyl)amino]acetyl} pyrrolidine-2-carboxamide 302 [00463] (2S,4R)-1-[2- (carbamoylamino)acetyl]-N-[(S)- (5-cyclopropyl-6-fluoropyridin-2- yl)(phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide 303 [00464] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-[2-(1-methyl-5-oxo-4,5- dihydro-1H-1,2,4-triazol-3- yl)acetyl]pyrrolidine-2- carboxamide 304 [00465] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-[2-(4-methyl-5-oxo-4,5- dihydro-1H-1,2,4-triazol-3- yl)acetyl]pyrrolidine-2- carboxamide 305 [00466] embedded image (2S,4R)-1-{2-[(azetidine-1- carbonyl)amino]acetyl}-N-[(S)-(5- cyclopropyl-6-fluoropyridin-2- yl)(phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide 306 [00467] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-[2-(4-methyl-5-oxo-4,5- dihydro-1,3,4-oxadiazol-2- yl)acetyl]pyrrolidine-2- carboxamide 307 [00468] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-{2-[4-(trifluoromethyl)- 1H-1,2,3-triazol-5- yl]acetyl}pyrrolidine-2- carboxamide 308 [00469] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-{2-[(2-methylpyrimidin- 4-yl)amino]acetyl}pyrrolidine-2- carboxamide 309 [00470] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-{2-[(1,3-oxazol-2- yl)amino]acetyl}pyrrolidine-2- carboxamide 310 [00471] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-[(2S)-2- [(dimethylcarbamoyl)amino] propanoyl]-4-fluoropyrrolidine-2- carboxamide 311 [00472] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-[(2R)-2- [(dimethylcarbamoyl)amino] propanoyl]-4-fluoropyrrolidine-2- carboxamide 312 [00473] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-[2-(1,3-oxazol-2- yl)acetyl]pyrrolidine-2- carboxamide 313 [00474] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-[2-(5-methyl-1,3-oxazol- 2-yl)acetyl]pyrrolidine-2- carboxamide 314 [00475] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-[2-(4-methyl-1,3-oxazol- 2-yl)acetyl]pyrrolidine-2- carboxamide 315 [00476] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-{2-[(3,3-difluoroazetidine-1- carbonyl)amino]acetyl}-4- fluoropyrrolidine-2-carboxamide 316 [00477] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-[2-(5-methyl-2-oxo-2,3- dihydro-1,3,4-oxadiazol-3- yl)acetyl]pyrrolidine-2- carboxamide 317 [00478] embedded image (2S,4R)-1-{2-[4-(azetidin-1-yl)-2H- 1,2,3-triazol-2-yl]acetyl}-N-[(S)-(5- cyclopropyl-6-fluoropyridin-2- yl)(phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide 318 [00479] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-{2-[4-(3,3-difluoroazetidin-1-yl)- 2H-1,2,3-triazol-2-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 319 [00480] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-{2-[4-(diethylamino)-2H-1,2,3- triazol-2-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 320 [00481] (1S,2S,5R)-N-[(S)-(5-cyclopropyl- 6-fluoropyridin-2- yl)(phenyl)methyl]-3-[2-(1H-1,2,3- triazol-5-yl)acetyl]-3- azabicyclo[3.1.0]hexane-2- carboxamide 321 [00482] embedded image (2S,5S)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 5-methyl-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 322 [00483] (2S,4R)-4-fluoro-N-((S)-(3-fluoro- 4- isopropylphenyl)(phenyl)methyl)- 1-(2-(5-(trifluoromethyl)-1H-1,2,3- triazol-1-yl)acetyl)pyrrolidine-2- carboxamide 323 [00484] embedded image (2S,5S)-N-[(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]-5- methyl-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 324 [00485] (1S,3S,5S)-N-[(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]-2-[2- (1H-1,2,3-triazol-5-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3- carboxamide 325 [00486] embedded image (1S,2S,5R)-N-[(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]-3-[2- (1H-1,2,3-triazol-5-yl)acetyl]-3- azabicyclo[3.1.0]hexane-2- carboxamide 326 [00487] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 327 [00488] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-(2- hydroxy-2- methylpropanoyl)pyrrolidine-2- carboxamide 328 [00489] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (1H-1,2,3-tetrazol-5- yl)acetyl]pyrrolidine-2- carboxamide 329 [00490] embedded image (2S,4R)-4-fluoro-N-[(R)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (1H-1,2,3-tetrazol-5- yl)acetyl]pyrrolidine-2- carboxamide 330 [00491] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (1H-1,2,3,4-tetrazol-1- yl)acetyl]pyrrolidine-2- carboxamide 331 [00492] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (1H-1,2,3-triazol-1- yl)acetyl]pyrrolidine-2- carboxamide 332 [00493] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2-(5- methyl-1,3,4-oxadiazol-2- yl)acetyl]pyrrolidine-2- carboxamide 333 [00494] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[1- (1,3,4-oxadiazol-2- yl)cyclopropanecarbonyl]pyrrolidine- 2-carboxamide 334 [00495] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- methyl-2-(1,3,4-oxadiazol-2- yl)propanoyl]pyrrolidine-2- carboxamide 335 [00496] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2-(1- methyl-1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 336 [00497] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2-(1- methyl-1H-1,2,3-triazol-4- yl)acetyl]pyrrolidine-2- carboxamide 337 [00498] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2-(1- methyl-1H-pyrazol-5- yl)acetyl]pyrrolidine-2- carboxamide 338 [00499] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (1,2-oxazol-5-yl)acetyl]pyrrolidine- 2-carboxamide 339 [00500] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2-(4- methyl-2,5-dioxopiperazin-1- yl)acetyl]pyrrolidine-2- carboxamide 340 [00501] (2S,4R,5S)-4-fluoro-N-[(S)-[3- fluoro-4-(propan-2- yl)phenyl](phenyl)methyl]-5- methyl-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 341 [00502] embedded image (5S)-N-[(S)-[3-fluoro-4-(propan-2- yl)phenyl](phenyll)methyl]-4-[2- (1H-1,2,3-triazol-5-yl)acetyl]-4- azaspiro[2.4]heptane-5- carboxamide 342 [00503] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (pyridazin-4-yl)acetyl]pyrrolidine- 2-carboxamide 343 [00504] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (pyridazin-3-yl)acetyl]pyrrolidine- 2-carboxamide 344 [00505] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (pyrazin-2-yl)acetyl]pyrrolidine-2- carboxamide 345 [00506] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (pyrimidin-5-yl)acetyl]pyrrolidine- 2-carboxamide 346 [00507] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (pyrimidin-4-yl)acetyl]pyrrolidine- 2-carboxamide 347 [00508] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (pyridin-4-yl)acetyl]pyrrolidine-2- carboxamide 348 [00509] (2S,4R)-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (pyridin-3-yl)acetyl]pyrrolidine-2- carboxamide 349 [00510] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (pyridin-2-yl)acetyl]pyrrolidine-2- carboxamide 350 [00511] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2-(1- methyl-1H-pyrazol-3- yl)acetyl]pyrrolidine-2- carboxamide 351 [00512] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (1,3,5-trimethyl-1H-pyrazol-4- yl)acetyl]pyrrolidine-2- carboxamide 352 [00513] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2-(5- methyl-2,4-dioxo-1,2,3,4- tetrahydropyrimidin-1- yl)acethyl]pyrrolidine-2- carboxamide 353 [00514] embedded image (2S,4R)-1-[2-(3,5-dimethyl-2,4- dioxo-1,2,3,4-tetrahydropyrimidin- 1-yl)acetyl]-4-fluoro-N-[(S)-[3- fluoro-4-(propan-2- yl)phenyl](phenyl)methyl] pyrrolidine-2-carboxamide 354 [00515] (2S,4R)-1-[2-(1H-1,3-benzodiazol- 1-yl)acetyl]-4-fluoro-N-[(S)-[3- fluoro-4-(propan-2- yl)phenyl](phenyl)methyl] pyrrolidine-2-carboxamide 355 [00516] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2-(1- methyl-1H-pyrazol-4- yl)acetyl]pyrrolidine-2- carboxamide 356 [00517] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-(2- {imidazo[1,2-a]pyridin-3- yl}acetyl)pyrrolidine-2- carboxamide 357 [00518] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (quinolin-6-yl)acetyl]pyrrolidine-2- carboxamide 358 [00519] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-(2- {[1,2,4]triazolo[1,5-a]pyridin-6- yl}acetyl)pyrrolidine-2- carboxamide 359 [00520] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-{2-[5- (trifluoromethyl)-1H-1,2,3,4- tetrazol-1-yl]acetyl}pyrrolidine-2- carboxamide 360 [00521] 2-[(2S,4R)-4-fluoro-2-{[(S)-[3- fluoro-4-(propan-2- yl)phenyl](phenyll)methyl] carbamoyl}pyrrolidin-1-yl]-2- oxoethyl-N,N-dimethylcarbamate 361 [00522] embedded image (2S,4R)-1-{2- [(dimethylcarbamoyl)amino]acetyl}- 4-fluoro-N-[(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl] pyrrolidine-2-carboxamide 362 [00523] (2S,4R)-1-{2- [(dimethylcarbamoyl)(methyl) amino]acetyl}-4-fluoro-N-[(S)-[3- fluoro-4-(propan-2- yl)phenyl](phenyl)methyl] pyrrolidine-2-carboxamide 363 [00524] embedded image 2-[(2S,4R)-4-fluoro-2-{[(S)-[3- fluoro-4-(propan-2- yl)phenyl](phenyl)methyl]carbamoyl} pyrrolidin-1-yl]-2-oxoethyl piperazine-1-carboxylate 364 [00525] 1-tert-butyl 4-{2-[(2S,4R)-4-fluoro- 2-{[(S)-[3-fluoro-4-(propan-2- yl)phenyl](phenyl)methyl]carbamoyl} pyrrolidin-1-yl]-2-oxoethyl} piperazine-1,4-dicarboxylate 365 [00526] embedded image N-{2-(2S,4R)-4-fluoro-2-{[(S)-[3- fluoro-4-(propan-2- yl)phenyl](phenyl)methyl]carbamoyl} pyrrolidin-1-yl]-2- oxoethyl}piperazine-1-carboxamide 366 [00527] tert-butyl 4-({2-[(2S,4R)-4-fluoro- 2-{[(S)-[3-fluoro-4-(propan-2- yl)phenyl](phenyl)methyl]carbamoyl} pyrrolidin-1-yl]-2- oxoethyl}carbamoyl)piperazine-1- carboxylate 367 [00528] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2-(4- methyl-1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 368 [00529] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-{2-[4- (trifluoromethyl)-1H-1,2,3-triazol- 5-yl]acetyl}pyrrolidine-2- carboxamide 369 [00530] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-{2-[4- (piperazin-1-yl)-1H-1,2,3-triazol-5- yl]acetyl}pyrrolidine-2- carboxamide 370 [00531] tert-butyl 4-(5-{2-[(2S,4R)-4- fluoro-2-{[(S)-[3-fluoro-4-(propan- 2- yl)phenyl](phenyl)methyl]carbamoyl} pyrrolidin-1-yl]-2-oxoethyl}- 1H-1,2,3-triazol-4-yl)piperazine-1- carboxylate 371 [00532] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-{2-[4- (morpholin-4-yl)-1H-1,2,3-triazol- 5-yl]acetyl}pyrrolidine-2- carboxamide 372 [00533] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-{2-[4- (trifluoromethyl)-1H-1,2,3-triazol- 1-yl]acetyl}pyrrolidine-2- carboxamide 373 [00534] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2-(4- methyl-1H-1,2,3-triazol-1- yl)acetyl]pyrrolidine-2- carboxamide 374 [00535] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2-(5- methyl-1H-1,2,3-triazol-1- yl)acetyl]pyrrolidine-2- carboxamide 375 [00536] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-{2-[4- (piperazin-1-yl)-1H-1,2,3-triazol-1- yl]acetyl}pyrrolidine-2- carboxamide 376 [00537] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-{2-[4- (piperazin-1-yl)-2H-1,2,3-triazol-2- yl]acetyl}pyrrolidine-2- carboxamide 377 [00538] embedded image (2S,4R)-1-{2-[4-(dimethylamino)- 1H-1,2,3-triazol-1-yl]acetyl}-4- fluoro-N-[(S)-[3-fluoro-4-(propan- 2- yl)phenyl](phenyl)methyl] pyrrolidine-2-carboxamide 378 [00539] (2S,4R)-1-{2-[4-(dimethylamino)- 2H-1,2,3-triazol-2-yl]acetyl}-4- fluoro-N-[(S)-[3-fluoro-4-(propan- 2- yl)phenyl](phenyl)methyl] pyrrolidine-2-carboxamide 379 [00540] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-(2-{3- oxo-2H,3H-[1,2,4]triazolo[4,3- a]pyridin-8-yl}acetyl)pyrrolidine-2- carboxamide 380 [00541] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (1H-imidazol-1- yl)acetyl]pyrrolidine-2- carboxamide 381 [00542] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[(5S)- 2-oxo-1,3-oxazolidine-5- carbonyl]pyrrolidine-2- carboxamide 382 [00543] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[(5R)- 2-oxo-1,3-oxazolidine-5- carbonyl]pyrrolidine-2- carboxamide 383 [00544] embedded image (2S,4R)-1-{2-[5-(difluoromethyl)- 1,3,4-oxadiazol-2-yl]acetyl}-4- fluoro-N-[(S)-[3-fluoro-4-(propan- 2- yl)phenyl](phenyl)methyl] pyrrolidine-2-carboxamide 384 [00545] (2S,4R)-4-fluoro-N-[(1S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (4H-1,2,4-triazol-4- yl)acetyl]pyrrolidine-2- carboxamide 385 [00546] embedded image (2S,4R)-1-(2-(1H-1,2,3-triazol-5- yl)acetyl)-4-fluoro-N-((S)-(6- fluoro-5-isopropylpyridin-2- yl)(phenyl)methyl)pyrrolidine-2- carboxamide 386 [00547] (2S,4R)-1-[2-(3,5-dimethyl-2,4- dioxo-1,2,3,4-tetrahydropyrimidin- 1-yl)acetyl]-4-fluoro-N-[(S)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 387 [00548] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(2- methylquinolin-5- yl)acetyl]pyrrolidine-2- carboxamide 388 [00549] (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(5-methyl- 2,4-dioxo-1,2,3,4- tetrahydropyrimidin-1- yl)acetyl]pyrrolidine-2- carboxamide 389 [00550] embedded image (2S,4R)-1-[2-(1H-1,3-benzodiazol- 1-yl)acetyl]-4-fluoro-N-[(S)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 390 [00551] (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(4H-1,2,4- triazol-4-yl)acetyl]pyrrolidine-2- carboxamide 391 [00552] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-(2-{3-oxo- 2H,3H-[1,2,4]triazolo[4,3- a]pyridin-8-yl}acetyl)pyrrolidine-2- carboxamide 392 [00553] (2S,4R)-1-{2-[4-(dimethylamino)- 2H-1,2,3-triazol-2-yl]acetyl}-4- fluoro-N-[(S)-[6-fluoro-5-(propan- 2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 393 [00554] embedded image (2S,4R)-1-{2-[4-(dimethylamino)- 1H-1,2,3-triazol-1-yl]acetyl}-4- fluoro-N-[(S)-[6-fluoro-5-(propan- 2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 394 [00555] (2S,4R)-1-{2- [(dimethylcarbamoyl)amino]acetyl}- 4-fluoro-N-[(S)-[6-fluoro-5- (propan-2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 395 [00556] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-{2- [(methylcarbamoyl)amino]acetyl} pyrrolidine-2-carboxamide 396 [00557] (2S,4R)-1-[2- (carbamoylamino)acetyl]-4-fluoro- N-[(S)-[6-fluoro-5-(propan-2- yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 397 [00558] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(1-methyl- 5-oxo-4,5-dihydro-1H-1,2,4-triazol- 3-yl)acetyl]pyrrolidine-2- carboxamide 398 [00559] (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(4-methyl- 5-oxo-4,5-dihydro-1H-1,2,4-triazol- 3-yl)acetyl]pyrrolidine-2- carboxamide 399 [00560] embedded image (2S,4R)-1-{2-[(azetidine-1- carbonyl)amino]acetyl}-4-fluoro- N-[(S)-[6-fluoro-5-(propan-2- yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 400 [00561] (2S,4R)-1-{2-[5-(difluoromethyl)- 1H-1,2,3-tetrazol-1-yl]acetyl}-4- fluoro-N-[(S)-[6-fluoro-5-(propan-2- yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 401 [00562] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(4-methyl- 5-oxo-4,5-dihydro-1,3,4-oxadiazol- 2-yl)acetyl]pyrrolidine-2- carboxamide 402 [00563] (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(4-methyl- 5-oxo-4,5-dihydro-1,2,4-oxadiazol- 3-yl)acetyl]pyrrolidine-2- carboxamide 403 [00564] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-{2-[4- (trifluoromethyl)-1H-1,2,3-triazol- 5-yl]acetyl}pyrrolidine-2- carboxamide 404 [00565] (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-{2-[(2- methylpyrimidin-4- yl)amino]acetyl}pyrrolidine-2- carboxamide 405 [00566] embedded image (2S,4R)-1-[(2S)-2- [(dimethylcarbamoyl)amino] propanoyl]-4-fluoro-N-[(S)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 406 [00567] (2S,4R)-1-[(2R)-2- [(dimethylcarbamoyl)amino] propanoyl]-4-fluoro-N-[(S)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 407 [00568] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(1,3- oxazol-2-yl)acetyl]pyrrolidine-2- carboxamide 408 [00569] (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(5-methyl- 1,3-oxazol-2-yl)acetyl]pyrrolidine- 2-carboxamide 409 [00570] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(4-methyl- 1,3-oxazol-2-yl)acetyl]pyrrolidine- 2-carboxamide 410 [00571] (2S,4R)-1-{2-[(3,3- difluoroazetidine-1- carbonyl)amino]acetyl}-4-fluoro- N-[(S)-[6-fluoro-5-(propan-2- yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 411 [00572] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(5-methyl- 2-oxo-2,3-dihydro-1,3,4-oxadiazol- 3-yl)acetyl]pyrrolidine-2- carboxamide 412 [00573] (2S,4R)-1-{2-[4-(azetidin-1-yl)-2H- 1,2,3-triazol-2-yl]acetyl}-4-fluoro- N-[(S)-[6-fluoro-5-(propan-2- yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 413 [00574] embedded image (2S,4R)-1-{2-[4-(3,3- difluoroazetidin-1-yl)-2H-1,2,3- triazol-2-yl]acetyl}-4-fluoro-N- [(S)-[6-fluoro-5-(propan-2- yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 414 [00575] (2S,4R)-1-{2-[4-(diethylamino)- 2H-1,2,3-triazol-2-yl]acetyl}-4- fluoro-N-[(S)-[6-fluoro-5-(propan- 2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 415 [00576] embedded image (1S,2S,5R)-N-[(S)-[6-fluoro-5- (propan-2-yl)pyridin-2- yl](phenyl)methyl]-3-[2-(1H-1,2,3- triazol-5-yl)acetyl]-3- azabicyclo[3.1.0]hexane-2- carboxamide 416 [00577] (2S,5S)-N-[(S)-[6-fluoro-5- (propan-2-yl)pyridin-2- yl](phenyl)methyl]-5-methyl-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 417 [00578] embedded image (2S,4R)-1-(2-(1H- benzo[d]imidazol-1-yl)acetyl)-N- ((S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl)-4- fluoropyrrolidine-2-carboxamide 418 [00579] (2S,4R)-1-acetyl-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide 419 [00580] (2S,5S)-1-acetyl-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl)methyl]-5- methylpyrrolidine-2-carboxamide 420 [00581] embedded image (1S,3S,5S)-2-acetyl-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl)methyl]-2- azabicyclo[3.1.0]hexane-3- carboxamide 421 [00582] (2S)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-1-(2- acetamidoacetyl)pyrrolidine-2- carboxamide 422 [00583] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[3-(1,3-oxazol-2- yl)propanoyl]pyrrolidine-2- carboxamide 423 [00584] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(3-oxomorpholin-4- yl)acetyl]pyrrolidine-2- carboxamide 424 [00585] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(2-oxo-1,3- oxazolidin-3-yl)acetyl]pyrrolidine-2- carboxamide 425 [00586] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(3-methyl-2- oxoimidazolidin-1- yl)acetyl]pyrroldine-2- carboxamide 426 [00587] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1,3,4-oxadiazol-2- yl)acetyl]pyrrolidine-2- carboxamide 427 [00588] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-1- {2-[5-(difluoromethyl)-1,3,4- oxadiazol-2-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 428 [00589] (2S,4R)-N-[(S)-4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-{2-[5-(trifluoromethyl)- 1,3,4-oxadiazol-2- yl]acetyl}pyrrolidine-2- carboxamide 429 [00590] embedded image (2S,4R)-1-[2-(5-cyclopropyl-1,3,4- oxadiazol-2-yl)acetyl]-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide 430 [00591] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1H-1,2,3-tetrazol-5- yl)acetyl]pyrrolidine-2- carboxamide 431 [00592] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1H-1,2,3,4-tetrazol-1- yl)acetyl]pyrrolidine-2- carboxamide 432 [00593] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(5-methyl-1H-1,3,4- tetrazol-1-yl)acetyl]pyrrolidine-2- carboxamide 433 [00594] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(5-methyl-2H-1,3,4- tetrazol-2-yl)acetyl]pyrrolidine-2- carboxamide 434 [00595] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(5-methyl-4H-1,2,4- triazol-3-yl)acetyl]pyrrolidine-2- carboxamide 435 [00596] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1H-pyrazol-1- yl)acetyl]pyrrolidine-2- carboxamide 436 [00597] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1H-pyrazol-5- yl)acetyl]pyrrolidine-2- carboxamide 437 [00598] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1H-pyrazol-4- yl)acetyl]pyrrolidine-2- carboxamide 438 [00599] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1,2-oxazol-3- yl)acetyl]pyrrolidine-2- carboxamide 439 [00600] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 440 [00601] embedded image (1S,2S,5R)-N-[(S)-(4-cyclopropyl- 3-fluorophenyl)(phenyl)methyl]-3- [2-(1H-1,2,3-triazol-5-yl)acetyl]-3- azabicyclo[3.1.0]hexane-2- carboxamide 441 [00602] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-1- {2- [(dimethylcarbamoyl)amino]acetyl}- 4-fluoropyrrolidine-2-carboxamide 442 [00603] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(5-methyl-2,4-dioxo- 1,2,3,4-tetrahydropyrimidin-1- yl)acetyl]pyrrolidine-2- carboxamide 443 [00604] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(quinolin-5- yl)acetyl]pyrrolidine-2- carboxamide 444 [00605] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-1-[2- (3,5-dimethyl-1H-pyrazol-4- yl)acetyl]-4-fluoropyrrolidine-2- carboxamide 445 [00606] 2-[(2S,4R)-2-{[(S)-(4-cyclopropyl- 3- fluorophenyl)(phenyl)methyl] carbamoyl}-4-fluoropyrrolidin-1-yl]-2- oxoethyl 4-methylpiperazine-1- carboxylate 446 [00607] embedded image 2-[(2S,4R)-2-{[(S)-(4-cyclopropyl- 3- fluorophenyl)(phenyl)methyl] carbamoyl}-4-fluoropyrrolidin-1-yl]-2- oxoethyl 4-(2,2,2- trifluoroethyl)piperazine-1- carboxylate 447 [00608] 2-[(2S,4R)-2-{[(S)-(4-cyclopropyl- 3- fluorophenyl)(phenyl)methyl] carbamoyl}-4-fluoropyrrolidin-1-yl]-2- oxoethyl 4- (cyclopropylmethyl)piperazine-1- carboxylate 448 [00609] embedded image 2-[(2S,4R)-2-{[(S)-(4-cyclopropyl- 3- fluorophenyl)(phenyl)methyl] carbamoyl}-4-fluoropyrrolidin-1-yl]-2- oxoethyl 4-(2- methoxyethyl)piperazine-1- carboxylate 449 [00610] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(3-methyl-2,4-dioxo- 1,2,3,4-tetrahydropyrimidin-1- yl)acetyl]pyrrolidine-2- carboxamide 450 [00611] embedded image (2S,4R)-1-[2-(1H-1,2,3- benzotriazol-1-yl)acetyl]-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide 451 [00612] 2-[(2S,4R)-2-{[(S)-(4-cyclopropyl- 3- fluorophenyl)(phenyl)methyl] carbamoyl}-4-fluoropyrrolidin-1-yl]-2- oxoethyl azetidine-1-carboxylate 452 [00613] embedded image N-{2-[(2S,4R)-2-{[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl)methyl] carbamoyl}-4-fluoropyrrolidin-1-yl]- 2-oxoethyl}morpholine-4- carboxamide 453 [00614] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1-oxo-2,3-dihydro-1H- isoindol-2-yl)acetyl]pyrrolidine-2- carboxamide 454 [00615] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(2-oxo-2,3-dihydro-1H- indol-1-yl)acetyl]pyrrolidine-2- carboxamide 455 [00616] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1-methyl-2-oxo-2,3- dihydro-1H-indol-3- yl)acetyl]pyrrolidine-2- carboxamide 456 [00617] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(2-oxo-2,3-dihydro-1H- 1,3-benzodiazol-1- yl)acetyl]pyrrolidine-2- carboxamide 457 [00618] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(3-methyl-2-oxo-2,3- dihydro-1H-1,3-benzodiazol-1- yl)acetyl]pyrrolidine-2- carboxamide 458 [00619] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1H-indazol-3- yl)acetyl]pyrrolidine-2- carboxamide 459 [00620] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1-methyl-1H-indazol- 3-yl)acetyl]pyrrolidine-2- carboxamide 460 [00621] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1H-indol-2- yl)acetyl]pyrrolidine-2- carboxamide 461 [00622] tert-butyl 2-{2-[(2S,4R)-2-{[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl)methyl] carbamoyl}-4-fluoropyridin-1-yl]-2- oxoethyl}-1H-indole-1-carboxylate 462 [00623] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1-methyl-1H-indol-2- yl)acetyl]pyrrolidine-2- carboxamide 463 [00624] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1-methyl-1H-indol-3- yl)acetyl]pyrrolidine-2- carboxamide 464 [00625] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(2-methyl-1H-1,3- benzodiazol-1- yl)acetyl]pyrrolidine-2- carboxamide 465 [00626] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(2-oxopiperazin-1- yl)acetyl]pyrrolidine-2- carboxamide 466 [00627] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-{2-[2-oxo-4-(2,2,2- trifluoroethyl)piperazin-1- yl]acetyl}pyrrolidine-2- carboxamide 467 [00628] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(2-oxo-2,3-dihydro-1H- indol-3-yl)acetyl]pyrrolidine-2- carboxamide 468 [00629] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(4-methyl-1H-imidazol- 1-yl)acetyl]pyrrolidine-2- carboxamide 469 [00630] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-1- {2-[(1-ethyl-1H-1,2,3-triazol-4- yl)amino]acetyl}-4- fluoropyrrolidine-2-carboxamide 470 [00631] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-1- {2-[(2-ethyl-2H-1,2,3-triazol-4- yl)amino]acetyl}-4- fluoropyrrolidine-2-carboxamide 471 [00632] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-{2-[(pyrazin-2- yl)amino]acetyl}pyrrolidine-2- carboxamide 472 [00633] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-{2-[(2-methylpyrimidin--4 yl)amino]acetyl}pyrrolidine-2- carboxamide 473 [00634] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-1- {2-[(1-ethyl-1H-1,2,3-triazol-4- yl)(methyl)amino]acetyl}-4- fluoropyrrolidine-2-carboxamide 474 [00635] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-1- {2-[(2-ethyl-2H-1,2,3-triazol-4- yl)(methyl)amino]acetyl}-4- fluoropyrrolidine-2-carboxamide 475 [00636] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-{2-[methyl(pyrazin-2- yl)amino]acetyl}pyrrolidine-2- carboxamide 476 [00637] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-{2-[methyl(2- methylpyrimidin-4- yl)amino]acetyl}pyrrolidine-2- carboxamide 477 [00638] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(2-methylquinolin-5- yl)acetyl]pyrrolidine-2- carboxamide 478 [00639] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-(2-{[1,2,4]triazolo[1,5- a]pyridin-6-yl}acetyl)pyrrolidine-2- carboxamide 479 [00640] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-(2-{imidazo[1,2-a]pyridin- 3-yl}acetyl)pyrrolidine-2- carboxamide 480 [00641] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(2-methylquinolin-6- yl)acetyl]pyrrolidine-2- carboxamide 481 [00642] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(4H-1,2,4-triazol-4- yl)acetyl]pyrrolidine-2- carboxamide 482 [00643] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-(2-{3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyridin-8- yl}acetyl)pyrrolidine-2- carboxamide 483 [00644] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-1- {2-[4-(dimethylamino)-2H-1,2,3- triazol-2-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 484 [00645] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-1- {2-[4-(dimethylamino)-1H-1,2,3- triazol-1-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 485 [00646] tert-butyl N-[(5-{2-[(2S,4R)-2- {[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl] carbamoyl}-4-fluoropyrrolidin-1- yl]-2-oxoethyl}-1,3,4-oxadiazol-2- yl)methyl]carbamate 486 [00647] embedded image N-{2-[(2S,4R)-2-{[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl)methyl] carbamoyl}-4-fluoropyrrolidin-1-yl]- 2-oxoethyl}-4-methylpiperazine-1- carboxamide 487 [00648] N-{2-[(2S,4R)-2-{[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl)methyl] carbamoyl}-4-fluoropyrrolidin-1-yl]- 2-oxoethyl}-4-(2,2,2- trifluoroethyl)piperazine-1- carboxamide 488 [00649] embedded image N-{2-[(2S,4R)-2-{[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl)methyl] carbamoyl}-4-fluoropyrrolidin-1-yl]- 2-oxoethyl}-4-(2- methoxyethyl)piperazine-1- carboxamide 489 [00650] (2S,4R)-1-{2-[5-(aminomethyl)- 1,3,4-oxadiazol-2-yl]acetyl}-N- [(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide 490 [00651] embedded image N-{2-[(2S,4R)-2-{[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl)methyl] carbamoyl}-4-fluoropyrrolidin-1-yl]- 2-oxoethyl}-4- (cyclopropylmethyl)piperazine-1- carboxamide 491 [00652] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(5-oxo-4,5-dihydro-1H- 1,2,4-triazol-3- yl)acetyl]pyrrolidine-2- carboxamide 492 [00653] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(5-oxo-4,5-dihydro- 1,2,4-oxadiazol-3- yl)acetyl]pyrrolidine-3- carboxamide 493 [00654] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[3-(5-oxo-4,5-dihydro-1H- 1,2,4-triazol-3- yl)propanoyl]pyrrolidine-3- carboxamide 494 [00655] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(4-methyl-5-oxo-4,5- dihydro-1,2,4-oxadiazol-3- yl)acetyl]pyrrolidine-2- carboxamide 495 [00656] (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-1- {2-[(3,3-difluoroazetidine-1- carbonyl)amino]acetyl}-4- fluoropyrrolidine-2-carboxamide 496 [00657] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-(2-{[3- (trifluoromethyl)azetidine-1- carbonyl]amino}acetyl)pyrrolidine- 2-carboxamide 497 [00658] (2S,4R)-1-(2-(1H-1,2,3-triazol-5- yl)acetyl)-N-((S) or (R)-(5- cyclopropylpyridin-2- yl)(phenyl)methyl)-4- fluoropyrrolidine-2-carboxamide 498 [00659] embedded image (2S,4R)-1-(2-(1H-1,2,3-triazol-5- yl)acetyl)-N-((R) or (S)-(5- cyclopropylpyridin-2- yl)(phenyl)methyl)-4- fluoropyrrolidine-2-carboxamide 499 [00660] (2S,4R)-1-acetyl-N-[(S) or (R)-(5- cyclopropylpyridin-2- yl)(phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide 500 [00661] (2S,4R)-1-acetyl-N-[(R) or (S)-(5- cyclopropylpyridin-2- yl)(phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide (second eluting isomer) 501 [00662] embedded image (2S,4R)-N-((S)-(5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-y)(phenyl)methyl)- 1-(2-(3-ethyl-5-methyl-2,4-dioxo- 3,4-dihydropyrimidin-1(2H)- yl)acetyl)-4-fluoropyrrolidine-2- carboxamide 502 [00663] (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 4-fluoro-1-[2-(5-methyl-2-oxo-2,3- dihydro-1,3,4-oxadiazol-3- yl)acetyl]pyrrolidine-2- carboxamide 503 [00664] embedded image (2S,4R)-1-{2-[(azetidine-1- carbonyl)amino]acetyl}-N-[(S)-[5- (3,3-difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 4-fluoropyrrolidine-2-carboxamide 504 [00665] (2S,4R)-1-[2-(1H-1,3-benzodiazol- 1-yl)acetyl]-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 4-fluoropyrrolidine-2-carboxamide 505 [00666] embedded image (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 4-fluoro-1-[2-(1,3-oxazol-2- yl)acetyl]pyrrolidine-2- carboxamide 506 [00667] (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 4-fluoro-1-[2-(5-methyl-2,4-dioxo- 1,2,3,4-tetrahydropyrimidin-1- yl)acetyl]pyrrolidine-2- carboxamide 507 [00668] embedded image (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 1-{2- [(dimethylcarbamoyl)amino]acetyl}- 4-fluoropyrrolidine-2-carboxamide 508 [00669] (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 4-fluoro-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 509 [00670] embedded image (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 4-fluoro-1-[2-(5-methyl-1,3-oxazol- 2-yl)acetyl]pyrrolidine-2- carboxamide 510 [00671] (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 4-fluoro-1-{2-[4-(trifluoromethyl)- 1H-1,2,3-triazol-5- yl]acetyl}pyrrolidine-2- carboxamide 511 [00672] embedded image (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 4-fluoro-1-[2-(4-methyl-1,3-oxazol- 2-yl)acetyl]pyrrolidine-2- carboxamide 512 [00673] (2S,4R)-1-{2-[(3,3- difluoroazetidine-1- carbonyl)amino]acetyl}-N-[(S)-[5- (3,3-diflluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 4-fluoropyrrolidine-2-carboxamide 513 [00674] embedded image (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 1-{2-[5-(difluoromethyl)-1H- 1,2,3,4-tetrazol-1-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 514 [00675] (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 1-[2-(2,4-dioxo-1,2,3,4- tetrahydropyrimidin-1-yl)acetyl]-4- fluoropyrrolidine-2-carboxamide 515 [00676] embedded image (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 1-[2-(3-ethyl-2,4-dioxo-1,2,3,4- tetrahydropyrimidin-1-yl)acetyl]-4- fluoropyrrolidine-2-carboxamide 516 [00677] (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 4-fluoro-1-[2-(6-oxo-1,6- dihydropyridin-3- yl)acetyl]pyrrolidine-2- carboxamide 517 [00678] embedded image (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 4-fluoro-1-[2-(2-oxo-1,2- dihydropyridin-3- yl)acetyl]pyrrolidine-2- carboxamide 518 [00679] (2S,4R)-N-[(R)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 1-[2-(3-ethyl-5-methyl-2,4-dioxo- 1,2,3,4-tetrahydropyrimidin-1- yl)acetyl]-4-fluoropyrrolidine-2- carboxamide 519 [00680] embedded image (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 1-[2-(1-ethyl-6-oxo-1,6- dihydropyridin-3-yl)acetyl]-4- fluoropyrrolidine-2-carboxamide 520 [00681] (2S,4R)-N-[(R)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 4-fluoro-1-[2-(6-oxo-1,6- dihydropyridin-3- yl)acetyl]pyrrolidine-2- carboxamide 521 [00682] embedded image (2S,4R)-N-[(R)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 4-fluoro-1-[2-(2-oxo-1,2- dihydropyridin-3- yl)acetyl]pyrrolidine-2- carboxamide 522 [00683] (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 4-fluoro-1-[2-(5-methyl-6-oxo-1,6- dihydropyridin-3- yl)acetyl]pyrrolidine-2- carboxamide 523 [00684] embedded image (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 1-[2-(1-ethyl-5-methyl-6-oxo-1,6- dihydropyridin-3-yl)acetyl]-4- fluoropyrrolidine-2-carboxamide 524 [00685] (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 1-[2-(6-ethoxy-5-methylpyridin-3- yl)acetyl]-4-fluoropyrrolidine-2- carboxamide 525 [00686] embedded image (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 1-[2-(1-ethyl-5-methyl-2-oxo-1,2- dihydropyridin-3-yl)acetyl]-4- fluoropyrrolidine-2-carboxamide 526 [00687] (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 1-[2-(1-ethyl-2-oxo-1,2- dihydropyridin-3-yl)acetyl]-4- fluoropyrrolidine-2-carboxamide 527 [00688] embedded image (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 1-[2-(4-ethyl-5-oxo-4,5- dihydropyrazin-2-yl)acetyl]-4- fluoropyrrrolidine-2-carboxamide 528 [00689] (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 4-fluoro-1-{2-[4-(trifluoromethyl)- 1,3-oxazol-2-yl]acetyl}pyrrolidine- 2-carboxamide 529 [00690] embedded image (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 4-fluoro-1-[2-(3-oxo-3,4- dihydropyrazin-2- yl)acetyl]pyrrolidine-2- carboxamide 530 [00691] (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 4-fluoro-1-[2-(5-oxo-4,5- dihydropyrazin-2- yl)acetyl]pyrrolidine-2- carboxamide 531 [00692] embedded image (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)-6- fluoropyridin-2-yl](phenyl)methyl]- 1-[2-(4-ethyl-3-oxo-3,4- dihydropyrazin-2-yl)acetyl]-4- fluoropyrrolidine-2-carboxamide 532 [00693] (2S,4R)-N-((S)-(5-(3,3- difluorocyclobutyl)pyridin-2- yl)(phenyl)methyl)-1- ((dimethylcarbamoyl)glycyl)-4- fluoropyrrolidine-2-carboxamide 533 [00694] embedded image (2S,4R)-1-{2-[(azetidine-1- carbonyl)amino]acetyl}-N-[(S)-[5- (3,3-difluorocyclobutyl)pyridin-2- yl](phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide 534 [00695] (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)pyridin-2- yl](phenyl)methyl]-4-fluoro-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 535 [00696] embedded image (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)pyridin-2- yl](phenyl)methyl]-4-fluoro-1-[2- (5-methyl-2,4-dioxo-1,2,3,4- tetrahydropyrimidin-1- yl)acetyl]pyrrolidine-2- carboxamide 536 [00697] (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)pyridin-2- yl](phenyl)methyl]-4-fluoro-1-[2- (5-methyl-1,3-oxazol-2- yl)acetyl]pyrrolidine-2- carboxamide 537 [00698] embedded image (2S,4R)-1-[2-(1H-1,3-benzodiazol- 1-yl)acetyl]-N-[(S)-[5-(3,3- difluorocyclobutyl)pyridin-2- yl](phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide 538 [00699] (2S,4R)-1-{2-[(3,3- difluoroazetidine-1- carbonyl)amino]acetyl}-N-[(S)-[5- (3,3-difluorocyclobutyl)pyridin-2- yl](phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide 539 [00700] embedded image (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)pyridin-2- yl](phenyl)methyl]-4-fluoro-1-[2- (1,3-oxazol-2-yl)acetyl]pyrrolidine- 2-carboxamide 540 [00701] (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)pyridin-2- yl](phenyl)methyl]-4-fluoro-1-[2- (4-methyl-1,3-oxazol-2- yl)acetyl]pyrrolidine-2- carboxamide 541 [00702] embedded image (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)pyridin-2- yl](phenyl)methyl]-4-fluoro-1-[2- (5-methyl-2-oxo-2,3-dihydro-1,3,4- oxadiazol-3-yl)acetyl]pyrrolidine- 2-carboxamide 542 [00703] (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)pyridin-2- yl](phenyl)methyl]-4-fluoro-1-{2- [4-(trifluoromethyl)-1H-1,2,3- triazol-5-yl]acetyl}pyrrolidine-2- carboxamide 543 [00704] embedded image (2S,4R)-N-[(S)-[5-(3,3- difluorocyclobutyl)pyridin-2- yl](phenyl)methyl]-4-fluoro-1-{2- [4-(trifluoromethyl)-1,3-oxazol-2- yl]acetyl}pyrrolidine-2- carboxamide 544 [00705] (2S,4R)-1-((azetidine-1- carbonyl)glycyl)-N-((S)-(4-(3,3- difluorocyclobutyl)-3- fluorophenyl)(phenyl)methyl)-4- fluoropyrrolidine-2-carboxamide 545 [00706] embedded image (2S,4R)-1-((azetidine-1- carbonyl)glycyl)-N-((R)-(4-(3,3- difluorocyclobutyl)-3- fluorophenyl)(phenyl)methyl)-4- fluoropyrrolidine-2-carboxamide 546 [00707] (2S,4R)-N-[(S)-[4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl)methyl]-4- fluoro-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 547 [00708] embedded image (2S,4R)-N-[(S)-[4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl)methyl]-1- {2- [(dimethylcarbamoyl)amino]acetyl}- 4-fluoropyrrolidine-2-carboxamide 548 [00709] (2S,4R)-N-[(R)-[4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl)methyl]-1- {2- [(dimethylcarbamoyl)amino]acetyl}- 4-fluoropyrrolidine-2-carboxamide 549 [00710] embedded image (2S,4R)-1-[2-(1H-1,3-benzodiazol- 1-yl)acetyl]-N-[(S)-[4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide 550 [00711] (2S,4R)-N-[(S)-[4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl)methyl]-4- fluoro-1-[2-(5-methyl-1,3-oxazol-2- yl)acetyl]pyrrolidine-2- carboxamide 551 [00712] embedded image (2S,4R)-N-[(S)-[4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl)methyl]-4- fluoro-1-[2-(5-methyl-2,4-dioxo- 1,2,3,4-tetrahydropyrimidin-1- yl)acetyl]pyrrolidine-2- carboxamide 552 [00713] (2S,4R)-N-[(S)-[4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl)methyl]-4- fluoro-1-[2-(1,3-oxazol-2- yl)acetyl]pyrrolidine-2- carboxamide 553 [00714] embedded image (2S,4R)-N-[(S)-[4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl)methyl]-4- fluoro-1-{2-[4-(trifluoromethyl)- 1H-1,2,3-triazol-5- yl]acetyl}pyrrolidine-2- carboxamide 554 [00715] (2S,4R)-N-[(S)-[4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl)methyl]-4- fluoro-1-[2-(4-methyl-1,3-oxazol-2- yl)acetyl]pyrrolidine-2- carboxamide 555 [00716] embedded image (2S,4R)-N-[(S)-[4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl)methyl]-4- fluoro-1-{2-[4-(trifluoromethyl)- 1,3-oxazol-2-yl]acetyl}pyrrolidine- 2-carboxamide 556 [00717] (2S,4R)-4-fluoro-N-((S)-(3-fluoro- 4-(1- methylcyclopropyl)phenyl)(phenyl) methyl)-1-(2-(5-methyl-2,4-dioxo- 3,4-dihydropyrimidin-1(2H- yl)acetyl)pyrrolidine-2- carboxamide 557 [00718] embedded image (2S,4R)-4-fluoro-N-((R)-(3-fluoro- 4-(1- methylcyclopropyl)phenyl)(phenyl) methyl)-1-(2-(5-methyl-2,4-dioxo- 3,4-dihydropyrimidin-1(2H)- yl)acetyl)pyrrolidine-2- carboxamide 558 [00719] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl)phenyl](phenyl) methyl]-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 559 [00720] embedded image (2S,4R)-4-fluoro-N-[(R)-[3-fluoro- 4-(1- methylcyclopropyl)phenyl](pyridin- 3-yl)methyl]-1-[2-(1H-1,2,3- triazol-5-yl)acetyl]pyrrolidine-2- carboxamide 560 [00721] 2-[(2S,4R)-4-fluoro-2-{[(S)-[3- fluoro-4-(1- methylcyclopropyl)phenyl](phenyl) methyl]carbamoyl}pyrrolidin-1-yl]- 2-oxoethyl azetidine-1-carboxylate 561 [00722] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl)phenyl](phenyl) methyl]-1-[2-(1-methyl-1H-indol- 2-yl)acetyl]pyrrolidine-2- carboxamide 562 [00723] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl)phenyl](phenyl) methyl]-1-[2-(2-oxopiperazin-1- yl)acetyl]pyrrolidine-2- carboxamide 563 [00724] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl)phenyl](phenyl)- methyl]-1-[2-(1-methyl-1H-indol- 3-yl)acetyl]pyrrolidine-2- carboxamide 564 [00725] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl)phenyl](phenyl) methyl]-1-[2-(1-methyl-1H- indazol-3-yl)acetyl]pyrrolidine-2- carboxamide 565 [00726] embedded image N-{2-[(2S,4R)-4-fluoro-2-{[(S)-[3- fluoro-4-(1- methylcyclopropyl)phenyl](phenyl) methyl]carbamoyl}pyrrolidin-1-yl]- 2-oxoethyl}morpholine-4- carboxamide 566 [00727] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl)phenyl](phenyl) methyl]-1-[2-(2-methyl-1H-1,3- benzodiazol-1- yl)acetyl]pyrrolidine-2- carboxamide 567 [00728] embedded image (2S,4R)-1-[(2R) or (2S)-2-(1H-1,3- benzodiazol-1-yl)propanoyl]-4- fluoro-N-[(S)-[3-fluoro-4-(1- methylcyclopropyl)phenyl](phenyl) methyl]pyrrolidine-2-carboxamide 568 [00729] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl)phenyl](phenyl) methyl]-1-[2-(3-methyl-2-oxo-2,3- dihydro-1H-1,3-benzodiazol-1- yl)acetyl]pyrrolidine-2- carboxamide 569 [00730] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl)phenyl](phenyl) methyl]-1-[2-(3-methyl-2,4-dioxo- 1,2,3,4-tetrahydropyrimidin-1- yl)acetyl]pyrrolidine-2- carboxamide 570 [00731] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl)phenyl](phenyl) methyl]-1-[2-(2-oxo-2,3-dihydro- 1H-1,3-benzodiazol-1- yl)acetyl]pyrrolidine-2- carboxamide 571 [00732] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl)phenyl](phenyl) methyl]-1-[2-(1H-indazol-3- yl)acetyl]pyrrolidine-2- carboxamide 572 [00733] (2S,4R)-1-[2-(2,5-dioxopiperazin- 1-yl)acetyl]-4-fluoro-N-[(S)-[3- fluoro-1-(1- methylcyclopropyl)phenyl](phenyl) methyl]pyrrolidine-2-carboxamide 573 [00734] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl)phenyl](phenyl) methyl]-1-[2-(1-oxo-2,3-dihydro- 1H-isoindol-2- yl)acetyl]pyrrolidine-2- carboxamide 574 [00735] (2S,4R)-1-[(2S) or 2R)-2-(1H-1,3- benzodiazol-1-yl)propanoyl]-4- fluoro-N-[(S)-[3-fluoro-4-(1- methylcyclopropyl)phenyl](phenyl) methyl]pyrrolidine-2-carboxamide 575 [00736] embedded image (2S,4R)-1-[2-(1H-1,2,3- benzotriazol-1-yl)acetyl]-4-fluoro- N-[(S)-[3-fluoro-4-(1- methylcyclopropyl)phenyl](phenyl) methyl]pyrrolidine-2-carboxamide 576 [00737] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl)phenyl](phenyl) methyl]-1-[2-(2-oxo-2,3-dihydro- 1H-indol-1-yl)acetyl]pyrrolidine-2- carboxamide 577 [00738] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl)phenyl](phenyl) methyl]-1-[2-(1-methyl-2-oxo-2,3- dihydro-1H-indol-3- yl)acetyl]pyrrolidine-2- carboxamide 578 [00739] 2,2,2-trifluoroethyl 4-{2-[(2S,4R)- 4-fluoro-2-{[(S)-[3-fluoro-4-(1- methylcyclopropyl)phenyl](phenyl) methyl]carbamoyl}pyrrolidin-1-yl]- 2-oxoethyl}-3-oxopiperazine-1- carboxylate 579 [00740] embedded image 2-[(2S,4R)-4-fluoro-2-{[(S)-[3- fluoro-4-(1- methylcyclopropyl)phenyl](phenyl) methyl]carbamoyl}pyrrolidin-1-yl]- 2-oxoethyl 4-(2- methoxyethyl)piperazine-1- carboxylate 580 [00741] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl)phenyl](phenyl) methyl]-1-{2-[2-oxo-4-(2,2,2- trifluoroethyl)piperazin-1- yl]acetyl}pyrrolidine-2- carboxamide 581 [00742] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl)phenyl](phenyl) methyl]-1-[2-(2-oxo-2,3-dihydro- 1H-indol-3-yl)acetyl]pyrrolidine-2- carboxamide 582 [00743] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl)phenyl](phenyl) methyl]-1-[2-(4H-1,2,4-triazol-4- yl)acetyl]pyrrolidine-2- carboxamide 583 [00744] embedded image 2-[(2S,4R)-4-fluoro-2-{[(S)-[3- fluoro-4-(1- methylcyclopropyl)phenyl](phenyl) methyl]carbamoyl}pyrrolidin-1-yl]- 2-oxoethyl 4-methylpiperazine-1- carboxylate 584 [00745] 2-[(2S,4R)-4-fluoro-2-{[(S)-[3- fluoro-4-(1- methylcyclopropyl)phenyl](phenyl) methyl]carbamoyl}pyrrolidin-1-yl]- 2-oxoethyl-4- (cyclopropylmethyl)piperazine-1- carboxylate 585 [00746] embedded image 2-[(2S,4R)-4-fluoro-2-{[(S)-[3- fluoro-4-(1- methylcyclopropyl)phenyl](phenyl) methyl]carbamoyl}pyrrolidin-1-yl]- 2-oxoethyl 4-(2,2,2- trifluoroethyl)piperazine-1- carboxylate 586 [00747] (2S,4R)-1-((R) or (S)-2-(1H- benzo[d]imidazol-1-yl)propanoyl)- 4-fluoro-N-((S)-6-fluoro-5-(1- methylcyclopropyl)pyridin-2- yl)(phenyl)methyl)pyrrolidine-2- carboxamide 587 [00748] embedded image (2S,4R)-1-((S) or (R)-2-(1H- benzo[d]imidazol-1-yl)propanoyl)- 4-fluoro-N-((S)-(6-fluoro-5-(1- methylcyclopropyl)pyridin-2- yl)(phenyl)methyl)pyrrolidine-2- carboxamide 588 [00749] (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(1-methylcyclopropyl)pyridin-2- yl](phenyl)methyl]-1-[2-(1H- indazol-3-yl)acetyl]pyrrolidine-2- carboxamide 589 [00750] embedded image N-{2-[(2S,4R)-4-fluoro-2-{[(S)-[6- fluoro-5-(1- methylcyclopropyl)pyridin-2- yl](phenyl)methyl]carbamoyl} pyrrolidin-1-yl]-2- oxoethyl}morpholine-4- carboxamide 590 [00751] (2S,4R)-4-fluoro-N-[(R)-[6-fluoro- 5-(1-methylcyclopropyl)pyridin-2- yl](phenyl)methyl]-1-[2-(1H- indazol-3-yl)acetyl]pyrrolidine-2- carboxamide 591 [00752] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(1-methylcyclopropyl)pyridin-2- yl](phenyl)methyl]-1-[2-(1-methyl- 1H-indol-2-yl)acetyl]pyrrolidine-2- carboxamide 592 [00753] (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(1-methylcyclopropyl)pyridin-2- yl](phenyl)methyl]-1-[2-(1-methyl- 1H-indol-3-yl)acetyl]pyrrolidine-2- carboxamide 593 [00754] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(1-methylcyclopropyl)pyridin-2- yl](phenyl)methyl]-1-[2-(2-methyl- 1H-1,3-benzodiazol-1- yl)acetyl]pyrrolidine-2- carboxamide 594 [00755] (2S,4R)-1-[2-(1H-1,2,3- benzotriazol-1-yl)acetyl]-4-fluoro- N-[(S)-[6-fluoro-5-(1- methylcyclopropyl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 595 [00756] embedded image (2S,4R)-1-[2-(1H-1,3-benzodiazol- 1-yl)acetyl]-4-fluoro-N-[(S)-[6- fluoro-5-(1- methylcyclopropyl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 596 [00757] (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(1-methylcyclopropyl)pyridin-2- yl](phenyl)methyl]-1-[2-(1-methyl- 1H-indazol-3-yl)acetyl]pyrrolidine- 2-carboxamide 597 [00758] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(1-methylcyclopropyl)pyridin-2- yl](phenyl)methyl]-1-[2-(1-methyl- 2-oxo-2,3-dihydro-1H-indol-3- yl)acetyl]pyrrolidine-2- carboxamide 598 [00759] (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(1-methylcyclopropyl)pyridin-2- yl](phenyl)methyl]-1-[2-(1H-indol- 2-yl)acetyl]pyrrolidine-2- carboxamide 599 [00760] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(1-methylcyclopropyl)pyridin-2- yl](phenyl)methyl]-1-[2-(2-oxo- 2,3-dihydro-1H-1,3-benzodiazol-1- yl)acetyl]pyrrolidine-2- carboxamide 600 [00761] (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(1-methylcyclopropyl)pyridin-2- yl](phenyl)methyl]-1-[2-(3-methyl- 2-oxo-2,3-dihydro-1H-1,3- benzodiazol-1- yl)acetyl]pyrrolidine-2- carboxamide 601 [00762] embedded image tert-butyl 2-{2-[(2S,4R)-4-fluoro-2- {[(S)-[6-fluoro-5-(1- methylcyclopropyl)pyridin-2- yl](phenyl)methyl]carbamoyl} pyrrolidin-1-yl]-2-oxoethyl}-1H- indole-1-carboxylate 602 [00763] (2S,4R)-1-(2-(5-(difluoromethyl)- 1,3,4-oxadiazol-2-yl)acetyl)-4- fluoro-N-((S)-(5-isopropyl-4- methylpyridin-2- yl)(phenyl)methyl)pyrrolidine-2- carboxamide 603 [00764] embedded image (2S,4R)-1-acetyl-N-[(S) or (R)-(5- cyclobutylpyridin-2- yl)(phenyl)methyl}-4- fluoropyrrolidine-2- carboxamide 604 [00765] (2S,4R)-4-fluoro-N-[(S) or (R)-[4- methyl-5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(1H-1,2,3- triazol-5-yl)acetyl]pyrrolidine-2- carboxamide 605 [00766] (2S,4R)-4-fluoro-N-[(S) or (R)-[4- fluoro-5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(1H-1,2,3- triazol-5-yl)acetyl]pyrrolidine-2- carboxamide 606 [00767] embedded image (2S,4R)-N-[(S) or (R)-[4- (difluoromethyl)-5-(propan-2- yl)pyridin-2-yl](phenyl)methyl]-4- fluoro-1-[2-(1H-1,2,3-triazol-4- yl)acetyl]pyrrolidine-5- carboxamide 607 [00768] (2S,4R)-4-fluoro-N-[(S) or (R)-[6- methyl-5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(1H-1,2,3- triazol-5-yl)acetyl]pyrrolidine-2- carboxamide 608 [00769] embedded image (2S,4R)-4-fluoro-N-[(S) or (R)- phenyl[5-(propan-2-yl)-4- (trifluoromethyl)pyridin-2- yl]methyl]-1-[2-(1H-1,2,3-triazol- 5-yl)acetyl]pyrrolidine-2- carboxamide 609 [00770] (2S,4R)-1-{2-[5-(difluoromethyl)- 1,3,4-oxadiazol-2-yl]acetyl}-4- fluoro-N-[(S) or (R)-[6-methyl-5- (propan-2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 610 [00771] embedded image (2S,4R)-N-[(S) or (R)-(5- cyclobutylpyridin-2- yl)(phenyl)methyl]-4-fluoro-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 611 [00772] (2S,4R)-N-[(S) or (R)-(5-tert- butylpyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 612 [00773] embedded image (2S,4R)-4-fluoro-N-[(S) or (R)-[6- methoxy-5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(1H-1,2,3- triazol-5-yl)acetyl]pyrrolidine-2- carboxamide 613 [00774] (2S,4R)-1-(2-(1H-1,2,3-triazol-5- yl)acetyl)-N-((R)-(2-aminopyridin- 3-yl)(3-fluoro-4- isopropylphenyl)methyl)-4- fluoropyrrolidine-2-carboxamide 614 [00775] embedded image (2S,4R)-1-acetyl-4-fluoro-N-[(S)- [4-(propan-2-yl)phenyl](1H- pyrazol-5-yl)methyl]pyrrolidine-2- carboxamide 615 [00776] (2S)-N-[(R) or (S)-(4-cyclopropyl- 3-fluorophenyl)(1H-pyrazol-5- yl)methyl]-1-(2- acetamidoacetyl)pyrrolidine-2- carboxamide 616 [00777] (2S,4R)-4-fluoro-N-[(R) or (S)-[3- fluoro-4-(propan-2-yl)phenyl](5- fluoropyridin-2-yl)methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 617 [00778] embedded image (2S,4R)-4-fluoro-N-[(R) or (S)-[3- fluoro-4-(propan-2-yl)phenyl](5- fluoropyridin-3-yl)methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 618 [00779] (2S,4R)-N-[(S) or (R)-(2- aminopyridin-4-yl](3-fluoro-4- (propan-2-yl)phenyl]methyl]-4- fluoro-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 619 [00780] embedded image (2S,4R)-4-fluoro-N-[(R) or (S)-[3- fluoro-4-(propan-2-yl)phenyl](3- fluoropyridin-4-yl)methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 620 [00781] (2S,4R)-N-[(R) or (S)-(6- aminopyridin-3-yl)[3-fluoro-4- (propan-2-yl)phenyl]methyl]-4- fluoro-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 621 [00782] embedded image (2S,4R)-N-[(R) or (S)-(6- aminopyridin-2-yl)[3-fluoro-4- (propan-2-yl)phenyl]methyl]-4- fluoro-1-[2-(1H-(1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 622 [00783] (2S,4R)-N-[(R) or (S)-(2- aminopyridin-3-yl)[3-methyl-4- (propan-2-yl)phenyl]methyl]-1-{2- [(dimethylcarbamoyl)amino]acetyl}- 4-fluoropyrrolidine-2-carboxamide 623 [00784] embedded image (2S,4R)-4-fluoro-N-[(R) or (S)-[3- fluoro-4-(propan-2-yl)phenyl](1H- pyrazol-5-yl)methyl]-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 624 [00785] (2S,4R)-N-[(R) or (S)-(2- aminopyridin-3-yl)[3-methyl-4- (propan-2-yl)phenyl]methyl]-4- fluoro-1-[2-(1H-1,2,3-triazol-5- y)acetyl]pyrrolidine-2- carboxamide 625 [00786] embedded image (2S,4R)-N-[(R) or (S)-(2- aminopyridin-3-yl)[3-methyl-4- (propan-2-yl)phenyl]methyl]-4- fluoro-1-[2-(1,3,5-trimethyl-1H- pyrazol-4-yl)acetyl]pyrrolidine-2- carboxamide 626 [00787] (2S,4R)-4-fluoro-N-[(R) or (S)-[3- fluoro-4-(1- methylcyclopropyl)phenyl](2- methoxypyridin-3-yl)methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 627 [00788] embedded image (2S,4R)-4-fluoro-N-[(R) or (S)-[3- fluoro-4-(1- methylcyclopropyl)phenyl](2- methylpyridin-3-yl)methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 628 [00789] (2S,4R)-4-fluoro-N-[(R) or (S)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl]({imidazo[1,5-a]pyridin-3- yl})methyl]-1-[2-(1H-1,2,3-triazol- 5-yl)acetyl]pyrrolidine-2- carboxamide 629 [00790] embedded image (2S,4R)-4-fluoro-N-[(S) or (R)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl]({imidazo[1,5-a]pyridin-1- yl})methyl]-1-[2-(1H-1,2,3-triazol- 5-yl)acetyl]pyrrolidine-2- carboxamide 630 [00791] (2S,4R)-4-fluoro-N-[(S) or (R)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl](1H-pyrazol-5-yl)methyl]-1-[2- (1,3-oxazol-2-yl)acetyl]pyrrolidine- 2-carboxamide 631 [00792] embedded image (2S,4R)-4-fluoro-N-[(S) or (R)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl]({imidazo[1,5-a]pyridin-7- yl})methyl]-1-[2-(1H-1,2,3-triazol- 5-yl)acetyl]pyrrolidine-2- carboxamide 632 [00793] (2S,4R)-4-fluoro-N-[(S) or (R)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl](1H-indazol-6-yl)methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 633 [00794] embedded image (2S,4R)-4-fluoro-N-[(R) or (S)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl](1H-indazol-6-yl)methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 634 [00795] (2S,4R)-1-acetyl-4-fluoro-N-[(S) or (R)-[6-fluoro-5-(propan-2- yl)pyridin-2-yl](1H-indazol-6- yl)methyl]pyrrolidine-2- carboxamidee 635 [00796] embedded image (2S,4R)-1-acetyl-4-fluoro-N-[(S) or (R)-[6-fluoro-5-(propan-2- yl)pyridin-2-yl](1-methyl-1H- indazol-6-yl)methyl]pyrrolidine-2- carboxamide 636 [00797] (2S,4R)-1-acetyl-4-fluoro-N-[(S) or (R)-[6-fluoro-5-(propan-2- yl)pyridin-2-yl](2-methyl-2H- indazol-6-yl)methyl]pyrrolidine-2- carboxamide 637 [00798] embedded image (2S,4R)-1-acetyl-N-[(S) or (R)-(5- cyclopropyl-6-fluoropyridin-2- yl)(1H-indazol-6-yl)methyl]-4- fluoropyrrolidine-2-carboxamide 638 [00799] methyl (3-((S)-((2S,4R)-1-(2-(1H- 1,2,3-triazol-6-yl)acetyl)-4- fluoropyrrolidine-2- carboxamido)(6-fluoro-5- isopropylpyridin-2- yl)methyl)benzyl)carbamate 639 [00800] embedded image (2S)-1-acetyl-N-[(R)-(2- methoxyphenyl)[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 640 [00801] (2S)-1-acetyl-N-[(R)-(2- methylphenyl)[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 641 [00802] (2S)-1-acetyl-N-[(S) or (R)-(2- methylphenyl)[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 642 [00803] embedded image (2S,4R)-1-acetyl-N-[(R) or (S)-(2- aminophenyl)[4-(propan-2- yl)phenyl]methyl]-4- fluoropyrrolidine-2-carboxamide 643 [00804] (2S)-N-[(R) or (S)-(4-cyclopropyl- 3-fluorophenyl)(2-oxo-2,3-dihydro- 1,3-benzoxazol-7-yl)methyl]-1-(2- acetamidoacetyl)pyrrolidine-2- carboxamide 644 [00805] (2S)-N-[(R) or (2-oxo-2,3-dihydro- 1H-1,3-benzodiazol-4-yl)[4- (propan-2-yl)phenyl]methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 645 [00806] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2-yl)phenyl](3- fluorophenyl)methyl]-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 646 [00807] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2-yl)phenyl](4- fluorophenyl)methyl]-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 647 [00808] embedded image (2S,4R)-4-fluoro-N-[(R)-[3-fluoro- 4-(propan-2-yl)phenyl](3- fluorophenyl)methyl]-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 648 [00809] (2S)-N-[(S)-(4-cyclopropyl-3- fluorophenyl)(2-oxo-2,3-dihydro- 1H-1,3-benzodiazol-4-yl)methyl]- 1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 649 [00810] embedded image (2S,4R)-N-[(R)-(3- acetamidophenyl)[4-(propan-2- yl)phenyl]methyl]-4-fluoro-1-[2-(1- methyl-1H-1,2,3-triazol-4- yl)acetyl]pyrrolidine-2- carboxamide 650 [00811] (2S,4R)-N-[(R) or (S)-(4- cyclopropyl-3-fluorophenyl)(1- methyl-2-oxo-2,3-dihydro-1H-1,3- benzodiazol-4-yl)methyl]-4-fluoro- 1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 651 [00812] embedded image (2S,4R)-4-fluoro-N-[(S) or (R)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl](3-methoxyphenyl]methyl]-1-[2- (1H-1,2,3-triazol-5-yl)acetyl] pyrrolidine-2-carboxamide 652 [00813] (2S,4R)-N-[(S) or (R)- cyclopropyl[3-fluoro-4-(propan-2- yl)phenyl]methyl]-4-fluoro-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 653 [00814] embedded image (2S,4R)-N-[(1S) or (1R)-2- cyclopropyl-1-[3-fluoro-4-(propan- 2-yl)phenyl]ethyl]-4-fluoro-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 654 [00815] (2S,4R)-1-acetyl-4-fluoro-N-[(S) or (R)-[6-fluoro-5-(propan-2- yl)pyridin-2-yl](3- methoxyphenyl)methyl]pyrrolidine- 2-carboxamide 655 [00816] embedded image (2S,4R)-N-[(S)-[3- (acetamidomethyl)phenyl][6- fluoro-5-(propan-2-yl)pyridin-2- yl]methyl]-4-fluoro-1-[2-(1H-1,2,3- triazol-5-yl)acetyl]pyrrolidine-2- carboxamide 656 [00817] (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2-yl](3- {[(methylcarbamoyl)amino]methyl} phenyl)methyl]-1-[2-(1H-1,2,3- triazol-5-yl)acetyl]pyrrolidine-2- carboxamide 657 [00818] embedded image (2S,4R)-N-[(S) or (R)-(5- cyclopropyl-6-fluoropyridin-2- yl)(2-fluorophenyl)methyl]-1-{2- [5-(difluoromethyl)-1H-1,2,3,4- tetrazol-1-yl]acetyl}-4- fluoropyrroldine-2-carboxamide 658 [00819] (2S,4R)-N-[(S) or (R)-(5- cyclopropyl-6-fluoropyridin-2- yl)(4-fluorophenyl)methyl]-1-{2- [5-(difluoromethyl)-1H-1,2,3,4- tetrazol-1-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 659 [00820] embedded image (2S,4R)-1-(((1H-1,2,3-triazol-5- yl)methyl)sulfonyl)-N-((S)-(3,5- difluoro-4- isopropylphenyl)(phenyl)methyl)- 4-fluoropyrrolidine-2-carboxamide 660 [00821] (2S,4R)-1-acetyl-N-[(S) or (R)-(4- cyclobutyl-3- fluorophenyl)(phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide 661 [00822] (2S,4R)-N-[(S) or (R)-[3,5- difluoro-4-(propan-2- yl)(phenyl](phenyl)methyl]-4- fluoro-1-[2-(1,3-oxazol-2- yl)acetyl]pyrrolidine-2- carboxamide 662 [00823] embedded image (2S,4R)-N-[(S)-(4-cyclopropyl-3,5- difluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1,3-oxazol-2- yl)acetyl]pyrrolidine-2- carboxamide 663 [00824] (2S,4R)-4-fluoro-N-[(S)-[2-methyl- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (1,3-oxazol-2-yl)acetyl]pyrrolidine- 2-carboxamide 664 [00825] embedded image (2S,4R)-N-[(S)-(3-chloro-4- cyclopropylphenyl](phenyl)methyl]- 4-fluoro-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 665 [00826] (2S,4R)-N-[(S)-(4-cyclopropyl-3- methylphenyl](phenyl)methyl]-4- fluoro-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 666 [00827] embedded image (2S,4R)-N-[(R) or (S)-[3,5- difluoro-4-(propan-2- yl)phenyl](phenyl)methyl]-4- fluoro-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 667 [00828] (2S,4R)-N-[(S) or (R)-[3,5- difluoro-4-(propan-2- yl)phenyl](phenyl)methyl]-4- fluoro-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 668 [00829] embedded image (2S,4R)-N-[(S) or (R)-[3,5- difluoro-4-(propan-2- yl)phenyl](phenyl)methyl]-4- fluoro-1-[2-(1H-1,2,3-triazol-1- yl)acetyl]pyrrolidine-2- carboxamide 669 [00830] (2S,4R)-N-[(S)-[3,5-difluoro-4- (propan-2- yl)phenyl](phenyl)methyl]-4- fluoro-1-[2-(1H-1,2,3-tetrazol-1- yl)acetyl]pyrrolidine-2- carboxamide 670 [00831] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-methyl- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 671 [00832] (2S,4R)-N-[(R)-[3-chloro-4- (propan-2- yl)phenyl](phenyl)methyl]-4- fluoro-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 672 [00833] embedded image (2S,4R)-N-[(S)-[3-chloro-4- (propan-2- yl)phenyl](phenyl)methyl]-4- fluoro-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 673 [00834] (2S,4R)-N-[(R) or (S)-(4- cyclobutyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 674 [00835] embedded image (2S,4R)-N-[(S) or (R)-(4- cyclobutyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 675 [00836] (2S,4R)-N-[(S) or (R)-(4- cyclobutyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1H-1,2,3,4-tetrazol-1- yl)acetyl]pyrrolidine-2- carboxamide 676 [00837] embedded image (2S,4R)-N-[(R) or (S)-{4-[(2R) or (2S)-butan-2-yl]-3- fluorophenyl}(phenyl)methyl]-4- fluoro-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 677 [00838] (2S,4R)-N-[(S) or (R)-{4-[(2R) or (2S)-butan-2-yl]-3- fluorophenyl}(phenyl)methyl]-4- fluoro-1-(2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 678 [00839] embedded image (2S,4R)-4-fluoro-N-[(R) or (S)-[3- fluoro-5-methyl-4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 679 [00840] (2S,4R)-N-[(S)-[3- (difluoromethyl)-4-(propan-2- yl)phenyl](phenyl)methyl]-4- fluoro-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 680 [00841] embedded image (2S,4R)-4-fluoro-N-[(S) or (R)-[3- fluoro-5-methyl-4-(propan-2- yl)phenyl](phenyl)methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 681 [00842] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(1- methylcyclobutyl)phenyl](phenyl) methyl]-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 682 [00843] embedded image (2S,4R)-N-[(S) or (R)-(4- cyclopropyl-3-fluoro-5- methylphenyl)(phenyl)methyl]-4- fluoro-1-[2-(5-methyl-2H-1,2,3- tetrazol-2-yl)acetyl]pyrrolidine-2- carboxamide 683 [00844] (2S,4R)-4-fluoro-N-[(S) or (R)- phenyl[4-(propan-2-yl)-3- (trifluoromethyl)phenyl)methyl]-1- [2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 684 [00845] embedded image (2S,4R)-4-fluoro-N-[(R)-[3-fluoro- 4-(1- methylcyclobutyl)phenyl](phenyl) methyl]-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 685 [00846] (2S,4R)-N-[(S)-(4-tert-butyl-3- fluorophenyl)(phenyl)methyl]-4- fluoro-1-[2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 686 [00847] embedded image (2S,4R)-1-(2-(1H-1,2,3-triazol-5- yl)acetyl)-N-((S)-(3-(1H-pyrazol-5- yl)phenyl)(6-fluoro-5- isopropylpyridin-2-yl)methyl)-4- fluoropyrrolidine-2-carboxamide 687 [00848] (2S,4R)-1-(2-(1H-1,2,3-triazol-5- yl)acetyl)-N-((R)-(3-(1H-pyrazol-5- yl)phenyl)(6-fluoro-5- isopropylpyridin-2-yl)methyl)-4- fluoropyrrolidine-2-carboxamide 688 [00849] embedded image (2S,4R)-N-((S) or (R)-(3-(4H-1,2,4- triazol-3-yl)phenyl)(6-fluoro-5- isopropylpyridin-2-yl)methyl)-1- acetyl-4-fluoropyrrolidine-2- carboxamide 689 [00850] (2S,4R)-N-((R) or (S)-(3-(4H-1,2,4- triazol-3-yl)(phenyl)(6-fluoro-5- isopropylpyridin-2-yl)methyl)-1- acetyl-4-fluoropyrrolidine-2- carboxamide 690 [00851] embedded image (2S,4R)-1-acetyl-4-fluoro-N-[(S) or (R)-[6-fluoro-5-(propan-2- yl)pyridin-2-yl][3-(1H-pyrazol-5- yl)phenyl]methyl]pyrrolidine-2- carboxamide 691 [00852] (2S,4R)-1-(2-acetamidoacetyl)-4- fluoro-N-[(S) or (R)-[6-fluoro-5- (propan-2-yl)pyridin-2-yl][3-(1H- pyrazol-5- yl)phenyl]methyl]pyrrolidine-2- carboxamide 692 [00853] embedded image (2S,4R)-4-fluoro-N-[(R) or (S)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl][3-(1,3-oxazol-5- yl)phenyl]methyl]-1-[2-(1H-1,2,3- triazol-5-yl)acetyl]pyrrolidine-2- carboxamide 693 [00854] (2S,4R)-4-fluoro-N-[(S) or (R)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl][3-(1,3-oxazol-5- yl)phenyl]methyl]-1-[2-(1H-1,2,3- triazol-5-yl)acetyl]pyrrolidine-2- carboxamide 694 [00855] embedded image (2S,4R)-4-fluoro-N-[(S) or (R)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl][3-(1,2-oxazol-5- yl)phenyl]methyl]-1-[2-(1H-1,2,3- triazol-5-yl)acetyl]pyrrolidine-2- carboxamide 695 [00856] (2S,4R)-1-acetyl-4-fluoro-N-[(S) or (R)-[6-fluoro-5-(propan-2- yl)pyridin-2-yl][3-(1-methyl-1H- pyrazol-5- yl)phenyl]methyl]pyrrolidine-2- carboxamide 696 [00857] embedded image (2S,4R)-1-acetyl-4-fluoro-N-[(S) or (R)-[6-fluoro-5-(propan-2-yl) pyridin-2-yl][3-(3-methyl-1H- pyrazol-5- yl)phenyl]methyl]pyrrolidine-2- carboxamide 697 [00858] (2S,4R)-1-acetyl-N-[(S) or (R)-[3- (1,3-dimethyl-1H-pyrazol-5- yl)phenyl][6-fluoro-5-(propan-2- yl)pyridin-2-yl]methyl]-4- fluoropyrrolidine-2-carboxamide 698 [00859] embedded image (2S,4R)-1-acetyl-4-fluoro-N-[(S) or (R)-[6-fluoro-5-(propan-2- yl)pyridin-2-yl][3-(1,2-oxazol-5- yl)phenyl]methyl]pyrrolidine-2- carboxamide 699 [00860] (2S,4R)-1-acetyl-4-fluoro-N-[(S) or (R)-[6-fluoro-5-(propan-2- yl)pyridin-2-yl][3-(1H-pyrazol-1- yl)phenyl]methyl]pyrrolidine-2- carboxamide 700 [00861] embedded image (2S,4R)-1-acetyl-4-fluoro-N-[(S) or (R)-[6-fluoro-5-(propan-2- yl)pyridin-2-yl][3-(1,3,4-oxadiazol- 2-yl)phenyl]methyl]pyrrolidine-2- carboxamide 701 [00862] (2S)-1-(oct-7-ynoyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 702 [00863] (2S,4R)-4-fluoro-1-(1-methyl-1H- indazole-5-carbonyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 703 [00864] embedded image (2S,4R)-4-fluoro-1-[2-(4- methoxyphenyl)cyclopropane- carbonyl]-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 704 [00865] (2S,4R)-4-fluoro-1-(7-oxo-5,6,7,8- tetrahydro-1,8-naphthyridine-2- carbonyl)-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 705 [00866] embedded image (2S,4R)-4-fluoro-1-[2-(2- methylpropoxy)pyridine-4- carbonyl]-N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 707 [00867] (2S,4R)-4-fluoro-1-[4-(1H- imidazol-1-yl)pyridine-2-carbonyl]- N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 708 [00868] embedded image (2S,4R)-4-fluoro-N-[(S)-phenyl[4- (propan-2-yl)phenyl]methyl]-1- {[(pyridin-3- yl)carbamoyl]carbonyl}pyrrolidine- 2-carboxamide 709 [00869] (2S,4R)-4-fluoro-1-(5-methoxy-1- methyl-1H-pyrazole-3-carbonyl)- N-[(S)-phenyl[4-(propan-2- yl)phenyl]methyl]pyrrolidine-2- carboxamide 710 [00870] embedded image (2S,4R)-1-[2-(1,4-dimethyl-5-oxo- 4,5-dihydro-1H-1,2,4-triazol-3- yl)acetyl]-4-fluoro-N-[(S)- phenyl[5-(propan-2-yl)pyridin-2- yl]methyl]pyrrolidine-2- carboxamide 711 [00871] (2S,4R)-1-{2-[4-(azetidin-1-yl)-1H- 1,2,3-triazol-1-yl]acetyl}-4-fluoro- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 712 [00872] embedded image (2S,4R)-4-fluoro-1-[2-(5-methoxy- 1-methyl-1H-1,2,4-triazol-3- yl)acetyl]-N-[(S)-phenyl[5-(propan- 2-yl)pyridin-2- yl]methyl]pyrrolidine-2- carboxamide 713 [00873] (2S,4R)-1-{2-[5-(diethylamino)- 1H-1,2,3-triazol-1-yl]acetyl}-4- fluoro-N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 714 [00874] embedded image (2S,4R)-1-{2-[5-(3,3- difluoroazetidin-1-yl)-1H-1,2,3- triazol-1-yl]acetyl}-4-fluoro-N- [(S)-phenyl[5-(propan-2-yl)pyridin- 2-yl]methyl]pyrrolidine-2- carboxamide 715 [00875] (2S,4R)-1-{2-[5-(azetidin-1-yl)-1H- 1,2,3-triazol-1-yl]acetyl}-4-fluoro- N-[(S)-phenyl[5-(propan-2- yl)pyridin-2-yl]methyl]pyrrolidine- 2-carboxamide 716 [00876] embedded image (2S,4R)-1-[2-(1H-1,3-benzodiazol- 1-yl)acetyl]-N-[(R)-(5-cyclopropyl- 6-fluoropyridin-2- yl)(phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide 717 [00877] (2S,4R)-N-[(R)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-{2-[4-(dimethylamino)-2H-1,2,3- triazol-2-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 718 [00878] embedded image (2S,4R)-N-[(R)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-(2-{3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyridin-8- yl}acetyl)pyrrolidine-2- carboxamide 719 [00879] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-[2-(4-methyl-5-oxo-4,5- dihydro-1,2,4-oxadiazol-3- yl)acetyl]pyrrolidine-2- carboxamide 720 [00880] embedded image (2S,4R)-N-[(R)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-{2-[(2-methylpyrimidin- 4-yl)amino]acetyl}pyrrolidine-2- carboxamide 721 [00881] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-{2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 722 [00882] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-[2-(1,4-dimethyl-5-oxo-4,5- dihydro-1H-1,2,4-triazol-3- yl)acetyl]-4-fluoropyrrolidine-2- carboxamide 723 [00883] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-[2-(1H-pyrazol-1- yl)acetyl]pyrrolidine-2- carboxamide 724 [00884] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-[2-(5-methyl-1H- pyrazol-1-yl)acetyl]pyrrolidine-2- carboxamide 725 [00885] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-{2-[5-(difluoromethyl)-1H- pyrazol-1-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 726 [00886] embedded image (2S,4R)-1-{2-[4-(azetidin-1-yl)-1H- 1,2,3-triazol-1-yl]acetyl}-N-[(S)-(5- cyclopropyl-6-fluoropyridin-2- yl)(phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide 727 [00887] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-[2-(2,4-dioxo-1,2,3,4- tetrahydropyrimidin-1-yl)acetyl]-4- fluoropyrrolidine-2-carboxamide 728 [00888] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-{2-[4-(trifluoromethyl)- 1H-pyrazol-1-yl]acetyl}pyrrolidine- 2-carboxamide 729 [00889] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-{2-[3-(difluoromethyl)-1H- pyrazol-1-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 730 [00890] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-{2-[3-(trifluoromethyl)- 1H-pyrazol-1-yl]acetyl}pyrrolidine- 2-carboxamide 731 [00891] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-[2-(2-oxo-1,2- dihydropyridin-3- yl)acetyl]pyrrolidine-2- carboxamide 732 [00892] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl)- 4-fluoro-1-[2-(5-methyl-6-oxo-1,6- dihydropyridin-3- yl)aceyl]pyrrolidine-2- carboxamide 733 [00893] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-[2-(3-ethyl-5-methyl-2,4-dioxo- 1,2,3,4-tetrahydropyrimidin-1- yl)acetyl]-4-fluoropyrrolidine-2- carboxamide 734 [00894] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-[2-(6-oxo-1,6- dihydropyridin-3- yl)acetyl]pyrrolidine-2- carboxamide 735 [00895] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-[2-(3-ethyl-2,4-dioxo-1,2,3,4- tetrahydropyrimidin-1-yl)acetyl]-4- fluoropyrrolidine-2-carboxamide 736 [00896] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-[2-(1-ethyl-6-oxo-1,6- dihydropyridin-3-yl)acetyl]-4- fluoropyrrolidine-2-carboxamide 737 [00897] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-[2-(6-ethoxy-5-methylpyridin-3- yl)acetyl]-4-fluoropyrrolidine-2- carboxamide 738 [00898] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-{2-[4-(trifluoromethyl)- 1,3-oxazol-2-yl]acetyl}pyrrolidine- 2-carboxamide 739 [00899] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-[2-(1-ethyl-5-methyl-6-oxo-1,6- dihydropyridin-3-yl)acetyl]-4- fluoropyrrolidine-2-carboxamide 740 [00900] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-[2-(1-ethyl-5-methyl-2-oxo-1,2- dihydropyridin-3-yl)acetyl]-4- fluoropyrrolidine-2-carboxamide 741 [00901] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-[2-(1-ethyl-2-oxo-1,2- dihydropyridin-3-yl)acetyl]-4- fluoropyrrolidine-2-carboxamide 742 [00902] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-[2-(4-ethyl-5-oxo-4,5- dihydropyrazin-2-yl)acetyl]-4- fluoropyrrolidine-2-carboxamide 743 [00903] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-[2-(5-methoxy-1- methyl-1H-1,2,4-triazol-3- yl)acetyl]pyrrolidine-2- carboxamide 744 [00904] embedded image (2S,4R)-1-(2- {[benzyl(trifluoromethyl)carbamoyl] amino}acetyl)-N-[(S)-(5- cyclopropyl-6-fluoropyridin-2- yl)(phenyl)methyl]-4- fluoropyrroldine-2-carboxamide 745 [00905] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-{2-[5-(trifluoromethyl)- 1H-1,2,3-triazol-1- yl]acetyl}pyrrolidine-2- carboxamide 746 [00906] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-[2-(5-oxo-4,5- dihydropyrazin-2- yl)acetyl]pyrrolidine-2- carboxamide 747 [00907] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-{2-[5-(difluoromethyl)-1H-1,2,3- triazol-1-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 748 [00908] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-{2-[5-(diethylamino)-1H-1,2,3- triazol-1-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 749 [00909] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-{2-[3-(difluoromethyl)-1-methyl- 1H-pyrazol-4-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 750 [00910] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)phenyl)methyl]- 1-{2-[5-(difluoromethyl)-3-methyl- 1H-pyrazol-1-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 751 [00911] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-{2-[5-(difluoromethyl)-1-methyl- 1H-pyrazol-4-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 752 [00912] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-{2-[3-(difluoromethyl)-5-methyl- 1H-pyrazol-1-yl]aceetyl}-4- fluoropyrrolidine-2-carboxamide 753 [00913] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-[2-(4-ethyl-3-oxo-3,4- dihydropyrazin-2-yl)acetyl]-4- fluoropyrrolidine-2-carboxamide 754 [00914] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-{2-[4-(difluoromethyl)-1-methyl- 1H-pyrazol-5-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 755 [00915] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-{2-[5-(trifluoromethyl)- 1H-1,2,3,4-tetrazol-1- yl]acetyl}pyrrolidine-2- carboxamide 756 [00916] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-{2-[4-(difluoromethyl)-1H-1,2,3- triazol-5-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 757 [00917] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-{2-[4-(difluoromethyl)-1-methyl- 1H-pyrazol-3-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 758 [00918] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-{2-[5-(3,3-difluoroazetidin-1-yl)- 1H-1,2,3-triazol-1-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 759 [00919] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-{2-[3-(difluoromethyl)-4H-1,2,4- triazol-4-yl]acetyl}-4- fluoropyrrolidine-2-carboxamide 760 [00920] embedded image (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 4-fluoro-1-{2-[5-(trifluoromethyl)- 1H-pyrazol-1-yl]acetyl}pyrrolidine- 2-carboxamide 761 [00921] (2S,4R)-N-[(S)-(5-cyclopropyl-6- fluoropyridin-2-yl)(phenyl)methyl]- 1-[2-(4,5-dimethyl-1,3-oxazol-2- yl)acetyl]-4-fluoropyrrolidine-2- carboxamide 762 [00922] embedded image (2S,4R)-1-{2-[5-(azetidin-1-yl)-1H- 1,2,3-triazol-1-yl]acetyl}-N-[(S)-(5- cyclopropyl-6-fluoropyridin-2- yl)(phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide 763 [00923] (2S,3R,4R)-N-[(S)-(5-cyclopropyl- 6-fluoropyridin-2- yl)(phenyl)methyl]-1-{2-[5- (difluoromethyl)-1H-1,2,3,4- tetrazol-1-yl]acetyl}-4-fluoro-3- hydroxypyrrolidine-2-carboxamide 764 [00924] embedded image (2S,3S,4S)-N-[(S)-(5-cyclopropyl- 6-fluoropyridin-2- yl)(phenyl)methyl]-1-{2-[5- (difluoromethyl)-1H-1,2,3,4- tetrazol-1-yl]acetyl}-4-fluoro-3- hydroxypyrrolidine-2-carboxamide 765 [00925] (2S,4R)-1-[(2S)-3-carbamoyl-2- acetamidopropanoyl]-4-fluoro-N- [(S)-[3-fluoro-4-(propan-2- yl)phenyl](phenyl)methyl] pyrrolidine-2-carboxamide 766 [00926] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[(2R) or (2S)-2-(1H-1,2,3,4-tetrazol-1- yl)propanoyl]pyrroldine-2- carboxamide 767 [00927] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-[(2S)- or (2R)-2-(1H-1,2,3,4-tetrazol-1- yl)propanoyl]pyrrolidine-2- carboxamide 768 [00928] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[(2R) or (2S)-2-(1H-imidazol-1- yl)propanoyl]pyrrolidine-2- carboxamide 769 [00929] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[(2R) or (2S)-2-(1H-1,2,3-triazol-5- yl)propanoyl]pyrrolidine-2- carboxamide 770 [00930] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[(2S) or (2R)-2-(1H-1,2,3-triazol-5- ylpropanoyl]pyrrolidine-2- carboxamide 771 [00931] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[(2S)- or (2R)-2-(1H-imidazol-1- yl)propanoyl]pyrrolidine-2- carboxamide 772 [00932] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[(1H- 1,2,3-triazol-5- yl)methanesulfonyl]pyrrolidine-2- carboxamide 773 [00933] (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[(2R)- or (2S)-2-hydroxy-2-(1H-1,2,3- triazol-5-yl)acetyl]pyrrolidine-2- carboxamide 774 [00934] embedded image (2S,4R)-4-fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl]-1-[(2S) or (2R)-2-hydroxy-2-(1H-1,2,3- triazol-5-yl)acetyl]pyrrolidine-2- carboxamide 775 [00935] (2S,4R)-1-{2-[4-(dimethylamino)- 1H-1,2,3-triazol-5-yl]acetyl}-4- fluoro-N-[(S)-[3-fluoro-4-(propan- 2- yl)phenyl](phenyl)methyl] pyrrolidine-2-carboxamide 776 [00936] embedded image (2S,4R)-4-fluoro-N-[(R*)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(1H-1,2,3- triazol-5-yl)acetyl]pyrroldine-2- carboxamide 777 [00937] (2S,4R)-1-[2-(3,5-dimethyl-2,4- dioxo-1,2,3,4-tetrahydropyrimidin- 1-yl)acetyl]-4-fluoro-N-[(R*)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 778 [00938] embedded image (2S,4R)-4-fluoro-N-[(R*)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(5-methyl- 2,4-dioxo-1,2,3,4- tetrahydropyrimidin-1- yl)acetyl]pyrrolidine-2- carboxamide 779 [00939] (2S,4R)-1-[2-(1,4-dimethyl-5-oxo- 4,5-dihydro-1H-1,2,4-triazol-3- yl)acetyl]-4-fluoro-N-[(S)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 780 [00940] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-(3-{3-oxo- 2H,3H-[1,2,4]triazolo[4,3- a]pyridin-2- yl}propanoyl)pyrrolidine-2- carboxamide 781 [00941] (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(1H- pyrazol-1-yl)acetyl]pyrrolidine-2- carboxamide 782 [00942] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(5-methyl- 1H-pyrazol-1-yl)acetyl]pyrrolidine- 2-carboxamide 783 [00943] (2S,4R)-1-{2-[5-(difluoromethyl)- 1H-pyrazol-1-yl]acetyl}-4-fluoro- N-[(S)-[6-fluoro-5-(propan-2- yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 784 [00944] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(5-methyl- 6-oxo-1,6-dihydropyridin-3- yl)acetyl]pyrrolidine-2- carboxamide 785 [00945] (2S,4R)-1-[2-(2,4-dioxo-1,2,3,4- tetrahydropyrimidin-1-yl)acetyl]-4- fluoro-N-[(S)-[6-fluoro-5-(propan- 2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 786 [00946] embedded image (2S,4R)-1-[2-(3-ethyl-2,4-dioxo- 1,2,3,4-tetrahydropyrimidin-1- yl)acetyl-4-fluoro-N-[(S)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 787 [00947] (2S,4R)-1-{2-[4-(azetidin-1-yl)-1H- 1,2,3-triazol-1-yl]acetyl}-4-fluoro- N-[(S)-[6-fluoro-5-(propan-2- yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 788 [00948] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-{2-[4- (trifluoromethyl)-1H-pyrazol-1- yl]acetyl}pyrrolidine-2- carboxamide 789 [00949] (2S,4R)-1-{2-[3-(difluoromethyl)- 1H-pyrazol-1-yl]acetyl}-4-fluoro- N-[(S)-[6-fluoro-5-(propan-2- yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 790 [00950] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-{2-[3- (trifluoromethyl)-1H-pyrazol-1- yl]acetyl}pyrrolidine-2- carboxamide 791 [00951] (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(6-oxo- 1,6-dihydropyridin-3- yl)acetyl]pyrrolidine-2- carboxamide 792 [00952] embedded image (2S,4R)-1-[2-(1-ethyl-6-oxo-1,6- dihydropyridin-3-yl)acetyl]-4- fluoro-N-[(S)-[6-fluoro-5-(propan- 2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 793 [00953] (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(2-oxo- 1,2-dihydropyridin-3- yl)acetyl]pyrrolidine-2- carboxamide 794 [00954] embedded image (2S,4R)-1-[2-(3-ethyl-5-methyl- 2,4-dioxo-1,2,3,4- tetrahydropyrimidin-1-yl)acetyl]-4- fluoro-N-[(S)-[6-fluoro-5-(propan- 2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 795 [00955] (2S,4R)-1-[2-(1-ethyl-2-oxo-1,2- dihydropyridin-3-yl)acetyl]-4- fluoro-N-[(S)-[6-fluoro-5-(propan- 2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 796 [00956] embedded image (2S,4R)-1-[2-(1-ethyl-5-methyl-6- oxo-1,6-dihydropyridin-3- yl)acetyl]-4-fluoro-N-[(S)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 797 [00957] (2S,4R)-1-[2-(4-ethyl-5-oxo-4,5- dihydropyrazin-2-yl)acetyl]-4- fluoro-N-[(S)-[6-fluoro-5-(propan- 2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 798 [00958] embedded image (2S,4R)-1-[2-(6-ethoxy-5- methylpyridin-3-yl)acetyl]-4- fluoro-N-[(S)-[6-fluoro-5-(propan- 2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 799 [00959] (2S,4R)-1-[2-(1-ethyl-5-methyl-2- oxo-1,2-dihydropyridin-3- yl)acetyl]-4-fluoro-N-[(S)-[6- fluoro-5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 800 [00960] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(5- methoxy-1-methyl-1H-1,2,4- triazol-3-yl)acetyl]pyrrolidine-2- carboxamide 801 [00961] (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-{2-[4- (trifluoromethyl)-1,3-oxazol-2- yl]acetyl}pyrrolidine-2- carboxamide 802 [00962] embedded image (2S,4R)-4-fluoro-N-[(S)-[6-fluoro- 5-(propan-2-yl)pyridin-2- yl](phenyl)methyl]-1-[2-(5-oxo- 4,5-dihydropyrazin-2- yl)acetyl]pyrrolidine-2- carboxamide 803 [00963] (2S,4R)-1-{2-[5-(difluoromethyl)- 3-methyl-1H-pyrazol-1-yl]acetyl}- 4-fluoro-N-[(S)-[6-fluoro-5- (propan-2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 804 [00964] embedded image (2S,4R)-1-{2-[3-(difluoromethyl)- 5-methyl-1H-pyrazol-1-yl]acetyl}- 4-fluoro-N-[(S)-[6-fluoro-5- (propan-2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 805 [00965] (2S,4R)-1-{2-[5-(diethylamino)- 1H-1,2,3-triazol-1-yl]acetyl}-4- fluoro-N-[(S)-[6-fluoro-5-(propan- 2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 806 [00966] embedded image (2S,4R)-1-[2-(4-ethyl-3-oxo-3,4- dihydropyrazin-2-yl)acetyl]-4- fluoro-N-[(S)-[6-fluoro-5-(propan- 2-yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 807 [00967] (2S,4R)-1-{2-[5-(3,3- difluoroazetidin-1-yl)-1H-1,2,3- triazol-1-yl]acetyl}-4-fluoro-N- [(S)-[6-fluoro-5-(propan-2- yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 808 [00968] embedded image (2S,4R)-1-{2-[5-(azetidin-1-yl)-1H- 1,2,3-triazol-1-yl]acetyl}-4-fluoro- N-[(S)-[6-fluoro-5-(propan-2- yl)pyridin-2- yl](phenyl)methyl]pyrrolidine-2- carboxamide 809 [00969] (2S,4R)-1-[(2S) or (2R)-2-(1H-1,3- benzodiazol-1-yl)propanoyl]-N- [(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide 810 [00970] embedded image (2S,4R)-1-[(2R) or (2S)-2-(1H-1,3- benzodiazol-1-yl)propanoyl]-N- [(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl)methyl]-4- fluoropyrrolidine-2-carboxamide

[0485] In some embodiments, provided herein is a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from the group consisting of: [0486] 1-cyclopropanecarbonyl-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0487] 1-acetyl-4-hydroxy-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0488] 1-acetyl-3-hydroxy-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0489] 1-acetyl-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0490] 1-acetyl-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0491] 1-(3-carbamoyl-2-acetamidopropanoyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0492] tert-butyl N-{2-oxo-2-[2-({phenyl[4-(propan-2-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]ethyl}carbamate; [0493] 1-(2-hydroxyacetyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0494] 1-(2-acetamidoacetyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0495] 1-acetyl-N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; [0496] 1-(3-carbamoylpropanoyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0497] 1-acetyl-N-[(5-cyclopropylpyridin-2-yl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; [0498] 2-acetyl-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-2-azabicyclo[3.1.0]hexane-3-carboxamide; [0499] 1-{2-[N-(carbamoylmethyl)acetamido]acetyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0500] 1-acetyl-5-methyl-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0501] 1-[2-(1,3-oxazol-2-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0502] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(4H-1,2,4-triazol-3-yl)acetyl]pyrrolidine-2-carboxamide; [0503] 4-fluoro-1-{2-[(3-methyloxetan-3-yl)amino]acetyl}-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0504] 4-acetamido-5-[4-fluoro-2-({phenyl[4-(propan-2-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-5-oxopentanoic acid; [0505] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0506] 1-(3-acetamidopropanoyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0507] 4-fluoro-1-[2-(2-oxopyrrolidin-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0508] 4-fluoro-1-[2-(1,3-oxazol-5-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0509] 1-(4-acetamidobutanoyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0510] 2-acetyl-N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide; [0511] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-(2-acetamidoacetyl)pyrrolidine-2-carboxamide; [0512] 3-acetyl-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-3-azabicyclo[3.1.0]hexane-2-carboxamide; [0513] 4-fluoro-1-[2-(2-oxo-1,3-oxazolidin-3-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0514] 4-fluoro-1-[2-(oxetan-3-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0515] 4-fluoro-1-[2-(3-oxomorpholin-4-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0516] 1-acetyl-N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-5-methylpyrrolidine-2-carboxamide; [0517] 4-fluoro-1-[2-(1-methyl-1H-pyrazol-5-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0518] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-pyrazol-1-yl)acetyl]pyrrolidine-2-carboxamide; [0519] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(3-oxomorpholin-4-yl)acetyl]pyrrolidine-2-carboxamide; [0520] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-4H-1,2,4-triazol-3-yl)acetyl]pyrrolidine-2-carboxamide; [0521] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[3-(1,3-oxazol-2-yl)propanoyl]pyrrolidine-2-carboxamide; [0522] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3,4-tetrazol-1-yl)acetyl]pyrrolidine-2-carboxamide; [0523] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(2-oxo-1,3-oxazolidin-3-yl)acetyl]pyrrolidine-2-carboxamide; [0524] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-pyrazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0525] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3,4-tetrazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0526] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1,2-oxazol-3-yl)acetyl]pyrrolidine-2-carboxamide; [0527] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-pyrazol-1-yl)acetyl]pyrrolidine-2-carboxamide; [0528] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-1,2,3-triazol-1-yl)acetyl]pyrrolidine-2-carboxamide; [0529] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(2H-1,2,3,4-tetrazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0530] 4-fluoro-1-[2-(1,3,4-oxadiazol-2-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0531] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-pyrazol-4-yl)acetyl]pyrrolidine-2-carboxamide; [0532] 4-fluoro-1-{2-[(1,3-oxazol-2-yl)amino]acetyl}-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0533] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(3-methyl-2-oxoimidazolidin-1-yl)acetyl]pyrrolidine-2-carboxamide; [0534] 1-[2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)acetyl]-N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; [0535] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-{2-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]acetyl}pyrrolidine-2-carboxamide; [0536] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0537] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-{2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide; [0538] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[3-(1H-1,2,4-triazol-1-yl)propanoyl]pyrrolidine-2-carboxamide; [0539] 4-fluoro-1-[2-(1-methyl-1H-pyrazol-4-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0540] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-1,2,3,4-tetrazol-1-yl)acetyl]pyrrolidine-2-carboxamide; [0541] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyridazin-3-yloxy)acetyl]pyrrolidine-2-carboxamide; [0542] 4-fluoro-1-(1-methyl-5-oxopyrrolidine-2-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0543] 1-[2-(2-chloro-5-fluorophenyl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0544] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[4-(pyridin-3-yl)butanoyl]pyrrolidine-2-carboxamide; [0545] 4-fluoro-1-(3-oxo-octahydroindolizine-6-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0546] 4-fluoro-1-(2-oxopiperidine-4-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0547] 1-[2-(2-cyano-4-methoxyphenyl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0548] 4-fluoro-1-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl}-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0549] 4-fluoro-1-[4-(1H-imidazol-1-yl)butanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0550] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyrimidin-5-yl)acetyl]pyrrolidine-2-carboxamide; [0551] 4-fluoro-1-(4-methylpyrimidine-5-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0552] 4-fluoro-1-[2-(2-oxo-1,2-dihydropyridin-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0553] 1-[3-(3,5-dimethyl-1,2-oxazol-4-yl)propanoyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0554] 4-fluoro-1-[2-(3-fluoro-4-methoxyphenyl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0555] 4-fluoro-1-(1,3-oxazole-5-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0556] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[4-(pyridin-4-yl)butanoyl]pyrrolidine-2-carboxamide; [0557] 1-[(dimethylcarbamoyl)carbonyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0558] 4-fluoro-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0559] 4-fluoro-1-[2-(1H-imidazol-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0560] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-pyrazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0561] 4-fluoro-1-[2-methyl-3-(1H-1,2,4-triazol-1-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0562] 4-fluoro-1-[2-(5-fluoropyridin-2-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0563] 4-fluoro-1-[2-(5-methyl-1H-indol-3-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0564] 1-[2-(4-acetamidophenyl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0565] 4-fluoro-1-[2-(1H-imidazol-4-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0566] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[3-(pyridin-3-yl)propanoyl]pyrrolidine-2-carboxamide; [0567] 4-fluoro-1-[2-(4-methoxyphenyl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0568] 1-[2-(1,5-dimethyl-1H-pyrazol-3-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0569] 4-fluoro-1-[3-(2-methylpyridin-3-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0570] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyrimidin-2-yl)acetyl]pyrrolidine-2-carboxamide; [0571] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[3-(pyrazin-2-yl)propanoyl]pyrrolidine-2-carboxamide; [0572] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(2H-1,2,3-triazol-2-yl)acetyl]pyrrolidine-2-carboxamide; [0573] 1-[3-(2,6-dimethylpyridin-3-yl)propanoyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0574] 1-[2-(1H-1,2,3-benzotriazol-1-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0575] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)acetyl]pyrrolidine-2-carboxamide; [0576] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyridin-3-yloxy)acetyl]pyrrolidine-2-carboxamide; [0577] 4-fluoro-1-[3-(1H-imidazol-5-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0578] 4-fluoro-1-[3-(5-methyl-1,3,4-thiadiazol-2-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0579] 1-[3-(3,5-dimethyl-1H-pyrazol-1-yl)propanoyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0580] 1-(3-cyanopropanoyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0581] 1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0582] 4-fluoro-1-[2-(5-methyl-1,2,4-oxadiazol-3-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0583] 4-fluoro-1-[2-(1-methyl-1H-indol-2-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0584] 4-fluoro-1-[3-(5-methylpyridin-2-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0585] 1-(2-ethyl-1,3-oxazole-4-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0586] 4-fluoro-1-[2-(2-methyl-1,3-thiazol-4-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0587] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyrazin-2-yl)acetyl]pyrrolidine-2-carboxamide; [0588] 4-fluoro-1-[2-methyl-3-(1H-pyrazol-1-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0589] 4-fluoro-1-[3-(1H-indol-3-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0590] 4-fluoro-1-[2-methyl-3-(pyridin-4-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0591] 4-fluoro-1-[2-(4-fluoro-1H-indol-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0592] 4-fluoro-1-{4-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-a][1,4]diazepine-2-carbonyl}-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0593] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-{2-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]acetyl}pyrrolidine-2-carboxamide; [0594] 4-fluoro-1-(6-oxopiperidine-3-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0595] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyrrolidine-1-sulfonyl)acetyl]pyrrolidine-2-carboxamide; [0596] 1-[2-(1,2-benzoxazol-3-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0597] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-(2-{[1,2,4]triazolo[1,5-a]pyridin-6-yl}acetyl)pyrrolidine-2-carboxamide; [0598] 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0599] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-pyrazol-1-yl)propanoyl]pyrrolidine-2-carboxamide; [0600] 4-fluoro-1-[3-(3-methoxypyridin-2-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0601] 4-fluoro-1-[2-(1H-imidazol-1-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0602] 1-[2-(3,5-dimethyl-1,2-oxazol-4-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0603] 4-fluoro-1-[2-(1-methyl-1H-pyrazol-3-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0604] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[3-(1H-1,2,3-triazol-1-yl)propanoyl]pyrrolidine-2-carboxamide; [0605] 4-fluoro-1-[3-(1H-imidazol-2-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0606] 4-fluoro-1-[2-(2-methylphenoxy)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0607] 4-fluoro-1-[2-(3-methyl-1,2-oxazol-5-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0608] 4-fluoro-1-(3-methyloxetane-3-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0609] 1-[2-(4-chloro-1H-pyrazol-1-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0610] 1-(1-ethyl-1H-pyrazole-5-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0611] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyridin-2-yl)propanoyl]pyrrolidine-2-carboxamide; [0612] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[3-(pyrimidin-5-yl)propanoyl]pyrrolidine-2-carboxamide; [0613] 4-fluoro-1-(3-methoxy-1-methyl-1H-pyrazole-4-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0614] 4-fluoro-1-[2-(5-methyl-1,3,4-oxadiazol-2-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0615] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[3-(1H-pyrazol-4-yl)propanoyl]pyrrolidine-2-carboxamide; [0616] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1,3-thiazol-4-yl)acetyl]pyrrolidine-2-carboxamide; [0617] 4-fluoro-1-[4-(2-methyl-1H-imidazol-1-yl)butanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0618] 4-fluoro-1-(2-{imidazo[1,2-a]pyridin-3-yl}acetyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0619] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[3-(pyridin-2-yl)propanoyl]pyrrolidine-2-carboxamide; [0620] 4-fluoro-1-[2-(3-methyl-1,2,4-oxadiazol-5-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0621] 1-[2-(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0622] 4-fluoro-1-[3-(6-methylpyridin-3-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0623] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-(3-{1H-pyrrolo[2,3-b]pyridin-3-yl}propanoyl)pyrrolidine-2-carboxamide; [0624] 4-fluoro-1-(2-oxo-1,3-oxazolidine-5-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0625] 4-fluoro-1-[2-(4-methyl-1H-pyrazol-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0626] 4-fluoro-1-[3-(1-methyl-1H-pyrazol-4-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0627] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-1,2,4-triazol-1-yl)acetyl]pyrrolidine-2-carboxamide; [0628] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[5-(pyridin-4-yl)-1H-pyrazole-3-carbonyl]pyrrolidine-2-carboxamide; [0629] 4-fluoro-1-[3-(2-methylpyridin-4-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0630] 4-fluoro-1-(2-hydroxy-3-methylbutanoyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0631] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-(3-{1H-pyrrolo[2,3-b]pyridin-5-yl}propanoyl)pyrrolidine-2-carboxamide; [0632] 4-fluoro-1-[4-oxo-4-(pyrrolidin-1-yl)butanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0633] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(quinolin-6-yl)acetyl]pyrrolidine-2-carboxamide; [0634] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyridin-4-yl)acetyl]pyrrolidine-2-carboxamide; [0635] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(2,2,2-trifluoroacetamido)acetyl]pyrrolidine-2-carboxamide; [0636] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyridin-3-yloxy)propanoyl]pyrrolidine-2-carboxamide; [0637] 4-fluoro-1-[2-(1H-indol-3-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0638] 1-(2-cyclopropyl-2-oxoacetyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0639] 4-fluoro-1-[2-(5-fluoro-2-methoxyphenyl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0640] 4-fluoro-1-[2-(6-methoxypyridin-2-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0641] 4-fluoro-1-[2-(2-oxo-1,2-dihydropyridin-1-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0642] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyridin-3-yl)acetyl]pyrrolidine-2-carboxamide; [0643] 1-[2-(3,5-dimethyl-1H-pyrazol-4-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0644] 1-[2-(2,5-dioxoimidazolidin-1-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0645] 1-[2-(2,5-dimethyl-1,3-thiazol-4-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0646] 4-fluoro-1-[2-methyl-3-(pyridin-2-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0647] 4-fluoro-1-[2-(2-oxo-1,2-dihydropyrazin-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0648] 4-fluoro-1-[2-(N-methylacetamido)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0649] 4-fluoro-1-[2-methyl-2-(pyridin-2-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0650] 4-fluoro-1-[2-(2-oxopiperidin-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0651] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(quinolin-5-yl)acetyl]pyrrolidine-2-carboxamide; [0652] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[3-(1H-1,2,4-triazol-1-yl)benzoyl]pyrrolidine-2-carboxamide; [0653] 4-fluoro-1-{[(2-methylpropyl)carbamoyl]carbonyl}-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0654] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-1,2,3,4-tetrazol-1-yl)propanoyl]pyrrolidine-2-carboxamide; [0655] 4-fluoro-1-(2-oxo-1,2,3,4-tetrahydroquinoline-7-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0656] 4-fluoro-1-[2-(2-methyl-1,3-thiazol-5-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0657] 4-fluoro-1-[3-(6-oxo-1,6-dihydropyridazin-3-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0658] 4-fluoro-1-[2-(4-methyl-1H-pyrazol-1-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0659] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyridin-2-yl)acetyl]pyrrolidine-2-carboxamide; [0660] 4-fluoro-1-[2-(3-methyl-1H-pyrazol-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0661] 4-fluoro-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0662] 1-(2-acetamidopyridine-4-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0663] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-pyrazol-3-yl)acetyl]pyrrolidine-2-carboxamide; [0664] N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-3-[2-(1H-1,2,3-triazol-5-yl)acetyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide; [0665] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)acetyl]pyrrolidine-2-carboxamide; [0666] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1,3,4-oxadiazol-2-yl)acetyl]pyrrolidine-2-carboxamide; [0667] 4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0668] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0669] N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-2-[2-(1H-1,2,3-triazol-5-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide; [0670] N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-5-methyl-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0671] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-(2-hydroxy-2-methylpropanoyl)pyrrolidine-2-carboxamide; [0672] 4-fluoro-1-[2-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0673] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3,4-tetrazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0674] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-2H-1,2,3,4-tetrazol-2-yl)acetyl]pyrrolidine-2-carboxamide; [0675] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-3-[2-(1H-1,2,3-triazol-5-yl)acetyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide; [0676] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-1-yl)acetyl]pyrrolidine-2-carboxamide; [0677] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3,4-tetrazol-1-yl)acetyl]pyrrolidine-2-carboxamide; [0678] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(4H-1,2,4-triazol-4-yl)acetyl]pyrrolidine-2-carboxamide; [0679] 4-fluoro-1-[2-(4-methyl-4H-1,2,4-triazol-3-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0680] 4-fluoro-1-[2-(1-methyl-1H-1,2,3-triazol-5-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0681] 4-fluoro-1-[2-(1-methyl-1H-1,2,3-triazol-4-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0682] 4-fluoro-1-[2-(1,2-oxazol-4-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0683] 4-fluoro-1-[2-(1,2-oxazol-3-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0684] 4-fluoro-1-[2-(3-methyl-1H-1,2,4-triazol-5-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0685] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1-methyl-1H-pyrazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0686] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1-methyl-1H-pyrazol-3-yl)acetyl]pyrrolidine-2-carboxamide; [0687] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1-methyl-1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0688] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(pyridin-2-yl)acetyl]pyrrolidine-2-carboxamide; [0689] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(5-methyl-1,3,4-oxadiazol-2-yl)acetyl]pyrrolidine-2-carboxamide; [0690] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(pyridin-3-yl)acetyl]pyrrolidine-2-carboxamide; [0691] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(pyrimidin-4-yl)acetyl]pyrrolidine-2-carboxamide; [0692] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(pyrimidin-5-yl)acetyl]pyrrolidine-2-carboxamide; [0693] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(pyrazin-2-yl)acetyl]pyrrolidine-2-carboxamide; [0694] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(4-methyl-2,5-dioxopiperazin-1-yl)acetyl]pyrrolidine-2-carboxamide; [0695] 1-(2-cyanoacetyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0696] 4-fluoro-1-(2-methanesulfonylacetyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0697] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-1,2,3-triazol-1-yl)propanoyl]pyrrolidine-2-carboxamide; [0698] 1-(4-acetylmorpholine-2-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0699] 1-[2-(4-acetyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0700] 1-[2-(4-acetyl-2-oxopiperazin-1-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0701] 1-(1-acetylpiperidine-4-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0702] 1-(2,3-dihydroxypropanoyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0703] 1-{8-acetyl-8-azaspiro[4.5]decane-2-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0704] 4-fluoro-1-[3-(1H-imidazol-1-yl)-2-methylpropanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0705] 1-{6-acetyl-6-azaspiro[2.5]octane-1-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0706] 1-(1-acetyl-3-methylpyrrolidine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0707] 4-fluoro-1-[2-(N-methylacetamido)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0708] 1-{2-acetyl-5-oxa-2,6-diazaspiro[3.4]oct-6-ene-7-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0709] 1-[1-acetyl-2-(pyridin-3-yl)pyrrolidine-3-carbonyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0710] 4-fluoro-1-[5-(methoxymethyl)-1,2-oxazole-4-carbonyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0711] 1-{6-acetyl-5H,6H,7H,8H-pyrido[3,4-b]pyrazine-7-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0712] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-1,2,4-triazol-1-yl)propanoyl]pyrrolidine-2-carboxamide; [0713] 1-{5-acetyl-5-azaspiro[2.4]heptane-1-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0714] 1-[3-(1-acetylpyrrolidin-2-yl)propanoyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0715] 1-{4-[(1-acetylazetidin-3-yl)oxy]benzoyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0716] 4-fluoro-1-[3-methoxy-2-(N-methylacetamido)butanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0717] 1-[2-(1-acetylpyrrolidin-2-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0718] 1-{7-acetyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0719] 1-{5-acetyl-hexahydro-1H-furo[3,4-c]pyrrole-3a-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0720] 1-(1-acetylpyrrolidine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0721] 4-fluoro-1-[2-(3-methyl-1H-pyrazol-5-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0722] 1-{5-acetyl-2-oxa-5-azabicyclo[2.2.1]heptane-1-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0723] 1-[2-(1-acetylpiperidin-4-yl)propanoyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0724] 4-fluoro-1-[2-methyl-2-(1H-1,2,4-triazol-5-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0725] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-methyl-2-(1,3,4-oxadiazol-2-yl)propanoyl]pyrrolidine-2-carboxamide; [0726] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(pyridin-4-yl)acetyl]pyrrolidine-2-carboxamide; [0727] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-(2-{imidazo[1,2-a]pyridin-3-yl}acetyl)pyrrolidine-2-carboxamide; [0728] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-imidazol-1-yl)acetyl]pyrrolidine-2-carboxamide; [0729] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)acetyl]pyrrolidine-2-carboxamide; [0730] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1,2-oxazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0731] 1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide; [0732] N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-4-[2-(1H-1,2,3-triazol-5-yl)acetyl]-4-azaspiro[2.4]heptane-5-carboxamide; [0733] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-(2-{[1,2,4]triazolo[1,5-a]pyridin-6-yl}acetyl)pyrrolidine-2-carboxamide; [0734] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(quinolin-6-yl)acetyl]pyrrolidine-2-carboxamide; [0735] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1-methyl-1H-pyrazol-4-yl)acetyl]pyrrolidine-2-carboxamide; [0736] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(piperazin-1-yl)acetyl]pyrrolidine-2-carboxamide; [0737] 1-(1-acetyl-3-methylpiperidine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0738] 1-(1-acetyl-4-methylazepane-4-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0739] 1-(1-acetylazepane-4-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0740] 1-(1-acetylpiperidine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0741] 1-(4-acetylmorpholine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0742] 1-(2-{2-acetyl-2-azaspiro[3.4]octan-5-yl}acetyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0743] 1-{2-acetyl-2-azaspiro[4.4]nonane-6-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0744] 1-{2-acetyl-2-azabicyclo[2.2.2]octane-6-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0745] 1-[2-(1-acetylpiperidin-3-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0746] 1-(4-acetyl-1,4-oxazepane-2-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0747] 1-(1-acetyl-4-methylpiperidine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0748] 1-(4-acetyl-2-methylmorpholine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0749] 1-{5-acetyl-hexahydro-2H-furo[2,3-c]pyrrole-3-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0750] 1-{3-acetyl-3-azabicyclo[3.1.0]hexane-1-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0751] 1-{2-acetyl-octahydrocyclopenta[c]pyrrole-4-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0752] 1-{8-acetyl-8-azabicyclo[3.2.1]octane-3-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0753] 1-(1-acetyl-3-methylazetidine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0754] 1-{5-acetyl-hexahydro-2H-furo[2,3-c]pyrrole-2-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0755] 1-{3-acetyl-3-azabicyclo[3.2.1]octane-8-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0756] 1-(2-acetyl-octahydro-1H-isoindole-4-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0757] 1-{7-acetyl-7-azabicyclo[2.2.1]heptane-2-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0758] 1-{2-acetyl-5-oxa-2-azaspiro[3.4]octane-7-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0759] 1-[2-(1-acetyl-3-methylazetidin-3-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0760] 1-{2-acetyl-5-oxa-2-azaspiro[3.4]octane-6-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0761] 1-(1-acetyl-2-methylpiperidine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0762] 4-fluoro-1-{3-[N-(1-methyl-1H-pyrazol-3-yl)acetamido]propanoyl}-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0763] 1-(1-acetyl-3-fluoroazetidine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0764] 1-[2-(1-acetyl-3-methoxyazetidin-3-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0765] 1-{4-acetyl-hexahydro-2H-furo[3,2-b]pyrrole-6-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0766] 1-(1-acetyl-4-ethylpyrrolidine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0767] 1-{7-acetyl-1-oxo-2,7-diazaspiro[4.4]nonane-4-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0768] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[1-(1,3,4-oxadiazol-2-yl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide; [0769] 2-[4-fluoro-2-({[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl N,N-dimethylcarbamate; [0770] 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide; [0771] 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; [0772] 2-[4-fluoro-2-({phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl [0773] N,N-dimethylcarbamate; [0774] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1-methyl-1H-1,2,3-triazol-4-yl)acetyl]pyrrolidine-2-carboxamide; [0775] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide; [0776] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide; [0777] 1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0778] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide; [0779] 4-fluoro-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0780] 4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-1-[2-(quinolin-5-yl)acetyl]pyrrolidine-2-carboxamide; [0781] tert-butyl 4-({2-[4-fluoro-2-({[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}carbamoyl)piperazine-1-carboxylate; [0782] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-[2-(3,5-dimethyl-1H-pyrazol-4-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide; [0783] N-{2-[4-fluoro-2-({[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}piperazine-1-carboxamide; [0784] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(quinolin-5-yl)acetyl]pyrrolidine-2-carboxamide; [0785] 4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-1-[2-(1H-1,2,3,4-tetrazol-1-yl)acetyl]pyrrolidine-2-carboxamide; [0786] 1-[2-(4-acetylpiperazin-1-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0787] 4-fluoro-1-[2-(5-methyl-2-oxo-2,3-dihydro-1,3,4-oxadiazol-3-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0788] 1-[2-(3,5-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide; [0789] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0790] 1-{2-[(dimethylcarbamoyl)(methyl)amino]acetyl}-4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide; [0791] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-(2-oxo-1,3-oxazolidine-5-carbonyl)pyrrolidine-2-carboxamide; [0792] 2-[4-fluoro-2-({[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl piperazine-1-carboxylate; [0793] 1-[2-(3,5-dimethyl-1H-pyrazol-4-yl)acetyl]-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0794] 1-tert-butyl 4-{2-[4-fluoro-2-({[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl} piperazine-1,4-dicarboxylate; [0795] 1-{2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0796] 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0797] 1-{2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]acetyl}-4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide; [0798] tert-butyl N-({5-[2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl]-1,3,4-oxadiazol-2-yl}methyl)carbamate; [0799] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(pyridazin-4-yl)acetyl]pyrrolidine-2-carboxamide; [0800] 4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-1-{2-[5-(trifluoromethyl)-2H-1,2,3,4-tetrazol-2-yl]acetyl}pyrrolidine-2-carboxamide; [0801] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-5-methyl-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0802] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(pyridazin-3-yl)acetyl]pyrrolidine-2-carboxamide; [0803] N-[(5-cyclopropylpyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0804] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(2-oxopiperazin-1-yl)acetyl]pyrrolidine-2-carboxamide; [0805] N-[2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl]-4-methylpiperazine-1-carboxamide; [0806] N-[2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl]-4-(2,2,2-trifluoroethyl)piperazine-1-carboxamide; [0807] N-{2-[4-fluoro-2-({phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}-4-(2,2,2-trifluoroethyl)piperazine-1-carboxamide; [0808] N-[2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl]-4-(2-methoxyethyl)piperazine-1-carboxamide; [0809] 1-{2-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]acetyl}-N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; [0810] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(5-methyl-1H-1,2,3-triazol-1-yl)acetyl]pyrrolidine-2-carboxamide; [0811] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(4-methyl-1H-1,2,3-triazol-1-yl)acetyl]pyrrolidine-2-carboxamide; [0812] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-{2-[4-(piperazin-1-yl)-2H-1,2,3-triazol-2-yl]acetyl}pyrrolidine-2-carboxamide; [0813] N-[2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl]-4-(cyclopropylmethyl)piperazine-1-carboxamide; [0814] 4-(cyclopropylmethyl)-N-{2-[4-fluoro-2-({phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}piperazine-1-carboxamide; [0815] N-{2-[4-fluoro-2-({phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}-4-methylpiperazine-1-carboxamide; [0816] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(4-methyl-1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0817] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]acetyl}pyrrolidine-2-carboxamide; [0818] 4-fluoro-1-[2-(2-methylquinolin-5-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0819] tert-butyl N-[(5-{2-[4-fluoro-2-({phenyl[4-(propan-2-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}-1,3,4-oxadiazol-2-yl)methyl]carbamate; [0820] 1-{2-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]acetyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0821] 1-{2-[4-(dimethylamino)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide; [0822] tert-butyl 4-(5-{2-[4-fluoro-2-({[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate; [0823] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-(2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-8-yl}acetyl)pyrrolidine-2-carboxamide; [0824] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-{2-[5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]acetyl}pyrrolidine-2-carboxamide; [0825] 1-{2-[4-(dimethylamino)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide; [0826] 1-[2-(3,5-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; [0827] 1-{2-[5-(difluoromethyl)-2H-1,2,3,4-tetrazol-2-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0828] 1-{2-[5-(acetamidomethyl)-1,3,4-oxadiazol-2-yl]acetyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0829] 1-{2-[5-(aminomethyl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0830] 1-(2-{5-[(dimethylamino)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0831] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-{2-[4-(piperazin-1-yl)-1H-1,2,3-triazol-5-yl]acetyl}pyrrolidine-2-carboxamide; [0832] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-{2-[4-(morpholin-4-yl)-1H-1,2,3-triazol-5-yl]acetyl}pyrrolidine-2-carboxamide; [0833] 1-(2-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}acetyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0834] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(4H-1,2,4-triazol-4-yl)acetyl]pyrrolidine-2-carboxamide; [0835] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(4H-1,2,4-triazol-4-yl)acetyl]pyrrolidine-2-carboxamide; [0836] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-indazol-3-yl)acetyl]pyrrolidine-2-carboxamide; [0837] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-{2-[5-(trifluoromethyl)-1H-1,2,3,4-tetrazol-1-yl]acetyl}pyrrolidine-2-carboxamide; [0838] 1-[2-(1H-1,2,3-benzotriazol-1-yl)acetyl]-N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; [0839] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)acetyl]pyrrolidine-2-carboxamide; [0840] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide; [0841] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)acetyl]pyrrolidine-2-carboxamide; [0842] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetyl]pyrrolidine-2-carboxamide; [0843] N-[2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl]morpholine-4-carboxamide; [0844] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1-methyl-1H-indol-3-yl)acetyl]pyrrolidine-2-carboxamide; [0845] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1-methyl-1H-indol-2-yl)acetyl]pyrrolidine-2-carboxamide; [0846] 2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl azetidine-1-carboxylate; [0847] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1-methyl-1H-indazol-3-yl)acetyl]pyrrolidine-2-carboxamide; [0848] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(2-oxo-2,3-dihydro-1H-indol-1-yl)acetyl]pyrrolidine-2-carboxamide; [0849] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(2-methyl-1H-1,3-benzodiazol-1-yl)acetyl]pyrrolidine-2-carboxamide; [0850] 1-{2-[5-(acetamidomethyl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; [0851] 4-fluoro-1-[2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0852] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]pyrrolidine-2-carboxamide; [0853] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)acetyl]pyrrolidine-2-carboxamide; [0854] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetyl]pyrrolidine-2-carboxamide; [0855] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(4-methyl-1H-imidazol-1-yl)acetyl]pyrrolidine-2-carboxamide; [0856] 1-{2-[5-(difluoromethyl)-1H-1,2,3,4-tetrazol-1-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0857] 2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl 4-(cyclopropylmethyl)piperazine-1-carboxylate; [0858] 2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl 4-methylpiperazine-1-carboxylate; [0859] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(2-oxo-2,3-dihydro-1H-indol-3-yl)acetyl]pyrrolidine-2-carboxamide; [0860] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-(2-{imidazo[1,2-a]pyridin-3-yl}acetyl)pyrrolidine-2-carboxamide; [0861] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-(2-{[1,2,4]triazolo[1,5-a]pyridin-6-yl}acetyl)pyrrolidine-2-carboxamide; [0862] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-5-yl]acetyl}pyrrolidine-2-carboxamide; [0863] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-{2-[(pyrazin-2-yl)amino]acetyl}pyrrolidine-2-carboxamide; [0864] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-{2-[4-(piperazin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}pyrrolidine-2-carboxamide; [0865] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-{2-[(2-ethyl-2H-1,2,3-triazol-4-yl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide; [0866] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide; [0867] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-{2-[(1-ethyl-1H-1,2,3-triazol-4-yl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide; [0868] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(2-methylquinolin-6-yl)acetyl]pyrrolidine-2-carboxamide; [0869] 2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl 4-(2-methoxyethyl)piperazine-1-carboxylate; [0870] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-{2-[2-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl]acetyl}pyrrolidine-2-carboxamide; [0871] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-{2-[methyl(2-methylpyrimidin-4-yl)amino]acetyl}pyrrolidine-2-carboxamide; [0872] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(2-methylquinolin-5-yl)acetyl]pyrrolidine-2-carboxamide; [0873] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-{2-[(2-methylpyrimidin-4-yl)amino]acetyl}pyrrolidine-2-carboxamide; [0874] 4-fluoro-1-[2-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0875] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-{2-[methyl(pyrazin-2-yl)amino]acetyl}pyrrolidine-2-carboxamide; [0876] 4-fluoro-1-(2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-8-yl}acetyl)-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0877] 2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate; [0878] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(4H-1,2,4-triazol-4-yl)acetyl]pyrrolidine-2-carboxamide; [0879] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(4H-1,2,4-triazol-4-yl)acetyl]pyrrolidine-2-carboxamide; [0880] 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; [0881] 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; [0882] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-{2-[4-(dimethylamino)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide; [0883] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-{2-[4-(dimethylamino)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide; [0884] 1-{2-[4-(dimethylamino)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0885] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-(2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-8-yl}acetyl)pyrrolidine-2-carboxamide; [0886] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-(2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-8-yl}acetyl)pyrrolidine-2-carboxamide; [0887] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(2-methylquinolin-5-yl)acetyl]pyrrolidine-2-carboxamide; [0888] tert-butyl 2-[2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl]-1H-indole-1-carboxylate; [0889] 1-{2-[4-(dimethylamino)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0890] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-indol-2-yl)acetyl]pyrrolidine-2-carboxamide; [0891] 1-[2-(carbamoylamino)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; [0892] 1-{2-[4-(dimethylamino)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; [0893] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-{2-[(2-ethyl-2H-1,2,3-triazol-4-yl)(methyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide; [0894] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-{2-[(1-ethyl-1H-1,2,3-triazol-4-yl)(methyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide; [0895] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide; [0896] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[4-(dimethylamino)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide; [0897] 1-{2-[4-(dimethylamino)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; [0898] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[5-(dimethylamino)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide; [0899] 4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-1-[2-(4H-1,2,4-triazol-4-yl)acetyl]pyrrolidine-2-carboxamide; [0900] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propanoyl]pyrrolidine-2-carboxamide; [0901] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)acetyl]pyrrolidine-2-carboxamide; [0902] 4-fluoro-1-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0903] 1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; [0904] 4-fluoro-1-{2-[(methylcarbamoyl)amino]acetyl}-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0905] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-{2-[(2-methylpyrimidin-4-yl)amino]acetyl}pyrrolidine-2-carboxamide; [0906] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-{2-[(methylcarbamoyl)amino]acetyl}pyrrolidine-2-carboxamide; [0907] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)acetyl]pyrrolidine-2-carboxamide; [0908] 1-{2-[(azetidine-1-carbonyl)amino]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0909] 1-{2-[(azetidine-1-carbonyl)amino]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; [0910] 4-fluoro-1-{2-[(2-methylpyrimidin-4-yl)amino]acetyl}-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0911] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide; [0912] 1-[2-(carbamoylamino)acetyl]-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0913] 4-fluoro-1-[2-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0914] 4-fluoro-1-[3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propanoyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0915] 1-[2-(carbamoylamino)acetyl]-N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; [0916] 1-{2-[(azetidine-1-carbonyl)amino]acetyl}-N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; [0917] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[(methylcarbamoyl)amino]acetyl}pyrrolidine-2-carboxamide; [0918] 4-fluoro-1-[2-(1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0919] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)acetyl]pyrrolidine-2-carboxamide; [0920] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[(2-methylpyrimidin-4-yl)amino]acetyl}pyrrolidine-2-carboxamide; [0921] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)acetyl]pyrrolidine-2-carboxamide; [0922] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide; [0923] 4-fluoro-1-[2-(1,3-oxazol-2-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0924] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[5-(difluoromethyl)-1H-1,2,3,4-tetrazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide; [0925] 1-{2-[5-(difluoromethyl)-1H-1,2,3,4-tetrazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; [0926] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]pyrrolidine-2-carboxamide; [0927] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]pyrrolidine-2-carboxamide; [0928] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-5-yl]acetyl}pyrrolidine-2-carboxamide; [0929] 4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-1-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-5-yl]acetyl}pyrrolidine-2-carboxamide; [0930] 1-{2-[(dimethylcarbamoyl)amino]propanoyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; [0931] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-{2-[(3,3-difluoroazetidine-1-carbonyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide; [0932] N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-(2-{[3-(trifluoromethyl)azetidine-1-carbonyl]amino}acetyl)pyrrolidine-2-carboxamide; [0933] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-5-yl]acetyl}pyrrolidine-2-carboxamide; [0934] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[(dimethylcarbamoyl)amino]propanoyl}-4-fluoropyrrolidine-2-carboxamide; [0935] 4-fluoro-1-[2-(5-methyl-1,3-oxazol-2-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0936] 1-{2-[(dimethylcarbamoyl)amino]propanoyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0937] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(5-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide; [0938] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide; [0939] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide; [0940] 4-fluoro-1-[2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-4-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0941] 4-fluoro-1-(3-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}propanoyl)-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0942] 1-{2-[(3,3-difluoroazetidine-1-carbonyl)amino]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0943] 4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-1-(2-{[3-(trifluoromethyl)azetidine-1-carbonyl]amino}acetyl)pyrrolidine-2-carboxamide; [0944] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]pyrrolidine-2-carboxamide; [0945] 1-{2-[(3,3-difluoroazetidine-1-carbonyl)amino]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; [0946] 4-fluoro-1-[2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0947] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[(3,3-difluoroazetidine-1-carbonyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide; [0948] N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-3-[2-(1H-1,2,3-triazol-5-yl)acetyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide; [0949] 5-methyl-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0950] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(4-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide; [0951] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-(2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-8-yl}acetyl)pyrrolidine-2-carboxamide; [0952] 4-fluoro-1-[2-(4-methyl-1,3-oxazol-2-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0953] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]pyrrolidine-2-carboxamide; [0954] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(4-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide; [0955] 4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-1-[2-(1H-pyrazol-1-yl)acetyl]pyrrolidine-2-carboxamide; [0956] 1-{2-[4-(3,3-difluoroazetidin-1-yl)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; [0957] 1-{2-[4-(diethylamino)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; [0958] N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-5-methyl-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0959] 1-{2-[4-(3,3-difluoroazetidin-1-yl)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0960] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[(1,3-oxazol-2-yl)amino]acetyl}pyrrolidine-2-carboxamide; [0961] N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-3-[2-(1H-1,2,3-triazol-5-yl)acetyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide; [0962] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[4-(3,3-difluoroazetidin-1-yl)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide; [0963] 1-{2-[4-(diethylamino)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0964] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[4-(diethylamino)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide; [0965] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-5-methyl-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; [0966] 1-{2-[4-(azetidin-1-yl)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0967] 1-{2-[4-(azetidin-1-yl)-2H-1,2,3-triazol-2-yl]acetyl}-N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; [0968] 1-{2-[4-(azetidin-1-yl)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; [0969] 4-fluoro-1-[2-(5-methyl-2-oxo-2,3-dihydro-1,3,4-oxadiazol-3-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; [0970] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-2-oxo-2,3-dihydro-1,3,4-oxadiazol-3-yl)acetyl]pyrrolidine-2-carboxamide; [0971] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(5-methyl-2-oxo-2,3-dihydro-1,3,4-oxadiazol-3-yl)acetyl]pyrrolidine-2-carboxamide; and [0972] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-3-[2-(1H-1,2,3-triazol-5-yl)acetyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide, [0973] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(5-methyl-2-oxo-2,3-dihydro-1,3,4-oxadiazol-3-yl)acetyl]pyrrolidine-2-carboxamide [0974] 1-{2-[(azetidine-1-carbonyl)amino]acetyl}-N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoropyrrolidine-2-carboxamide [0975] 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoropyrrolidine-2-carboxamide [0976] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide [0977] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide [0978] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide [0979] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [0980] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(5-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide [0981] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-5-yl]acetyl}pyrrolidine-2-carboxamide [0982] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(4-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide [0983] 1-{2-[(3,3-difluoroazetidine-1-carbonyl)amino]acetyl}-N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoropyrrolidine-2-carboxamide [0984] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-{2-[5-(difluoromethyl)-1H-1,2,3,4-tetrazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide [0985] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [0986] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [0987] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(6-oxo-1,6-dihydropyridin-3-yl)acetyl]pyrrolidine-2-carboxamide [0988] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(2-oxo-1,2-dihydropyridin-3-yl)acetyl]pyrrolidine-2-carboxamide [0989] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(3-ethyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [0990] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [0991] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]pyrrolidine-2-carboxamide [0992] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(1-ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [0993] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(6-ethoxy-5-methylpyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [0994] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(1-ethyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [0995] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(1-ethyl-2-oxo-1,2-dihydropyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [0996] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(4-ethyl-5-oxo-4,5-dihydropyrazin-2-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [0997] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-{2-[4-(trifluoromethyl)-1,3-oxazol-2-yl]acetyl}pyrrolidine-2-carboxamide [0998] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(3-oxo-3,4-dihydropyrazin-2-yl)acetyl]pyrrolidine-2-carboxamide [0999] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(5-oxo-4,5-dihydropyrazin-2-yl)acetyl]pyrrolidine-2-carboxamide [1000] N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(4-ethyl-3-oxo-3,4-dihydropyrazin-2-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [1001] N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide [1002] 1-{2-[(azetidine-1-carbonyl)amino]acetyl}-N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoropyrrolidine-2-carboxamide [1003] N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1004] N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide [1005] N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(5-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide [1006] 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoropyrrolidine-2-carboxamide [1007] 1-{2-[(3,3-difluoroazetidine-1-carbonyl)amino]acetyl}-N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoropyrrolidine-2-carboxamide [1008] N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide [1009] N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(4-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide [1010] N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(5-methyl-2-oxo-2,3-dihydro-1,3,4-oxadiazol-3-yl)acetyl]pyrrolidine-2-carboxamide [1011] N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoro-1-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-5-yl]acetyl}pyrrolidine-2-carboxamide [1012] N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoro-1-{2-[4-(trifluoromethyl)-1,3-oxazol-2-yl]acetyl}pyrrolidine-2-carboxamide [1013] 1-{2-[(azetidine-1-carbonyl)amino]acetyl}-N-{[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl}-4-fluoropyrrolidine-2-carboxamide [1014] N-{[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl}-1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide [1015] 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-N-{[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl}-4-fluoropyrrolidine-2-carboxamide [1016] N-{[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl}-4-fluoro-1-[2-(5-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide [1017] N-{[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl}-4-fluoro-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide [1018] N-{[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl}-4-fluoro-1-[2-(1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide [1019] N-{[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl}-4-fluoro-1-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-5-yl]acetyl}pyrrolidine-2-carboxamide [1020] N-{[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl}-4-fluoro-1-[2-(4-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide [1021] N-{[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl}-4-fluoro-1-{2-[4-(trifluoromethyl)-1,3-oxazol-2-yl]acetyl}pyrrolidine-2-carboxamide [1022] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide [1023] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1024] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](pyridin-3-yl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1025] 2-[4-fluoro-2-({[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl azetidine-1-carboxylate [1026] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(1-methyl-1H-indol-2-yl)acetyl]pyrrolidine-2-carboxamide [1027] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(2-oxopiperazin-1-yl)acetyl]pyrrolidine-2-carboxamide [1028] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(1-methyl-1H-indol-3-yl)acetyl]pyrrolidine-2-carboxamide [1029] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(1-methyl-1H-indazol-3-yl)acetyl]pyrrolidine-2-carboxamide [1030] N-{2-[4-fluoro-2-({[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}morpholine-4-carboxamide [1031] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(2-methyl-1H-1,3-benzodiazol-1-yl)acetyl]pyrrolidine-2-carboxamide [1032] 1-[2-(1H-1,3-benzodiazol-1-yl)propanoyl]-4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide [1033] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)acetyl]pyrrolidine-2-carboxamide [1034] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide [1035] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)acetyl]pyrrolidine-2-carboxamide [1036] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(1H-indazol-3-yl)acetyl]pyrrolidine-2-carboxamide [1037] 1-[2-(2,5-dioxopiperazin-1-yl)acetyl]-4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide [1038] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetyl]pyrrolidine-2-carboxamide [1039] 1-[2-(1H-1,2,3-benzotriazol-1-yl)acetyl]-4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide [1040] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(2-oxo-2,3-dihydro-1H-indol-1-yl)acetyl]pyrrolidine-2-carboxamide [1041] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(1-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetyl]pyrrolidine-2-carboxamide [1042] 2,2,2-trifluoroethyl 4-{2-[4-fluoro-2-({[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}-3-oxopiperazine-1-carboxylate [1043] 2-[4-fluoro-2-({[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl 4-(2-methoxyethyl)piperazine-1-carboxylate [1044] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-{2-[2-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl]acetyl}pyrrolidine-2-carboxamide [1045] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(2-oxo-2,3-dihydro-1H-indol-3-yl)acetyl]pyrrolidine-2-carboxamide [1046] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(4H-1,2,4-triazol-4-yl)acetyl]pyrrolidine-2-carboxamide [1047] 2-[4-fluoro-2-({[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl 4-methylpiperazine-1-carboxylate [1048] 2-[4-fluoro-2-({[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl 4-(cyclopropylmethyl)piperazine-1-carboxylate [1049] 2-[4-fluoro-2-({[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate [1050] 1-[2-(1H-1,3-benzodiazol-1-yl)propanoyl]-4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1051] 4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}-1-[2-(1H-indazol-3-yl)acetyl]pyrrolidine-2-carboxamide [1052] N-{2-[4-fluoro-2-({[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}morpholine-4-carboxamide [1053] 4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}-1-[2-(1-methyl-1H-indol-2-yl)acetyl]pyrrolidine-2-carboxamide [1054] 4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}-1-[2-(1-methyl-1H-indol-3-yl)acetyl]pyrrolidine-2-carboxamide [1055] 4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}-1-[2-(2-methyl-1H-1,3-benzodiazol-1-yl)acetyl]pyrrolidine-2-carboxamide [1056] 1-[2-(1H-1,2,3-benzotriazol-1-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1057] 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1058] 4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}-1-[2-(1-methyl-1H-indazol-3-yl)acetyl]pyrrolidine-2-carboxamide [1059] 4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}-1-[2-(1-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetyl]pyrrolidine-2-carboxamide [1060] 4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}-1-[2-(1H-indol-2-yl)acetyl]pyrrolidine-2-carboxamide [1061] 4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}-1-[2-(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)acetyl]pyrrolidine-2-carboxamide [1062] 4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}-1-[2-(3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)acetyl]pyrrolidine-2-carboxamide [1063] tert-butyl 2-{2-[4-fluoro-2-({[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}-1H-indole-1-carboxylate [1064] 1-{2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]acetyl}-4-fluoro-N-{[4-methyl-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1065] 1-acetyl-N-[(5-cyclobutylpyridin-2-yl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide [1066] 4-fluoro-N-{[4-methyl-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1067] 4-fluoro-N-{[4-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1068] N-{[4-(difluoromethyl)-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1069] 4-fluoro-N-{[6-methyl-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1070] 4-fluoro-N-{phenyl[5-(propan-2-yl)-4-(trifluoromethyl)pyridin-2-yl]methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1071] 1-{2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]acetyl}-4-fluoro-N-{[6-methyl-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1072] N-[(5-cyclobutylpyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1073] N-[(5-tert-butylpyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1074] 4-fluoro-N-{[6-methoxy-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1075] N-[(2-aminopyridin-3-yl)[3-fluoro-4-(propan-2-yl)phenyl]methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1076] N-[(4-cyclopropyl-3-fluorophenyl)(1H-pyrazol-5-yl)methyl]-1-(2-acetamidoacetyl)pyrrolidine-2-carboxamide [1077] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](5-fluoropyridin-2-yl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1078] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](5-fluoropyridin-3-yl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1079] N-[(2-aminopyridin-4-yl)[3-fluoro-4-(propan-2-yl)phenyl]methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1080] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](3-fluoropyridin-4-yl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1081] N-[(6-aminopyridin-3-yl)[3-fluoro-4-(propan-2-yl)phenyl]methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1082] N-[(6-aminopyridin-2-yl)[3-fluoro-4-(propan-2-yl)phenyl]methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1083] N-[(2-aminopyridin-3-yl)[3-methyl-4-(propan-2-yl)phenyl]methyl]-1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide [1084] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](1H-pyrazol-5-yl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1085] N-[(2-aminopyridin-3-yl)[3-methyl-4-(propan-2-yl)phenyl]methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1086] N-[(2-aminopyridin-3-yl)[3-methyl-4-(propan-2-yl)phenyl]methyl]-4-fluoro-1-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)acetyl]pyrrolidine-2-carboxamide [1087] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](2-methoxypyridin-3-yl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1088] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](2-methylpyridin-3-yl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1089] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl]({imidazo[1,5-a]pyridin-3-yl})methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1090] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl]({imidazo[1,5-a]pyridin-1-yl})methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1091] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](1H-pyrazol-5-yl)methyl}-1-[2-(1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide [1092] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl]({imidazo[1,5-a]pyridin-7-yl})methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1093] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](1H-indazol-6-yl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1094] 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](1H-indazol-6-yl)methyl}pyrrolidine-2-carboxamide [1095] 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](1-methyl-1H-indazol-6-yl)methyl}pyrrolidine-2-carboxamide [1096] 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](2-methyl-2H-indazol-6-yl)methyl}pyrrolidine-2-carboxamide [1097] 1-acetyl-N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(1H-indazol-6-yl)methyl]-4-fluoropyrrolidine-2-carboxamide [1098] methyl N-({3-[({4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidin-2-yl}formamido)[6-fluoro-5-(propan-2-yl)pyridin-2-yl]methyl]phenyl}methyl)carbamate [1099] 1-acetyl-N-[(2-methoxyphenyl)[4-(propan-2-yl)phenyl]methyl]pyrrolidine-2-carboxamide [1100] 1-acetyl-N-[(2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]pyrrolidine-2-carboxamide [1101] 1-acetyl-N-[(2-methylphenyl)[5-(propan-2-yl)pyridin-2-yl]methyl]pyrrolidine-2-carboxamide [1102] N-[(4-cyclopropyl-3-fluorophenyl)(2-oxo-2,3-dihydro-1,3-benzoxazol-7-yl)methyl]-1-(2-acetamidoacetyl)pyrrolidine-2-carboxamide [1103] N-[(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl)[4-(propan-2-yl)phenyl]methyl]-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1104] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](3-fluorophenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1105] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](4-fluorophenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1106] N-[(4-cyclopropyl-3-fluorophenyl)(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl)methyl]-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1107] N-[(3-acetamidophenyl)[4-(propan-2-yl)phenyl]methyl]-4-fluoro-1-[2-(1-methyl-1H-1,2,3-triazol-4-yl)acetyl]pyrrolidine-2-carboxamide [1108] N-[(4-cyclopropyl-3-fluorophenyl)(1-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1109] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](3-methoxyphenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1110] N-{cyclopropyl[3-fluoro-4-(propan-2-yl)phenyl]methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1111] N-{2-cyclopropyl-1-[3-fluoro-4-(propan-2-yl)phenyl]ethyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1112] 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](3-methoxyphenyl)methyl}pyrrolidine-2-carboxamide [1113] N-{[3-(acetamidomethyl)phenyl][6-fluoro-5-(propan-2-yl)pyridin-2-yl]methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1114] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](3-{[(methylcarbamoyl)amino]methyl}phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1115] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(2-fluorophenyl)methyl]-1-{2-[5-(difluoromethyl)-1H-1,2,3,4-tetrazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide [1116] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(4-fluorophenyl)methyl]-1-{2-[5-(difluoromethyl)-1H-1,2,3,4-tetrazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide [1117] N-{[3,5-difluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-4-fluoro-1-[(1H-1,2,3-triazol-5-yl)methanesulfonyl]pyrrolidine-2-carboxamide [1118] 1-acetyl-N-[(4-cyclobutyl-3-fluorophenyl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide [1119] N-{[3,5-difluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-4-fluoro-1-[2-(1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide [1120] N-[(4-cyclopropyl-3,5-difluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide [1121] 4-fluoro-N-{[2-methyl-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide [1122] N-[(3-chloro-4-cyclopropylphenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1123] N-[(4-cyclopropyl-3-methylphenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1124] N-{[3,5-difluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1125] N-{[3,5-difluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-1-yl)acetyl]pyrrolidine-2-carboxamide [1126] N-{[3,5-difluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-4-fluoro-1-[2-(1H-1,2,3,4-tetrazol-1-yl)acetyl]pyrrolidine-2-carboxamide [1127] 4-fluoro-N-{[3-methyl-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1128] N-{[3-chloro-4-(propan-2-yl)phenyl](phenyl)methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1129] N-[(4-cyclobutyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1130] N-[(4-cyclobutyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3,4-tetrazol-1-yl)acetyl]pyrrolidine-2-carboxamide [1131] N-{[4-(butan-2-yl)-3-fluorophenyl](phenyl)methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1132] 4-fluoro-N-{[3-fluoro-5-methyl-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1133] N-{[3-(difluoromethyl)-4-(propan-2-yl)phenyl](phenyl)methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1134] 4-fluoro-N-{[3-fluoro-4-(1-methylcyclobutyl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1135] N-[(4-cyclopropyl-3-fluoro-5-methylphenyl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-2H-1,2,3,4-tetrazol-2-yl)acetyl]pyrrolidine-2-carboxamide [1136] 4-fluoro-N-{phenyl[4-(propan-2-yl)-3-(trifluoromethyl)phenyl]methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1137] N-[(4-tert-butyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1138] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1H-pyrazol-5-yl)phenyl]methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1139] 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(4H-1,2,4-triazol-3-yl)phenyl]methyl}pyrrolidine-2-carboxamide [1140] 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1H-pyrazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide [1141] 1-(2-acetamidoacetyl)-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1H-pyrazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide [1142] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1,3-oxazol-5-yl)phenyl]methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1143] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1,2-oxazol-5-yl)phenyl]methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1144] 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1-methyl-1H-pyrazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide [1145] 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(3-methyl-1H-pyrazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide [1146] 1-acetyl-N-{[3-(1,3-dimethyl-1H-pyrazol-5-yl)phenyl][6-fluoro-5-(propan-2-yl)pyridin-2-yl]methyl}-4-fluoropyrrolidine-2-carboxamide [1147] 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1,2-oxazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide [1148] 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1H-pyrazol-1-yl)phenyl]methyl}pyrrolidine-2-carboxamide [1149] 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1,3,4-oxadiazol-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide [1150] 1-(oct-7-ynoyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide [1151] 4-fluoro-1-(1-methyl-1H-indazole-5-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide [1152] 4-fluoro-1-[2-(4-methoxyphenyl)cyclopropanecarbonyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide [1153] 4-fluoro-1-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-2-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide [1154] 4-fluoro-1-[2-(2-methylpropoxy)pyridine-4-carbonyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide [1155] 4-fluoro-1-[3-(1H-imidazol-4-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide [1156] 4-fluoro-1-[4-(1H-imidazol-1-yl)pyridine-2-carbonyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide [1157] 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-{[(pyridin-3-yl)carbamoyl]carbonyl}pyrrolidine-2-carboxamide [1158] 4-fluoro-1-(5-methoxy-1-methyl-1H-pyrazole-3-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide [1159] 1-[2-(1,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide [1160] 1-{2-[4-(azetidin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide [1161] 4-fluoro-1-[2-(5-methoxy-1-methyl-1H-1,2,4-triazol-3-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide [1162] 1-{2-[5-(diethylamino)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide [1163] 1-{2-[5-(3,3-difluoroazetidin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide [1164] 1-{2-[5-(azetidin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide [1165] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-(2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-8-yl}acetyl)pyrrolidine-2-carboxamide [1166] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)acetyl]pyrrolidine-2-carboxamide [1167] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1168] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(1,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [1169] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(1H-pyrazol-1-yl)acetyl]pyrrolidine-2-carboxamide [1170] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-1H-pyrazol-1-yl)acetyl]pyrrolidine-2-carboxamide [1171] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[5-(difluoromethyl)-1H-pyrazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide [1172] 1-{2-[4-(azetidin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}-N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide [1173] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [1174] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}pyrrolidine-2-carboxamide [1175] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[3-(difluoromethyl)-1H-pyrazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide [1176] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}pyrrolidine-2-carboxamide [1177] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(2-oxo-1,2-dihydropyridin-3-yl)acetyl]pyrrolidine-2-carboxamide [1178] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]pyrrolidine-2-carboxamide [1179] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(3-ethyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [1180] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(6-oxo-1,6-dihydropyridin-3-yl)acetyl]pyrrolidine-2-carboxamide [1181] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [1182] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [1183] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(6-ethoxy-5-methylpyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [1184] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[4-(trifluoromethyl)-1,3-oxazol-2-yl]acetyl}pyrrolidine-2-carboxamide [1185] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(1-ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [1186] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(1-ethyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [1187] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(1-ethyl-2-oxo-1,2-dihydropyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [1188] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(4-ethyl-5-oxo-4,5-dihydropyrazin-2-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [1189] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(5-methoxy-1-methyl-1H-1,2,4-triazol-3-yl)acetyl]pyrrolidine-2-carboxamide [1190] 1-(2-{[benzyl(trifluoromethyl)carbamoyl]amino}acetyl)-N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide [1191] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]acetyl}pyrrolidine-2-carboxamide [1192] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(5-oxo-4,5-dihydropyrazin-2-yl)acetyl]pyrrolidine-2-carboxamide [1193] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[5-(difluoromethyl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide [1194] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[5-(diethylamino)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide [1195] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide [1196] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[5-(difluoromethyl)-3-methyl-1H-pyrazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide [1197] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide [1198] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide [1199] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(4-ethyl-3-oxo-3,4-dihydropyrazin-2-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [1200] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[4-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide [1201] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[5-(trifluoromethyl)-1H-1,2,3,4-tetrazol-1-yl]acetyl}pyrrolidine-2-carboxamide [1202] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[4-(difluoromethyl)-1H-1,2,3-triazol-5-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide [1203] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[4-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide [1204] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[5-(3,3-difluoroazetidin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide [1205] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[3-(difluoromethyl)-4H-1,2,4-triazol-4-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide [1206] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[5-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}pyrrolidine-2-carboxamide [1207] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(4,5-dimethyl-1,3-oxazol-2-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide [1208] 1-{2-[5-(azetidin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}-N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide [1209] N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[5-(difluoromethyl)-1H-1,2,3,4-tetrazol-1-yl]acetyl}-4-fluoro-3-hydroxypyrrolidine-2-carboxamide [1210] 1-(3-carbamoyl-2-acetamidopropanoyl)-4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide [1211] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3,4-tetrazol-1-yl)propanoyl]pyrrolidine-2-carboxamide [1212] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-imidazol-1-yl)propanoyl]pyrrolidine-2-carboxamide [1213] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)propanoyl]pyrrolidine-2-carboxamide [1214] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[(1H-1,2,3-triazol-5-yl)methanesulfonyl]pyrrolidine-2-carboxamide [1215] 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-hydroxy-2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1216] 1-{2-[4-(dimethylamino)-1H-1,2,3-triazol-5-yl]acetyl}-4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide [1217] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide [1218] 1-[2-(3,5-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1219] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide [1220] 1-[2-(1,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1221] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-(3-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}propanoyl)pyrrolidine-2-carboxamide [1222] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(1H-pyrazol-1-yl)acetyl]pyrrolidine-2-carboxamide [1223] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(5-methyl-1H-pyrazol-1-yl)acetyl]pyrrolidine-2-carboxamide [1224] 1-{2-[5-(difluoromethyl)-1H-pyrazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1225] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]pyrrolidine-2-carboxamide [1226] 1-[2-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1227] 1-[2-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1228] 1-{2-[4-(azetidin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1229] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-{2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}pyrrolidine-2-carboxamide [1230] 1-{2-[3-(difluoromethyl)-1H-pyrazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1231] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-{2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}pyrrolidine-2-carboxamide [1232] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(6-oxo-1,6-dihydropyridin-3-yl)acetyl]pyrrolidine-2-carboxamide [1233] 1-[2-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1234] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(2-oxo-1,2-dihydropyridin-3-yl)acetyl]pyrrolidine-2-carboxamide [1235] 1-[2-(3-ethyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1236] 1-[2-(1-ethyl-2-oxo-1,2-dihydropyridin-3-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1237] 1-[2-(1-ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1238] 1-[2-(4-ethyl-5-oxo-4,5-dihydropyrazin-2-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1239] 1-[2-(6-ethoxy-5-methylpyridin-3-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1240] 1-[2-(1-ethyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1241] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(5-methoxy-1-methyl-1H-1,2,4-triazol-3-yl)acetyl]pyrrolidine-2-carboxamide [1242] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-{2-[4-(trifluoromethyl)-1,3-oxazol-2-yl]acetyl}pyrrolidine-2-carboxamide [1243] 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(5-oxo-4,5-dihydropyrazin-2-yl)acetyl]pyrrolidine-2-carboxamide [1244] 1-{2-[5-(difluoromethyl)-3-methyl-1H-pyrazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1245] 1-{2-[3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1246] 1-{2-[5-(diethylamino)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1247] 1-[2-(4-ethyl-3-oxo-3,4-dihydropyrazin-2-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1248] 1-{2-[5-(3,3-difluoroazetidin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1249] 1-{2-[5-(azetidin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide [1250] 1-[2-(1H-1,3-benzodiazol-1-yl)propanoyl]-N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

Methods of Treatment

[1251] Provided herein is a method of modulating GYS1 in a cell, comprising exposing the cell to (i) a composition comprising an effective amount of a GYS1 inhibitor, or (ii) a pharmaceutical composition, comprising an effective amount of a GYS1 inhibitor, and one or more pharmaceutically acceptable excipients. In some embodiments, the GYS1 inhibitor is a small molecule. In some embodiments, the GYS1 inhibitor is selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2.

[1252] Provided herein is a method of modulating GYS1 in a cell, comprising exposing the cell to (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[1253] Provided herein is a method of inhibiting GYS1 in a cell, comprising exposing the cell to (i) a composition comprising an effective amount of a GYS1 inhibitor, or (ii) a pharmaceutical composition, comprising an effective amount of a GYS1 inhibitor, and one or more pharmaceutically acceptable excipients. In some embodiments, the GYS1 inhibitor is a small molecule. In some embodiments, the GYS1 inhibitor is selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2.

[1254] Provided herein is a method of inhibiting GYS1 in a cell, comprising exposing the cell to (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[1255] Provided herein is a method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual an effective amount of (i) a GYS1 inhibitor, or (ii) a pharmaceutical composition, comprising a GYS1 inhibitor, and one or more pharmaceutically acceptable excipients. In some embodiments, the GYS1 inhibitor is a small molecule. In some embodiments, the GYS1 inhibitor is selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2. In some embodiments, the individual has a GYS1-mediated disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease. In some embodiments, the GYS1-mediated disease, disorder, or condition is cancer. In some embodiments, the GYS1-mediated disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML). In some embodiments, the GYS1-mediated disease, disorder, or condition is Pompe disease. In some embodiments, the GYS1-mediated disease, disorder, or condition is late-onset Pompe disease (LOPD).

[1256] Provided herein is a method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[1257] Provided herein is a method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual (i) a composition comprising an effective amount of a compound of formula (I′), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I′), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[1258] Provided herein is a method of inhibiting glycogen synthesis in an individual in need thereof, comprising administering to the individual an effective amount of (i) a GYS1 inhibitor, or (ii) a pharmaceutical composition, comprising a GYS1 inhibitor, and one or more pharmaceutically acceptable excipients. In certain embodiments the GYS1 inhibitor is a compound of formula (I′), (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is (i) a composition comprising an effective amount of a compound of formula (I′), (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I′), (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the compounds and/or compositions inhibit the hGYS enzyme, and subsequently, the glycogen synthesis in cells.

[1259] Provided herein is a method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising subjecting the individual to glycogen substrate reduction therapy. In some embodiments, glycogen substrate reduction therapy reduces glycogen stores. In some embodiments, glycogen substrate reduction therapy comprises administering to the individual an effective amount of (i) a GYS1 inhibitor, or (ii) a pharmaceutical composition comprising a GYS1 inhibitor, and one or more pharmaceutically acceptable excipients. In some embodiments, the GYS1 inhibitor is a small molecule. In some embodiments, the GYS1 inhibitor is selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2. In some embodiments, the GYS1-mediated disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease. In some embodiments, the GYS1-mediated disease, disorder, or condition is cancer. In some embodiments, the GYS1-mediated disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML). In some embodiments, the GYS1-mediated disease, disorder, or condition is Pompe disease.

[1260] Provided herein is a method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the GYS1-mediated disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease. In some embodiments, the GYS1-mediated disease, disorder, or condition is cancer. In some embodiments, the GYS1-mediated disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML).

[1261] Provided herein is a method of treating a glycogen storage disease, disorder, or condition in an individual in need thereof, comprising subjecting the individual to glycogen substrate reduction therapy. In some embodiments, glycogen substrate reduction therapy reduces glycogen stores. In some embodiments, glycogen substrate reduction therapy comprises administering to the individual an effective amount of (i) a GYS1 inhibitor, or (ii) a pharmaceutical composition comprising a GYS1 inhibitor, and one or more pharmaceutically acceptable excipients. In some embodiments, the GYS1 inhibitor is a small molecule. In some embodiments, the GYS1 inhibitor is selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2. In some embodiments, the level of glycogen in the individual is reduced upon treatment. In some embodiments, the level of glycogen in muscle is reduced. In some embodiments, the level of glycogen is skeletal muscle is reduced. In some embodiments, the level of glycogen is reduced at least 10%, at least 20%, at least 30% or at least 50% upon administration of the compound. In some embodiments, the compounds provided herein are effective for treating a lysosomal disorder. In some embodiments, the glycogen storage disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease. In some embodiments, the glycogen storage disease, disorder, or condition is Pompe disease. In some embodiments, the individual has late onset Pompe Disease. In some embodiments, the GYS1 inhibitor comprises a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[1262] Provided herein is a method of treating a glycogen storage disease, disorder, or condition in an individual in need thereof, comprising administering to the individual (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the level of glycogen in the individual is reduced upon treatment. In some embodiments, the level of glycogen in muscle is reduced. In some embodiments, the level of glycogen is skeletal muscle is reduced. In some embodiments, the level of glycogen is reduced at least 10%, at least 20%, at least 30% or at least 50% upon administration of the compound. In some embodiments, the compounds provided herein are effective for treating a lysosomal disorder. In some embodiments, the glycogen storage disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.

[1263] Provided herein is a method of treating Pompe disease in an individual in need thereof, comprising administering to the individual (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the individual has infant onset Pompe disease. In some embodiments, the individual has non-classic infant-onset Pompe disease. In some embodiments, the individual has late-onset Pompe disease. In some embodiments, the individual has a deficiency in acid alfa glucosidase (GAA). In some embodiments, the individual has reduced expression of GAA.

[1264] In some embodiments, the compounds provided herein reduce and/or eliminate one or more symptoms associated with Pompe disease. In some embodiments, the compounds reduce and/or eliminate weak muscles, poor muscle tone, enlarged liver, failure to grow and gain weight, trouble breathing, feeding problems, infections in the respiratory system, problems with hearing, motor skill delay, heart enlargement, tiredness, lung infection, frequent falling, or irregular heartbeat. In some embodiments, the compounds herein delay progression of Pompe disease.

[1265] In some embodiments, the compounds provided herein increase the lifespan of the individual. In some embodiments, the lifespan is increased at least 5, at least 10, or at least 20 years upon treatment.

[1266] In some embodiments, the compounds provided herein prevent, reduce, or delay muscle weakness. In some embodiments, muscle weakness is determined by manual muscle testing, sit to stand test, heel-raise test, hand-held dynamometry, or hand grip dynamometry. In some embodiments, strength is graded according to the following scale: 0: No visible muscle contraction; 1: Visible muscle contraction with no or trace movement; 2: Limb movement, but not against gravity; 3: Movement against gravity but not resistance; 4: Movement against at least some resistance supplied by the examiner; 5: Full strength.

[1267] Also provided herein is a method of inhibiting a GYS1 enzyme in an individual comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the individual. In some embodiments the GYS1 enzyme is human GYS1 (hGYS1). In some embodiments, the compounds provided herein are inhibit GYS1 at a concentration of less than 10 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM. In some embodiments, the compounds provided herein inhibit GYS1 at a concentration of 1-10 μM, 0.01 to 1 μM, or 0.01 to 10 μM.

[1268] In some embodiments, the compounds have an IC.sub.50 of less than 10 nM, less than 10 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM. In some embodiments, the compounds provided herein have an IC.sub.50 of 1 to 10 nM, 1 to 10 μM, 0.01 to 1 μM, 0.01 to 10 μM, or 0.001 to 0.01 μM.

[1269] In some embodiments, glycogen synthesis is inhibited upon administration of a compound provided herein. In some embodiments, glycogen synthesis is reduced at least 10%, at least 20%, at least 40% or at least 50% upon administration.

[1270] In some embodiments, the individual receiving treatment is a juvenile human or an infant. In some embodiments, the individual is less than 10 years old, less than 9 years old, less than 8 years old, less than 7 years old, less than 6 years old, less than 5 years old, less than 4 years old, less than 3 years old, less than 2 years old, or less than one year old.

[1271] In some embodiments, the methods further comprise enzyme replacement therapy (ERT). Exemplary ERTs include alglucosidase alfa (human recombinant alpha-glucosidase (human GAA)) and those described in Byrne B J et al (2011). Pompe disease: design, methodology, and early findings from the Pompe Registry. Mol Genet Metab 103: 1-11 (herein incorporated by reference in its entirety). In some embodiments, the ERT is selected from the group consisting of Myozyme and Lumizyme. In some embodiments, the ERT is Myozyme. In some embodiments, the ERT is Lumizyme. In some embodiments, the individual has an advanced glycogen storage disease. In some embodiments, the individual has late onset Pompe Disease. Thus, provided herein is a method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising subjecting the individual to (a) glycogen substrate reduction therapy, such as administering to the individual an effective amount of (i) a GYS1 inhibitor, or (ii) a pharmaceutical composition comprising a GYS1 inhibitor, and one or more pharmaceutically acceptable excipients and (b) enzyme replacement therapy. In some embodiments, the GYS1-mediated disease, disorder, or condition is Pompe disease, such as late-onset Pompe disease. In some embodiments, the GYS1 inhibitor is a small molecule. In some embodiments, the GYS1 inhibitor is selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[1272] In some embodiments, the individual has a mutation in the GAA gene. In some embodiments, the mutation reduces the level of GAA protein. In some embodiments, the mutation is a loss-of-function mutation. In some embodiments, the mutation is a missense mutation. In some embodiments, the mutation is a deletion. In some embodiments, the mutation is a recessive mutation. In some embodiments, the mutation is a splicing variant.

[1273] In some embodiments of the foregoing, the administration is oral administration.

Kits

[1274] The present disclosure further provides kits for carrying out the methods of the invention. The kits may comprise a compound or pharmaceutically acceptable salt thereof as described herein and suitable packaging. The kits may comprise one or more containers comprising any compound described herein. In one aspect, a kit includes a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a label and/or instructions for use of the compound in the treatment of a disease or disorder described herein. The kits may comprise a unit dosage form of the compound.

[1275] Provided herein are kits, comprising (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating an GYS1-mediated disease, disorder, or condition in an individual in need thereof. Also provided herein are kits, comprising (i) a pharmaceutical composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients; and (ii) instructions for use in treating an GYS1-mediated disease, disorder, or condition in an individual in need thereof

[1276] Articles of manufacture are also provided, wherein the article of manufacture comprises a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in a suitable container. Also provided herein are articles of manufacture, comprising a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag.

ENUMERATED EMBODIMENTS

[1277] The following enumerated embodiments are also contemplated:

[1278] Embodiment 1. A compound of formula (I):

##STR00971##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: [1279] X.sup.1 and X.sup.2 are each independently H, C.sub.1-6alkyl, or C.sub.1-6alkoxy; [1280] X.sup.3 and X.sup.4 are each independently H, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, or 5-20 membered heteroaryl; [1281] X.sup.5 is H, C.sub.1-6alkyl, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl; [1282] Q.sup.1 is selected from (i) to (iii): [1283] (i) phenyl, wherein the phenyl of Q.sup.1 is substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), —NH—C(O)-(3-15 membered heterocyclyl), or C.sub.3-10cycloalkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl, [1284] (ii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo, and [1285] (iii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl; [1286] R.sup.1 is H or C.sub.1-6alkyl; [1287] R.sup.k is H, halo, —OH, —NH.sub.2, or —NH—C(O)C.sub.1-6alkyl; [1288] R.sup.m is H, —OH, or C.sub.1-6alkyl; [1289] R.sup.n is H, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl; [1290] or R.sup.k is taken together with either R.sup.m or R.sup.n, and the atoms to which they are attached, to form cyclopropyl; and [1291] R.sup.2 is selected from (i) to (vii): [1292] (i) C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is optionally substituted with one or more R.sup.a, wherein R.sup.a is: [1293] (a) —OH, [1294] (b) cyano, [1295] (c) C.sub.2-6alkynyl, [1296] (d) C.sub.6-20aryl, wherein the C.sub.6-20aryl of R.sup.a is optionally substituted with one or more halo, cyano, C.sub.1-6alkoxy, or —NH—C(O)—C.sub.1-6alkyl, [1297] (e) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b, wherein [1298] R.sup.b is halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, C.sub.3-10cycloalkyl, 3-15 membered heterocyclyl, or —C(O)—C.sub.1-6alkoxy, wherein [1299] the C.sub.1-6alkyl of R.sup.b is optionally substituted with one or more halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy, and [1300] the 3-15-membered heterocyclyl of R.sup.b is optionally substituted with one or more halo or —C(O)—C.sub.1-6alkoxy, [1301] (f) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c, wherein [1302] R.sup.c is halo, oxo, C.sub.1-6alkyl, C.sub.1-6alkoxy, —C(O)—C.sub.1-6alkyl, or —C(O)—C.sub.1-6alkoxy, wherein [1303] the C.sub.1-6alkyl of R.sup.c is optionally substituted with one or more halo or C.sub.2-6alkynyl, and [1304] the —C(O)—C.sub.1-6alkoxy of R.sup.c is optionally substituted with one or more halo, [1305] (g) —N(R.sup.c)(R.sup.d), wherein R.sup.c and R.sup.d are, independently of each other, H, C.sub.1-6alkyl, —C(O)—C.sub.1-6alkyl, —C(O)—C.sub.1-6alkoxy, —C(O)—NH.sub.2, —C(O)—NH(C.sub.1-6alkyl), —C(O)—N(C.sub.1-6alkyl).sub.2, —C(O)-(3-15 membered heterocyclyl), —CH.sub.2—C(O)—NH.sub.2, 3-15 membered heterocyclyl, or 5-20 membered heteroaryl, wherein [1306] the —C(O)—C.sub.1-6alkyl of R.sup.c or R.sup.d is optionally substituted with one or more halo, [1307] the 3-15 membered heterocyclyl and the 5-20 membered heteroaryl of R.sup.c or R.sup.d are independently optionally substituted with one or more C.sub.1-6alkyl, and [1308] the —C(O)-(3-15 membered heterocyclyl) of R.sup.c or R.sup.d is optionally substituted with one or more halo, —C(O)—C.sub.1-6alkoxy, or C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, [1309] (h) —O—R.sup.e, wherein R.sup.e is C.sub.1-6alkyl, C.sub.6-20aryl, —C(O)-(3-15 membered heterocyclyl), —C(O)—N—(C.sub.1-6alkyl).sub.2, or 5-20 membered heteroaryl, wherein [1310] the C.sub.1-6alkyl of R.sup.e is optionally substituted with one or more C.sub.1-6alkoxy, wherein the C.sub.1-6alkoxy is optionally substituted with one or more C.sub.2-6alkynyl, [1311] the C.sub.6-20aryl of R.sup.e is optionally substituted with one or more C.sub.1-6alkyl, and [1312] the —C(O)-(3-15 membered heterocyclyl) of R.sup.e is optionally substituted with one or more C.sub.1-6alkyl, C.sub.1-6alkoxy, or —C(O)—C.sub.1-6alkoxy, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, C.sub.1-6alkoxy, or C.sub.3-10cycloalkyl, [1313] (i) —C(O)—R.sup.e, wherein R.sup.e is —NH.sub.2, —OH, or 3-15 membered heterocyclyl, or [1314] (j) —S(O).sub.2—R.sup.f, wherein R.sup.f is C.sub.1-6alkyl or 3-15 membered heterocyclyl, provided that, when R.sup.2 is unsubstituted methyl, then either [1315] (1) Q.sup.1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, C.sub.3-10cycloalkyl, or —OH, or [1316] (2) Q.sup.1 is phenyl, wherein the phenyl of Q.sup.1 is substituted with at least one C.sub.3-6alkyl or at least one C.sub.3-10cycloalkyl, wherein the at least one C.sub.3-6alkyl is optionally substituted with one or more halo, and the at least one C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl, [1317] (ii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl of R.sup.2 is optionally substituted with one or more R.sup.q, wherein R.sup.q is 5-20 membered heteroaryl or C.sub.6-20aryl, wherein the C.sub.6-20aryl of R.sup.q is optionally substituted with one or more C.sub.1-6alkoxy, [1318] (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.2 is optionally substituted with one or more halo, oxo, C.sub.1-6alkyl, —C(O)—C.sub.1-6alkyl, or 5-20 membered heteroaryl, [1319] (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.2 is optionally substituted with one or more R.sup.s, wherein R.sup.s is C.sub.1-6alkyl, C.sub.1-6alkoxy, —NH—C(O)—C.sub.1-6alkyl, C.sub.6-20aryl, or 5-20 membered heteroaryl, wherein the C.sub.1-6alkyl of R.sup.s is optionally substituted with one or more C.sub.1-6alkoxy, [1320] (v) —N(R.sup.g)(R.sup.h), wherein R.sup.g and R.sup.h are independently H or C.sub.1-6alkyl, [1321] (vi) —C(O)—R.sup.j, wherein R.sup.j is C.sub.3-10cycloalkyl, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, or —NH (5-20 membered heteroaryl), and [1322] (vii) C.sub.6-20aryl, wherein the C.sub.6-20aryl of R.sup.2 is optionally substituted with one or more 5-20 membered heteroaryl or —O—R.sup.p, wherein R.sup.p is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.p is optionally substituted with one or more —C(O)—C.sub.1-6alkyl.

[1323] Embodiment 2. The compound of embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more C.sub.1-6alkyl or halo.

[1324] Embodiment 3. The compound of embodiment 1 or embodiment 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more C.sub.1-6alkyl or halo.

[1325] Embodiment 4. The compound of any one of embodiments 1-3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is pyridinyl, wherein the pyridinyl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more C.sub.1-6alkyl or halo.

[1326] Embodiment 5. The compound of any one of embodiments 1-4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is 2-pyridinyl or 3-pyridinyl, wherein the 2-pyridinyl or 3-pyridinyl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more C.sub.1-6alkyl or halo.

[1327] Embodiment 6. The compound of any one of embodiments 1-5, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is 2-pyridinyl, wherein the 2-pyridinyl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy, —NH.sub.2, or C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more C.sub.1-6alkyl or halo.

[1328] Embodiment 7. The compound of any one of embodiments 1-6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is 2-pyridinyl, wherein the 2-pyridinyl of Q.sup.1 is optionally substituted with one or more halo, C.sub.1-6alkyl, or C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more C.sub.1-6alkyl or halo.

[1329] Embodiment 8. The compound of any one of embodiments 1-7, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is 2-pyridinyl, wherein the 2-pyridinyl of Q.sup.1 is optionally substituted with one or more fluoro, chloro, methyl, iso-propyl, tert-butyl, cyclopropyl, or cyclobutyl, wherein the cyclopropyl and cyclobutyl are independently optionally substituted with one or more methyl or fluoro.

[1330] Embodiment 9. The compound of any one of embodiments 1-8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is selected from the group consisting of

##STR00972##

[1331] Embodiment 10. The compound of any one of embodiments 1-9, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is selected from the group consisting of

##STR00973##

[1332] Embodiment 11. The compound of embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is phenyl, wherein the phenyl of Q.sup.1 is substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6 alkenyl, —NH.sub.2, —NH—C(O)—(C.sub.1-6alkyl), —NH—C(O)-(3-15 membered heterocyclyl), or C.sub.3-10cycloalkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl.

[1333] Embodiment 12. The compound of embodiment 1 or embodiment 11, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is phenyl, wherein the phenyl of Q.sup.1 is substituted with one or more halo, C.sub.1-6alkyl, C.sub.2-6 alkenyl, or C.sub.3-10cycloalkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, and the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl.

[1334] Embodiment 13. The compound of any one of embodiments 1, 11 and 12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is phenyl, wherein the phenyl of Q.sup.1 is substituted with one or more fluoro, chloro, methyl, iso-propyl, sec-butyl, tert-butyl, prop-1-en-2-yl, cyclopropyl, or cyclobutyl, wherein the methyl, iso-propyl, sec-butyl, and tert-butyl are independently optionally substituted with one or more halo, and the cyclopropyl and cyclobutyl are independently optionally substituted with one or more fluoro or methyl.

[1335] Embodiment 14. The compound of any one of embodiments 1 and 11-13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is selected from the group consisting of

##STR00974##

[1336] Embodiment 15. The compound of any one of embodiments 1 and 11-13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is selected from the group consisting of

##STR00975##

[1337] Embodiment 16. The compound of embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q.sup.1 is optionally substituted with one or more oxo.

[1338] Embodiment 17. The compound of embodiment 1 or embodiment 16, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q.sup.1 is

##STR00976##

[1339] Embodiment 18. The compound of any one of embodiments 1-17, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X.sup.1, X.sup.2, X.sup.3, X.sup.4, and X.sup.5 are each H.

[1340] Embodiment 19. The compound of any one of embodiments 1-18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.m is H, R.sup.n is H, and R.sup.k is H, halo, —OH, —NH.sub.2, or —NH—C(O)C.sub.1-6alkyl.

[1341] Embodiment 20. The compound of any one of embodiments 1-19, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.m is H, R.sup.n is H, and R.sup.k is halo, —OH, or —NH.sub.2.

[1342] Embodiment 21. The compound of any one of embodiments 1-20, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.m is H, R.sup.n is H, and R.sup.k is halo.

[1343] Embodiment 22. The compound of any one of embodiments 1-21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.m is H, R.sup.n is H, and R.sup.k is fluoro.

[1344] Embodiment 23. The compound of any one of embodiments 1-18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.k is taken together with either R.sup.m or R.sup.n, and the atoms to which they are attached, to form cyclopropyl.

[1345] Embodiment 24. The compound of any one of embodiments 1-23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.1 is H.

[1346] Embodiment 25. The compound of any one of embodiments 1-24, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is optionally substituted with one or more R.sup.a.

[1347] Embodiment 26. The compound of any one of embodiments 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b.

[1348] Embodiment 27. The compound of any one of embodiments 1-26, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b.

[1349] Embodiment 28. The compound of any one of embodiments 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy.

[1350] Embodiment 29. The compound of any one of embodiments 1-28, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro.

[1351] Embodiment 30. The compound of any one of embodiments 1-29, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is selected from the group consisting of

##STR00977##

[1352] Embodiment 31. The compound of any one of embodiments 1-30, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is

##STR00978##

[1353] Embodiment 32. The compound of any one of embodiments 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c.

[1354] Embodiment 33. The compound of any one of embodiments 1-25 and 32, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c.

[1355] Embodiment 34. The compound of any one of embodiments 1-25, 32, and 33, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c.

[1356] Embodiment 35. The compound of any one of embodiments 1-25 and 32-34, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more oxo or C.sub.1-6alkyl.

[1357] Embodiment 36. The compound of any one of embodiments 1-25 and 32-35, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is

##STR00979##

[1358] Embodiment 37. The compound of any one of embodiments 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e.

[1359] Embodiment 38. The compound of any one of embodiments 1-25 and 37, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e.

[1360] Embodiment 39. The compound of any one of embodiments 1-25, 37, and 38, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e, wherein R.sup.e is —C(O)-(3-15 membered heterocyclyl).

[1361] Embodiment 40. The compound of any one of embodiments 1-25 and 37-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is

##STR00980##

[1362] Embodiment 41. The compound of any one of embodiments 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d).

[1363] Embodiment 42. The compound of any one of embodiments 1-25 and 41, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d).

[1364] Embodiment 43. The compound of any one of embodiments 1-25, 41, and 42, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d is —C(O)—N(C.sub.1-6alkyl).sub.2.

[1365] Embodiment 44. The compound of any one of embodiments 1-25 and 41-43, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is

##STR00981##

[1366] Embodiment 45. The compound of embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-A):

##STR00982##

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein [1367] Y.sup.1 is CH or N; [1368] R.sup.x and R.sup.z are independently H, halo, C.sub.1-6alkyl, or —NH.sub.2, wherein, when Y.sup.1 is CH, the C.sub.1-6alkyl of R.sup.x or R.sup.z may be optionally substituted with one or more halo; and [1369] R.sup.y is (i) C.sub.1-6alkyl, (ii) C.sub.2-6alkenyl, or (iii) C.sub.3-10cycloalkyl, wherein the C.sub.3-10cycloalkyl is optionally substituted with one or more halo or C.sub.1-6alkyl.

[1370] Embodiment 46. The compound of embodiment 1 or embodiment 45, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.x is H, fluoro, or methyl, and [1371] R.sup.y is (i) isopropyl, or (ii) C.sub.3-4cycloalkyl, wherein the C.sub.3-4cycloalkyl is optionally substituted with one or more fluoro or methyl.

[1372] Embodiment 47. The compound of any one of embodiments 1, 45, and 46, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.k is H or halo.

[1373] Embodiment 48. The compound of any one of embodiments 1-24, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is optionally substituted with one or more R.sup.a.

[1374] Embodiment 49. The compound of any one of embodiments 1 and 45-48, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b.

[1375] Embodiment 50. The compound of any one of embodiments 1 and 45-49, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more R.sup.b.

[1376] Embodiment 51. The compound of any one of embodiments 1 and 45-50, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more C.sub.1-6alkyl, wherein the C.sub.1-6alkyl is optionally substituted with one or more halo, —NH.sub.2, —NH(C.sub.1-6alkyl), —N(C.sub.1-6alkyl).sub.2, —NH—C(O)C.sub.1-6alkyl, or —NH—C(O)—C.sub.1-6alkoxy.

[1377] Embodiment 52. The compound of any one of embodiments 1 and 45-51, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R.sup.a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro.

[1378] Embodiment 53. The compound of any one of embodiments 1 and 45-52, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is selected from the group consisting of

##STR00983##

[1379] Embodiment 54. The compound of any one of embodiments 1 and 45-53, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is

##STR00984##

[1380] Embodiment 55. The compound of any one of embodiments 1 and 45-48, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c.

[1381] Embodiment 56. The compound of any one of embodiments 1, 45-48, and 55, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c.

[1382] Embodiment 57. The compound of any one of embodiments 1, 45-48, 55, and 56, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more R.sup.c.

[1383] Embodiment 58. The compound of any one of embodiments 1, 45-48, and 55-57, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R.sup.a is optionally substituted with one or more oxo or C.sub.1-6alkyl.

[1384] Embodiment 59. The compound of any one of embodiments 1, 45-48, and 55-58, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is

##STR00985##

[1385] Embodiment 60. The compound of any one of embodiments 1 and 45-48, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e.

[1386] Embodiment 61. The compound of any one of embodiments 1, 45-48, and 60, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e.

[1387] Embodiment 62. The compound of any one of embodiments 1, 45-48, 60, and 61, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —O—R.sup.e, wherein R.sup.e is —C(O)-(3-15 membered heterocyclyl).

[1388] Embodiment 63. The compound of any one of embodiments 1, 45-48, and 60-62, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is

##STR00986##

[1389] Embodiment 64. The compound of any one of embodiments 1, 45-48, and 60-63, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is C.sub.1-6alkyl, wherein the C.sub.1-6alkyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d).

[1390] Embodiment 65. The compound of any one of embodiments 1, 45-48, and 60-64, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R.sup.c)(R.sup.d).

[1391] Embodiment 66. The compound of any one of embodiments 1, 45-48, and 60-65, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is methyl, wherein the methyl of R.sup.2 is substituted with one or more R.sup.a, wherein R.sup.a is —N(R)(R.sup.d), wherein one of R.sup.c and R.sup.d is H, and the other of R.sup.c and R.sup.d is —C(O)—N(C.sub.1-6alkyl).sub.2.

[1392] Embodiment 67. The compound of any one of embodiments 1, 45-48, and 60-66, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R.sup.2 is

##STR00987##

[1393] Embodiment 68. The compound of embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from Table 1.

[1394] Embodiment 69. A pharmaceutical composition comprising (i) a compound of any one of embodiments 1-68, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

[1395] Embodiment 70. A method of modulating GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any one or embodiments 1-68, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of embodiment 69.

[1396] Embodiment 71. A method of inhibiting GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any one or embodiments 1-68, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of embodiment 69.

[1397] Embodiment 72. A method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual an effective amount of a compound of any one of embodiments 1-68, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of embodiment 69.

[1398] Embodiment 73. A method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a compound of any one of embodiments 1-68, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of embodiment 69.

[1399] Embodiment 74. The method of embodiment 73, wherein the disease, disorder, or condition is a glycogen storage disorder (GSD).

[1400] Embodiment 75. The method of embodiment 73 or embodiment 74, wherein the disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.

[1401] Embodiment 76. The method of any one of embodiments 73-75, wherein the disease, disorder, or condition is Pompe disease.

[1402] Embodiment 77. The method of embodiment 73, wherein the disease, disorder, or condition is cancer.

[1403] Embodiment 78. The method of embodiment 73 or embodiment 77, wherein the disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML).

[1404] Embodiment 79. The method of embodiment 73, wherein the individual has a GAA mutation.

[1405] Embodiment 80. The method of embodiment 79, wherein the GAA mutation is a loss-of-function mutation.

[1406] Embodiment 81. A kit, comprising (i) a compound of any one of embodiments 1-68, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of embodiment 69, and (ii) instructions for use in treating an GYS1-mediated disease, disorder, or condition in an individual in need thereof.

[1407] Embodiment 82. The kit of embodiment 81, wherein the disease, disorder, or condition is a glycogen storage disorder (GSD).

[1408] Embodiment 83. The kit of embodiment 81 or embodiment 82, wherein the disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.

[1409] Embodiment 84. The kit of any one of embodiments 81-83, wherein the disease, disorder, or condition is Pompe disease.

[1410] Embodiment 85. The kit of embodiment 81, wherein the disease, disorder, or condition is cancer.

[1411] Embodiment 86. The kit of embodiment 81 or embodiment 85, wherein the disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML).

[1412] Embodiment 87. The kit of embodiment 81, wherein the individual has a GAA mutation.

[1413] Embodiment 88. The kit of embodiment 87, wherein the GAA mutation is a loss-of-function mutation.

[1414] Embodiment 89. A method of modulating GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a GYS1 modulator, or a pharmaceutical composition comprising a GYS1 modulator.

[1415] Embodiment 90. A method of inhibiting GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a GYS1 inhibitor, or a pharmaceutical composition comprising a GYS1 inhibitor.

[1416] Embodiment 91. A method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual an effective amount of a GYS1 inhibitor, or a pharmaceutical composition comprising a GYS1 inhibitor.

[1417] Embodiment 92. A method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising subjecting the individual to glycogen substrate reduction therapy.

[1418] Embodiment 93. The method of embodiment 92, wherein the disease, disorder, or condition is a glycogen storage disorder (GSD).

[1419] Embodiment 94. The method of embodiment 92 or embodiment 93, wherein the disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.

[1420] Embodiment 95. The method of any one of embodiments 92-94, wherein the disease, disorder, or condition is Pompe disease.

[1421] Embodiment 96. The method of embodiment 92, wherein the disease, disorder, or condition is cancer.

[1422] Embodiment 97. The method of embodiment 92 or embodiment 96, wherein the disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML).

[1423] Embodiment 98. The method of embodiment 92, wherein the individual has a GAA mutation.

[1424] Embodiment 99. The method of embodiment 98, wherein the GAA mutation is a loss-of-function mutation.

[1425] Embodiment 100. The method of any one of embodiments 89-91 wherein the GYS1 inhibitor is selective for GYS1 over GYS2.

[1426] Embodiment 101. The method of embodiment 100, wherein the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2.

[1427] Embodiment 102. The method of any one of embodiments 92-99 wherein the glycogen substrate reduction therapy comprises administering to the individual a GYS1 inhibitor.

[1428] Embodiment 103. The method of embodiment 102, wherein the GYS1 inhibitor is a small molecule.

[1429] Embodiment 104. The method of embodiment 103, wherein the GYS1 inhibitor is selective for GYS1 over GYS2.

[1430] Embodiment 105. The method of embodiment 104, wherein the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2.

Methods of Preparing

[1431] The present disclosure further provides processes for preparing the compounds of present invention. In some aspect, provided herein are processes of preparing a compound of formula (I′) or formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-D1), (I-D2), (I-E), (I-F), (I-G), (I-H) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[1432] In some embodiments, a process for preparing a compound of formula (I′) or formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprises reacting a compound of formula (I′-1):

##STR00988##

or a salt thereof, with a compound of formula R.sup.2COOH in the presence of a coupling reagent.

[1433] In some embodiments, the coupling reagent comprises EDCCl, TCFH, or T3P. In some embodiments, the process further comprises the presence of a base. In some embodiments, the base comprises an amine. In some embodiments, the amine is DMAP, NMM, or a trialkylamine.

[1434] In some embodiments, a process for preparing a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprises [1435] (a) reacting a compound of formula (I′-2):

##STR00989## [1436] or a salt thereof, with a compound of formula (I′-3):

##STR00990##

wherein PG is a protecting group, [1437] in the presence of a coupling reagent to provide a compound of formula I′-4:

##STR00991## [1438] followed by [1439] (b) contacting the compound of formula (I′-4) with an acid to provide a compound of formula (I′).

[1440] In some embodiments, the protecting group is an oxycarbonyl group. In some embodiments the protecting group is a tert-butoxycarbonyl.

[1441] In some embodiments, the coupling reagent comprises EDCCl, TCFH, or T3P. In some embodiments, the process further comprises the presence of a base. In some embodiments, the base comprises an amine. In some embodiments, the amine is DMAP, NMM, or a trialkylamine.

[1442] In some embodiments the acid is HCl or TFA.

EXAMPLES

[1443] The following synthetic reaction schemes, which are detailed in the Schemes and Examples, are merely illustrative of some of the methods by which the compounds of the present disclosure, or an embodiment or aspect thereof, can be synthesized. Various modifications to these synthetic reaction schemes can be made, as will be apparent to those of ordinary skill in the art.

[1444] The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

[1445] Although certain exemplary embodiments are depicted and described herein, the compounds of the present disclosure, or any variation or embodiment thereof, may be prepared using appropriate starting materials according to the methods described generally herein and/or by methods available to one of ordinary skill in the art.

Synthetic Examples

[1446] As depicted in the Schemes and Examples below, in certain exemplary embodiments, compounds of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, are prepared according to the general procedures. The general methods below, and other methods known to synthetic chemists of ordinary skill in the art, can be applied to all formulae, variations, embodiments, and species described herein.

Schemes

[1447] ##STR00992## ##STR00993##

[1448] Compounds of the formula S1-10 may be prepared according to the general synthetic scheme outlined in Scheme 1.

[1449] Condensation of a chiral sulfinamide such as S1-2 with an aldehyde such as S1-1 provides sulfinimine S1-3. Addition of a reagent such as phenylmagnesium bromide at low temperature, followed by warming to ambient temperature provides benzhydryl sulfinamide S1-4. Sulfinamide S1-3 can be converted to the corresponding amine hydrochloride salt upon treatment with HCl in a solvent such as EtOAc. Amide bond formation between S1-5 and a substituted proline analog such as S1-6 may be achieved with a carbodiimide reagent such as EDCI and DMAP as a catalyst. Removal of the N-Boc group of S1-7 via treatment with a protic acid such as trifluoroacetic acid gives rise to amines such as S1-8. Proline amides such as S1-10 may then be generated by coupling with a carboxylic acid such as S1-9 using a coupling agent such as T3P and NMM as a base.

##STR00994## ##STR00995##

[1450] Compounds of the formula S2-12 may be prepared according to the general synthetic scheme outlined in Scheme 2.

[1451] Directed ortho-metalation of pyridine S2-1 with an amide base such as LDA in an aprotic solvent such as THF at −78° C. followed by reaction with a ketone such as acetone can generate pyridine S2-2. Treatment of S2-2 with a reducing agent such as triethyl silane and a protic acid such as trifluoroacetic acid generates a mixture of compounds, S2-3 and S2-4. This mixture can be converted to S2-3 by reduction with hydrogen gas and a metal catalyst such as PtO.sub.2. Metal-halogen exchange can be affected by treatment of S2-3 at −78° C. with n-butyllithium, and the pyridyllithium intermediate may then be reacted with sulfinimine S2-5 to generate S2-6. Treatment with a protic acid such as HCl generates the amine S2-7. Coupling of amine S2-7 with proline derivative S2-8 using TCFH and N-methylimidazole base gives rise to S2-9. Removal of the proline N-Boc group by treatment with a protic acid such as HCl, in an aprotic solvent such as 1,4-dioxane, provides amine S2-10. Amine S2-10 may then be reacted with carboxylic acid S2-11 to generate S2-12, using methods described in Scheme 1.

##STR00996## ##STR00997##

[1452] Compounds of the formulae S3-13 and S3-14 may be prepared according to the general synthetic scheme outlined in Scheme 3.

[1453] Condensation of racemic sulfinimide S3-2 with pyridyl aldehyde S3-1 generates sulfinimine S3-3. Reaction with arylmagnesium bromide S3-4 generates S3-5, as a racemate. A Suzuki cross-coupling of S3-5 with a boronic acid such as S3-6 using a palladium catalyst such as Pd(dppf)Cl.sub.2 and an inorganic base such as K.sub.3PO.sub.4 generates compound S3-7. Treatment of S3-7 with a protic acid such as HCl in an aprotic solvent mixture such as EtOAc/DCM provides amine S3-8. S3-8 may then be coupled with carboxylic acid S3-9 and processed to compounds S3-13 and S3-14 using methods outlined in Scheme 1. If desired, mixtures of stereoisomers may be further purified to provide S3-13 and S3-14 as single isomers, using methods such as reverse-phase HPLC or chiral SFC.

##STR00998## ##STR00999## ##STR01000##

[1454] Compounds of the formula S4-17 may be prepared according to the general synthetic scheme outlined in Scheme 4.

[1455] Reaction of pyridine S3-1 with an electrophilic brominating agent such as NBS gives pyridine S4-2. Suzuki cross-coupling with cyclopropylboronic acid, using a catalyst such as palladium acetate, a ligand such as tricyclohexyl phosphine, and an inorganic base such K.sub.3PO.sub.4 in a mixed solvent system such as 1,4-dioxane and water, provides S4-3. Conversion of S4-3 to pyridyl bromide S4-5 can be achieved with a Sandmeyer reaction under the action of isopentyl nitrite and cupric bromide in dibromomethane solvent. Suzuki cross coupling of potassium vinyltrifluoroborate with S4-6 using a palladium catalyst such as Pd(dppf)Cl.sub.2 and an inorganic base such as K.sub.3PO.sub.4. Oxidative cleavage of olefin S4-6 with NaIO.sub.4 and K.sub.2OsO.sub.4.2H.sub.2O in a THE generates aldehyde S4-7. Condensation with sulfinimide S4-8 generates sulfinimine S4-9. Reaction of S4-9 with aryl Grignard reagent S4-10 in a solvent such as DCM at low temperature gives rise to S4-11. Cleavage of sulfinimide S4-11 with a HCl in EtOAc generates amine salt S4-12. S4-12 may then be joined with carboxylic acid S4-13 using a coupling agent such as T3P and a base such as NMM in DMF to produce S4-14. Removal of the N-Boc group with HCl in EtOAc generates amine S4-15, which may then be processed to S4-17 using the procedure described in Scheme 3.

##STR01001##

[1456] Compounds of the general formula S5-14 can be prepared according to the general scheme outlined in Scheme 5.

[1457] Radical bromination of S5-1 with NBS and catalytic AIBN provides S5-2. Oxidation under the action NMMO gives aldehyde S5-3. Condensation of aldehyde with sulfinimide S5-4 using an inorganic base such as cesium carbonate provide sulfinimine S5-5. Addition of an aryl Grignard reagent such as phenylmagnesium bromide at low temperature provides S5-6. Cleavage of the sulfinimide to generate a primary amine salt can be achieved upon treatment with a protic acid such as HCl in a solvent such as EtOAc. Amide bond formation with proline derivative S5-8 proceeds as previously described to give S5-9. Photoredox coupling of triflate S5-10 with S5-9 using an iridium photocatalyst such as (Ir[dF(CF.sub.3)ppy].sub.2(dtbpy))PF.sub.6, a nickel co-catalyst such as NiCl.sub.2.glyme, a ligand such as 4,4-di-tert-butyl-2,2-bipyridyl, sodium carbonate as base, and tris(trimethylsilyl)silane and blue LED gives cyclobutyl adduct S5-11. Removal of the proline Boc protecting group with HCl in EtOAc, followed by amide bond formation under the action of T3P and NMM in DCM gives compounds of formula S5-14.

##STR01002## ##STR01003## ##STR01004##

[1458] Compounds of the general formula S6-19 can be prepared according to the general scheme outlined in Scheme 6.

[1459] Reduction of carboxylic acid S6-1 with borane-methylsulfide complex gives alcohol S6-2. Conversion of S6-2 to alkyl bromide S6-3 is achieved by treatment with triphenylphosphine and NBS in a solvent such as DCM. Selective displacement of the primary bromide can be achieved upon reaction with TMSCN and TBAF in acetonitrile to provide S6-4. Double alkylation of nitrile S6-4 with a di-triflate such as S6-5 gives rise to cyclobutane S6-6. Hydrolysis of the nitrile on treatment with sulfuric acid at elevated temperature gives acid S6-7. Decarboxylation can be achieved by reaction with KF in DMSO at high temperature to provide S6-8. Suzuki-type cross coupling with potassium vinyltrifluoroborate, a palladium catalyst such as tetrakis triphenylphosphine palladium(0) and a base such as cesium carbonate generates S6-9. Lemieux-Johnson oxidation of S6-9 gives aldehyde S6-10, which may then be condensed with sulfinimide S6-11 under conditions previously described to give S6-12. Addition of an aryl Grignard reagent such as phenylmagnesium bromide to S6-12 gives S6-13. Generation of primary amine salt S6-14 may occur upon treatment with HCl in dioxane. Coupling of S6-14 with proline derivative S6-15 using chloro-N,N,N,N′-tetramethylformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI) gives S6-16. Boc deprotection and proline amide bond formation as described in Scheme 5 gives compounds of formula S6-19.

##STR01005## ##STR01006##

[1460] Compounds of the general formulae S7-12 and S7-13 can be prepared according to the general scheme outlined in Scheme 7.

[1461] Condensation of sulfinimide S7-2 with aldehyde S7-1 as previously described, followed by addition of an aryl Grignard reagent such as phenylmagnesium bromide, gives S7-4. Generation of the amine salt and coupling with proline derivative S7-6 may be achieved under conditions previously described. Photoredox coupling of cyclobutyl bromide S7-8 under conditions like those described in Scheme 5 gives S7-9. As previously described, Boc deprotection and amide bond formation generates compounds of formula S7-12. A minor stereoisomer such as S7-13 may also be isolated at this stage.

##STR01007## ##STR01008## ##STR01009##

[1462] Compounds of the general formula 3 S8-14 and S8-15 can be prepared according to the general scheme outlined in Scheme 8.

[1463] An alternative generation of benzhydryl fragments begins with cross-coupling of S8-1 with isopropenylboronic acid pinacol ester with a catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and potassium carbonate as base in a mixed dioxane/water solvent at elevated temperature gives S8-2. Simmons-Smith cyclopropanation gives S8-3. Reduction of ester S8-3 with DIBAL-H, followed by oxidation with MnO.sub.2 gives aldehyde S8-5. Aldehyde S8-5 may then be processed over several steps previously described to give compounds of formula S8-14. Minor diastereomers which could not be separated in previous steps may be isolated at this stage, giving S8-15.

##STR01010## ##STR01011## ##STR01012##

[1464] Compounds of the general formula S9-15 can be prepared according to the general scheme outlined in Scheme 9.

[1465] An alternative approach to cyclopropane containing analogs begins with directed metalation of S9-1 with LDA and reaction with acetone to generate S9-2. Dehydration under the action of a protic acid such asp-toluene sulfonic acid in toluene at elevated temperature generates olefin S9-3. Cyclopropanation under conditions described in Scheme 8 gives S9-5. Partial reduction of S9-5 to aldehyde S9-6 can be achieved with DIBAL-H in THF at low temperature. Condensation of aldehyde S9-6 with racemic sulfinimide S9-7 gives S9-8. Addition of a Grignard reagent and deprotection under conditions previously described gives amine salt S9-10 as a racemate. Coupling with proline derivative S9-11 under standard conditions and Boc deprotection generates an intermediate which can be further purified by chiral SFC to give amine S9-13 as a single isomer. Conversion to compounds of formula S9-15 occurs under conditions previous described. If the R.sup.2 substituent bears stereogenic atoms that are mixtures, additional purification by chiral SFC may be utilized to generate single isomer analogs.

##STR01013##

[1466] Compounds of the general formula S10-5 can be prepared according to the general scheme outlined in Scheme 10.

[1467] An alternative approach to compounds of formula S10-5 starts with condensation of pyridine S10-1 with sulfinimide S10-2. Addition of an aryllithium reagent such as phenyllithium provides S10-4. Deprotection under standard conditions gives amine salts of formula S10-5, which may be further elaborated as described in the Schemes 1-9 and Schemes 11-15.

##STR01014## ##STR01015##

[1468] Compounds of the general formula S11-12 can be prepared according to the general scheme outlined in Scheme 11.

[1469] Yet another alternative approach to amine intermediates such as S11-6 starts with pyridine S11-1. Bis-carbamate formation, followed by treatment copper (II) triflate gives pyridine S11-3. Conversion of S11-3 to the corresponding Grignard reagent with isopropylmagnesium chloride-lithium chloride complex followed by addition to a racemic sulfinimine such as S11-4 gives S11-5. Selective cleavage of the sulfinamide may occur on reaction with iodine at elevated temperature. Coupling with proline derivative S11-7 and further processing to generate compounds of formula S11-12 occurs as previously described. If necessary, mixtures of stereoisomers may be further purified using chiral SFC, to generate compounds as single isomers.

##STR01016## ##STR01017##

[1470] Compounds of the general formula S12-9 can be prepared according to the general scheme outlined in Scheme 12.

[1471] An alternative sequence enabling late-stage elaboration of the benzhydryl moieties begins with lithiation of S12-1 and addition of sulfinimine S12-2. Oxidative cleavage with iodine generates S12-4. Coupling with proline derivative S12-5 generates S12-6. Cleavage of the Boc group with TFA generates amine S12-7. Treatment with an acylating agent such as methyl chloroformate and NMI as base gives bis-carbamate S12-8. Selective cleavage of the triazole carbamate moiety can be achieved by reaction with potassium carbonate and methanol at elevated temperature, to generate compounds of formula S12-9.

##STR01018##

[1472] Compounds of the general formula S13-5 can be prepared according to the general scheme outlined in Scheme 13.

[1473] Sulfonamides of formula S13-5 can be generated starting from 513-1. Boc cleavage as previously described gives S13-2. Reaction of S13-2 with sulfonyl chloride S13-3 using a tertiary amine base such as DIPEA gives S13-4. Cleavage of the triazole N-benzyl group occurs under standard hydrogenation conditions to give 513-5.

##STR01019##

[1474] Compounds of the general formulae S14-6 and S14-7 can be prepared according to the general scheme outlined in Scheme 14.

[1475] Bromobenzene analogs bearing heterocycles such as pyrazoles can undergo metalation using an excess of n-BuLi and addition to sulfinimines such as S14-2 to give adducts such as S14-3. Conversion to the amine HCl salt can occur under previously described conditions. Coupling with proline derivative S14-5 under previously described conditions gives compounds of formulae S14-6 and S14-7, which can be isolated as single isomers using methods such as reverse phase prep-HPLC or chiral SFC.

##STR01020##

[1476] Compounds of the general formula S15-10 and S15-11 can be prepared according to the general scheme outlined in Scheme 15.

[1477] An alternative strategy that enables late-stage elaboration to generate compounds of formulae 515-10 and 515-11 begins by selective metal-halogen exchange with 515-1 and addition to sulfinimine S15-2 to generate S15-3. Generation of the amine HCl salt and coupling to proline derivative S15-5 under conditions previously described gives S15-6. S16-6 may then undergo palladium catalyzed borylation to generate boronate ester S15-7. Suzuki-type cross coupling under conditions previously described, using an aryl or heteroaryl bromide such as S15-8 gives S15-9. Cleavage of the trityl protecting from the triazole moiety under protic acid conditions gives compounds of formula S15-10 and S15-11, which can be isolated as single isomers using methods such as flash column chromatography, reverse phase HPLC, or chiral SFC.

[1478] Abbreviations used are those conventional in the art and are in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75.sup.th Ed. The following examples are intended to be illustrative only and not limiting in any way.

TABLE-US-00002 ° C. degrees Celsius μL microliter [M + XX].sup.+ observed mass AC.sub.50 half-maximal activity concentration ACN acetonitrile app apparent (NMR) BH.sub.3•THF borane-tetrahydrofuran complex BBr.sub.3 boron tribromide Calc'd calculated Cbz-Cl benzyl chloroformate CO.sub.2 carbon dioxide Cs.sub.2CO.sub.3 cesium carbonate d deuterated (NMR solvents) d doublet (NMR) dd doublet of doublets (NMR) DCM dichloromethane DIAD diisopropyl azodicarboxylate DMF N,N-dimethylformamide EC.sub.50 half-maximal effective concentration EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ESI electrospray ionization EtOAc ethyl acetate EtOH ethanol eq equivalents g grams h hours H hydrogen HCl hydrochloric acid HPLC high-performance liquid chromatography IC.sub.50 half-maximal inhibitory concentration In vacuo in a vacuum IUPAC International Union of Pure and Applied Chemistry MHz megahertz J J-coupling value (NMR) K.sub.2CO.sub.3 potassium carbonate LDA lithium diisopropylamide LiHMDS lithium bis(trimethylsilyl)amide MeOH Methanol MeCN acetonitrile m multiplet (NMR) mg milligrams min minutes mL milliliter mmol millimole mM millimolar M molarity or molar MS mass spectrometry MsCl methanesulfonyl chloride MTBE methyl tert-butyl ether n/a not applicable NBS N-bromosuccinimide NH.sub.4 ammonium NH.sub.4OH ammonium hydroxide NH.sub.4HCO.sub.3 ammonium bicarbonate Na.sub.2SO.sub.4 sodium sulfate NaBH.sub.3CN sodium cyanoborohydride NMI N-methylimidazole NMM N-methylmorpholine NMR nuclear magnetic resonance NaOH sodium hydroxide PCy.sub.3 Tricyclohexylphosphine PdCl.sub.2(dppf) [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) pH potential of hydrogen PPh.sub.3 triphenyl phosphine s singlet (NMR) SFC super fluid chromatography t triplet (NMR) T3P Propanephosphonic acid anhydride TBAB tetrabutylammonium bromide TEA triethylamine TFA trifluoroacetic acid TFCH N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate THF tetrahydrofuran TMSCl trimethylsilyl chloride wt. % weight percent

Intermediate A-1: Synthesis of 2-(1H-1,2,3-triazol-5-yl)acetic acid

[1479] ##STR01021##

[1480] Step a: To a mixture of but-3-ynoic acid (7.5 g, 89.2 mmol, 1 eq), Cu(OAc).sub.2 (1.62 g, 8.92 mmol, 0.1 eq) and sodium ascorbate (3.53 g, 17.8 mmol, 0.2 eq) in H.sub.2O (75 mL) and t-BuOH (75 mL) at 0° C. was added, in portions, benzyl azide (BnN.sub.3, 13.9 g, 93.7 mmol, 90% purity, 1.05 eq). The resulting mixture was warmed to 25° C. and stirred for 12 h. The mixture was then filtered and the solids were washed with water (2×20 mL) and dried under reduced pressure to afford 2-(1-benzyl-1H-1,2,3-triazol-4-yl)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.11N.sub.3O.sub.2: 218.1; found 218.1.

[1481] Step b: A suspension of 2-(1-benzyl-1H-1,2,3-triazol-4-yl)acetic acid (5 g, 23 mmol, 1 eq) and Pd/C (2.45 g, 10% wt. %) in i-PrOH (300 mL) was stirred under H.sub.2 (50 psi) at 25° C. for 5 h. The reaction mixture was then filtered through a pad of Celite, and the filter cake was washed with CH.sub.2Cl.sub.2 (3×30 mL). The filtrate was concentrated under reduced pressure to give 2-(1H-1,2,3-triazol-5-yl)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.4H.sub.5N.sub.3O.sub.2: 128.1; found 128.1.

Intermediate A-2: Synthesis of 2-(5-(difluoromethyl)-1H-tetrazol-1-yl)acetic acid

[1482] ##STR01022##

[1483] Step a: To a solution of 2,2-difluoroacetic acid (50.0 g, 520 mmol, 1.00 eq) in dry DCM (200 mL) at 0° C. was added a catalytic amount of DMF (4 mL) and oxalyl dichloride (66.1 g, 520 mmol, 45.6 mL, 1.00 eq), sequentially. The resulting mixture was warmed to 20° C. and stirred for 1 h. The reaction mixture was then cooled to 0° C. and a solution of 2-ethoxy-2-oxoethan-1-aminium chloride (80.0 g, 573 mmol, 1.10 eq), TEA (105 g, 1.04 mol, 2.00 eq) and DMAP (7.37 g, 52.1 mmol, 0.10 eq) in DCM (500 mL) was added. The reaction mixture was warmed to 20° C. and stirred for 1 h. The reaction mixture was then quenched with water (100 mL) and extracted with dichloromethane (3×200 mL). The combined organic extracts were washed with brine (500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give ethyl (2,2-difluoroacetyl)glycinate. This compound was carried forward to the next step without further characterization.

[1484] Step b: To a solution of ethyl (2,2-difluoroacetyl)glycinate (25.0 g, 138 mmol, 1.00 eq) in toluene (250 mL) at 25° C. was added 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2λ.sup.5,4λ.sup.5-dithiadiphosphetane (Lawesson's reagent, 67.0 g, 165 mmol, 1.20 eq) under N.sub.2. The resulting mixture was warmed to 110° C. and stirred for 1 h. The reaction mixture was then cooled to 25° C., and poured into water (300 mL) and NaOCl (˜10% aqueous, 100 mL). The resulting mixture was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (2×200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give ethyl (2,2-difluoroethanethioyl)glycinate. This compound was carried forward to the next step without further characterization.

[1485] Step c: To a mixture of ethyl (2,2-difluoroethanethioyl)glycinate (12.5 g, 63.4 mmol, 1.00 eq) and azido(trimethyl)silane (14.6 g, 127 mmol, 2.00 eq) in DCM (120 mL) at 0° C. under N.sub.2 was added SnCl.sub.4 (41.2 g, 158 mmol, 2.50 eq). The resulting mixture was warmed to 25° C. and stirred for 2 h. The reaction mixture was then cooled to 0° C. and quenched by addition of saturated aqueous NaHCO.sub.3 (200 mL). The resulting biphasic mixture was extracted with DCM (2×100 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by silica gel chromatography to give ethyl 2-(5-(difluoromethyl)-1H-tetrazol-1-yl)acetate. This compound was carried forward to the next step without further characterization.

[1486] Step d: Ethyl 2-(5-(difluoromethyl)-1H-tetrazol-1-yl)acetate (6.50 g, 31.5 mmol, 1.00 eq) was dissolved in aqueous HCl (6 M, 65 mL) at 20° C. The resulting mixture was warmed to 100° C. and stirred for 20 h. The reaction mixture was then concentrated under reduced pressure to give 2-(5-(difluoromethyl)-1H-tetrazol-1-yl)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.4H.sub.4F.sub.2N.sub.4O.sub.2: 179.0; found 179.0.

Intermediate A-3: Synthesis of 2-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)acetic acid

[1487] ##STR01023##

[1488] Step a: To a solution of ethyl 2-azidoacetate (200 mg, 94% purity, 1.5 mmol, 1 eq) in toluene (5 mL) was added ethyl 4,4,4-trifluorobut-2-ynoate (500 mg, 3.0 mmol, 2 eq). The mixture was warmed to 115° C. and stirred for 16 h. The reaction mixture was then cooled to 0° C., quenched with MeOH (10 mL) and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give a mixture of ethyl 1-(2-ethoxy-2-oxoethyl)-4-(trifluoromethyl)-1H-1,2,3-triazole-5-carboxylate and ethyl 1-(2-ethoxy-2-oxoethyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylate. This compound was carried forward to the next step without further characterization.

[1489] Step b: To a mixture of ethyl 1-(2-ethoxy-2-oxoethyl)-4-(trifluoromethyl)-1H-1,2,3-triazole-5-carboxylate and ethyl 1-(2-ethoxy-2-oxoethyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylate (220.00 mg, 745 μmol, 1 eq) in 1:1 dioxane:H.sub.2O (4 mL) at 25° C. was added NaOH (60 mg, 1.1 mmol, 1.5 eq). The resulting mixture was stirred at for 16 h. The reaction mixture was then quenched with HCl (6 M, 1 mL) in H.sub.2O (10 mL) and extracted with DCM (3×20 mL). The aqueous phase was lyophilized to afford a crude solid, which was immediately dissolved in DMSO (3 mL). To the resulting mixture was added Ag.sub.2CO.sub.3 (140 mg, 508 μmol, 0.5 eq), followed by AcOH (6 mg, 100 μmol, 0.1 eq). The mixture was warmed to 130° C. and stirred for 16 h. The reaction mixture was then quenched with H.sub.2O (30 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (2×15 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by prep-HPLC to give 2-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl) acetic acid. LC-MS (ESI): m/z: [M−H].sup.− calculated for C.sub.5H.sub.4F.sub.3N.sub.3O.sub.2: 194.0; found 194.1.

Intermediate A-4: Synthesis of 2-(1H-benzo[d]imidazol-1-yl)acetic acid

[1490] ##STR01024##

[1491] Step a: To a solution of 1H-benzo[d]imidazole (10.0 g, 84.6 mmol, 1 eq) in DMF (100 mL) was added Cs.sub.2CO.sub.3 (33.1 g, 102 mmol, 1.2 eq) and tert-butyl 2-bromoacetate (18.2 g, 93.1 mmol, 1.1 eq). The mixture was stirred at 25° C. for 2 h. The reaction mixture was then filtered and the filtrate was diluted with EtOAc (200 mL). The combined organic extracts were washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give compound tert-butyl 2-(1H-benzo[d]imidazol-1-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.13H.sub.16N.sub.2O.sub.2: 233.1; found 233.1.

[1492] Step b: To a solution of tert-butyl 2-(1H-benzo[d]imidazol-1-yl)acetate (16.8 g, 72.3 mmol, 1 eq) in EtOAc (100 mL) was added HCl/EtOAc (4 M, 200 mL). The mixture was warmed to 60° C. and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure. The resulting crude product was triturated with petroleum ether at 25° C. for 10 min and filtered to give 2-(1H-benzo[d]imidazol-1-yl)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.9H.sub.8N.sub.2O.sub.2: 177.1; found 177.0.

Intermediate A-5: Synthesis of 2-(3-ethyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid

[1493] ##STR01025##

[1494] Step a: To a mixture of iodoethane (1.27 g, 8.15 mmol, 3 eq) and 2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid (500 mg, 2.72 mmol, 1 eq) in DMF (6 mL) at 20° C. under N.sub.2 was added K.sub.2CO.sub.3 (1.88 g, 13.5 mmol, 5 eq) in one portion. The resulting mixture was warmed to 70° C. and stirred for 2 h. After this time, the reaction mixture was cooled to 0° C., and the reaction was quenched by addition H.sub.2O (30 mL). The resulting biphasic mixture was then extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a crude residue that was purified by column chromatography to obtain ethyl 2-(3-ethyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.16N.sub.2O.sub.4: 241.1; found 241.1.

[1495] Step b: To a solution of ethyl 2-(3-ethyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate (450 mg, 1.87 mmol, 1 eq) in THF (5 mL) and H.sub.2O (5 mL) at 20° C. under N.sub.2 was added LiOH (89.7 mg, 3.75 mmol, 2 eq) in one portion. The resulting mixture was stirred at 20° C. for 2 h. After this time, the reaction mixture was diluted with H.sub.2O (20 mL), and the pH of the solution was adjusted to pH=3 by addition of aqueous HCl (2M). The resulting mixture was then extracted with EtOAc (3×10 mL). The combined organic extracts were then washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to obtain 2-(3-ethyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.9H.sub.12N.sub.2O.sub.4: 213.1; found 213.1.

Intermediate A-6: Synthesis of 2-((azetidine-1-carbonyl)oxy)acetic acid

[1496] ##STR01026##

[1497] Step a: To a solution of benzyl 2-hydroxyacetate (0.96 g, 5.78 mmol, 821 μL, 1 eq) in THF (10 mL) at 0° C. was added triphosgene (686 mg, 2.31 mmol, 0.4 eq) followed by DIPEA (2.09 g, 16.2 mmol, 2.82 mL, 2.8 eq), and the resulting mixture was stirred at 0° C. for 0.5 h before it was warmed to 25° C. and stirred for 0.5 h. A solution of azetidine (330 mg, 5.78 mmol, 390 μL, 1 eq) in THF (10 mL) and DIPEA (1.05 g, 8.09 mmol, 1.41 mL, 1.4 eq) were then added, and the resulting mixture was stirred at 25° C. for 12 h. The reaction mixture was then diluted with saturated aqueous NaHCO.sub.3 (20 mL), and the resulting biphasic mixture was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 2-(benzyloxy)-2-oxoethyl azetidine-1-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.13H.sub.15NO.sub.4: 250.1; found 250.2.

[1498] Step b: To a mixture of 2-(benzyloxy)-2-oxoethyl azetidine-1-carboxylate (250 mg, 1.00 mmol, 1 eq) in DCE (5 mL) at 25° C. under N.sub.2 was added TEA (20.3 mg, 200 μmol, 27.9 μL, 0.2 eq), Pd(OAc).sub.2 (56.3 mg, 251 μmol, 0.25 eq) and Et.sub.3SiH (233 mg, 2.01 mmol, 320 μL, 2 eq). The resulting mixture was stirred at 60° C. for 2 h before it was filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure to give 2-((azetidine-1-carbonyl)oxy)acetic acid. LC-MS (ESI): m/z: [M−H].sup.− calculated for C.sub.6H.sub.9NO.sub.4: 158.0; found 158.1.

[1499] The following compounds in Table B-1 were synthesized using procedures similar to Intermediate A-6 using the appropriate starting materials.

TABLE-US-00003 TABLE B-1 Exact Intermediate mass No. Structure IUPAC (g/mol) LCMS, Found [M + H].sup.+ B-1-1 [01027] embedded image 2-((4-(tert- butoxycarbonyl)piper- azine-1- carbonyl)oxy)acetic acid 288.1 189.1 [M − Boc + H].sup.+

Intermediate A-7: Synthesis of 2-(1-benzyl-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1H-1,2,3-triazol-5-yl)acetic acid

[1500] ##STR01028##

[1501] Step a: To a mixture of but-3-ynoic acid (5.00 g, 59.5 mmol, 1.00 eq) in benzyl alcohol (19.3 g, 178 mmol, 18.6 mL, 3.00 eq) at 25° C. was added aqueous HCl (12 M, 297 μL, 37.0% purity, 0.06 eq) in one portion. The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then quenched by addition of H.sub.2O (30 mL) at 25° C., and the resulting biphasic mixture was extracted with EtOAc (3×10 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give benzyl but-3-ynoate. This compound was carried forward to the next step without further characterization.

[1502] Step b: To a mixture of benzyl azide (3.00 g, 22.5 mmol, 1.00 eq) in THF (45 mL) at 25° C. under N.sub.2 was added LiI (12.1 g, 90.1 mmol, 3.46 mL, 4.00 eq), copper (II) perchlorate hexahydrate (16.7 g, 45.1 mmol, 2.00 eq), and tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA, 1.20 g, 2.25 mmol, 0.100 eq) in one portion. The resulting mixture was stirred at 25° C. for 5 min before TEA (2.28 g, 22.5 mmol, 3.14 mL, 1.00 eq) and benzyl but-3-ynoate (4.32 g, 24.8 mmol, 1.10 eq) were added, and the resulting mixture was stirred at 30° C. for 6 h. The reaction mixture was then quenched by addition H.sub.2O (30 mL), and the resulting biphasic mixture was extracted with EtOAc (3×10 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give benzyl 2-(1-benzyl-4-iodo-1H-1,2,3-triazol-5-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.18H.sub.16IN.sub.3O.sub.2: 434.0; found 434.1.

[1503] Step c: To a mixture of tert-butyl piperazine-1-carboxylate (645 mg, 3.46 mmol, 5.00 eq) and benzyl 2-(1-benzyl-4-iodo-1H-1,2,3-triazol-5-yl)acetate (300 mg, 693 μmol, 1.00 eq) in toluene (10 mL) at 25° C. under N.sub.2 was added XPhos (83.0 mg, 173 μmol, 0.250 eq), Pd(OAc).sub.2 (34.0 mg, 152 μmol, 0.220 eq) and Cs.sub.2CO.sub.3 (677 mg, 2.08 mmol, 3.00 eq) in one portion. The resulting mixture was stirred at 80° C. for 6 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl 4-(1-benzyl-5-(2-(benzyloxy)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.27H.sub.33N.sub.5O.sub.4: 492.2; found 492.3.

[1504] Step d: To a mixture of tert-butyl 4-(1-benzyl-5-(2-(benzyloxy)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate (200 mg, 406 μmol, 1.00 eq) in DCE (5 mL) at 25° C. under N.sub.2 were added TEA (8.0 mg, 81.3 μmol, 11.3 μL, 0.2 eq), Et.sub.3SiH (95.0 mg, 813 μmol, 130 μL, 2.00 eq), Pd(OAc).sub.2 (23.0 mg, 102 μmol, 0.250 eq) in one portion. The resulting mixture was stirred at 25° C. for 60 min before it was quenched by addition H.sub.2O (10 mL). The resulting biphasic mixture was then extracted with EtOAc (3×10 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 2-(1-benzyl-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1H-1,2,3-triazol-5-yl)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.20H.sub.27N.sub.5O.sub.4: 402.2; found 402.3.

[1505] The following compounds in Table B-2 were synthesized using procedures similar to Intermediate A-7 using the appropriate starting materials.

TABLE-US-00004 TABLE B-2 Exact Intermediate mass No. Structure IUPAC (g/mol) LCMS, Found [M + H].sup.+ B-2-1 [01029] embedded image 2-(1-benzyl-4- morpholino-1H- 1,2,3-triazol-5- yl)acetic acid 302.1 303.2

Intermediate A-8: Synthesis of 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-hydroxyacetic acid

[1506] ##STR01030##

[1507] Step a: To a solution of 2-(1-benzyl-1H-1,2,3-triazol-4-yl)acetic acid (2.00 g, 9.21 mmol, 1 eq) in MeOH (20 mL) at 25° C. was added SOCl.sub.2 (109.54 mg, 920.71 μmol, 66.79 μL, 0.1 eq). The resulting mixture was warmed to 70° C. and stirred for 3 h. The reaction mixture was then quenched with water (20 mL), and the resulting biphasic mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give methyl 2-(1-benzyl-1H-1,2,3-triazol-4-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.12H.sub.13N.sub.3O.sub.2: 232.1; found 232.1.

[1508] Step b: To a solution of methyl 2-(1-benzyl-1H-1,2,3-triazol-4-yl)acetate (500 mg, 2.16 mmol, 1 eq) and 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (847.45 mg, 3.24 mmol, 1.5 eq) in THF (5 mL) at −65° C. under N.sub.2 was added NaHMDS (1 M in THF, 3.24 mL, 1.5 eq) in THF (5 mL) in a dropwise manner. The resulting mixture was stirred at −65° C. for 2 h. The reaction mixture was adjusted to pH=7 by addition of saturated aqueous NH.sub.4Cl solution. The resulting biphasic solution was extracted with EtOAc (3×10 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-hydroxyacetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.11N.sub.3O.sub.3: 234.1; found 234.1.

Intermediate A-9: Synthesis of 2-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)acetic acid

[1509] ##STR01031##

[1510] Step a: To a solution of 3-bromo-2-hydrazineylpyridine (2 g, 10.6 mmol, 1 eq) in THF (20 mL) at 0° C. was added CDI (2.24 g, 13.8 mmol, 1.3 eq). The resulting mixture was warmed to 25° C. and stirred for 2 h. The mixture was then poured into water (20 mL), resulting in the precipitation of a solid. The mixture was then filtered, and the filter cake was washed with water. The washed solid was then dried under reduced pressure to give 8-bromo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.6H.sub.4BrN.sub.3O: 214.0; found 213.9.

[1511] Step b: To a mixture of 8-bromo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (500 mg, 2.34 mmol, 1 eq) and Pd(t-Bu.sub.3P).sub.2 (239 mg, 467 μmol, 0.2 eq) in THF (30 mL) was added (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (1 M in THF, 14.02 mL, 6 eq). The resulting mixture was degassed and purged with N.sub.2, and then the mixture was warmed to 80° C. and stirred for 2 h under N.sub.2 atmosphere. The mixture was then filtered, and H.sub.2O (10 mL) was added to the filtrate. The resulting biphasic mixture was extracted with EtOAc (2×10 mL). The combined organic extracts were washed with brine (2×15 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl 2-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)acetate. LC-MS (ESI): m/z: [M−H].sup.− calculated for C.sub.12H.sub.15N.sub.3O.sub.3: 248.1; found 248.1.

[1512] Step c: To a solution of tert-butyl 2-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)acetate (50 mg, 201 μmol, 1 eq) in DCM (2 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL, 67.3 eq). The resulting mixture was stirred at 25° C. for 15 h. The mixture was then concentrated under reduced pressure to give 2-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)acetic acid. LC-MS (ESI): m/z: [M−CO.sub.2H−H].sup.− calculated for C.sub.8H.sub.7N.sub.3O.sub.3: 148.1; found 148.2.

Intermediate A-10: Synthesis of 2-(2-methylquinolin-5-yl)acetic acid

[1513] ##STR01032##

[1514] Step a: To a mixture of methyl 2-(2-chloroquinolin-5-yl)acetate (200 mg, 849 μmol, 1 eq) and dimethylzinc (1 M in toluene, 2.55 mL, 3.00 eq) in dioxane (2 mL) at 25° C. under N.sub.2 was added Pd(dppf)Cl.sub.2 (124 mg, 170 μmol, 0.20 eq) in one portion. The mixture was then degassed and charged with N.sub.2. The reaction mixture was then warmed to 75° C. and stirred for 1 h. The reaction mixture was then cooled to 25° C. and poured into water (10 mL). The resulting biphasic mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 2-(2-methylquinolin-5-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.13H.sub.13NO.sub.2: 216.1; found 216.1.

[1515] Step b: Methyl 2-(2-methylquinolin-5-yl)acetate (90 mg, 418 μmol, 1.00 eq) was added to aqueous HCl (6 M, 0.5 mL) in one portion at 25° C. The reaction mixture was then warmed to 100° C. and stirred for 16 h. The reaction mixture was then concentrated under reduced pressure to give 2-(2-methylquinolin-5-yl)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.12H.sub.11NO.sub.2: 202.1; found 202.1.

[1516] The following compounds in Table B-3 were synthesized using procedures similar to Intermediate A-10 using the appropriate starting materials.

TABLE-US-00005 TABLE B-3 Exact Intermediate mass No. Structure IUPAC (g/mol) LCMS, Found [M + H].sup.+ B-3-1 [01033] embedded image 2-(2- methylquinolin-6- yl)acetic acid 201.1 202.2

Intermediate A-11: Synthesis of 2-(5-(difluoromethyl)-2H-tetrazol-2-yl)acetic acid

[1517] ##STR01034##

[1518] Step a: A mixture of ethyl 1H-tetrazole-5-carboxylate (25.0 g, 175 mmol, 1.00 eq), tert-butyl 2-bromoacetate (37.7 g, 193 mmol, 28.5 mL, 1.10 eq) and TEA (26.7 g, 263 mmol, 36.7 mL, 1.50 eq) in THF (250 mL) was warmed to 80° C. and stirred for 1 h. The reaction mixture was then cooled and quenched with water (200 mL), and the resulting biphasic mixture was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (400 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give ethyl 2-(2-(tert-butoxy)-2-oxoethyl)-2H-tetrazole-5-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.16N.sub.4O.sub.4: 257.1; found 257.1.

[1519] Step b: To a solution of ethyl 2-(2-(tert-butoxy)-2-oxoethyl)-2H-tetrazole-5-carboxylate (35.0 g, 136 mmol, 1.00 eq) in THF (180 mL) at −20° C. under N.sub.2 was added DIBAL-H (1 M in THF, 273 mL, 2.00 eq) in a dropwise manner. The mixture was then warmed to 20° C. and stirred for 1 h. The mixture was then cooled to 0° C. and quenched with water (300 mL) before it was stirred for 10 min. The resulting biphasic mixture was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl 2-(5-(hydroxymethyl)-2H-tetrazol-2-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.14N.sub.4O.sub.3: 215.1; found 215.1.

[1520] Step c: To a solution of tert-butyl 2-(5-(hydroxymethyl)-2H-tetrazol-2-yl)acetate (2.00 g, 9.34 mmol, 1.00 eq) in DCM (20 mL) at 20° C. was added PCC (4.02 g, 18.6 mmol, 2.00 eq) and silica gel (4.00 g). The resulting mixture was stirred at 20° C. for 40 h. The reaction mixture was then diluted with water (20 mL), and the resulting biphasic mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl 2-(5-formyl-2H-tetrazol-2-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.12N.sub.4O.sub.3: 213.1; found 213.1.

[1521] Step d: To a solution of tert-butyl 2-(5-formyl-2H-tetrazol-2-yl)acetate (400 mg, 1.88 mmol, 1.00 eq) in DCM (4 mL) at 20° C. was added BAST (1.25 g, 5.64 mmol, 1.24 mL, 3.00 eq). The resulting mixture was stirred for 1 h. The mixture was then diluted with water (10 mL), and the resulting biphasic mixture was extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl 2-(5-(difluoromethyl)-2H-tetrazol-2-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.12F.sub.2N.sub.4O.sub.2: 235.1; found 235.1.

[1522] Step e: A solution of tert-butyl 2-(5-(difluoromethyl)-2H-tetrazol-2-yl)acetate (200 mg, 853 μmol, 1.00 eq) in HCl/EtOAc (4 M, 3 mL) was stirred at 20° C. for 16 h. The reaction mixture was then concentrated under reduced pressure to give 2-(5-(difluoromethyl)-2H-tetrazol-2-yl)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.4H.sub.4F.sub.2N.sub.4O.sub.2: 179.0; found 179.0.

Intermediate A-12: Synthesis of 2-methyl-2-(1,3,4-oxadiazol-2-yl)propanoic acid

[1523] ##STR01035##

[1524] Step a: To a solution of benzyl tert-butyl malonate (4.5 g, 17.9 mmol, 1 eq) in DMF (40 mL) at 20° C. was added Cs.sub.2CO.sub.3 (14.6 g, 44.9 mmol, 2.5 eq) and iodomethane (10.2 g, 71.9 mmol, 4.48 mL, 4 eq). The resulting mixture was then warmed to 50° C. and stirred for 2 h. The reaction mixture was then cooled to 0° C. and quenched by addition of H.sub.2O (30 mL). The resulting biphasic mixture was then extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (3×50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 1-benzyl 3-(tert-butyl) 2,2-dimethylmalonate, which was carried forward to the next step without further characterization.

[1525] Step b: To a solution of 1-benzyl 3-(tert-butyl) 2,2-dimethylmalonate (4.6 g, 16.5 mmol, 1 eq) in DCM (40 mL) at 25° C. was added TFA (15.0 g, 132 mmol, 9.8 mL, 8.00 eq), and the resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was then concentrated under reduced pressure to give 3-(benzyloxy)-2,2-dimethyl-3-oxopropanoic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.12H.sub.14O.sub.4: 223.1; found 223.1.

[1526] Step c: To a solution of 3-(benzyloxy)-2,2-dimethyl-3-oxopropanoic acid (1 g, 4.50 mmol, 1 eq) and tert-butyl hydrazinecarboxylate (654 mg, 4.95 mmol, 1.1 eq) in DMF (10 mL) at 0° C. was added triethylamine (1.37 g, 13.5 mmol, 1.88 mL, 3 eq) and HATU (1.88 g, 4.95 mmol, 1.1 eq). The resulting mixture was warmed to 25° C. and stirred for 2 h. The reaction mixture was then quenched by addition of H.sub.2O (30 mL), and the resulting biphasic mixture was then extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (40 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl 2-(3-(benzyloxy)-2,2-dimethyl-3-oxopropanoyl)hydrazine-1-carboxylate, which was carried forward to the next step without further characterization.

[1527] Step d: To a solution of tert-butyl 2-(3-(benzyloxy)-2,2-dimethyl-3-oxopropanoyl)hydrazine-1-carboxylate (1 g, 2.97 mmol, 1 eq) in EtOAc (20 mL) at 25° C. was added HCl in EtOAc (4 M, 17.4 mL, 23.6 eq). The resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was then concentrated under reduced pressure to give benzyl 3-hydrazineyl-2,2-dimethyl-3-oxopropanoate, which was carried forward to the next step without further characterization.

[1528] Step e: To a solution of benzyl 3-hydrazineyl-2,2-dimethyl-3-oxopropanoate (0.7 g, 2.50 mmol, 1 eq) in trimethoxymethane (10 mL) at 25° C. was added 4-methylbenzenesulfonic acid (43.0 mg, 249 μmol, 0.1 eq). The resulting mixture was warmed to 105° C. and stirred for 12 h. The reaction mixture was then cooled and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give benzyl 2-methyl-2-(1,3,4-oxadiazol-2-yl)propanoate, which was carried forward to the next step without further characterization.

[1529] Step f: To a solution of benzyl 2-methyl-2-(1,3,4-oxadiazol-2-yl)propanoate (0.4 g, 1.62 mmol, 1 eq), TEA (32.8 mg, 324 μmol, 45.2 μL, 0.2 eq) and tert-butyldimethylsilane (378 mg, 3.25 mmol, 2 eq) in DCE (5 mL) at 25° C. under N.sub.2 was added Pd(OAc).sub.2 (91.2 mg, 406 μmol, 0.25 eq). The resulting mixture was warmed to 60° C. and stirred for 4 h. The reaction mixture was then filtered through a pad of Celite, and the pad was washed with EtOAc (2×200 mL). The combined filtrates were concentrated under reduced pressure, and the crude residue obtained was purified by prep-HPLC to give 2-methyl-2-(1,3,4-oxadiazol-2-yl)propanoic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.6H.sub.8N.sub.2O.sub.3: 157.0; found 157.1.

Intermediate A-13: Synthesis of 2-(5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1H-1,2,3-triazol-1-yl)acetic acid

[1530] ##STR01036##

[1531] Step a: To a solution of 5-bromo-1H-1,2,3-triazole (2.0 g, 13.5 mmol, 1 eq) and ethyl 2-bromoacetate (3.39 g, 20.3 mmol, 2.2 mL, 1.5 eq) in DMSO (15 mL) was added DIPEA (5.24 g, 40.6 mmol, 7.06 mL, 3 eq). The resulting mixture was warmed to 50° C. and stirred for 4 h. The reaction mixture was then cooled to 0° C. and quenched by addition of H.sub.2O (20 mL), and the resulting biphasic mixture was then extracted with EtOAc (2×20 mL). The combined organic extracts were washed with H.sub.2O (20 mL) and brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(5-bromo-1H-1,2,3-triazol-1-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.6H.sub.8BrN.sub.3O.sub.2: 234.0; found 234.0.

[1532] Step b: To a mixture of ethyl 2-(5-bromo-1H-1,2,3-triazol-1-yl)acetate (250 mg, 1.07 mmol, 1 eq), tert-butyl piperazine-1-carboxylate (1 g, 5.4 mmol, 5 eq), Cs.sub.2CO.sub.3 (1.1 g, 3.2 mmol, 3 eq), and XPhos (113 mg, 0.12 eq) in toluene (10 mL) was added Pd(OAc).sub.2 (60 mg, 0.12 eq). The resulting mixture was then degassed and placed under an N.sub.2 atmosphere. The reaction mixture was then warmed to 100° C. and stirred for 16 h. The reaction mixture was then cooled to room temperature and filtered through a pad of Celite, and the filter cake was washed with toluene (2×10 mL). The combined filtrates were then concentrated under reduced pressure, and the crude residue obtained was purified by column chromatography to give tert-butyl 4-(1-(2-ethoxy-2-oxoethyl)-1H-1,2,3-triazol-5-yl)piperazine-1-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.15H.sub.25N.sub.5O.sub.4: 340.2; found 340.1.

[1533] Step c: To a solution of tert-butyl 4-(1-(2-ethoxy-2-oxoethyl)-1H-1,2,3-triazol-5-yl)piperazine-1-carboxylate (95 mg, 280 μmol, 1 eq) in MeOH (4 mL) was added LiOH.H.sub.2O (23.5 mg, 560 μmol, 2 eq), and the resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was then concentrated under reduced pressure, and the residue obtained was dissolved in H.sub.2O (5 mL). The resulting aqueous solution was extracted with EtOAc (2×5 mL), and then the aqueous phase was adjusted to pH 5-6 with aqueous HCl (3 M). The resulting aqueous solution was then extracted with EtOAc (2×6 mL), and the combined organic extracts were washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 2-(5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1H-1,2,3-triazol-1-yl)acetic acid. LC-MS (ESI): m/z: [M−t-Bu+H].sup.+ calculated for C.sub.13H.sub.21N.sub.5O.sub.4: 256.1; found 256.0.

[1534] The following compounds in Table B-4 were synthesized using procedures similar to Intermediate A-13 using the appropriate starting materials.

TABLE-US-00006 TABLE B-4 Exact Intermediate mass No. Structure IUPAC (g/mol) LCMS, Found [M + H].sup.+ B-4-1 [01037] embedded image 2-(5-(3,3- difluoroazetidin-1- yl)-1H-1,2,3- triazol-1-yl)acetic acid 218.1 391.0 B-4-2 [01038] 2-(5-(azetidin-1- yl)-1H-1,2,3- triazol-1-yl)acetic acid 182.1 183.2

Intermediate A-14: Synthesis of 2-(4-(dimethylamino)-1H-1,2,3-triazol-1-yl)acetic acid

[1535] ##STR01039##

[1536] Step a: To a mixture of 5-nitro-1H-1,2,3-triazole (11.3 g, 99.1 mmol, 1 eq) and ethyl 2-bromoacetate (24.8 g, 149 mmol, 16.4 mL, 1.5 eq) in DMSO (100 mL) at 25° C. was added DIPEA (38.4 g, 297 mmol, 51.8 mL, 3 eq), and the resulting mixture was stirred at 25° C. for 3 h. The reaction mixture was then cooled to 0° C. and quenched by addition of H.sub.2O (100 mL), and the resulting biphasic mixture was then extracted with EtOAc (2×70 mL). The combined organic extracts were washed with H.sub.2O (50 mL) and brine (2×50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(4-nitro-1H-1,2,3-triazol-1-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.6H.sub.8N.sub.4O.sub.4: 201.0; found 201.0.

[1537] Step b: To a solution of ethyl 2-(4-nitro-1H-1,2,3-triazol-1-yl)acetate (11 g, 54.9 mmol, 1 eq) in EtOAc (300 mL) was added Pd/C (1.5 g, 10% purity) under N.sub.2. The suspension was then degassed under vacuum and placed under an H.sub.2 atmosphere. The resulting mixture was then stirred under H.sub.2 (15 psi) at 25° C. for 8 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to give ethyl 2-(4-amino-1H-1,2,3-triazol-1-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.6H.sub.10N.sub.4O.sub.2: 171.1; found 171.1.

[1538] Step c: A mixture of ethyl 2-(4-amino-1H-1,2,3-triazol-1-yl)acetate (8 g, 47.0 mmol, 1 eq) and paraformaldehyde (14.1 g, 470 mmol, 10 eq) in AcOH (100 mL) was stirred at 25° C. for 60 min. The reaction mixture was then cooled to 0° C. before NaBH.sub.3CN (8.86 g, 141 mmol, 3 eq) was added in one portion. The resulting mixture was warmed to 25° C. and stirred for 15 h. The reaction mixture was then cooled to 0° C. and quenched by addition H.sub.2O (100 mL). The pH of the resulting mixture was adjusted to pH=6 using aqueous NaOH (4 M) before it was filtered. The filtrate was then extracted with EtOAc (2×150 mL). The combined organic extracts were washed with brine (2×100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(4-(dimethylamino)-1H-1,2,3-triazol-1-yl)acetate, which was carried forward to the next step without further characterization.

[1539] Step d: To a solution of ethyl 2-(4-(dimethylamino)-1H-1,2,3-triazol-1-yl)acetate (7 g, 35.3 mmol, 1 eq) in MeOH (70 mL) and H.sub.2O (20 mL) at 25° C. was added LiOH.H.sub.2O (2.96 g, 70.6 mmol, 2 eq). The resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was then concentrated under reduced pressure. The aqueous solution obtained was then adjusted to pH 5-6 using aqueous HCl (3 M), and the resulting mixture was concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give 2-(4-(dimethylamino)-1H-1,2,3-triazol-1-yl)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.6H.sub.10N.sub.4O.sub.2: 171.1; found 171.1.

[1540] The following compounds in Table B-5 were synthesized using procedures similar to Intermediate A-14 using the appropriate starting materials.

TABLE-US-00007 TABLE B-5 Exact Intermediate mass No. Structure IUPAC (g/mol) LCMS, Found [M + H].sup.+ B-5-1 [01040] embedded image 2-(5- (dimethylamino)- 1H-1,2,3-triazol-1- yl)acetic acid 170.1 171.1 B-5-2 [01041] 2-(5- (diethylamino)-1H- 1,2,3-triazol-1- yl)acetic acid 198.1 199.0

Intermediate A-15: Synthesis of (2-methylpyrimidin-4-yl)glycine

[1541] ##STR01042##

[1542] Step a: To a solution of 4-chloro-2-methylpyrimidine (300 mg, 2.33 mmol, 1 eq) in i-PrOH (3.00 mL) at 25° C. was added TEA (708 mg, 7.00 mmol, 3 eq) and tert-butyl 2-aminoacetate (367 mg, 2.80 mmol, 1.2 eq). The resulting mixture was warmed to 80° C. and stirred for 2 h. The reaction mixture was then quenched by addition H.sub.2O (10 mL), and the resulting biphasic mixture was then extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (2×10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (2-methylpyrimidin-4-yl)glycinate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.17N.sub.3O.sub.2: 224.1; found 224.1.

[1543] Step b: To a solution of tert-butyl (2-methylpyrimidin-4-yl)glycinate (310 mg, 1.39 mmol, 1 eq) in EtOAc (1.00 mL) was added HCl in EtOAc (4 M, 3 mL, 8.64 eq). The resulting mixture was stirred at 25° C. for 4 h. The reaction mixture was then concentrated under reduced pressure to give (2-methylpyrimidin-4-yl)glycine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.7H.sub.9N.sub.3O.sub.2: 168.1; found 168.1.

[1544] The following compounds in Table B-6 were synthesized using procedures similar to Intermediate A-15 using the appropriate starting materials.

TABLE-US-00008 TABLE B-6 Exact Intermediate mass No. Structure IUPAC (g/mol) LCMS, Found [M + H].sup.+ B-6-1 [01043] embedded image N-methyl-N-(2- methylpyrimidin-4- yl)glycine 181.1 182.1

Intermediate A-16: Synthesis of (3,3-difluoroazetidine-1-carbonyl)glycine

[1545] ##STR01044##

[1546] Step a: To a solution of tert-butyl 2-aminoacetate (1.00 g, 7.62 mmol, 1 eq) in THF (10 mL) at 0° C. under N.sub.2 was added CDI (1.36 g, 8.39 mmol, 1.1 eq) and DIPEA (2.96 g, 22.9 mmol, 3 eq). The resulting mixture was stirred at 0° C. for 1 h. 3,3-difluoroazetidine (987 mg, 7.62 mmol, 1 eq, HCl salt) was then added, and the resulting mixture was warmed to 60° C. and stirred for 1 h. The reaction mixture was then diluted with H.sub.2O (50 mL) and filtered. The filter cake was washed with H.sub.2O (20 mL), and the washed solid was dried under reduced pressure to give tert-butyl (3,3-difluoroazetidine-1-carbonyl)glycinate. LC-MS (ESI): m/z: [M−t-Bu+H+H].sup.+ calculated for C.sub.10H.sub.16F.sub.2N.sub.2O.sub.3: 195.0; found 195.0.

[1547] Step b: A solution tert-butyl (3,3-difluoroazetidine-1-carbonyl)glycinate (1.3 g, 5.19 mmol, 1 eq) in HCl in dioxane (4 M, 30 mL) was stirred at 20° C. for 1 h. The reaction mixture was then concentrated under reduced pressure, and the crude residue obtained was triturated with MTBE (20 mL) to give (3,3-difluoroazetidine-1-carbonyl)glycine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.6H.sub.8F.sub.2N.sub.2O.sub.3: 195.0; found 195.0.

[1548] The following compounds in Table B-7 were synthesized using procedures similar to Intermediate A-16 using the appropriate starting materials.

TABLE-US-00009 TABLE B-7 Exact Intermediate mass No. Structure IUPAC (g/mol) LCMS, Found [M + H].sup.+ B-7-1 [01045] embedded image (azetidine-1- carbonyl)glycine 158.1 159.1

Intermediate A-17: Synthesis of N-(1-ethyl-1H-1,2,3-triazol-4-yl)-N-methylglycine

[1549] ##STR01046##

[1550] Step a: To a solution of 4-nitro-1H-1,2,3-triazole (4.00 g, 35.1 mmol, 1 eq) in DMA (80 mL) at 0° C. was added NaH (1.47 g, 36.8 mmol, 60% purity, 1.05 eq). The resulting mixture was stirred at 0° C. for 0.5 h. EtI (8.20 g, 52.6 mmol, 4.21 mL, 1.5 eq) was then added in one portion, and the resulting mixture was warmed to 20° C. and stirred for 3 h. The reaction mixture was then quenched with H.sub.2O (150 mL), and the resulting biphasic mixture was extracted with EtOAc (2×50 mL). The combined organic extracts were concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 1-ethyl-4-nitro-1H-1,2,3-triazole. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.4H.sub.6N.sub.4O.sub.2: 143.0; found 143.1.

[1551] Step b: A mixture of 1-ethyl-4-nitro-1H-1,2,3-triazole 1.6 g, 11.3 mmol, 1 eq) and Pd/C (400 mg, 10% purity) in EtOH (20 mL) was degassed with H.sub.2. The degassed mixture was then warmed to 40° C. and stirred under H.sub.2 (50 psi) for 3 h. The reaction mixture was then cooled and filtered, and the filtrate was concentrated under reduced pressure to give 1-ethyl-1H-1,2,3-triazol-4-amine, which was carried forward to the next step without further purification or characterization.

[1552] Step c: A mixture of 1-ethyl-1H-1,2,3-triazol-4-amine (600 mg, 5.35 mmol, 1 eq) and Cs.sub.2CO.sub.3 (1.74 g, 5.35 mmol, 1 eq) in DMF (3 mL) was stirred at 25° C. for 0.5 h before tert-butyl 2-bromoacetate (1.15 g, 5.89 mmol, 1.1 eq) was added in one portion, and the resulting mixture was warmed to 50° C. and stirred for 12 h. The reaction mixture was then quenched with H.sub.2O (10 mL) and extracted with EtOAc (2×20 mL). The organic extracts were concentrated under reduced pressure, and the crude residue obtained was purified by column chromatography to give tert-butyl (1-ethyl-1H-1,2,3-triazol-4-yl)glycinate. LC-MS (ESI): m/z: [M−t-Bu+H+H].sup.+ calculated for C.sub.10H.sub.18N.sub.4O.sub.2: 171.1; found 171.1.

[1553] Step d: To a solution of tert-butyl (1-ethyl-1H-1,2,3-triazol-4-yl)glycinate (280 mg, 1.24 mmol, 1 eq) in DMA (2 mL) at 0° C. was added NaH (49 mg, 1.24 mmol, 60% purity, 1 eq), and the resulting mixture was stirred at 0° C. for 0.5 h. CH.sub.3I (175 mg, 1.24 mmol, 1 eq) was then added, and the resulting mixture was warmed to 20° C. and stirred for 3 h. The mixture was then quenched with H.sub.2O (10 mL), and the biphasic mixture was extracted with EtOAc (2×10 mL). The organic extracts were concentrated under reduced pressure, and the crude residue obtained was purified by prep-TLC to give tert-butyl N-(1-ethyl-1H-1,2,3-triazol-4-yl)-N-methylglycinate. LC-MS (ESI): m/z: [M−t-Bu+H+H].sup.+ calculated for C.sub.11H.sub.20N.sub.4O.sub.2: 185.1; found 185.1.

[1554] Step e: A solution of tert-butyl N-(1-ethyl-1H-1,2,3-triazol-4-yl)-N-methylglycinate (130 mg, 541 μmol, 1 eq) in TFA (2.00 g, 17.56 mmol, 32.5 eq) was stirred at 50° C. for 1 h. The reaction mixture was then cooled and concentrated under reduced pressure to give N-(1-ethyl-1H-1,2,3-triazol-4-yl)-N-methylglycine, which was used without any additional purification. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.7H.sub.12N.sub.4O.sub.2: 185.1; found 185.2.

[1555] The following compounds in Table B-8 were synthesized using procedures similar to Intermediate A-17 using the appropriate starting materials.

TABLE-US-00010 TABLE B-8 Exact Intermediate mass No. Structure IUPAC (g/mol) LCMS, Found [M + H].sup.+ B-8-1 [01047] embedded image (1-ethyl-1H-1,2,3- triazol-4-yl)glycine 170.1 171.1 B-8-2 [01048] N-(2-ethyl-2H- 1,2,3-triazol-4-yl)- N-methylglycine 184.1 185.1 B-8-3 [01049] (2-ethyl-2H-1,2,3- triazol-4-yl)glycine 170.1 171.1

Intermediate A-18: Synthesis of 2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetic acid

[1556] ##STR01050##

[1557] Step a: To a solution of 5-(chloromethyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 678 μmol, 1 eq) in MeCN (2 mL) at 0° C. was added TMSCN (100 mg, 1.02 mmol, 127 μL, 1.5 eq) and TBAF (1 M in THF, 1.02 mL, 1.5 eq). The resulting mixture was warmed to 20° C. and stirred for 3 h. The reaction mixture was then quenched with H.sub.2O (5 mL) and extracted with EtOAc (2×10 mL). The organic extracts were then concentrated under reduced pressure to give 2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetonitrile. LC-MS (ESI): m/z: [M−H].sup.− calculated for C.sub.5H.sub.6N.sub.4O: 137.0; found 137.2.

[1558] Step b: A mixture of 2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetonitrile (30 mg, 217 μmol, 1 eq) in aqueous HCl (12 M, 7.60 mL) was stirred at 60° C. for 1 h. The mixture was then concentrated under reduced pressure to give 2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetic acid. LC-MS (ESI): m/z: [M−H].sup.− calculated for C.sub.5H.sub.7N.sub.3O.sub.3: 156.0; found 156.2.

[1559] The following compounds in Table B-9 were synthesized using procedures similar to Intermediate A-18 using the appropriate starting materials.

TABLE-US-00011 TABLE B-9 Exact Intermediate mass No. Structure IUPAC (g/mol) LCMS, Found [M + H].sup.+ B-9-1 [01051] embedded image 2-(1-methyl-5-oxo- 4,5-dihydro-1H- 1,2,4-triazol-3- yl)acetic acid 157.0 156.1 [M − H].sup.−

Intermediate A-19: Synthesis of 1-trityl-1H-indazole-6-carbaldehyde

[1560] ##STR01052##

[1561] Step a: To a solution of 6-bromo-1H-indazole (8 g, 40.6 mmol, 1 eq) in DMF (50 mL) was added trityl chloride (TrtCl, 12.4 g, 44.6 mmol, 1.1 eq) and TEA (7.06 mL, 50.7 mmol, 1.25 eq). The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water, and the resulting biphasic mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was triturated with MTBE (30 mL) and filtered to give 6-bromo-1-trityl-1H-indazole, which was carried forward to the next step without further purification or characterization.

[1562] Step b: To a mixture of 6-bromo-1-trityl-1H-indazole (16.7 g, 38.0 mmol, 1 eq), potassium vinyltrifluoroborate (10.1 g, 76.0 mmol, 2 eq) and TEA (15.8 mL, 14.0 mmol, 3 eq) in i-PrOH (160 mL), was added Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (1.55 g, 1.90 mmol, 0.05 eq) under N.sub.2. The resulting mixture was then degassed and placed under an N.sub.2 atmosphere. The reaction mixture was then warmed to 100° C. and stirred for 2 h under N.sub.2. After cooling, the mixture was filtered, and the filter cake was washed with ethyl acetate (3×100 mL). The combined filtrates were concentrated, and the crude residue obtained was purified by column chromatography to give 1-trityl-6-vinyl-1H-indazole LC-MS (ESI): m/z: [2M+Na].sup.+ calculated for C.sub.28H.sub.22N.sub.2: 795.4; found 795.3.

[1563] Step c: To a solution of 1-trityl-6-vinyl-1H-indazole (14.2 g, 36.7 mmol, 1 eq) in THF:H.sub.2O (5:1) (300 mL) at 0° C. was added NaIO.sub.4 (31.4 g, 146 mmol, 4 eq) and K.sub.2OsO.sub.4.2H.sub.2O (676 mg, 1.84 mmol, 0.05 eq). The resulting mixture was warmed to 50° C. and stirred for 1 h. The reaction mixture was then cooled to 25° C. and quenched with sat. aq. Na.sub.2S.sub.2O.sub.3 (100 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL), and the combined extracts were dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 1-trityl-1H-indazole-6-carbaldehyde.

Intermediate A-20: Synthesis of 3-(isoxazol-5-yl)benzaldehyde

[1564] ##STR01053##

[1565] Step a: To a solution of 1-(3-bromophenyl)ethan-1-one (18.5 g, 92.9 mmol, 1 eq) in toluene (150 mL) was added N,N-dimethylformamide dimethyl acetal (37 mL, 346 mmol, 3.7 eq) at 20° C. The resulting mixture was warmed to 120° C. and stirred for 1 h. The reaction mixture was then cooled to 20° C. and quenched with water (100 mL), and the resulting biphasic mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (E)-1-(3-bromophenyl)-3-(dimethylamino)prop-2-en-1-one. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.12BrNO: 254.1; found 254.1.

[1566] Step b: To a solution of (E)-1-(3-bromophenyl)-3-(dimethylamino)prop-2-en-1-one (8 g, 31.4 mmol, 1 eq) in EtOH (50 mL) was added NH.sub.2OH.HCl (2.63 g, 37.7 mmol, 1.2 eq). The resulting mixture was warmed to 85° C. and stirred for 2 h. The reaction mixture was then cooled to 25° C. and quenched with water (50 mL), and the resulting biphasic mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 5-(3-bromophenyl)isoxazole. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.9H.sub.6BrNO: 224.0; found 224.1.

[1567] Step c: To a mixture of 5-(3-bromophenyl)isoxazole (8 g, 28.5 mmol, 1 eq), potassium vinyltrifluoroborate (7.65 g, 57.1 mmol, 2 eq) and TEA (11.9 mL, 85.6 mmol, 3 eq) in i-PrOH (50 mL) was added Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (1.17 g, 1.43 mmol, 0.05 eq) under N.sub.2. The resulting mixture was degassed and placed under N.sub.2, and the reaction mixture was then warmed to 100° C. and stirred for 1 h. The reaction mixture was then cooled, quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 5-(3-vinylphenyl)isoxazole. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.9NO: 172.1; found 172.1.

[1568] Step d: To a solution of 5-(3-vinylphenyl)isoxazole (1.8 g, 10.5 mmol, 1 eq) in THF (50 mL) and H.sub.2O (10 mL) was added NaIO.sub.4 (9.00 g, 42.0 mmol, 4 eq) and potassium osmate dihydrate (194 mg, 525 μmol, 0.05 eq). The resulting mixture was warmed to 50° C. and stirred for 1 h. The reaction mixture was then cooled and quenched with water (50 mL), and the resulting biphasic mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 3-(isoxazol-5-yl)benzaldehyde. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.7NO.sub.2: 174.0; found 174.0.

Intermediate A-21: Synthesis of 2-(5-(diethylamino)-1H-1,2,3-triazol-1-yl)acetic acid

[1569] ##STR01054##

[1570] Step a: A mixture of ethyl 2-azidoacetate (8 g, 61.9 mmol, 7.08 mL, 1 eq), (iodoethynyl)trimethylsilane (15.2 g, 68.1 mmol, 1.1 eq), copper iodide (1.18 g, 6.20 mmol, 0.1 eq), DIPEA (16.0 g, 123 mmol, 21.5 mL, 2 eq) and 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium ditetrafluoroborate (F-TEDA, 32.9 g, 92.9 mmol, 1.5 eq) in H.sub.2O (80 mL) was degassed and placed under an N.sub.2 atmosphere. The reaction mixture was then stirred for 16 h. The reaction mixture was then diluted with water and extracted with EtOAc (2×200 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(5-iodo-1H-1,2,3-triazol-1-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.6H.sub.8IN.sub.3O.sub.2: 282.0; found 281.9.

[1571] Step b: To a solution of ethyl 2-(5-iodo-1H-1,2,3-triazol-1-yl)acetate (700 mg, 2.49 mmol, 1 eq) in toluene (5 mL) was added N-ethylethanamine (911 mg, 12.4 mmol, 5 eq) and Cs.sub.2CO.sub.3 (1.62 g, 4.98 mmol, 2 eq). The resulting mixture was degassed and placed under an N2 atmosphere, and then XPhos (949 mg, 1.99 mmol, 0.8 eq) and Pd(OAc).sub.2 (112 mg, 498 μmol, 0.2 eq) were added. The resulting mixture was then degassed and placed under an N.sub.2 atmosphere, warmed to 100° C., and stirred for 16 h. After cooling, the reaction mixture was concentrated under reduced pressure. Water (15 mL) was added, and the resulting mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (3×10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(5-(diethylamino)-1H-1,2,3-triazol-1-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.18N.sub.4O.sub.2: 227.1; found 227.2.

[1572] Step c: To a solution of ethyl 2-(5-(diethylamino)-1H-1,2,3-triazol-1-yl)acetate (200 mg, 883 μmol, 1 eq) in THF (2 mL) at 0° C. was added LiOH (23.3 mg, 972 μmol, 4.85 mL, 1.1 eq) in water (0.5 mL), and the resulting mixture was warmed to 25° C. and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give 2-(5-(diethylamino)-1H-1,2,3-triazol-1-yl)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.14N.sub.4O.sub.2: 199.1; found 199.2.

Intermediate A-22: Synthesis of 2-(5-(difluoromethyl)-1H-1,2,3-triazol-1-yl)acetic acid

[1573] ##STR01055##

[1574] Step a: To a solution of ethynyltriisopropylsilane (15 g, 82.3 mmol, 18.5 mL, 1 eq) in THF (200 mL) at −70° C. was added n-BuLi (2.5 M in hexane, 29.6 mL, 0.9 eq) in a dropwise manner. After 30 min, DMF (10.8 g, 148 mmol, 11.39 mL, 1.8 eq) was added in a dropwise manner, and the resulting mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was then quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 3-(triisopropylsilyl)propiolaldehyde.

[1575] Step b: To a solution of ethyl 2-azidoacetate (2.56 g, 19.8 mmol, 1 eq) in toluene (60 mL) was added 3-(triisopropylsilyl)propiolaldehyde (5 g, 23.8 mmol, 1.2 eq). The resulting mixture was then warmed to 80° C. and stirred for 16 h. After cooling, the reaction mixture was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(5-formyl-4-(triisopropylsilyl)-1H-1,2,3-triazol-1-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.16H.sub.29N.sub.3O.sub.3Si: 340.2; found 340.3.

[1576] Step c: To a solution of ethyl 2-(5-formyl-4-(triisopropylsilyl)-1H-1,2,3-triazol-1-yl)acetate (4.5 g, 13.3 mmol, 1 eq) in DCM (40 mL) at 0° C. was added DAST (5.34 g, 33.1 mmol, 2.5 eq) dropwise in a dropwise manner. The resulting mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was then slowly added into ice-water (50 mL), and the resulting biphasic mixture was extracted with DCM (3×50 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and filtered, concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(5-(difluoromethyl)-4-(triisopropylsilyl)-1H-1,2,3-triazol-1-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.16H.sub.29F.sub.2N.sub.3O.sub.2Si: 362.2; found 362.3.

[1577] Step d: To a solution of 2-(5-(difluoromethyl)-4-(triisopropylsilyl)-1H-1,2,3-triazol-1-yl)acetate (1 g, 2.77 mmol, 1 eq) in THF (20 mL) was added TBAF (1.45 g, 5.53 mmol, 2 eq). The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then poured into ice-water (20 mL), and the resulting biphasic mixture was extracted with EtOAc (2×20 mL). The water phase was adjusted to pH 3-4 with aqueous HCl (2N) and then extracted with EtOAc (3×30 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure to give 2-(5-(difluoromethyl)-1H-1,2,3-triazol-1-yl)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.5H.sub.5F.sub.2N.sub.3O.sub.2: 178.0; found 178.0.

Intermediate A-23: Synthesis of 2-(1-ethyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)acetic acid

[1578] ##STR01056##

[1579] Step a: To a solution of 3-bromo-5-methylpyridin-2(1H)-one (5 g, 26.6 mmol, 1 eq) and K.sub.2CO.sub.3 (7.35 g, 53.2 mmol, 2 eq) in DMSO (30 mL) was added iodoethane (5.39 g, 34.6 mmol, 1.3 eq). The resulting mixture was warmed to 40° C. and stirred for 4 h. The reaction mixture was then cooled and quenched with H.sub.2O (30 mL), and the resulting biphasic mixture was then extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 3-bromo-1-ethyl-5-methylpyridin-2(1H)-one. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.10BrNO: 216.0; found 216.1.

[1580] Step b: A mixture of 3-bromo-1-ethyl-5-methylpyridin-2(1H)-one (0.1 g, 462 μmol, 1 eq), tert-butyl((1-methoxyvinyl)oxy)dimethylsilane (261 mg, 1.39 mmol, 3 eq), LiF (72.0 mg, 2.78 mmol, 6 eq), and bis(tri-tert-butylphosphine)palladium(0) (23.6 mg, 46.2 μmol, 0.1 eq) in DMF (4 mL) was degassed and placed under an N.sub.2 atmosphere. The reaction mixture was then warmed to 100° C. under in a microwave and stirred for 2 h. The reaction mixture was then cooled and quenched with H.sub.2O (10 mL), and the resulting biphasic mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 2-(1-ethyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.15NO.sub.3: 210.1; found 210.1.

[1581] Step c: To a solution of methyl 2-(1-ethyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)acetate (0.25 g, 1.19 mmol, 1 eq) in EtOH (3 mL) was added a solution of LiOH.H.sub.2O (100 mg, 2.39 mmol, 2 eq) in H.sub.2O (1 mL). The resulting mixture was stirred for 2 h and then concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give 2-(1-ethyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.13NO.sub.3: 196.1; found 196.2.

Intermediate A-24: Synthesis of 2-(5-oxo-4,5-dihydropyrazin-2-yl)acetic acid

[1582] ##STR01057##

[1583] Step a: To a solution of 2,5-dibromopyrazine (2 g, 8.41 mmol, 1 eq) in DMF (20 mL) was added K.sub.2CO.sub.3 (1.51 g, 10.9 mmol, 1.3 eq) and diethyl propanedioate (1.62 g, 10.1 mmol, 1.52 mL, 1.2 eq). The resulting mixture was warmed to 110° C. and stirred for 4 h. The reaction mixture was then cooled and diluted with H.sub.2O (10 mL). The resulting biphasic mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (2×20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give diethyl 2-(5-bromopyrazin-2-yl)malonate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.13BrN.sub.2O.sub.4: 317.0; found 317.0.

[1584] Step b: Diethyl 2-(5-bromopyrazin-2-yl)malonate (700 mg, 2.21 mmol, 1 eq) was added to aqueous KOH (10 M, 7 mL), and the resulting mixture was warmed to 120° C. and stirred for 16 h. The reaction mixture was then cooled to room temperature, and the pH was adjusted to pH=1 with aqueous HCl (6 N). The reaction mixture was then concentrated under reduced pressure, and the crude residue obtained was purified by prep-HPLC to give 2-(5-oxo-4,5-dihydropyrazin-2-yl)acetic acid. LC-MS (ESI): m/z: [M−H].sup.− calculated for C.sub.6H.sub.6N.sub.2O.sub.3: 153.0; found 153.1.

Intermediate A-25: Synthesis of 2-(4-(azetidin-1-yl)-2H-1,2,3-triazol-2-yl)acetic acid

[1585] ##STR01058##

[1586] Step a: A mixture of 1H-1,2,3-triazole (10 g, 144 mmol, 1 eq) and N-iodosuccinimide (81.4 g, 361 mmol, 2.5 eq) in NMP (100 mL) under N.sub.2 atmosphere was warmed to 80° C. and stirred for 1 h. The reaction mixture was then cooled to 0° C. and quenched with saturated aqueous Na.sub.2SO.sub.3 (15 mL). The resulting precipitate was collected by filtration. The solid was then diluted with H.sub.2O (50 mL), and the resulting mixture was extracted with EtOAc (2×50 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 4,5-diiodo-1H-1,2,3-triazole. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.2H.sub.12N.sub.3: 321.8; found 321.8.

[1587] Step b: A mixture of 5-diiodo-1H-1,2,3-triazole (4 g, 12.4 mmol, 1 eq) and Na.sub.2SO.sub.3 (4.71 g, 37.4 mmol, 3 eq) in H.sub.2O (40 mL) under N.sub.2 atmosphere was warmed to 80° C. and stirred for 2 h. The reaction mixture was then cooled and diluted with H.sub.2O (20 mL). The resulting biphasic mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 4-iodo-1H-1,2,3-triazole, which was carried forward without further purification. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.2H.sub.21N.sub.3: 195.9; found 195.9.

[1588] Step c: To a mixture of 4-iodo-1H-1,2,3-triazole (2 g, 10.2 mmol, 1 eq) and tert-butyl 2-bromoacetate (5 g, 25.6 mmol, 2.50 eq) in DMSO (20 mL) under N.sub.2 atmosphere was added DIPEA (3.98 g, 30.7 mmol, 3 eq). The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then quenched with H.sub.2O (30 mL), and the resulting biphasic mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl 2-(4-iodo-2H-1,2,3-triazol-2-yl)acetate, which was carried forward to the next step without further characterization.

[1589] Step d: To a solution of tert-butyl 2-(4-iodo-2H-1,2,3-triazol-2-yl)acetate (1 g, 3.24 mmol, 1 eq) in dry toluene (25 mL) was added azetidine (923 mg, 16.2 mmol, 5 eq), Cs.sub.2CO.sub.3 (3.16 g, 9.71 mmol, 3 eq), and XPhos (1.23 g, 2.59 mmol, 0.8 eq) at 25° C., The resulting mixture was then degassed and placed under an N.sub.2 atmosphere before Pd(OAc).sub.2 (145 mg, 647 μmol, 0.2 eq) was added. The resulting mixture was then degassed, placed under an N.sub.2 atmosphere, warmed to 100° C., and stirred for 16 h. The reaction mixture was then cooled, and water (30 mL) was added. The resulting biphasic mixture was then extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl 2-(4-(azetidin-1-yl)-2H-1,2,3-triazol-2-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.18N.sub.4O.sub.2: 239.1; found 239.2.

[1590] Step e: A solution of tert-butyl 2-(4-(azetidin-1-yl)-2H-1,2,3-triazol-2-yl)acetate (370 mg, 1.55 mmol, 1 eq) in TFA (3 mL, 40.5 mmol) was stirred at 25° C. for 1 h. The mixture was then concentrated under reduced pressure, and the crude residue obtained was triturated with MTBE (3 mL) to give 2-(4-(azetidin-1-yl)-2H-1,2,3-triazol-2-yl)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.7H.sub.10N.sub.4O.sub.2: 183.1; found 183.2.

[1591] The following compounds in Table B-10 were synthesized using procedures similar to Intermediate A-25 using the appropriate starting materials.

TABLE-US-00012 TABLE B-10 Exact Intermediate mass No. Structure IUPAC (g/mol) LCMS, Found [M + ].sup.+ B-10-1 [01059] embedded image 2-(4-(azetidin-1- yl)-1H-1,2,3- triazol-1-yl)acetic acid 182.1 183.2

Intermediate A-26: Synthesis of 2-(3-(difluoromethyl)-4H-1,2,4-triazol-4-yl)acetic acid

[1592] ##STR01060##

[1593] Step a: To a solution of ethyl (2,2-difluoroethanethioyl)glycinate (2 g, 9.29 mmol, 1 eq) and formic hydrazide (669 mg, 11.1 mmol, 1.2 eq) in DCM (100 mL) at 0° C. was added silver benzoate (4.26 g, 18.5 mmol, 2 eq) and AcOH (1.67 g, 27.8 mmol, 3 eq). The resulting mixture was then warmed to 20° C. and stirred for 16 h. The reaction mixture was then filtered, and the filtrate was quenched by addition of ice-water (100 mL). The resulting biphasic mixture was then extracted with DCM (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(3-(difluoromethyl)-5-hydroxy-1,5-dihydro-4H-1,2,4-triazol-4-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.7H.sub.11F.sub.2N.sub.3O.sub.3: 224.1; found 224.0.

[1594] Step b: A mixture of ethyl 2-(3-(difluoromethyl)-5-hydroxy-1,5-dihydro-4H-1,2,4-triazol-4-yl)acetate (1 g, 4.48 mmol, 1 eq) and 4-methylbenzenesulfonic acid (77.1 mg, 448 μmol, 0.1 eq) in THF (20 mL) was stirred at 20° C. for 16 hours under N.sub.2. The reaction mixture was then concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(3-(difluoromethyl)-4H-1,2,4-triazol-4-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.7H.sub.9F.sub.2N.sub.3O.sub.2: 206.1; found 206.0.

[1595] Step c: To a solution of ethyl 2-(3-(difluoromethyl)-4H-1,2,4-triazol-4-yl)acetate (100 mg, 487 μmol, 1 eq) in H.sub.2O (1 mL) and MeOH (5 mL) was added LiOH.H.sub.2O (40.9 mg, 974 μmol, 2 eq) at 20° C. The resulting mixture was then stirred at 20° C. for 2 h. The reaction mixture was then concentrated under reduced pressure to remove MeOH. The resulting mixture was then adjusted to pH 3-4 using aqueous HCl (1 M), and the aqueous mixture was then extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (50 mL), dried over with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 2-(3-(difluoromethyl)-4H-1,2,4-triazol-4-yl)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.5H.sub.5F.sub.2N.sub.3O.sub.2: 178.0; found 178.1.

Intermediate A-27: Synthesis of 2-(4-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)acetic acid

[1596] ##STR01061##

[1597] Step a: To a solution of POBr.sub.3 (81.8 g, 285 mmol, 29.0 mL, 7 eq) in DMF (40 mL) at 0° C. was added 1-methyl-1H-pyrazol-5-ol (4 g, 40.7 mmol, 1 eq). The resulting mixture was warmed to 50° C. and stirred for 2 h. After cooling, the reaction mixture was quenched by addition saturated aq. Na.sub.2CO.sub.3 (100 mL) at 0° C. The resulting biphasic mixture was extracted with EtOAc (2×250 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 5-bromo-1-methyl-1H-pyrazole-4-carbaldehyde. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.5H.sub.5BrN.sub.2O: 189.0; found 188.9.

[1598] Step b: To a solution of 5-bromo-1-methyl-pyrazole-4-carbaldehyde (2.5 g, 13.2 mmol, 1 eq) in DCM (20 mL) at 0° C. was added DAST (8.53 g, 52.9 mmol, 4 eq) in a dropwise manner. The resulting mixture was warmed to 20° C. and stirred for 12 h. The reaction mixture was then cooled to 0° C. and quenched by addition H.sub.2O (30 mL). The resulting biphasic mixture was extracted with DCM (3×10 mL). The combined organic extracts were washed with brine (30 mL), dried over with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 5-bromo-4-(difluoromethyl)-1-methyl-1H-pyrazole. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.5H.sub.5BrF.sub.2N.sub.2: 211.0; found 210.9.

[1599] Step c: To a solution of 5-bromo-4-(difluoromethyl)-1-methyl-1H-pyrazole (200 mg, 947 μmol, 1 eq) in DMF (2 mL) was added lithium fluoride (147 mg, 5.69 mmol, 6 eq) and tert-tert-butyl((1-methoxyvinyl)oxy)dimethylsilane (535 mg, 2.84 mmol, 3 eq). The resulting mixture was then degassed and placed under an N.sub.2 atmosphere. Bis(tri-tert-butylphosphine)palladium(0) (48.4 mg, 94.7 μmol, 0.1 eq) was then added, and the resulting mixture was warmed to 100° C. using a microwave and stirred for 1.5 h. After cooling, the reaction mixture was then quenched by addition of H.sub.2O (15 mL). The resulting biphasic mixture was then filtered and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 2-(4-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.10F.sub.2N.sub.2O.sub.2: 205.1; found 205.1.

[1600] Step d: To a solution of methyl 2-(4-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)acetate (75 mg, 367 μmol, 1 eq) in EtOH (1 mL) and H.sub.2O (0.5 mL) was added LiOH.H.sub.2O (30.8 mg, 734 μmol, 2 eq), and the resulting mixture was stirred at 20° C. for 1 h. The reaction mixture was then quenched by addition of H.sub.2O (5 mL), and the resulting biphasic mixture was extracted with EtOAc (2×5 mL). The aqueous phase pH was then adjusted to pH 3-4 with aqueous HCl (1M), and the aqueous phase was extracted with EtOAc (2×5 mL). The second set of organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 2-(4-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.7H.sub.8F.sub.2N.sub.2O.sub.2: 190.0; found 190.1.

Intermediate A-28: Synthesis of 2-(4-(difluoromethyl)-1H-1,2,3-triazol-5-yl)acetic acid

[1601] ##STR01062##

[1602] Step a: A mixture of compound ethyl 4,4-difluoro-3-oxobutanoate (12.0 g, 72.2 mmol, 1 eq), TEA (21.9 g, 217 mmol, 30.1 mL, 3 eq) and azidomethylbenzene (9.62 g, 72.2 mmol, 1 eq) in DMSO (100 mL) was heated and stirred at 70° C. for 16 h. After cooling the mixture was poured into ice-water (100 mL) and extracted with EtOAc (2×200 mL). The combined organic layers were washed with aqueous HCl (0.5 M, 100 mL) and brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4 filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give ethyl 1-benzyl-5-(difluoromethyl)-1H-1,2,3-triazole-4-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.13H.sub.13F.sub.2N.sub.3O.sub.2: 282.2; found 282.2.

[1603] Step b: To a mixture of ethyl 1-benzyl-5-(difluoromethyl)-1H-1,2,3-triazole-4-carboxylate (3.00 g, 10.7 mmol, 1 eq) in THF (100 mL) was added DIBAL-H (1 M in THF, 64.0 mL, 6 eq) at 0° C. The resulting mixture was warmed to 25° C. and stirred for 1 h. The mixture was quenched by addition of sat. aq. NH.sub.4Cl (10 mL), and the pH was adjusted to 5 with aqueous HCl (4M) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give (1-benzyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)methanol LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.11F.sub.2N.sub.3O: 240.1; found 240.1.

[1604] Step c: To a solution of compound (1-benzyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)methanol (2.00 g, 8.36 mmol, 1 eq) and 1,3-dimethylthiourea (DMTU, 392 mg, 3.76 mmol, 0.45 eq) in DCM (20 mL) was added NBS (2.23 g, 12.5 mmol, 1.5 eq) at 0° C. The resulting mixture was warmed to 25° C. and stirred for 2 h. The mixture was quenched with H.sub.2O (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with brine (80 mL), dried over with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 1-benzyl-4-(bromomethyl)-5-(difluoromethyl)-1H-1,2,3-triazole. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.10BrN.sub.3: 301.9; found 301.9.

[1605] Step d: To a solution of compound 1-benzyl-4-(bromomethyl)-5-(difluoromethyl)-1H-1,2,3-triazole (800 mg, 2.65 mmol, 1 eq) and TMSCN (276 mg, 2.78 mmol, 1.05 eq) in MeCN (20 mL) was added TBAF (1 M, 3.97 mL, 1.5 eq) at 0° C. The resulting mixture was warmed to 25° C. and stirred for 30 min. The mixture was quenched by addition of sat. aq. NaHCO.sub.3 (30 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (20 mL), dried over with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 2-(1-benzyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)acetonitrile. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.12H.sub.10F.sub.2N.sub.4: 249.0; found 249.0.

[1606] Step e: A mixture of 2-(1-benzyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)acetonitrile (880 mg, 3.55 mmol, 1 eq) in concentrated HCl (20 mL) was stirred at 80° C. for 2 h. After cooling, the mixture was concentrated under reduced pressure. The resulting residue was washed with THF (40 mL) and filtered. The filtrate was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 2-(1-benzyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.12H.sub.11F.sub.2N.sub.3O.sub.2: 268.0; found 268.0.

[1607] Step f: To a solution of 2-(1-benzyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)acetic acid (300 mg, 1.12 mmol, 1 eq) and concentrated HCl (11.4 mg, 112 μmol, 0.1 eq) in i-PrOH (10 mL) was added Pd/C (100 mg, 10% purity) under N.sub.2. The suspension was degassed under vacuum and purged with H.sub.2 several times. The mixture was stirred under H.sub.2 (50 psi) at 25° C. for 16 h. The reaction mixture was filtered through a pad of celite and concentrated under reduced pressure to give 2-(4-(difluoromethyl)-1H-1,2,3-triazol-5-yl)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.5H.sub.5F.sub.2N.sub.3O.sub.2: 178.0; found 178.0.

Intermediate A-29: Synthesis of 2-(5-(trifluoromethyl)-1H-tetrazol-1-yl)acetic acid

[1608] ##STR01063##

[1609] Step a: To a solution of ethyl glycinate hydrochloride (10 g, 71.6 mmol, 1 eq) in DCM (100 mL) at 0° C. was added trifluoroacetic anhydride (22.5 g, 107 mmol, 14.9 mL, 1.5 eq) and TEA (36.2 g, 358 mmol, 5 eq). The mixture was then warmed to 20° C. and stirred for 3 h. The reaction mixture was then poured into H.sub.2O (100 mL), and the resulting biphasic mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl (2,2,2-trifluoroacetyl)glycinate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.6H.sub.8F.sub.3NO.sub.3: 200.0; found 200.0.

[1610] Step b: To a solution of ethyl (2,2,2-trifluoroacetyl)glycinate (11 g, 55.2 mmol, 1 eq) in toluene (200 mL) at 20° C. was added Lawesson's reagent (26.8 g, 66.2 mmol, 1.2 eq). The reaction mixture was then warmed to 110° C. and stirred for 1 h. After cooling to 20° C., the reaction mixture was poured into H.sub.2O (100 mL), and the resulting biphasic mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl (2,2,2-trifluoroethanethioyl)glycinate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.6H.sub.8F.sub.3NO.sub.2S: 216.0; found 215.9.

[1611] Step c: To a mixture of ethyl (2,2,2-trifluoroethanethioyl)glycinate (2 g, 9.29 mmol, 1 eq) and TMSN.sub.3 (2.14 g, 18.5 mmol, 2.44 mL, 2 eq) in DCM (40 mL) at 0° C. under a N2 atmosphere was added SnCl.sub.4 (6.05 g, 23.2 mmol, 2.71 mL, 2.5 eq). The reaction mixture was then warmed to 20° C. and stirred for 16 h. The reaction mixture was then cooled to 0° C. and quenched by slow addition of saturated aq. NaHCO.sub.3 (200 mL). The resulting biphasic mixture was extracted with EtOAc (2×200 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(5-(trifluoromethyl)-1H-tetrazol-1-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.6H.sub.7F.sub.3N.sub.4O.sub.2: 225.0; found 225.0.

[1612] Step d: To a solution of ethyl 2-(5-(trifluoromethyl)-1H-tetrazol-1-yl)acetate (500 mg, 2.23 mmol, 1 eq) in MeOH (10 mL) and H.sub.2O (1 mL) at 20° C. was added LiOH.H.sub.2O (187 mg, 4.46 mmol, 2 eq). The resulting mixture was stirred at 20° C. for 16 h. The reaction mixture was then adjusted to pH 3-4 with aqueous HCl (1M) and stirred for 5 min. The resulting mixture was then filtered and concentrated under reduced pressure to give 2-(5-(trifluoromethyl)-1H-tetrazol-1-yl)acetic acid which was used without further purification. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.4H.sub.3F.sub.3N.sub.4O.sub.2: 197.0; found 196.9.

Intermediate A-30: Synthesis of 2-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)acetic acid

[1613] ##STR01064##

[1614] Step a: A mixture of ethyl 4,4,4-trifluoro-3-oxobutanoate (1.00 g, 5.43 mmol, 1 eq) and ethyl 2-azidoacetate (701 mg, 5.43 mmol, 1 eq) in toluene (10 mL) was warmed to 120° C. and stirred for 16 h. After cooling, the reaction mixture was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 1-(2-ethoxy-2-oxoethyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.12F.sub.3N.sub.3O.sub.4: 296.1; found 296.1.

[1615] Step b: A mixture of ethyl 1-(2-ethoxy-2-oxoethyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylate (300 mg, 1.02 mmol, 1 eq) and NaOH (203 mg, 5.08 mmol, 5 eq) in H.sub.2O (1 mL) and MeOH (10 mL) was stirred at 20° C. for 2 h. The reaction mixture was then acidified to pH=2 with concentrated aq. HCl (12 N). The reaction mixture was concentrated under reduced pressure to give 1-(carboxymethyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.6H.sub.4F.sub.3N.sub.3O.sub.4: 240.0; found 240.1.

[1616] Step c: A mixture of 1-(carboxymethyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylic acid (250 mg, 1.05 mmol, 1 eq) and Ag.sub.2CO.sub.3 (28.8 mg, 104 μmol, 0.1 eq) in DMSO (1 mL) and AcOH (6.28 mg, 104 μmol, 0.1 eq) was warmed to 120° C. and stirred for 16 h. After cooling, the reaction mixture was acidified to pH=2 with concentrated aq. HCl (12 N). The reaction mixture was then concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give 2-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.5H.sub.4F.sub.3N.sub.3O.sub.2: 196.0; found 196.1.

Intermediate A-31: Synthesis of (benzyl(trifluoromethyl)carbamoyl)glycine

[1617] ##STR01065##

[1618] Step a. To a solution of AgF (1.02 g, 8.04 mmol, 6 eq) in CH.sub.3CN (10 mL) at 0° C. under an atmosphere of N.sub.2 was added (isothiocyanatomethyl)benzene (0.2 g, 1.34 mmol, 177 μL, 1 eq) in a dropwise manner. Triphosgene (199 mg, 670 μmol, 0.5 eq) was then added. The resulting reaction mixture was warmed to 25° C. and stirred for 16 h. The reaction mixture was then added to MTBE (20 mL) and stirred for 10 min. The precipitate generated was filtered to give benzyl (trifluoromethyl)carbamic fluoride, which was carried forward to the next step without further purification or characterization.

[1619] Step b. To as solution of benzyl (trifluoromethyl)carbamic fluoride (0.3 g, 1.36 mmol, 1 eq) in DCM (5 mL) was added benzyl glycinate (448 mg, 2.71 mmol, 2 eq), DIPEA (526 mg, 4.07 mmol, 3 eq), and DMAP (16 mg, 136 μmol, 0.1 eq). The resulting reaction mixture was stirred at 20° C. for 16 h. The reaction was then quenched with water (20 mL), and the resulting biphasic mixture was extracted with DCM (3×20 mL). The combined organic extracts were washed with brine (2×10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give benzyl (benzyl(trifluoromethyl)carbamoyl)glycinate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.18H.sub.17F.sub.3N.sub.2O.sub.3: 367.1; found 367.1.

[1620] Step c. To a solution of benzyl (benzyl(trifluoromethyl)carbamoyl)glycinate (150 mg, 409 μmol, 1 eq) in MeOH (3 mL) was added Pd/C (50 mg, 40.9 μmol, 10% purity, 0.1 eq). The resulting mixture was stirred at 25° C. for 16 h under H.sub.2 (15 psi). The reaction mixture was then filtered and concentrated under reduced pressure to give (benzyl(trifluoromethyl)carbamoyl)glycine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.11F.sub.3N.sub.2O.sub.3: 277.1; found 277.1.

Intermediate A-32: Synthesis of 2-(5-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid

[1621] ##STR01066##

[1622] Step a: To a solution of ethyl aminoglycinate hydrochloride (3 g, 19.4 mmol, 1 eq) in EtOH (30 mL) was added NaOH (776 mg, 19.4 mmol, 1 eq) and ethyl (Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (5.13 g, 21.4 mmol, 254 μL, 1.1 eq). The reaction was then stirred at 25° C. for 2 h. The reaction mixture was then concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 1-(2-ethoxy-2-oxoethyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.13F.sub.3N.sub.2O.sub.4: 295.1; found 295.2.

[1623] Step b: A mixture of ethyl 1-(2-ethoxy-2-oxoethyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (3.5 g, 11.9 mmol, 1 eq) and LiOH.H.sub.2O (3.49 g, 83.2 mmol, 7 eq) in THF (20 mL) and H.sub.2O (20 mL) at 25° C. was stirred for 12 h. The reaction mixture was then extracted with EtOAc (50 mL). The combined organic extracts were washed with water (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 1-(carboxymethyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.7H.sub.5F.sub.3N.sub.2O.sub.4: 239.0; found 239.1.

[1624] Step c: A mixture of 1-(carboxymethyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (400 mg, 1.68 mmol, 1 eq), Cu.sub.2O (24.0 mg, 168 μmol, 17.2 μL, 0.1 eq) and 1,10-phenantholine (30.3 mg, 168 μmol, 0.1 eq) in NMP (3 mL) were warmed to 150° C. and stirred for 3 h. The reaction mixture was then concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give 2-(5-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.6H.sub.5F.sub.3N.sub.2O.sub.2: 195.0; found 195.0.

Intermediate A-33: Synthesis of (Z)-2-((3-((2-(trimethylsilyl)ethoxy)methyl)oxazol-2(3H)-ylidene)amino)acetic acid

[1625] ##STR01067##

[1626] Step a: To a mixture of oxazol-2-amine (640 mg, 7.61 mmol, 1 eq) and NaHCO.sub.3 (639 mg, 7.61 mmol, 296 μL, 1 eq) in MeCN (20 mL) at 0° C. under N.sub.2 was added SEMCl (1.27 g, 7.61 mmol, 1.35 mL, 1 eq). The resulting mixture was warmed to 25° C. and stirred for 16 h. The reaction mixture was then quenched with H.sub.2O (10 mL), and resulting biphasic mixture was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (20 mL), dried over with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 3-((2-(trimethylsilyl)ethoxy)methyl)oxazol-2(3H)-imine, which was carried forward to the next step without further purification or characterization.

[1627] Step b: A mixture of 3-((2-(trimethylsilyl) ethoxy) methyl) oxazol-2(3H)-imine (1.4 g, 6.53 mmol, 1 eq), K.sub.2CO.sub.3 (1.81 g, 13 mmol, 2 eq) and ethyl 2-bromoacetate (1.64 g, 9.80 mmol, 1.08 mL, 1.5 eq) in MeCN (50 mL) was warmed to 70° C. and stirred for 3 h. After cooling, the reaction was quenched with H.sub.2O (20 mL), and the resulting biphasic mixture was extracted with EtOAc (2×30 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crud residue obtained was purified by column chromatography to give ethyl (Z)-2-((3-((2-(trimethylsilyl)ethoxy)methyl)oxazol-2(3H)-ylidene)amino)acetate, which was carried forward to the next step without further characterization.

[1628] Step 3: A mixture of ethyl (Z)-2-((3-((2-(trimethylsilyl)ethoxy)methyl)oxazol-2(3H)-ylidene)amino)acetate (500 mg, 1.66 mmol, 1 eq) and LiOH.H.sub.2O (210 mg, 4.99 mmol, 3 eq) in MeOH (8 mL) and H.sub.2O (1 mL) was stirred at 40° C. for 1 h. After cooling, the reaction was diluted with H.sub.2O (10 mL). The pH of the resulting solution was adjusted to pH=5 using aqueous HCl (4M). The resulting mixture was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (10 mL), dried over with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give (Z)-2-((3-((2-(trimethylsilyl)ethoxy)methyl)oxazol-2(3H)-ylidene)amino)acetic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.20N.sub.2O.sub.4Si: 273.1; found 273.1.

Intermediate A-34: Synthesis of 3-(difluoromethyl)-4-isopropylbenzaldehyde

[1629] ##STR01068##

[1630] Step a: To a solution of methyl 4-bromo-3-formylbenzoate (4.50 g, 18.5 mmol, 1 eq) in DCM (45 mL) at 0° C. was added 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-λ.sup.4-sulfanamine (BAST, 10.5 mL, 48.1 mmol, 2.6 eq). The mixture was warmed to 25° C. and stirred for 40 min. The mixture was then poured into ice-water (50 mL) and stirred for 5 min. Saturated aqueous NaHCO.sub.3 was then added to adjust the pH to 8. The resulting biphasic mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (3×30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 4-bromo-3-(difluoromethyl)benzoate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.9H.sub.7BrF.sub.2O.sub.2: 265.0; found 264.9.

[1631] Step b: To a mixture of methyl 4-bromo-3-(difluoromethyl)benzoate (4.30 g, 16.2 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (3.27 g, 19.5 mmol, 1.20 eq), and Cs.sub.2CO.sub.3 (10.6 g, 32.5 mmol, 2.00 eq) in dioxane (43 mL) and H.sub.2O (4 mL) at 25° C. under N2 was added Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (1.32 g, 1.62 mmol, 0.10 eq). The resulting mixture was then degassed and then charged with N.sub.2. The mixture was then warmed to 110° C. and stirred for 30 min. After cooling to room temperature, the mixture was poured into water (20 mL) and stirred for 5 min. The resulting biphasic mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (2×50 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduce pressure. The crude residue obtained was purified by column chromatography to give methyl 3-(difluoromethyl)-4-(prop-1-en-2-yl)benzoate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.12H.sub.12F.sub.2O.sub.2: 227.1; found 227.1.

[1632] Step c: To a solution of methyl 3-(difluoromethyl)-4-(prop-1-en-2-yl)benzoate (2.40 g, 10.6 mmol, 1.00 eq) in MeOH (30 mL) at 25° C. was added Pd/C (1.12 g, 1.06 mmol, 10% purity, 0.1 eq) under N.sub.2. The suspension was then degassed under vacuum and purged with H.sub.2. The reaction mixture was then stirred under H.sub.2 (15 psi) at 25° C. for 1 h. The reaction mixture was then filtered and concentrated under reduced pressure to give methyl 3-(difluoromethyl)-4-isopropylbenzoate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.12H.sub.14F.sub.2O.sub.2: 229.1; found 229.1.

[1633] Step d: To a solution of methyl 3-(difluoromethyl)-4-isopropylbenzoate (2.35 g, 10.3 mmol, 1 eq) in THF (30 mL) at −70° C. under N.sub.2 was added DIBAL-H (1 M in THF, 20.6 mL, 2.00 eq) dropwise. The reaction mixture was then stirred at −70° C. for 2 h under N.sub.2. The reaction mixture was the warmed to 0° C. and quenched by addition of water (20 mL). The resulting biphasic mixture was then filtered and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine (2×20 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (3-(difluoromethyl)-4-isopropylphenyl)methanol. LC-MS (ESI): m/z: [M−OH].sup.+ calculated for C.sub.11H.sub.14F.sub.2O: 183.1; found 183.1.

[1634] Step e: To a mixture of (3-(difluoromethyl)-4-isopropylphenyl)methanol (1.80 g, 8.99 mmol, 1.00 eq) and silica gel (2.91 g) in DCM (20 mL) at 25° C. under N.sub.2 was added PCC (2.91 g, 13.48 mmol, 1.50 eq). The resulting mixture was stirred at 25° C. for 30 min. The reaction mixture was then filtered and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 3-(difluoromethyl)-4-isopropylbenzaldehyde. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.12F.sub.2O: 199.1; found 199.1.

Intermediate A-35: Synthesis of 4-isopropyl-3-methylbenzaldehyde

[1635] ##STR01069##

[1636] Step a: To a mixture of 4-bromo-3-methylbenzaldehyde (5 g, 25.1 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (8.44 g, 50.2 mmol, 2 eq), and K.sub.2CO.sub.3 (10.4 g, 75.4 mmol, 3 eq) in dioxane (60 mL) and H.sub.2O (6 mL) was added Pd(dppf)Cl.sub.2 (551 mg, 754 μmol, 0.03 eq). The resulting mixture was degassed and purged with N.sub.2, and then the mixture was warmed to 80° C. and stirred for 16 h under N.sub.2 atmosphere. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 3-methyl-4-(prop-1-en-2-yl)benzaldehyde (4 g, crude). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.12O: 161.1; found 161.1.

[1637] Step b: To a solution of 3-methyl-4-(prop-1-en-2-yl)benzaldehyde (4 g, 25.0 mmol, 1 eq) in EtOAc (40 mL) and MeOH (20 mL) was added Rh(PPh.sub.3)Cl (1.15 g, 1.25 mmol, 0.05 eq) under argon. The resulting suspension was then degassed under vacuum and placed under an H.sub.2 atmosphere. The resulting mixture was then stirred under H.sub.2 (15 psi) at 25° C. for 16 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to give 4-isopropyl-3-methylbenzaldehyde. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.14O: 163.1; found 163.1.

Intermediate A-36: Synthesis of 4-fluoro-2-iodo-5-isopropylpyridine

[1638] ##STR01070##

[1639] Step a: To a mixture of 5-bromo-4-fluoropyridin-2-amine (3 g, 15.7 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (3.96 g, 23.5 mmol, 1.5 eq), and K.sub.2CO.sub.3 (6.51 g, 47.1 mmol, 3 eq) in H.sub.2O (3 mL) and dioxane (30 mL) was added Pd(dppf)Cl.sub.2 (460 mg, 629 μmol, 0.04). The resulting mixture was degassed and purged with N.sub.2, and then the mixture was warmed to 90° C. and stirred for 16 h under N.sub.2 atmosphere. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-fluoro-5-(prop-1-en-2-yl)pyridin-2-amine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.9FN.sub.2: 153; found 153.2.

[1640] Step b: To a solution of 4-fluoro-5-(prop-1-en-2-yl)pyridin-2-amine (2.2 g, 14.4 mmol, 1 eq) in EtOAc (50 mL) was added Pd/C (1 g, 10% purity) under N.sub.2. The suspension was then degassed under vacuum and placed under an H.sub.2 atmosphere. The resulting mixture was then stirred under H.sub.2 (20 psi) at 20° C. for 16 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to give 4-fluoro-5-isopropylpyridin-2-amine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.11FN.sub.2: 155.1; found 155.0.

[1641] Step c: To a mixture of 4-fluoro-5-isopropylpyridin-2-amine (2 g, 12.9 mmol, 1 eq) and KI (21.5 g, 129 mmol, 10 eq) in diiodomethane (69.4 g, 259 mmol, 20.9 mL, 20 eq) was added t-BuONO (6.69 g, 64.8 mmol, 5 eq). The resulting mixture was degassed and purged with N.sub.2, and then the mixture was stirred for 16 h under N.sub.2 atmosphere at 20° C. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography to give 4-fluoro-2-iodo-5-isopropylpyridine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.9FIN: 266.0; found 265.9.

Intermediate A-37: 3-chloro-4-cyclopropylbenzaldehyde

[1642] ##STR01071##

[1643] Step a: To a mixture of cyclopropylboronic acid (2.30 g, 26.7 mmol, 1.30 eq), 4-bromo-3-chlorobenzaldehyde (4.5 g, 20.5 mmol, 1.00 eq), and K.sub.3PO.sub.4 (10.0 g, 47.1 mmol, 2.30 eq) in dioxane (40.0 mL) and H.sub.2O (4.00 mL) was added Pd(dppf)Cl.sub.2 (750 mg, 1.02 mmol, 0.05 eq). The resulting mixture was degassed and purged with N.sub.2, and then the mixture was warmed to 90° C. and stirred for 16 h under N.sub.2 atmosphere. The reaction mixture was then dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 3-chloro-4-cyclopropylbenzaldehyde. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.9ClO: 181.0; found 181.1.

Intermediate A-38: 4-cyclopropyl-3,5-difluorobenzaldehyde

[1644] ##STR01072##

[1645] Step a: To a solution of 4-bromo-3,5-difluorobenzoic acid (2.7 g, 11.4 mmol, 1 eq), Et.sub.3N (3.46 g, 34.2 mmol, 4.76 mL, 3 eq) and N,O-dimethylhydroxylammonium chloride (1.33 g, 13.7 mmol, 1.2 eq) in DMF (25 mL) at 0° C. was added HATU (4.55 g, 11.9 mmol, 1.05 eq). The resulting mixture was stirred at 0° C. for 1 h. The reaction was then quenched by addition of H.sub.2O (80 mL) at 0° C., and the resulting biphasic mixture was then extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (80 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-bromo-3,5-difluoro-N-methoxy-N-methylbenzamide. This compound was carried forward to the next step without further characterization.

[1646] Step b: To a mixture of 4-bromo-3,5-difluoro-N-methoxy-N-methylbenzamide (3.15 g, 11.3 mmol, 1 eq), cyclopropylboronic acid (1.45 g, 16.8 mmol, 1.5 eq), K.sub.3PO.sub.4 (7.16 g, 33.7 mmol, 3 eq), and PCy.sub.3 (315 mg, 1.12 mmol, 0.1 eq) in toluene (60 mL) and H.sub.2O (6 mL) was added Pd(OAc).sub.2 (253 mg, 1.12 mmol, 0.1 eq). The resulting mixture was degassed and purged with N.sub.2, and the resulting mixture was warmed to 90° C. and stirred for 12 h under N.sub.2 atmosphere. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-cyclopropyl-3,5-difluoro-N-methoxy-N-methylbenzamide. This compound was carried forward to the next step without further characterization.

[1647] Step c: To a solution of 4-cyclopropyl-3,5-difluoro-N-methoxy-N-methylbenzamide (2.50 g, 10.4 mmol, 1 eq) in THF (20 mL) at −5° C. under N.sub.2 was added DIBAL-H (1 M in THF, 13.47 mL, 1.3 eq). The resulting mixture was then warmed to 0° C. and stirred for 3 h. The reaction mixture was then poured into ice-water (20 mL), adjusted to pH=7 with aq. HCl (4M), and extracted with Et.sub.20 (3×20 mL). The combined organic extracts were washed with brine (40 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-cyclopropyl-3,5-difluorobenzaldehyde.

Intermediate A-39: 2-cyclopropyl-1-fluoro-5-iodo-3-methylbenzene

[1648] ##STR01073##

[1649] Step a: To a solution of 3-fluoro-5-methylaniline (15.0 g, 120 mmol, 1.00 eq) in DMF (100 mL) at 0° C. was added NBS (21.5 g, 121 mmol, 1.01 eq). The resulting mixture was stirred at 0° C. for 0.5 h. The reaction mixture was then warmed to 25° C. and stirred for 1 h. The reaction mixture was then diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with saturated aqueous NaHCO.sub.3, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-bromo-3-fluoro-5-methylaniline. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.7H.sub.7BrFN: 204.0; found 204.0.

[1650] Step b: To a solution of 4-bromo-3-fluoro-5-methylaniline (8.0 g, 39.2 mmol, 1.00 eq), tricyclohexylphosphine (2.20 g, 7.84 mmol, 0.20 eq), cyclopropylboronic acid (4.04 g, 47.0 mmol, 1.20 eq), and K.sub.3PO.sub.4 (25.0 g, 118 mmol, 3.00 eq) in toluene (160 mL) and H.sub.2O (32 mL) was added Pd(OAc).sub.2 (880 mg, 3.92 mmol, 0.10 eq). The resulting mixture was degassed and purged with N.sub.2. The reaction mixture was then warmed to 100° C. and stirred for 16 h under N.sub.2. After cooling to the room temperature, the reaction mixture was extracted with ethyl acetate (3×80 mL). The combined organic extracts were washed with saturated aqueous NaHCO.sub.3, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-cyclopropyl-3-fluoro-5-methylaniline. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.12FN: 166.1; found 166.1.

[1651] Step c: To a solution of 4-cyclopropyl-3-fluoro-5-methylaniline (4.00 g, 24.21 mmol, 1 eq) in MeCN (40 mL) was added a solution of H.sub.2SO.sub.4 (18 M, 3.36 mL, 98% purity, 2.50 eq) in H.sub.2O (40 mL). After stirring 10 min, the reaction mixture was cooled to 0° C., and a solution of NaNO.sub.2 (3.34 g, 48.4 mmol, 2.00 eq) in H.sub.2O (40 mL) was added over 20 min. A solution of KI (16.1 g, 96.8 mmol, 4.00 eq) in H.sub.2O (40 mL) was then added to the reaction mixture at 0° C. The reaction mixture was then warmed to 25° C. and stirred under N.sub.2 atmosphere or 0.5 h. The reaction mixture was then extracted with ethyl acetate (3×600 mL). The combined organic extracts were washed with saturated aqueous NaHCO.sub.3, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 2-cyclopropyl-1-fluoro-5-iodo-3-methylbenzene.

Intermediate A-40: 3-fluoro-4-(1-methylcyclopropyl)benzaldehyde

[1652] ##STR01074##

[1653] Step a: To a solution of methyltriphenylphosphonium iodide (14.0 g, 34.6 mmol, 1.5 eq) in THF (50.0 mL) was added t-BuOK (3.88 g, 34.6 mmol, 1.5 eq). The resulting mixture was stirred at 25° C. for 30 min. To this mixture was added a solution of 1-(4-bromo-2-fluorophenyl)ethan-1-one (5.00 g, 23.0 mmol, 1 eq) in THF (5.00 mL) at 25° C. The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then cooled to 0° C. and quenched by addition H.sub.2O (100 mL), and the resulting biphasic mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-bromo-2-fluoro-1-(prop-1-en-2-yl)benzene, which was carried forward to the next step without further characterization.

[1654] Step b: To a solution of ZnEt.sub.2 (1 M in hexane, 18.6 mL, 4 eq) in DCM (5.00 mL) at 0° C. under N.sub.2 atmosphere was added TFA (2.12 g, 18.6 mmol, 1.38 mL, 4 eq). The resulting mixture was stirred at 0° C. for 30 min before CH.sub.2I.sub.2 (4.98 g, 18.6 mmol, 1.50 mL, 4 eq) in DCM (5.00 mL) was added dropwise at 0° C. The resulting mixture was stirred at 0° C. for 30 min before 4-bromo-2-fluoro-1-(prop-1-en-2-yl)benzene (1.00 g, 4.65 mmol, 1 eq) in DCM (5.00 mL) was added dropwise at 0° C. The resulting mixture was then warmed to 25° C. and stirred for 16 h. The reaction mixture was then cooled to 0° C. and quenched by addition of aq. HCl (1N, 50 mL). The resulting biphasic mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (2×50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-bromo-2-fluoro-1-(1-methylcyclopropyl)benzene, which was carried forward to the next step without further characterization.

[1655] Step c: To a solution of 4-bromo-2-fluoro-1-(1-methylcyclopropyl)benzene (5 g, 21.8 mmol, 1 eq) in THF (80 mL) at −60° C. under N.sub.2 atmosphere was added n-BuLi (2.5 M in hexane, 8.72 mL, 1 eq). After 30 min, DMF (4.79 g, 65.4 mmol, 3 eq) was added dropwise at −60° C. The resulting mixture was allowed to warm to 25° C. and stirred for 2 h. The reaction mixture was then cooled to 0° C. and quenched by addition saturated aqueous NH.sub.4Cl (150 mL). The resulting biphasic mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (2×50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 3-fluoro-4-(1-methylcyclopropyl)benzaldehyde. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.11FO: 179.1; found 179.1.

Intermediate A-41: 6-fluoro-5-(1-methylcyclopropyl)picolinaldehyde

[1656] ##STR01075##

[1657] Step a: To a solution of 2-bromo-6-fluoropyridine (12.5 g, 71.0 mmol, 1.00 eq) in THF (125 mL) at −65° C. under N.sub.2 atmosphere was added LDA (2 M in THF, 35.5 mL, 1.00 eq) in a dropwise manner. The reaction mixture was stirred at −65° C. for 0.5 h before acetone (6.19 g, 106 mmol, 1.50 eq) was added in a dropwise manner at −65° C. The reaction mixture was then stirred at −65° C. for 0.5 h before it was warmed to 0° C., quenched by addition of H.sub.2O (60 mL), and stirred for 5 min. The resulting biphasic mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 2-(6-bromo-2-fluoropyridin-3-yl)propan-2-ol. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.9BrFNO: 234.0; found 234.0.

[1658] Step b: To a solution of 2-(6-bromo-2-fluoropyridin-3-yl)propan-2-ol (13.5 g, 57.7 mmol, 1.00 eq) in toluene (135 mL) was added TsOH (1.99 g, 11.5 mmol, 0.2 eq). The reaction mixture was then warmed to 125° C. and stirred for 16 h. The reaction mixture was then filtered and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 6-bromo-2-fluoro-3-(prop-1-en-2-yl)pyridine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.7BrFN: 216.0; found 215.9.

[1659] Step c: To a solution of 6-bromo-2-fluoro-3-(prop-1-en-2-yl)pyridine (6.50 g, 30.1 mmol, 1.00 eq) in MeOH (65 mL) was added TEA (6.09 g, 60.1 mmol, 2.00 eq) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (2.46 g, 3.01 mmol, 0.10 eq). The reaction mixture was then placed under a CO atmosphere (50 psi), warmed to 60° C., and stirred for 1.5 h. The reaction mixture was then concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 6-fluoro-5-(prop-1-en-2-yl)picolinate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.10FNO.sub.2: 196.1; found 196.1.

[1660] Step d: To a solution of ZnEt.sub.2 (1 M in hexane, 102 mL, 5.00 eq) at 0° C. was added TFA (102 mmol, 7.6 mL, 5.00 eq) in DCM (24 mL) in a dropwise manner. The resulting mixture was stirred at 0° C. for 30 min before CH.sub.2I.sub.2 (27.4 g, 102 mmol, 5.0 eq) in DCM (22 mL) was added in a dropwise manner. The resulting mixture was stirred at 0° C. for 30 min before methyl 6-fluoro-5-(prop-1-en-2-yl)picolinate (4 g, 20 mmol, 1.0 eq) in DCM (12 mL) was added in a dropwise manner at 0° C. The resulting mixture was then warmed to 25° C. and stirred for 15 h. The reaction mixture was then cooled to 0° C. and quenched by addition of saturated aq. NH.sub.4Cl (100 ml). The resulting biphasic mixture was then extracted with ethyl acetate (3×500 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give methyl 6-fluoro-5-(1-methylcyclopropyl)picolinate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.12FNO.sub.2: 210.1; found 210.1.

[1661] Step e: A solution of methyl 6-fluoro-5-(1-methylcyclopropyl)picolinate (1.25 g, 5.97 mmol, 1 eq) in THF (12.5 mL) was degassed and purged with N.sub.2. The resulting solution was cooled to −65° C., and then DIBAL-H (1 M in THF, 11.95 mL, 2 eq) was added in a dropwise manner. The resulting mixture was stirred at −65° C. for 2 h. The reaction mixture was then warmed to 0° C. and quenched by addition of water (20 mL). The resulting biphasic mixture was then filtered and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine (2×20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 6-fluoro-5-(1-methylcyclopropyl)picolinaldehyde. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.10FNO: 180.1; found 180.1.

Intermediate A-42: 4-(tert-butyl)-3-fluorobenzaldehyde

[1662] ##STR01076##

[1663] Step a: To a mixture of 3-fluorophenol (10.0 g, 89.20 mmol, 8.20 mL, 1 eq) and AlCl.sub.3 (4.76 g, 35.7 mmol, 1.95 mL, 0.4 eq) in DCM (150 mL) under N.sub.2 was added 2-chloro-2-methyl-propane (12.4 g, 134 mmol, 14.8 mL, 1.5 eq) in a dropwise manner. The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then quenched with water (50 mL), and the resulting biphasic mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water (3×50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-(tert-butyl)-3-fluorophenol. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.13FO: 169.1; found 169.1.

[1664] Step b: To a solution of 4-(tert-butyl)-3-fluorophenol (3.80 g, 22.6 mmol, 1 eq) and TEA (6.86 g, 67.8 mmol, 9.43 mL, 3 eq) in DCM (15 mL) at 0° C. was added Tf.sub.2O (3.19 g, 11.3 mmol, 1.86 mL, 0.5 eq) in a dropwise manner. The resulting mixture was warmed to 25° C. and stirred for 2 h. The reaction was then diluted with H.sub.2O (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-(tert-butyl)-3-fluorophenyl trifluoromethanesulfonate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.12F.sub.4O.sub.3S: 301.0; found 301.1.

[1665] Step c: To a solution of 4-(tert-butyl)-3-fluorophenyl trifluoromethanesulfonate (2.00 g, 6.66 mmol, 1 eq), Et.sub.3SiH (1.55 g, 13.3 mmol, 2.13 mL, 2 eq), and Na.sub.2CO.sub.3 (1.41 g, 13.3 mmol, 2 eq) in DMF (15 mL) under N.sub.2 atmosphere was added Pd(dppf)Cl.sub.2 (487 mg, 666 μmol, 0.1 eq). The resulting mixture was placed under CO atmosphere (50 psi), warmed to 75° C., and stirred for 5 h. The reaction mixture was then diluted with H.sub.2O (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine (3×10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-(tert-butyl)-3-fluorobenzaldehyde. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.13FO: 181.1; found 181.1.

Intermediate A-43: 3-fluoro-4-(1-methylcyclobutyl)benzaldehyde

[1666] ##STR01077##

[1667] Step a: To a solution of 1-bromo-2-fluoro-4-methoxybenzene (23.0 g, 112 mmol, 1 eq) in THF (200 mL) at −78° C. under N.sub.2 atmosphere was added n-BuLi (2.5 M in hexane, 50 mL, 125.0 mmol, 1.1 eq). The resulting mixture was stirred at −78° C. for 1 h before cyclobutanone (7.86 g, 112 mmol, 8.3 mL, 1 eq) was added in a dropwise manner. The resulting mixture was stirred at −78° C. for 2 h. The reaction was then quenched by addition of saturated aqueous NH.sub.4Cl (200 mL), and the resulting biphasic mixture was extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with water (50 mL) and brine (3×250 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 1-(2-fluoro-4-methoxyphenyl)cyclobutan-1-ol. This compound was carried forward to the next step without further characterization.

[1668] Step b: To a solution of 1-(2-fluoro-4-methoxyphenyl)cyclobutan-1-ol (5 g, 25.4 mmol, 1 eq) in DCM (40 mL) at −78° C. was added titanium tetrachloride (9.6 g, 50.9 mmol, 9.67 mL, 2 eq), and the resulting mixture was stirred at −78° C. for 1 h. A solution of dimethylzinc (1 M in heptane, 76.45 mL, 3 eq) was added at −78° C. in a dropwise manner. The resulting mixture was warmed to 25° C. and stirred for 1 h. The reaction mixture was then poured into ice-water (30 mL), and the resulting biphasic mixture was extracted with DCM (50 mL). The organic extracts were then washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 2-fluoro-4-methoxy-1-(1-methylcyclobutyl)benzene. This compound was carried forward to the next step without further characterization.

[1669] Step c: To a solution of 2-fluoro-4-methoxy-1-(1-methylcyclobutyl)benzene (1.5 g, 7.7 mmol, 1 eq) in DCM (2 mL) at −78° C. was added BBr.sub.3 (1 M, 23.17 mL, 3 eq). The resulting mixture was stirred at −78° C. for 0.5 h. The reaction mixture was then warmed to 25° C. and stirred for 1 h. The reaction mixture was then quenched by addition of H.sub.2O (100 mL), and the resulting biphasic mixture was extracted with DCM (2×50 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 3-fluoro-4-(1-methylcyclobutyl)phenol. This compound was carried forward to the next step without further characterization.

[1670] Step d: To a solution of 3-fluoro-4-(1-methylcyclobutyl)phenol (1.3 g, 7.2 mmol, 1 eq) and TEA (1.4 g, 14.4 mmol, 2.01 mL, 2 eq) in DCM (15 mL) at 0° C. was added Tf.sub.2O (2.44 g, 8.66 mmol, 1.43 mL, 1.2 eq). The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was then warmed to 20° C. and stirred for 1 h. The reaction mixture was then diluted with DCM (22 ml) and washed with H.sub.2O (20 mL). The organic solution was then dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 3-fluoro-4-(1-methylcyclobutyl)phenyl trifluoromethanesulfonate. This compound was carried forward to the next step without further characterization.

[1671] Step e: To a solution of 3-fluoro-4-(1-methylcyclobutyl)phenyl trifluoromethanesulfonate (2.2 g, 7.0 mmol, 1 eq), Na.sub.2CO.sub.3 (1.49 g, 14.09 mmol, 2 eq), and TESH (1.64 g, 14.1 mmol, 2.25 mL, 2 eq) in DMF (40 mL) was added Pd(dppf)Cl.sub.2 (515 mg, 704 μmol, 0.1 eq). The resulting mixture was then placed under CO atmosphere (50 psi), warmed to 70° C., and stirred for 4 h. The reaction mixture was then cooled to 20° C. and diluted with ethyl acetate (50 mL). The organic solution was then washed with H.sub.2O (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 3-fluoro-4-(1-methylcyclobutyl)benzaldehyde.

Intermediate A-44: 4-cyclobutyl-3-fluorobenzaldehyde

[1672] ##STR01078##

[1673] Step a: To a solution of 4-bromo-3-fluorobenzaldehyde (5 g, 24.63 mmol, 1 eq) and 4-methylbenzenesulfonic acid (848 mg, 4.93 mmol, 0.2 eq) in MeOH (50 mL) was added trimethyl orthoformate (5.23 g, 49.3 mmol, 5.40 mL, 2 eq). The resulting mixture was warmed to 70° C. and stirred for 1 h. The reaction mixture was then poured into ice-water (150 mL) and stirred for 3 min. The resulting biphasic mixture was extracted with ethyl acetate (3×80 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 1-bromo-4-(dimethoxymethyl)-2-fluorobenzene. LC-MS (ESI): m/z: [M−OMe].sup.+ calculated for C.sub.9H.sub.10BrFO.sub.2: 217.0; found 217.0.

[1674] Step b: To a solution of 1-bromo-4-(dimethoxymethyl)-2-fluorobenzene (1.4 g, 5.62 mmol, 1 eq), cyclobutylboronic acid (5.62 g, 56.2 mmol, 10 eq), and K.sub.2CO.sub.3 (1.55 g, 11.2 mmol, 2 eq) in toluene (12 mL) and H.sub.2O (3 mL) under N.sub.2 was added Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (918 mg, 1.12 mmol, 0.2 eq). The resulting mixture was warmed to 100° C. and stirred for 1 h. The reaction mixture was then poured into ice-water and stirred for 3 min. The resulting biphasic mixture was extracted with ethyl acetate (3×80 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 1-cyclobutyl-4-(dimethoxymethyl)-2-fluorobenzene, which was carried forward to the next step without further characterization.

[1675] Step c: To a solution of 1-cyclobutyl-4-(dimethoxymethyl)-2-fluorobenzene (1 g, 4.46 mmol, 1 eq) in THF (5 mL) at 15° C. was added aq. HCl (1 M, 10.00 mL, 2.24 eq). The resulting mixture was stirred at 15° C. for 1 h. The mixture was poured into ice-water (30 mL) and stirred for 2 min. The resulting biphasic mixture was extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 4-cyclobutyl-3-fluorobenzaldehyde, which was used without further purification. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.11FO: 179.1; found 179.1.

Intermediate A-45: 4-(sec-butyl)-3-fluorobenzaldehyde

[1676] ##STR01079##

[1677] Step a: To a mixture of 4-bromo-3-fluorobenzaldehyde (5.00 g, 24.6 mmol, 1 eq), KOAc (6.04 g, 61.6 mmol, 2.5 eq), and bis(pinacolato)diboron (7.51 g, 29.6 mmol, 1.2 eq) in dioxane (50 mL) was added Pd(dppf)Cl.sub.2 (1.80 g, 2.46 mmol, 0.1 eq). The resulting mixture was degassed and purged with N.sub.2. The reaction mixture was then warmed to 100° C. and stirred for 3 h. The reaction mixture was then filtered, and the filter cake was washed with 10:1 EtOAc/MeOH (3×200 mL). The combined filtrate and washes were concentrated under reduced pressure. The crude residue obtained was poured into H.sub.2O (100 mL), adjusted to pH=10 with sat. aqueous Na.sub.2CO.sub.3, and extracted with ethyl acetate (3×100 mL). The organic extracts were discarded. The aqueous phase was then adjusted to pH=4 with aq. HCl (4M) and extracted with EtOAc (3×100 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde, which was carried forward to the next step without further characterization.

[1678] Step b: To a mixture of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (3.00 g, 12.0 mmol, 1 eq), 2-bromobut-1-ene (1.62 g, 12.0 mmol, 1 eq), and K.sub.2CO.sub.3 (3.32 g, 24.0 mmol, 2 eq) in dioxane (60 mL) and H.sub.2O (6 mL) was added Pd(dppf)Cl.sub.2 (439 mg, 600 μmol, 0.05 eq). The reaction was degassed and purged with N.sub.2. The resulting mixture was then warmed to 90° C. and stirred for 16 h. The reaction mixture was then cooled, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-(but-1-en-2-yl)-3-fluorobenzaldehyde, which was carried forward to the next step without further characterization.

[1679] Step c: To a solution of 4-(but-1-en-2-yl)-3-fluorobenzaldehyde (1.70 g, 9.54 mmol, 1 eq) in MeOH (20 mL) and ethyl acetate (20 mL) was added Rh(PPh.sub.3).sub.3Cl (883 mg, 954 μmol, 0.1 eq) under N.sub.2. The resulting suspension was degassed under vacuum and purged with H.sub.2. The resulting mixture was then stirred under H.sub.2 (15 psi) at 25° C. for 2 h. The reaction mixture was then filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-(sec-butyl)-3-fluorobenzaldehyde. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.13FO: 181.1; found 181.1.

Intermediate A-46: 5-cyclobutylpicolinaldehyde

[1680] ##STR01080##

[1681] Step a: To a solution of 5-bromopicolinaldehyde (20 g, 107.52 mmol, 1 eq) and trimethyl orthoformate (22.8 g, 215.05 mmol, 23.6 mL, 2 eq) in MeOH (50 mL) at 0° C. was added 4-methylbenzenesulfonic acid (3.70 g, 21.50 mmol, 0.2 eq) in MeOH (5 mL). The resulting mixture was warmed to 70° C. and stirred for 1 h. The reaction solution was then cooled and quenched with sat. aqueous NaHCO.sub.3 to reach pH=7. The resulting biphasic mixture was then extracted with EtOAc (2×200 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 5-bromo-2-(dimethoxymethyl)pyridine. LC-MS (ESI): m/z: [M−OMe].sup.+ calculated for C.sub.8H.sub.10BrNO.sub.2: 200.0; found 200.1.

[1682] Step b: To a mixture of 5-bromo-2-(dimethoxymethyl)pyridine (2.5 g, 10.77 mmol, 1 eq) and Pd(dppf)Cl.sub.2 (394 mg, 538.62 μmol, 0.05 eq) in THF (2 mL) at 0° C. was added cyclobutylmagnesium bromide (0.5 M, 86.2 mL, 4 eq). The resulting mixture was warmed to 30° C. and stirred for 16 h. The reaction mixture was then diluted with water and extracted with EtOAc (150 mL). The organic extracts were washed with brine (150 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 5-cyclobutyl-2-(dimethoxymethyl)pyridine, which was carried forward to the next step without further characterization.

[1683] Step c: To a solution of 5-cyclobutyl-2-(dimethoxymethyl)pyridine (0.9 g, 4.34 mmol, 1 eq) in H.sub.2O (9 mL) was added H.sub.2SO.sub.4 (5 M, 1.04 mL, 1.2 eq). The resulting mixture was warmed to 80° C. and stirred for 2 h. The reaction mixture was then adjusted to pH=7 with sat. aqueous NaHCO.sub.3. The resulting biphasic mixture was then extracted with EtOAc (80 mL). The organic extracts were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 5-cyclobutylpicolinaldehyde. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.11NO: 162.1; found 162.1.

Intermediate A-47: (2S,4R,5S)-1-(tert-butoxycarbonyl)-4-fluoro-5-methylpyrrolidine-2-carboxylic acid

[1684] ##STR01081##

[1685] Step a: To a mixture of 1-(tert-butyl) 2-methyl (2S,4S,5S)-4-hydroxy-5-methylpyrrolidine-1,2-dicarboxylate (150 mg, 0.57 mmol, 1 eq) in DCM (4 mL) at −78° C. under N2 atmosphere was added DAST (466 mg, 2.89 mmol, 5 eq) in a dropwise manner. The resulting mixture was warmed to 25° C. and stirred for 16 h. The reaction mixture was then diluted with H.sub.2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 1-(tert-butyl) 2-methyl (2S,4R,5S)-4-fluoro-5-methylpyrrolidine-1,2-dicarboxylate, which was carried forward to the next step without further characterization.

[1686] Step b: To a mixture of 1-(tert-butyl) 2-methyl (2S,4R,5S)-4-fluoro-5-methylpyrrolidine-1,2-dicarboxylate (40 mg, 0.15 mmol, 1 eq) in THF (2 mL) at 25° C. was added a solution of LiOH.H.sub.2O (7 mg, 0.16 mmol, 1.1 eq) in H.sub.2O (2 mL). The resulting mixture was stirred at 25° C. for 1 hr. The reaction mixture was then concentrated under reduced pressure. The crude residue was then diluted with water (3 mL) and washed with MTBE (3×5 mL). The aqueous phase was then adjusted to pH=4 with aq. HCl (1 N) and extracted with EtOAc (3×5 mL). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give (2S,4R,5S)-1-(tert-butoxycarbonyl)-4-fluoro-5-methylpyrrolidine-2-carboxylic acid. LC-MS (ESI): m/z: [M−H].sup.− calculated for C.sub.11H.sub.18FNO.sub.4: 246.1; found 246.2.

Intermediate A-48: (2S,3RS,4RS)—N—((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-4-fluoro-3-hydroxypyrrolidine-2-carboxamide

[1687] ##STR01082##

[1688] Step a: To a mixture of (S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (9 g, 42.2 mmol, 1 eq) and Cs.sub.2CO.sub.3 (15.1 g, 46.4 mmol, 1.1 eq) in DMF (100 mL) at 0° C. was added BnBr (8.66 g, 50.6 mmol, 1.2 eq) in a dropwise manner. The resulting suspension was degassed under vacuum and purged with N.sub.2. The reaction mixture was then warmed to 25° C. and stirred for 12 h. The reaction mixture was then quenched with H.sub.2O (100 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 2-benzyl 1-(tert-butyl) (S)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate. LC-MS (ESI): m/z: [M−t-Bu+H+H].sup.+ calculated for C.sub.17H.sub.21NO.sub.4: 248.1; found 248.1.

[1689] Step b: To a solution of 2-benzyl 1-(tert-butyl) (S)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (4.7 g, 15.5 mmol, 1 eq) and BHT (341 mg, 1.55 mmol, 0.1 eq) in DCM (200 mL) at 25° C. was added 3-chloroperbenzoic acid (31.5 g, 154 mmol, 85% purity, 10 eq). The reaction was warmed to 45° C. and stirred for 12 h. After cooling to 25° C., the reaction was quenched with saturated aqueous Na.sub.2S203, and the resulting biphasic mixture extracted with DCM (2×200 mL). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography and prep-HPLC to give 2-benzyl 3-(tert-butyl) (1S,2S,5R)-6-oxa-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate and 2-benzyl 3-(tert-butyl) (1R,2S,5S)-6-oxa-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate as separate diastereomers. LC-MS (ESI): m/z: [M−t-Bu+H+H].sup.+ calculated for C.sub.17H.sub.21NO.sub.5: 264.1; found 264.0.

[1690] Step c: To a solution of 2-benzyl 3-(tert-butyl) (1R,2S,5S)-6-oxa-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (600 mg, 1.88 mmol, 1 eq) in EtOAc (15 mL) was added Pd/C (500 mg, 1.88 mmol, 10% purity, 1.00 eq) under N.sub.2. The resulting suspension was degassed under vacuum and purged with H.sub.2. The resulting mixture was stirred under H.sub.2 (15 psi) at 25° C. for 2 h. The reaction mixture was then filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-(tert-butoxycarbonyl)-6-oxa-3-azabicyclo[3.1.0]hexane-2-carboxylic acid. LC-MS (ESI): m/z: [M−t-Bu+H+H].sup.+ calculated for C.sub.10H.sub.15NO.sub.5 174.0; found 174.1.

[1691] Step d: To a solution of (1R,2S,5S)-3-(tert-butoxycarbonyl)-6-oxa-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (430 mg, 1.88 mmol, 1 eq), (S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methanaminium chloride (522 mg, 1.88 mmol, 1 eq), and N-methylmorpholine (NMM, 948 mg, 9.38 mmol, 5 eq) in DMF (5 mL) at −20° C. was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P, 1.43 g, 2.25 mmol, 50% purity, 1.2 eq). The resulting mixture was stirred at −20° C. for 1 h. The reaction mixture was then quenched with H.sub.2O (10 mL), and the resulting biphasic mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (1R,2S,5S)-2-(((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)carbamoyl)-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.25H.sub.28FN.sub.3O.sub.4: 454.2; found 454.2.

[1692] Step e: To a solution of tert-butyl (1R,2S,5S)-2-(((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)carbamoyl)-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (430 mg, 0.95 mmol, 1 eq) in DCM (12 mL) at −60° C. was added tetrafluoroboric acid diethyl ether complex (2.15 g, 6.64 mmol, 50% purity, 7 eq) in a dropwise manner. The resulting mixture was allowed to warm to 25° C. and stirred for 12 h. The mixture was adjusted to pH=7 with saturated aqueous NaHCO.sub.3 and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine (15 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-TLC to give (2S,3RS,4RS)—N—((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-4-fluoro-3-hydroxypyrrolidine-2-carboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.20H.sub.21F.sub.2N.sub.3O.sub.2: 374.2; found 374.3.

[1693] The following compounds in Table B-11 were synthesized using procedures similar to Intermediate A-48 using the appropriate starting materials.

TABLE-US-00013 TABLE B-11 Exact Intermediate mass No. Structure IUPAC (g/mol) LCMS, Found [M + H].sup.+ B-11-1 [01083] embedded image (2S,3RS,4RS)-N- ((S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl)- 4-fluoro-3- hydroxypyrrolidine- 2-carboxamide 373.2 374.1

Intermediate A-49: (3-methyloxetan-3-yl)glycine

[1694] ##STR01084##

[1695] Step a: To a solution of 3-methyloxetan-3-amine (500 mg, 5.74 mmol, 1 eq) in MeCN (10 mL) at 30° C. was added benzyl 2-bromoacetate (2.63 g, 11.5 mmol, 2 eq) and DIPEA (1.48 g, 11.5 mmol, 2 eq) in a dropwise manner. The resulting mixture was stirred at 30° C. for 16 h under N.sub.2. The reaction mixture was then diluted with H.sub.2O (20 mL), and the resulting biphasic mixture was extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give benzyl (3-methyloxetan-3-yl)glycinate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.13H.sub.17NO.sub.3: 236.1; found 236.1.

[1696] Step b: To a solution of benzyl (3-methyloxetan-3-yl)glycinate (100 mg, 425 μmol, 1 eq) in EtOH (2 mL) at 20° C. was added Pd/C (452 mg, 10% purity). The resulting mixture was stirred at 20° C. for 5 h under H.sub.2 (15 Psi). The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure to give (3-methyloxetan-3-yl)glycine. LC-MS (ESI): m/z: [M−H].sup.− calculated for C.sub.6H.sub.11NO.sub.3: 144.1; found 144.1.

Intermediate A-50: (1-benzyl-1H-1,2,3-triazol-4-yl)methanesulfonyl chloride

[1697] ##STR01085##

[1698] Step a: A mixture of 3-bromoprop-1-yne (25 g, 168 mmol, 80% purity, 1 eq) and Na.sub.2SO.sub.3 (25.4 g, 201 mmol, 1.2 eq) in MeOH (200 mL) was warmed to 80° C. and stirred for 16 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by re-crystallization from acetone to obtain sodium prop-2-yne-1-sulfonate, which was carried forward to the next step without further characterization.

[1699] Step b: To a mixture of sodium prop-2-yne-1-sulfonate (2 g, 14.0 mmol, 1 eq), sodium L-ascorbate (557 mg, 2.81 mmol, 0.2 eq), and CuSO.sub.4.5H.sub.2O (351 mg, 1.41 mmol, 0.1 eq) in H.sub.2O (10 mL) and t-BuOH (10 mL) at 20° C. was added benzyl azide (BnN.sub.3, 1.97 g, 14.7 mmol, 1.05 eq). The resulting mixture was stirred at 20° C. for 16 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give (1-benzyl-1H-1,2,3-triazol-4-yl)methanesulfonic acid. LC-MS (ESI): m/z: [M−H].sup.− calculated for C.sub.10H.sub.11N.sub.3O.sub.3S: 254.0; found 254.0.

[1700] Step c: To a mixture of (1-benzyl-1H-1,2,3-triazol-4-yl)methanesulfonic acid (300 mg, 947 μmol, 80% purity, 1 eq) in POCl.sub.3 (7.26 g, 47.4 mmol, 4.4 mL, 50 eq) was added DMF (6.93 mg, 94.8 μmol, 0.1 eq). The resulting mixture was the warmed to 60° C. and stirred for 2 h. The mixture was then concentrated under reduced pressure to give (1-benzyl-1H-1,2,3-triazol-4-yl)methanesulfonyl chloride, which was used without further purification or characterization.

Intermediate A-51: 2-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)acetic acid

[1701] ##STR01086##

[1702] Step a: To a solution of ethyl 2-(1H-tetrazol-5-yl)acetate (1.0 g, 6.40 mmol, 1 eq) in DCM (10 mL) was added 2,2-difluoroacetic anhydride (1.45 g, 8.33 mmol, 1.3 eq). The resulting mixture was stirred at 25° C. for 16 h before it was poured into ice water (20 mL). The resulting biphasic mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)acetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.7H.sub.8F.sub.2N.sub.2O.sub.3: 207.0; found 207.0.

[1703] Step b: To a solution of ethyl 2-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)acetate (60 mg, 291 μmol, 1 eq) in MeOH (1 mL) and H.sub.2O (1 mL) was added LiOH.H.sub.2O (13.4 mg, 320 μmol, 1.1 eq). The resulting mixture was stirred at 25° C. for 3 h. The reaction mixture was then poured into ice-water (5 mL), and the pH was adjusted to pH=3 with aqueous HCl (3M). The resulting biphasic mixture was extracted with EtOAc (3×5 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 2-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)acetic acid. LC-MS (ESI): m/z: [M−H].sup.− calculated for C.sub.5H.sub.4F.sub.2N.sub.2O.sub.3: 177.0; found 177.1.

Intermediate A-52: (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoropyrrolidine-2-carboxylic acid

[1704] ##STR01087##

[1705] Step a: To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (10.0 g, 42.9 mmol, 1 eq) and benzyl bromide (8.80 g, 51.5 mmol, 6.11 mL, 1.2 eq) in DMF (50 mL) at 20° C. was added Cs.sub.2CO.sub.3 (21.0 g, 64.3 mmol, 1.5 eq). The resulting mixture was stirred at 20° C. for 12 h before the reaction was quenched by addition of ice-water (100 mL). The resulting biphasic mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was triturated with petroleum ether to give 2-benzyl 1-(tert-butyl) (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate. LC-MS (ESI): m/z: [M+Na].sup.+ calculated for C.sub.17H.sub.22FNO.sub.4: 346.1; found 346.2.

[1706] Step b: To a solution of 2-benzyl 1-(tert-butyl) (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (12.7 g, 39.3 mmol, 1 eq) in EtOAc (50 mL) at 0° C. was added HCl in EtOAc (4 M, 180 mL). The resulting mixture was warmed to 25° C. and stirred for 30 min. The reaction mixture was then filtered, and the filter cake was washed with petroleum ether (3×50 mL) to give (2S,4R)-2-((benzyloxy)carbonyl)-4-fluoropyrrolidin-1-ium chloride. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.12H.sub.14FNO.sub.2: 224.1; found 224.1.

[1707] Step c: To a mixture of (2S,4R)-2-((benzyloxy)carbonyl)-4-fluoropyrrolidin-1-ium chloride (9.55 g, 36.8 mmol, 1 eq), 2-(1H-1,2,3-triazol-5-yl)acetic acid (5.61 g, 44.1 mmol, 1.2 eq) and N-methylimidazole (NMI, 15.1 g, 184 mmol, 5 eq) in DCM (45 mL) at 0° C. was added T3P (35.1 g, 55.1 mmol, 50% purity, 1.5 eq). The resulting mixture was warmed to 25° C. and stirred for 2 h. The reaction mixture was then quenched by addition of H.sub.2O (80 mL), and the resulting biphasic mixture was extracted with EtOAc (3×80 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was triturated with EtOAc to give benzyl (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoropyrrolidine-2-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.16H.sub.17FN.sub.4O.sub.3: 333.1; found 333.1.

[1708] Step d: To a mixture of benzyl (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoropyrrolidine-2-carboxylate (6.60 g, 19.9 mmol, 1 eq), Et.sub.3SiH (4.62 g, 39.7 mmol, 6.34 mL, 2 eq), and N-methylimidazole (NMI, 326 mg, 3.97 mmol, 0.2 eq) in DCE (132 mL) at 25° C. under N2 was added Pd(OAc).sub.2 (1.11 g, 4.96 mmol, 0.25 eq). The resulting mixture was warmed to 60° C. and stirred for 6 h. The reaction mixture was then filtered, and the filter cake was washed with EtOAc (3×50 mL). The combined filtrates were concentrated under reduced pressure to give (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoropyrrolidine-2-carboxylic acid. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.9H.sub.11FN.sub.4O.sub.3: 243.1; found 243.1.

[1709] The following compounds in Table B-12 were synthesized using procedures similar to Intermediate A-52 using the appropriate starting materials.

TABLE-US-00014 TABLE B-12 Exact Intermediate mass No. Structure IUPAC (g/mol) LCMS, Found [M + H].sup.+ B-12-1 [01088] embedded image (2S,4R)-1-acetyl-4- fluoropyrrolidine-2- carboxylic acid 175.1 176.0

Example S-1: Synthesis of (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoro-N—((S)-(4-isopropylphenyl)(phenyl)methyl)pyrrolidine-2-carboxamide

Compound 1

[1710] ##STR01089## ##STR01090##

[1711] Step a: To a mixture of 4-isopropylbenzaldehyde (25 g, 169 mmol, 25.6 mL, 1 eq) and (R)-2-methylpropane-2-sulfinamide (22.5 g, 186 mmol, 1.1 eq) in THF (150 mL) at 15° C. under N.sub.2 was added Ti(OiPr).sub.4 (76.9 g, 337 mmol, 2 eq). The system was degassed and then charged with nitrogen three times. The mixture was then warmed to 25° C. and stirred for 16 h under N.sub.2. The reaction was then quenched by addition of H.sub.2O (200 mL) at 0° C. and stirred for 20 min. The resulting mixture was then filtered, and the filter cake was washed with ethyl acetate (2×200 mL). The filtrate was then extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with saturated aqueous NH.sub.4Cl (200 mL) and brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give (R,E)-N-(4-isopropylbenzylidene)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.14H.sub.21NOS: 252.1; found 252.1.

[1712] Step b: To a solution of (R,E)-N-(4-isopropylbenzylidene)-2-methylpropane-2-sulfinamide (150 g, 596 mmol, 1.00 eq) in DCM (1500 mL) at −65° C. was added phenylmagnesium bromide (3.00 M in Et.sub.2O, 358 mL, 1073 mmol, 1.80 eq). The reaction mixture was warmed to 25° C. and stirred for 30 h. The reaction mixture was then cooled to 0° C. and quenched with saturated aqueous NH.sub.4Cl (2000 mL). The organic phase was isolated and the solvent was removed under reduced pressure to give (R)—N—((S)-(4-isopropylphenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide, which was used in the next step without further purification. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.20H.sub.27NOS: 330.2; found 330.3.

[1713] Step c: To a solution of (R)—N—((S)-(4-isopropylphenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (15 g, 45.5 mmol, 1 eq) in EtOAc (100 mL) at 0° C. was added HCl/EtOAc (4 M, 100 mL). The resulting mixture was then warmed to 20° C. and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure. The resulting crude residue was washed with MTBE (2×80 mL), and the resulting solid was collected by filtration. The solid obtained was dried under reduced pressure to give (S)-(4-isopropylphenyl)(phenyl)methanaminium chloride. LC-MS (ESI): m/z: [M−NH.sub.2].sup.+ calculated for C.sub.16H.sub.19N: 209.1; found 209.1.

[1714] Step d: To a solution of (S)-(4-isopropylphenyl)(phenyl)methanaminium chloride (15 g, 57.4 mmol, 1 eq) in DCM (150 mL) was added (2S,4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid (14.7 g, 63.1 mmol, 1.1 eq), DMAP (7.0 g, 57.4 mmol, 1 eq), and EDCI (11.0 g, 57.3 mmol, 1 eq) sequentially at −40° C. The reaction mixture was warmed over 30 min and stirred at 0° C. for 2 h. The reaction was then quenched with H.sub.2O (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (2S,4R)-4-fluoro-2-(((S)-(4-isopropylphenyl)(phenyl)methyl)carbamoyl)pyrrolidine-1-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.26H.sub.33FN.sub.2O.sub.3: 441.3; found 441.3.

[1715] Step e: To a solution of tert-butyl (2S,4R)-4-fluoro-2-(((S)-(4-isopropylphenyl)(phenyl)methyl)carbamoyl)pyrrolidine-1-carboxylate (24 g, 54.47 mmol, 1 eq) in DCM (240 mL) at 15° C. was added TFA (120 mL) in a dropwise manner. The resulting mixture was stirred at 15° C. for 1 h before the reaction mixture was adjusted to pH 5-6 with aq. NaHCO.sub.3 (1 M) and extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give (2S,4R)-4-fluoro-N—((S)-(4-isopropylphenyl)(phenyl)methyl)pyrrolidine-2-carboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.21H.sub.25FN.sub.2O: 341.2; found 341.1.

[1716] Step f: To a solution of (2S,4R)-4-fluoro-N—((S)-(4-isopropylphenyl)(phenyl)methyl)pyrrolidine-2-carboxamide (6.5 g, 19.1 mmol, 1 eq) and 2-(1H-1,2,3-triazol-5-yl)acetic acid (Intermediate A-1, 3.64 g, 28.6 mmol, 1.5 eq) in DMF (65 mL) at 0° C. was added NMM (5.79 g, 57.3 mmol, 3 eq) and T3P (18.2 g, 28.6 mmol, 50% in EtOAc, 1.5 eq). The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was then poured into H.sub.2O (200 mL) and extracted with EtOAc (2×200 mL). The combined organic extracts were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography and SFC to give (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoro-N—((S)-(4-isopropylphenyl)(phenyl)methyl)pyrrolidine-2-carboxamide. .sup.1H NMR (3:1 rotamer ratio, asterisk denotes distinct minor rotamer peaks, obscured peaks not reported, 400 MHz, DMSO-d6) δ 14.77 (br s, 1H), 9.25* (d, J=8.2 Hz, 1H), 8.87 (d, J=8.4 Hz, 1H), 7.98-7.41 (m, 1H), 7.35-7.26 (m, 4H), 7.26-7.11 (m, 5H), 6.11* (d, J=8.1 Hz, 1H), 6.03 (d, J=8.3 Hz, 1H), 5.48-5.22 (m, 1H), 4.82* (t, J=8.1 Hz, 1H), 4.58 (t, J=8.4 Hz, 1H), 4.13-3.88 (m, 1H), 3.88-3.66 (m, 3H), 3.55-3.38* (m, 1H), 2.92-2.62 (m, 1H), 2.47-2.35 (m, 1H), 2.28-1.89 (m, 1H), 1.18 (d, J=7.0, 1.4 Hz, 6H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.25H.sub.28FN.sub.5O.sub.2: 450.2; found 450.1.

[1717] The following compounds in Table T-1 were synthesized using procedures similar to Compound 1 using the appropriate starting materials.

TABLE-US-00015 TABLE T-1 Compound Exact mass LCMS, Found No. Structure IUPAC (g/mol) [M + H].sup.+ 2 [01091] embedded image (2S,4R)-4-fluoro-1-{3- [N-(1-methyl-1H- pyrazol-3- yl)acetamido]propanoyl}- N-[(2S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 533.3 534.3 3 [01092] (2S,4R)-1-[(3aS,6aS)-5- acetyl-hexahydro-1H- furo[3,4-c]pyrrole-3a- carbonyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 521.3 522.3 4 [01093] embedded image (2S,4R)-1-{7-acetyl-1- oxa-2,7- diazaspiro[4.4]non-2- ene-3-carbonyl}-4- fluoro-N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 534.3 535.2 5 [01094] (2S,4R)-4-fluoro-1- [(2S,3R)-3-methoxy-2- (N- methylacetamido)butan- oyl]-N-[(2S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 511.3 512.3 6 [01095] embedded image (2S,4R)-1-[(4S,5R)-7- acetyl-1-oxo-2,7- diazaspiro[4.4]nonane- 4-carbonyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 548.3 549.3 7 [01096] (2S,4R)-1-(2-{2-acetyl- 2-azaspiro[3.4]octan-5- yl}acetyl)-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 533.3 534.3 8 [01097] embedded image (2S,4R)-4-fluoro-1- [(5S)-2-oxo-1,3- oxazolidine-5- carbonyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 453.2 454.3 9 [01098] (2S,4R)-4-fluoro-N- [(2S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(1H-1,2,3,4-tetrazol- 1-yl)acetyl]pyrrolidine- 2-carboxamide 450.2 451.3 10 [01099] embedded image (2S,4R)-4-fluoro-1-[2- (5-methyl-1,3,4- oxadiazol-2-yl)acetyl]- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 464.2 465.2 11 [01100] (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [3-(1H-1,2,3-triazol-1- yl)propanoyl]pyrrolidine- 2-carboxamide 463.2 464.3 12 [01101] embedded image (2S,4R)-4-fluoro-1- (1,3-oxazole-5- carbonyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 435.2 436.1 13 [01102] (2S,4R)-1-(3- cyanopropanoyl)-4- fluoro-N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 421.2 422.3 14 [01103] (2S,4R)-4-fluoro-1-(2- methanesulfonylacetyl)- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 460.2 461.1 15 [01104] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(1,3-thiazol-4- yl)acetyl]pyrrolidine-2- carboxamide 465.2 466.2 16 [01105] (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(1H-1,2,4-triazol-1- yl)acetyl]pyrrolidine-2- carboxamide 449.2 450.2 17 [01106] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(2H-1,2,3-triazol-2- yl)acetyl]pyrrolidine-2- carboxamide 449.2 450.3 18 [01107] (2S,4R)-4-fluoro-1-[2- (1H-imidazol-4- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 448.2 449.2 19 [01108] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(1H-pyrazol-5- yl)acetyl]pyrrolidine-2- carboxamide 448.2 449.3 20 [01109] (2S,4R)-1-[2-(4-chloro- 1H-pyrazol-1- yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 482.2 483.2 21 [01110] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(pyridazin-3- yloxy)acetyl]pyrrolidine- 2-carboxamide 476.2 477.1 22 [01111] (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(1H-pyrazol-1- yl)acetyl]pyrrolidine-2- carboxamide 448.2 449.3 23 [01112] embedded image (2S,4R)-4-fluoro-1-[2- (1H-imidazol-1- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 448.2 449.3 24 [01113] (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(1H-1,2,3,4-tetrazol- 1- yl)propanoyl]pyrrolidine- 2-carboxamide 464.2 465.3 25 [01114] embedded image (2S,4R)-4-fluoro-1-(3- methyloxetane-3- carbonyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 438.2 439.3 26 [01115] (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(pyrazin-2- yl)acetyl]pyrrolidine-2- carboxamide 460.2 461.2 27 [01116] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(pyrimidin-5- yl)acetyl]pyrrolidine-2- carboxamide 460.2 461.2 28 [01117] (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(pyrimidin-2- yl)acetyl]pyrrolidine-2- carboxamide 460.2 461.2 29 [01118] embedded image (2S,4R)-4-fluoro-1-[2- (5-methyl-1,2,4- oxadiazol-3-yl)acetyl]- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 464.2 465.2 30 [01119] (2S,4R)-4-fluoro-1-(4- methylpyrimidine-5- carbonyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 460.2 461.1 31 [01120] embedded image (2S,4R)-4-fluoro-1-[2- (3-methyl-1,2,4- oxadiazol-5-yl)acetyl]- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 464.2 465.2 32 [01121] (2S,4R)-4-fluoro-1-[2- (2-oxo-1,2- dihydropyrazin-1- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 476.2 477.0 33 [01122] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(1H-1,2,3-triazol-1- yl)propanoyl]pyrrolidine- 2-carboxamide 463.2 464.1 34 [01123] (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(1H-1,2,4-triazol-1- yl)propanoyl]pyrrolidine- 2-carboxamide 463.2 464.3 35 [01124] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [3-(1H-1,2,4-triazol-1- yl)propanoyl]pyrrolidine- 2-carboxamide 463.2 464.2 36 [01125] (2S,4R)-4-fluoro-1-[2- (5-fluoropyridin-2- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 477.2 478.3 37 [01126] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(pyridin-2- yl)acetyl]pyrrolidine-2- carboxamide 459.2 460.3 38 [01127] (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(pyridin-3- yl)acetyl]pyrrolidine-2- carboxamide 459.2 460.3 39 [01128] (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(pyridin-4- yl)acetyl]pyrrolidine-2- carboxamide 459.2 460.3 40 [01129] embedded image (2S,4R)-4-fluoro-1-[2- (3-methyl-1,2-oxazol-5- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 463.2 464.4 41 [01130] (2S,4R)-4-fluoro-1-[2- (2-methyl-1,3-thiazol-5- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 479.2 480.3 42 [01131] embedded image (2S,4R)-1-(2-ethyl-1,3- oxazole-4-carbonyl)-4- fluoro-N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 463.2 464.3 43 [01132] (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(1H-pyrazol-1- yl)propanoyl]pyrrolidine- 2-carboxamide 462.2 463.3 44 [01133] embedded image (2S,4R)-4-fluoro-1-[2- (1H-imidazol-1- yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 462.2 463.3 45 [01134] (2S,4R)-4-fluoro-1-[3- (1H-imidazol-5- yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 462.2 463.2 46 [01135] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [3-(1H-pyrazol-4- yl)propanyl]pyrrolidine- 2-carboxamide 462.2 463.3 47 [01136] (2S,4R)-4-fluoro-1-[3- (1H-imidazol-2- yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 462.2 463.2 48 [01137] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(pyridin-3- yloxy)acetyl]pyrrolidine- 2-carboxamide 475.2 476.3 49 [01138] (2S,4R)-4-fluoro-1-[2- (1-methyl-1H-pyrazol- 3-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 462.2 463.3 50 [01139] embedded image (2S,4R)-4-fluoro-1-[2- (1-methyl-1H-pyrazol- 4-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 462.2 463.3 51 [01140] (2S,4R)-4-fluoro-1-[2- (2-oxo-1,2- dihydropyridin-1- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 475.2 476.3 52 [01141] embedded image (2S,4R)-4-fluoro-1-[2- (2-methyl-1,3-thiazol-4- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 479.2 480.3 53 [01142] (2S,4R)-1-(1-ethyl-1H- pyrazole-5-carbonyl)-4- fluoro-N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 462.2 463.3 54 [01143] embedded image (2S,4R)-4-fluoro-1-[2- (3-methyl-1H-pyrazol- 5-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 462.2 463.3 55 [01144] (2S,4R)-4-fluoro-1-[2- (3-methyl-1H-pyrazol- 1-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 462.2 463.3 56 [01145] embedded image (2S,4R)-4-fluoro-1-[2- (4-methyl-1H-pyrazol- 1-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 462.2 463.3 57 [01146] (2S,4R)-4-fluoro-1- [(2S)-1-methyl-5- oxopyrrolidine-2- carbonyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 465.2 466.3 58 [01147] embedded image (2S,4R)-4-fluoro-1-(6- oxopiperidine-3- carbonyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 465.2 466.2 59 [01148] (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [3-(pyrazin-2- yl)propanoyl]pyrrolidine- 2-carboxamide 474.2 475.2 60 [01149] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [3-(pyrimidin-5- yl)propanoyl]pyrrolidine- 2-carboxamide 474.2 475.2 61 [01150] (2S,4R)-4-fluoro-1-(3- methoxy-1-methyl-1H- pyrazole-4-carbonyl)- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 478.2 479.3 62 [01151] embedded image (2S,4R)-4-fluoro-1-[3- (5-methyl-1,3,4- thiadiazol-2- yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 494.2 495.2 63 [01152] (2S,4R)-1-[2-(2-chloro- 5-fluorophenyl)acetyl]- 4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 510.2 511.3 64 [01153] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(pyridin-2- yl)propanoyl]pyrrolidine- 2-carboxamide 473.2 474.3 65 [01154] (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [3-(pyridin-2- yl)propanoyl]pyrrolidine- 2-carboxamide 473.2 474.3 66 [01155] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [3-(pyridin-3- yl)propanoyl]pyrrolidine- 2-carboxamide 473.2 474.3 67 [01156] (2S,4R)-1-{2- [(dimethylcarbamoyl)a- mino]acetyl}-4-fluoro- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 468.3 469.3 68 [01157] embedded image (2S,4R)-1-[2-(1H-1,2,3- benzotriazol-1- yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 499.2 500.3 69 [01158] (2S,4R)-1-[2-(2,5- dimethyl-1,3-thiazol-4- yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 493.2 494.3 70 [01159] embedded image (2S,4R)-1-[2-(3,5- dimethyl-1,2-oxazol-4- yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 477.2 478.3 71 [01160] (2S,4R)-4-fluoro-1-[2- (N- methylacetamido)propa- noyl]-N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 467.3 468.3 72 [01161] embedded image (2S,4R)-1-(2- acetamidopyridine-4- carbonyl)-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 502.2 503.3 73 [01162] (2S,4R)-4-fluoro-1-[2- (2-oxo-1,2- dihydropyridin-1- yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 489.2 490.3 74 [01163] embedded image (2S,4R)-4-fluoro-1-{3- oxo-2H,3H- [1,2,4]triazolo[4,3- a]pyridine-8-carbonyl}- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 501.2 502.2 75 [01164] (2S,4R)-4-fluoro-1-[4- (1H-imidazol-1- yl)butanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 476.3 477.4 76 [01165] embedded image (2S,4R)-4-fluoro-1-[3- (1-methyl-1H-pyrazol- 4-yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 476.3 477.3 77 [01166] (2S,4R)-1-[2-(1H-1,3- benzodiazol-1- yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 498.2 499.3 78 [01167] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [5-(pyridin-4-yl)-1H- pyrazole-3- carbonyl]pyrrolidine-2- carboxamide 511.2 512.3 79 [01168] (2S,4R)-4-fluoro-1-[3- (1H-imidazol-1-yl)-2- methylpropanoyl]-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 476.3 477.3 80 [01169] embedded image (2S,4R)-4-fluoro-1-[2- methyl-3-(1H-pyrazol- 1-yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 476.3 477.3 81 [01170] (2S,4R)-4-fluoro-1-[2- (6-methoxypyridin-2- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 489.2 490.3 82 [01171] embedded image (2S,4R)-4-fluoro-1-[5- (methoxymethyl)-1,2- oxazole-4-carbonyl]-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 479.2 480.2 83 [01172] (2S,4R)-1-[2-(1,5- dimethyl-1H-pyrazol-3- yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 476.3 477.3 84 [01173] embedded image (2S,4R)-1-[2-(3,5- dimethyl-1H-pyrazol-4- yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 476.3 477.3 85 [01174] (2S,4R)-4-fluoro-1-[2- (2-oxopiperidin-1- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 479.3 480.3 86 [01175] embedded image (2S,4R)-4-fluoro-1-[2- (1H-indol-3-yl)acetyl]- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 497.2 498.3 87 [01176] (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- {2-[5-(propan-2-yl)- 1,2,4-oxadiazol-3- yl]acetyl}pyrrolidine-2- carboxamide 492.3 493.3 88 [01177] embedded image (2S,4R)-4-fluoro-1-[2- (4- methoxyphenyl)acetyl]- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 488.2 489.3 89 [01178] (2S,4R)-4-fluoro-1-[2- (3-fluoro-4- methoxyphenyl)acetyl]- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 506.2 507.3 90 [01179] embedded image (2S,4R)-4-fluoro-1-[2- (5-fluoro-2- methoxyphenyl)acetyl]- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 506.2 507.3 91 [01180] (2S,4R)-4-fluoro-1-[2- (2- methylphenoxy)acetyl]- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 488.2 489.3 92 [01181] embedded image (2S,4R)-4-fluoro-1-[2- methyl-2-(pyridin-2- yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 487.3 488.3 93 [01182] (2S,4R)-4-fluoro-1-(2- oxopiperidine-4- carbonyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 465.2 466.1 94 [01183] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [4-(pyridin-3- yl)butanoyl]pyrrolidine- 2-carboxamide 487.3 488.3 95 [01184] (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [4-(pyridin-4- yl)butanoyl]pyrrolidine- 2-carboxamide 487.3 488.3 96 [01185] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(quinolin-6- yl)acetyl]pyrrolidine-2- carboxamide 509.2 510.3 97 [01186] (2S,4R)-4-fluoro-1-(2- oxo-1,2,3,4- tetrahydroquinoline-7- carbonyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 513.2 514.3 98 [01187] embedded image (2S,4R)-4-fluoro-1-[2- methyl-3-(pyridin-4- yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 487.3 488.3 99 [01188] (2S,4R)-4-fluoro-1-[3- (2-methylpyridin-4- yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 487.3 488.3 100 [01189] embedded image (2S,4R)-4-fluoro-1-[3- (6-methylpyridin-3- yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 487.3 488.3 101 [01190] (2S,4R)-4-fluoro-1-[3- (5-methylpyridin-2- yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 487.3 488.3 102 [01191] embedded image (2S,4R)-4-fluoro-1-[3- (2-methylpyridin-3- yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 487.3 488.3 103 [01192] (2S,4R)-1-[3-(3,5- dimethyl-1,2-oxazol-4- yl)propanoyl]-4-fluoro- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 491.3 492.3 104 [01193] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- (3-{1H-pyrrolo[2,3- b]pyridin-3- yl}propanoyl)pyrrolidine- 2-carboxamide 512.3 513.3 105 [01194] (2S,4R)-4-fluoro-1-[4- (2-methyl-1H-imidazol- 1-yl)butanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 490.3 491.3 106 [01195] embedded image (2S,4R)-1-[3-(3,5- dimethyl-1H-pyrazol-1- yl)propanoyl]-4-fluoro- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 490.3 491.3 107 [01196] (2S,4R)-1-[2-(4- acetamidophenyl)acetyl]- 4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 515.3 516.3 108 [01197] embedded image (2S,4R)-4-fluoro-1-[4- oxo-4-(pyrrolidin-1- yl)butanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 493.3 494.3 109 [01198] (2S,4R)-4-fluoro-1-[3- (1H-indol-3- yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 511.3 512.3 110 [01199] embedded image (2S,4R)-1-[3-(2,6- dimethylpyridin-3- yl)propanoyl]-4-fluoro- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 501.3 502.3 111 [01200] (2S,4R)-4-fluoro-1- {[(2- methylpropyl)carbamoyl] carbonyl}-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 467.3 468.3 112 [01201] embedded image (2S,4R)-1-{4-[(1- acetylazetidin-3- yl)oxy]benzoyl}-4- fluoro-N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 557.3 558.3 113 [01202] (2S,4R)-1-(2- cyclopropyl-2- oxoacetyl)-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 436.2 437.3 114 [01203] embedded image (2S,4R)-4-fluoro-1-[3- (6-oxo-1,6- dihydropyridazin-3- yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 490.2 491.2 115 [01204] (2S,4R)-1- [(dimethylcarbamoyl)car- bonyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 439.2 440.2 116 [01205] embedded image (2S,4R)-1-[2-(4-acetyl- 3,4-dihydro-2H-1,4- benzoxazin-2- yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 557.3 558.3 117 [01206] (2S,4R)-1-[2-(2,5- dioxoimidazolidin-1- yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 480.2 481.1 118 [01207] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- (2-{[1,2,4]triazolo[1,5- a]pyridin-6- yl}acetyl)pyrrolidine-2- carboxamide 499.2 500.3 119 [01208] (2S,4R)-1-[2-(1,2- benzoxazol-3- yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 499.2 500.3 120 [01209] embedded image (2S,4R)-4-fluoro-1-[2- methyl-3-(1H-1,2,4- triazol-1-yl)propanoyl]- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 477.3 478.1 121 [01210] (2S,4R)-4-fluoro-1-(2- {imidazo[1,2-a]pyridin- 3-yl}acetyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 498.2 499.3 122 [01211] embedded image (2S,4R)-4-fluoro-1-(3- oxo-3,4-dihydro-2H- 1,4-benzoxazine-6- carbonyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 515.2 516.3 123 [01212] (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [3-(1H-1,2,4-triazol-1- yl)benzoyl]pyrrolidine- 2-carboxamide 511.2 512.3 124 [01213] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(pyridin-3- yloxy)propanoyl]pyrroli- dine-2-carboxamide 489.2 490.3 125 [01214] (2S,4R)-1-[2-(3,5- dimethyl-1H-pyrazol-1- yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 476.3 477.4 126 [01215] embedded image (2S,4R)-4-fluoro-1-[2- (5-methyl-2,4-dioxo- 1,2,3,4- tetrahydropyrimidin-1- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 506.2 507.3 127 [01216] (2S,4R)-4-fluoro-1-[2- (4-methyl-1H-pyrazol- 1-yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 476.3 477.4 128 [01217] embedded image (2S,4R)-4-fluoro-1-[2- (4-fluoro-1H-indol-1- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 515.2 516.3 129 [01218] (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(pyrrolidine-1- sulfonyl)acetyl]pyrrolidine- 2-carboxamide 515.2 516.3 130 [01219] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(quinolin-5- yl)acetyl]pyrrolidine-2- carboxamide 509.2 510.3 131 [01220] (2S,4R)-4-fluoro-1-{4- oxo-4H,5H,6H,7H,8H- pyrazolo[1,5- a][1,4]diazepine-2- carbonyl}-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 517.2 518.2 132 [01221] embedded image (2S,4R)-4-fluoro-1-[2- methyl-3-(pyridin-2- yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 487.3 488.3 133 [01222] (2S,4R)-1-[2-(2-cyano- 4- methoxyphenyl)acetyl]- 4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 513.2 514.3 134 [01223] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- (3-{1H-pyrrolo[2,3- b]pyridin-5- yl}propanoyl)pyrrolidine- 2-carboxamide 512.3 513.3 135 [01224] (2S,4R)-4-fluoro-1-[3- (3-methoxypyridin-2- yl)propanoyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 503.3 504.3 136 [01225] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(1,3,5-trimethyl-1H- pyrazol-4- yl)acetyl]pyrrolidine-2- carboxamide 490.3 491.3 137 [01226] (2S,4R)-4-fluoro-1-[2- (1-methyl-1H-indol-2- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 511.3 512.3 138 [01227] embedded image (2S,4R)-4-fluoro-1-[2- (5-methyl-1H-indol-3- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 511.3 512.3 139 [01228] (2S,4R)-4-fluoro-1-(3- oxo- octahydroindolizine-6- carbonyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 505.3 506.3 140 [01229] embedded image (2S,4R)-1-[(2R,3R)-1- acetyl-2-(pyridin-3- yl)pyrrolidine-3- carbonyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 556.3 557.2 141 [01230] (2S,4R)-1-(4- acetylmorpholine-2- carbonyl)-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 495.3 496.3 142 [01231] embedded image (2S,4R)-4-fluoro-1-[2- (N- methylacetamido)acetyl]- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 453.2 454.3 143 [01232] (2S,4R)-1-(1-acetyl-3- fluoroazetidine-3- carbonyl)-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 483.2 484.3 144 [01233] embedded image (2S,4R)-1-(1- acetylpiperidine-4- carbonyl)-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 493.3 494.2 145 [01234] (2S,4R)-4-fluoro-1- [(2R)-2-(N- methylacetamido)propa- noyl]-N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 467.3 468.3 146 [01235] embedded image (2S,4R)-1-(1-acetyl-3- methylazetidine-3- carbonyl)-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 479.3 480.3 147 [01236] (2S,4R)-1-(1- acetylpyrrolidine-3- carbonyl)-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 479.3 480.2 148 [01237] embedded image (2S,4R)-1-[(1S,5S)-3- acetyl-3- azabicyclo[3.1.0]hexane- 1-carbonyl]-4-fluoro- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 491.3 492.3 149 [01238] (2S,4R)-1-(4- acetylmorpholine-3- carbonyl)-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 495.3 496.3 150 [01239] embedded image (2S,4R)-1-[(1S)-5- acetyl-2-oxa-5- azabicyclo[2.2.1]heptane- 1-carbonyl]-4-fluoro- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 507.3 508.3 151 [01240] (2S,4R)-1-{2-acetyl-5- oxa-2,6- diazaspiro[3.4]oct-6- ene-7-carbonyl}-4- fluoro-N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 520.2 521.3 152 [01241] embedded image (2S,4R)-1-(1-acetyl-3- methylpyrrolidine-3- carbonyl)-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 493.3 494.3 153 [01242] (2S,4R)-1-[(3S)-1- acetylpiperidine-3- carbonyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 493.3 494.3 154 [01243] embedded image (2S,4R)-1-[2-(1-acetyl- 3-methylazetidin-3- yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 493.3 494.1 155 [01244] (2S,4R)-1-{2-[(2R)-1- acetylpyrrolidin-2- yl]acetyl}-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 493.3 494.3 156 [01245] embedded image (2S,4R)-1-{5-acetyl-5- azaspiro[2.4]heptane-1- carbonyl}-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 505.3 506.2 157 [01246] (2S,4R)-1-[(2S)-7- acetyl-7- azabicyclo[2.2.1]heptane- 2-carbonyl]-4-fluoro- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 505.3 506.3 158 [01247] embedded image (2S,4R)-1-[(2R)-4- acetyl-1,4-oxazepane-2- carbonyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 509.3 510.2 159 [01248] (2S,4R)-1-[(2S,3R)-4- acetyl-2- methylmorpholine-3- carbonyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 509.3 510.3 160 [01249] embedded image (2S,4R)-1-[2-(4-acetyl- 2-oxopiperazin-1- yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 522.3 523.3 161 [01250] (2S,4R)-1-[2-(1-acetyl- 3-methoxyazetidin-3- yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 509.3 510.3 162 [01251] embedded image (2S,4R)-1- [(2R,3aR,6aR)-5-acetyl- hexahydro-2H-furo[2,3- c]pyrrole-2-carbonyl]- 4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 521.3 522.2 163 [01252] (2S,4R)-1-{2-acetyl-5- oxa-2- oazaspiro[3.4]octane-6- carbonyl}-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 521.3 522.2 164 [01253] embedded image (2S,4R)-1-{2-acetyl-5- oxa-2- azaspiro[3.4]octane-7- carbonyl}-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 521.3 522.2 165 [01254] (2S,4R)-1- [(3R,3aS,6aS)-5-acetyl- hexahydro-2H-furo[2,3- c]pyrrole-3-carbonyl]- 4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 521.3 522.3 166 [01255] embedded image (2S,4R)-1- [(3aR,6S,6aR)-4-acetyl- hexahydro-2H-furo[3,2- b]pyrrole-6-carbonyl]- 4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 521.3 522.3 167 [01256] (2S,4R)-1-{6-acetyl- 5H,6H,7H,8H- pyrido[3,4-b]pyrazine- 7-carbonyl}-4-fluoro- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 543.3 544.2 168 [01257] embedded image (2S,4R)-1-(1-acetyl-3- methylpiperidine-3- carbonyl)-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 507.3 508.3 169 [01258] (2S,4R)-1-(1- acetylazepane-4- carbonyl)-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 507.3 508.2 170 [01259] embedded image (2S,4R)-1-[(3S,4R)-1- acetyl-4- methylpiperidine-3- carbonyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 507.3 508.3 171 [01260] (2S,4R)-1-{2-[(3S)-1- acetylpiperidin-3- yl]acetyl}-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 507.3 508.2 172 [01261] embedded image (2S,4R)-1-[3-(1- acetylpyrrolidin-2- yl)propanoyl]-4-fluoro- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 507.3 508.3 173 [01262] (2S,4R)-1-[(1R,5S,8S)- 3-acetyl-3- azabicyclo[3.2.1]octane- 8-carbonyl]-4-fluoro- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 519.3 520.3 174 [01263] embedded image (2S,4R)-1-{6-acetyl-6- azaspiro[2.5]octane-1- carbonyl}-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 519.3 520.2 175 [01264] (2S,4R)-1-{8-acetyl-8- azabicyclo[3.2.1]octane- 3-carbonyl}-4-fluoro- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 519.3 520.2 176 [01265] embedded image (2S,4R)-1-[(1S,4R)-2- acetyl-2- azabicyclo[2.2.2]octane- 6-carbonyl]-4-fluoro- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 519.3 520.3 177 [01266] (2S,4R)-1- [(3aS,4S,6aS)-2-acetyl- octahydrocyclopenta[c] pyrrole-4-carbonyl]-4- fluoro-N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 519.3 520.3 178 [01267] embedded image (2S,4R)-1-(1-acetyl-2- methylpiperidine-3- carbonyl)-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 507.3 508.3 179 [01268] (2S,4R)-1-[(3R,4S)-1- acetyl-4- ethylpyrrolidine-3- carbonyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 507.3 508.3 180 [01269] embedded image (2S,4R)-1-[2-(1- acetylpiperidin-4- yl)propanoyl]-4-fluoro- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 521.3 522.3 181 [01270] (2S,4R)-1-(1-acetyl-4- methylazepane-4- carbonyl)-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 521.3 522.2 182 [01271] embedded image (2S,4R)-1-{2-acetyl-2- azaspiro[4.4]nonane-6- carbonyl}-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 533.3 534.3 183 [01272] (2S,4R)-1- [(3aS,4R,7aS)-2-acetyl- octahydro-1H- isoindole-4-carbonyl]- 4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 533.3 534.0 184 [01273] embedded image (2S,4R)-1-{8-acetyl-8- azaspiro[4.5]decane-2- carbonyl}-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 547.3 548.3 185 [01274] (2S,4R)-4-fluoro-1-(2- hydroxy-3- methylbutanoyl)-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 440.2 441.3 186 [01275] embedded image (2S,4R)-1-(2,3- dihydroxypropanoyl)-4- fluoro-N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 428.2 429.3 187 [01276] (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(2,2,2- trifluoroacetamido)acetyl] pyrrolidine-2- carboxamide 493.2 494.1 188 [01277] embedded image (2S,4R)-1-(2- cyanoacetyl)-4-fluoro- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 407.2 408.1 189 [01278] (2S,4R)-1-{2-[N- (carbamoylmethyl)aceta- mido]acetyl}-4-fluoro- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 496.2 497.1 190 [01279] embedded image (2S,4R)-1-(3- acetamidopropanoyl)-4- fluoro-N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 453.2 454.1 191 [01280] (2S,4R)-1-(4- acetamidobutanoyl)-4- fluoro-N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 467.3 468.3 192 [01281] (2S,4R)-4-fluoro-1-[2- (2-oxopyrrolidin-1- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 465.2 466.2 193 [01282] embedded image (2S,4R)-4-fluoro-1-{2- [(3-methyloxetan-3- yl)amino]acetyl}-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 467.3 468.1 194 [01283] (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(4H-1,2,4-triazol-3- yl)acetyl]pyrrolidine-2- carboxamide 449.2 450.2 195 [01284] embedded image (2S,4R)-4-fluoro-1-[2- (1,3-oxazol-5- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 449.2 450.2 196 [01285] (4S)-4-acetamido-5- [(2S,4R)-4-fluoro-2- {[(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]carba- moyl}pyrrolidin-1-yl]- 5-oxopentanoic acid 511.2 512.3 197 [01286] embedded image (4R)-4-acetamido-5- [(2S,4R)-4-fluoro-2- {[(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]carba- moyl}pyrrolidin-1-yl]- 5-oxopentanoic acid 511.2 512.3 198 [01287] (2S,4R)-4-fluoro-1-{2- [(1,3-oxazol-2- yl)amino]acetyl}-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 464.2 465.1 199 [01288] embedded image (1S,3S,5S)-2-acetyl-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-2- azabicyclo[3.1.0]hexane- 3-carboxamide 376.2 377.1 200 [01289] (1R,3S,5R)-2-acetyl-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-2- azabicyclo[3.1.0]hexane- 3-carboxamide 376.2 377.1 201 [01290] (1S,2S,5R)-3-acetyl-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-3- azabicyclo[3.1.0]hexane- 2-carboxamide 376.2 377.1 202 [01291] embedded image (2RS,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(4H-1,2,4-triazol-4- yl)acetyl]pyrrolidine-2- carboxamide 449.2 450.3 203 [01292] (2S)-1- cyclopropanecarbonyl- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 390.2 391.3 204 [01293] (2S,4S)-1-acetyl-4- hydroxy-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 380.2 381.2 205 [01294] embedded image (2S,4R)-1-acetyl-4- hydroxy-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 380.2 381.3 206 [01295] (2S,3S)-1-acetyl-3- hydroxy-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 380.2 381.1 207 [01296] (2S,4R)-1-acetyl-4- fluoro-N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 382.2 422.2 208 [01297] embedded image (2S,4R)-1-[(2S)-3- carbamoyl-2- acetamidopropanoyl]-4- fluoro-N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 496.2 383.3 209 [01298] (2S,4R)-1-[(2R)-3- carbamoyl-2- acetamidopropanoyl]-4- fluoro-N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 496.2 497.1 210 [01299] embedded image tert-butyl N-{2-oxo-2- [(2S)-2-{[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]carba- moyl}pyrrolidin-1- yl]ethyl}carbamate 479.3 497.2 211 [01300] (2S)-1-(2- hydroxyacetyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 380.2 381.2 212 [01301] (2S)-1-(2- acetamidoacetyl)-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 421.2 422.2 213 [01302] embedded image (2S)-1-(3- carbamoylpropanoyl)- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 421.2 422.3 214 [01303] (2S,5S)-1-acetyl-5- methyl-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 378.2 379.2 215 [01304] (2S,5R)-1-acetyl-5- methyl-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 378.2 379.2 216 [01305] embedded image (2S)-1-[2-(1,3-oxazol- 2-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 431.2 432.3 217 [01306] (2S,4R)-4-fluoro-1-[2- (2-oxo-1,3-oxazolidin- 3-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 467.2 468.1 218 [01307] embedded image (2S,4R)-4-fluoro-1-[2- (oxetan-3-yl)acetyl]-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 438.2 439.3 219 [01308] (2S,4R)-4-fluoro-1-[2- (3-oxomorpholin-4- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 481.2 482.2 220 [01309] embedded image (2S,4RS)-4-fluoro-1-[2- (1-methyl-1H-pyrazol- 5-yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 462.2 463.2 221 [01310] (2S,4RS)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(1H-pyrazol-1- yl)acetyl]pyrrolidine-2- carboxamide 448.2 449.9 222 [01311] embedded image (2RS,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(1H-1,2,3-triazol-1- yl)acetyl]pyrrolidine-2- carboxamide 449.2 450.1 223 [01312] (2RS,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(2H-1,2,3,4-tetrazol- 5-yl)acetyl]pyrrolidine- 2-carboxamide 450.2 451.2 224 [01313] embedded image (2RS,4R)-4-fluoro-1-[2- (1,3,4-oxadiazol-2- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 450.2 451.1 225 [01314] (2RS,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(1H-pyrazol-3- yl)acetyl]pyrrolidine-2- carboxamide 448.2 449.2 226 [01315] embedded image (2RS,4R)-4-fluoro-1-[2- (5-methyl-1H-1,2,3,4- tetrazol-1-yl)acetyl]-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 464.2 465.3 227 [01316] (2RS,4R)-4-fluoro-1-[2- (4-methyl-4H-1,2,4- triazol-3-yl)acetyl]-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 463.2 464.3 228 [01317] embedded image (2RS,4R)-4-fluoro-1-[2- (1-methyl-1H-1,2,3- triazol-5-yl)acetyl]-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 463.2 464.3 229 [01318] (2RS,4R)-4-fluoro-1-[2- (1-methyl-1H-1,2,3- triazol-4-yl)acetyl]-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 463.2 464.2 230 [01319] embedded image (2S,4R)-4-fluoro-1-[2- (1,2-oxazol-4- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 449.2 450.3 231 [01320] (2S,4R)-4-fluoro-1-[2- (1,2-oxazol-3- yl)acetyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 449.2 450.3 232 [01321] embedded image (2S,4R)-4-fluoro-1-[2- (3-methyl-1H-1,2,4- triazol-5-yl)acetyl]-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 463.2 464.2 233 [01322] (2S,4R)-4-fluoro-1-[2- methyl-2-(1H-1,2,4- triazol-5-yl)propanoyl]- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 477.3 478.2 234 [01323] embedded image (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- [2-(piperazin-1- yl)acetyl]pyrrolidine-2- carboxamide 466.3 467.2 235 [01324] (2S,4R)-1-[2-(4- acetylpiperazin-1- yl)acetyl]-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 508.3 509.3 236 [01325] embedded image (2S,4R)-4-fluoro-1-[2- (5-methyl-2-oxo-2,3- dihydro-1,3,4- oxadiazol-3-yl)acetyl]- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 480.2 481.1 237 [01326] tert-butyl N-[(5-{2- [(2S,4R)-4-fluoro-2- {[(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]carba- moyl}pyrrolidin-1-yl]- 2-oxoethyl}-1,3,4- oxadiazol-2- yl)methyl]carbamate 579.3 580.3 238 [01327] embedded image (2S,4R)-1-{2-[5- (aminomethyl)-1,3,4- oxadiazol-2-yl]acetyl}- 4-fluoro-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 479.2 480.2 239 [01328] (2S,4R)-1-{2-[5- (acetamidomethyl)- 1,3,4-oxadiazol-2- yl]acetyl}-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 521.2 522.2 240 [01329] embedded image (2S,4R)-1-{2-[5- (aminomethyl)-1H- 1,2,3-triazol-1- yl]acetyl}-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 478.2 479.2 241 [01330] (2S,4R)-1-(2-{5- [(dimethylamino)methyl]- 1H-1,2,3-triazol-1- yl}acetyl)-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 506.3 507.2 242 [01331] embedded image (2S,4R)-1-(2-{5- [(dimethylamino)methyl]- 1,3,4-oxadiazol-2- yl}acetyl)-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 507.3 508.2 243 [01332] (2S,4R)-1-{2-[5- (acetamidomethyl)-1H- 1,2,3-triazol-1- yl]acetyl}-4-fluoro-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 520.3 521.2 701 [01333] embedded image (2S)-1-(oct-7-ynoyl)-N- [(S)-phenyl[4-(propan- 2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 444.3 445.5 702 [01334] (2S,4R)-4-fluoro-1-(1- methyl-1H-indazole-5- carobnyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 498.2 499.3 703 [01335] (2S,4R)-4-fluoro-1-[2- (4- methoxyphenyl)cyclopro- panecarbonyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 514.3 515.3 704 [01336] embedded image (2S,4R)-4-fluoro-1-(7- oxo-5,6,7,8-tetrahydro- 1,8-naphthyridine-2- carbonyl)-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 514.2 515.3 705 [01337] (2S,4R)-4-fluoro-1-[2- (2- methylpropoxy)pyridine- 4-carbonyl]-N-[(S)- phenyl[4-(propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 517.3 518.3 707 [01338] embedded image (2S,4R)-4-fluoro-1-[4- (1H-imidazol-1- yl)pyridine-2-carbonyl]- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 511.2 512.3 708 [01339] (2S,4R)-4-fluoro-N- [(S)-phenyl[4-(propan- 2-yl)phenyl]methyl]-1- {[(pyridin-3- yl)carbamoyl]carbonyl} pyrrolidine-2- carboxamide 488.2 489.2 709 [01340] embedded image (2S,4R)-4-fluoro-1-(5- methoxy-1-methyl-1H- pyrazole-3-carbonyl)- N-[(S)-phenyl[4- (propan-2- yl)phenyl]methyl]pyrrol- idine-2-carboxamide 478.2 479.3

Example S-2: Synthesis of (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoro-N—((S)-(5-isopropylpyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide

Compound 244

[1718] ##STR01341## ##STR01342##

[1719] Step a: To a solution of 5-bromopicolinaldehyde (15 g, 80.6 mmol, 1 eq) in DCM (150 mL) at 25° C. was added (S)-2-methylpropane-2-sulfinamide (10.8 g, 88.7 mmol, 1.1 eq) and Cs.sub.2CO.sub.3 (28.9 g, 88.7 mmol, 1.1 eq). The resulting mixture was degassed and charged with nitrogen three times before it was warmed to 40° C. and stirred 2 h under N.sub.2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give (S,E)-N-((5-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.13BrN.sub.2OS: 289.0; found 289.0.

[1720] Step b: A solution of (S,E)-N-((5-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (20 g, 69.2 mmol, 1 eq) in DCM (100 mL) was degassed with N.sub.2 and cooled to −70° C. To the cooled solution was added PhMgBr (3 M in Et.sub.2O, 27.7 mL, 1.2 eq) in a dropwise manner. The resulting reaction mixture was stirred at −70° C. for 2 h, warmed to room temperature, and stirred for another 1 h. The reaction mixture then was quenched with water (150 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (3×50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give (S)—N—((S)-(5-bromopyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.16H.sub.19BrN.sub.2OS: 367.0; found 367.0.

[1721] Step c: To a solution of (S)—N—((S)-(5-bromopyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (23 g, 62.6 mmol, 1 eq) in 1,4-dioxane (150 mL) and water (40 mL) at 25° C. was added 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15.8 g, 93.9 mmol, 1.5 eq), Cs.sub.2CO.sub.3 (40.8 g, 125 mmol, 2 eq) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (5.11 g, 6.26 mmol, 0.1 eq). The resulting mixture was degassed and charged with nitrogen three times, and the reaction mixture was warmed to 110° C. and stirred for 8 h. After cooling, the reaction mixture was concentrated under reduced pressure, and water (150 mL) was added. The resulting mixture was extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with brine (3×100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give (S)-2-methyl-N—((S)-phenyl(5-(prop-1-en-2-yl)pyridin-2-yl)methyl)propane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.19H.sub.24N.sub.20S: 329.2; found 329.2.

[1722] Step d: To a solution of (S)-2-methyl-N—((S)-phenyl(5-(prop-1-en-2-yl)pyridin-2-yl)methyl)propane-2-sulfinamide (11.5 g, 35 mmol, 1 eq) in MeOH (80 mL) at 25° C. was added PtO.sub.2 (795 mg, 3.50 mmol, 0.1 eq). The system was degassed and charged with hydrogen three times, and the reaction mixture was stirred under H.sub.2 atmosphere (15 psi) at 25° C. for 2 h. The mixture was then filtered through a pad of Celite, and the filter cake was washed with MeOH (2×30 mL). The filtrate was then concentrated under reduced pressure to give (S)—N—((S)-(5-isopropylpyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide, which was used directly for the next step without further purification. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.19H.sub.26N.sub.2OS: 331.2; found 331.2.

[1723] Step e: To a solution of (S)—N—((S)-(5-isopropylpyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (12.0 g, 36.3 mmol, 1 eq) in EtOAc (20 mL) at 25° C. was added HCl/EtOAc (4 M, 109 mL, 436 mmol, 12.0 eq). The resulting mixture was stirred for 1 h before it was filtered. The filter cake was then washed with petroleum ether, and the collected solid dried under reduced pressure to give (S)-(5-isopropylpyridin-2-yl)(phenyl)methanamine hydrochloride. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.15H.sub.18N.sub.2: 227.2; found 227.2.

[1724] Step f: To a solution of (S)-(5-isopropylpyridin-2-yl)(phenyl)methanamine hydrochloride (5.00 g, 19.0 mmol, 1 eq, HCl salt) in MeCN (70 mL) at −20° C. under N.sub.2 atmosphere was added 1-methyl-1H-imidazole (NMI, 4.69 g, 57.1 mmol, 3 eq) and (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (4.9 g, 20.1 mmol, 1.1 eq), and the resulting mixture was stirred for 10 min. To this mixture was added chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH, 5.87 g, 20.9 mmol, 1.1 eq) in portions. The resulting reaction mixture was stirred at −20° C. for 3 h under N.sub.2 atmosphere. The reaction mixture was then quenched with H.sub.2O (30 mL), and the resulting biphasic mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (3×30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give tert-butyl (2S,4R)-4-fluoro-2-(((S)-(5-isopropylpyridin-2-yl)(phenyl)methyl)carbamoyl)pyrrolidine-1-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.25H.sub.32FN.sub.3O.sub.3: 442.2; found 442.3.

[1725] Step g: To a solution of tert-butyl (2S,4R)-4-fluoro-2-(((S)-(5-isopropylpyridin-2-yl)(phenyl)methyl)carbamoyl)pyrrolidine-1-carboxylate (3.9 g, 8.8 mmol) in 1,4-dioxane (5 mL) at 0° C. was added HCl/dioxane (4 M, 50 mL), and the resulting mixture was stirred at 0° C. for 2 h. The reaction mixture was then concentrated at low temperature under reduced pressure. The resulting solid was washed with MTBE (3×10 mL), collected via filtration, and dried under reduced pressure to give (2S,4R)-4-fluoro-2-(((S)-(5-isopropylpyridin-2-yl)(phenyl)methyl)carbamoyl)pyrrolidin-1-ium chloride. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.20H.sub.24FN.sub.3O: 342.2; found 342.2.

[1726] Step h: To a solution of (2S,4R)-4-fluoro-2-(((S)-(5-isopropylpyridin-2-yl)(phenyl)methyl)carbamoyl)pyrrolidin-1-ium chloride (2.50 g, 6.62 mmol, 1 eq, HCl), 4-methylmorpholine (NMM, 2.01 g, 19.9 mmol, 3 eq), and 2-(1H-1,2,3-triazol-5-yl)acetic acid (Intermediate A-1, 1.26 g, 9.92 mmol, 1.5 eq) in DMF (30 mL) at 0° C. was added T3P (50% in ethyl acetate, 8.42 g, 13.3 mmol, 2 eq). The resulting mixture was then stirred at 0° C. for 2 h under N2 atmosphere. The reaction mixture was then quenched by addition of H.sub.2O (60 mL) at 0° C., and the biphasic mixture was extracted with DCM (3×15 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue was then purified by prep-HPLC to give (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoro-N—((S)-(5-isopropylpyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide. .sup.1H NMR (2.4:1 rotamer ratio, asterisk denotes distinct minor rotamer peaks, obscured peaks not reported, 400 MHz, DMSO-d6) δ 15.17-14.54 (m, 1H), 9.32* (d, J=8.0 Hz, 1H), 8.90 (d, J=8.3 Hz, 1H), 8.43* (d, J=2.3 Hz, 1H), 8.39 (d, J=2.3 Hz, 1H), 7.71-7.59 (m, 1H), 7.40-7.15 (m, 6H), 6.14* (d, J=7.9 Hz, 1H), 6.05 (d, J=8.2 Hz, 1H), 5.50-5.21 (m, 1H), 4.99-4.88* (m, 1H), 4.64 (t, J=8.3 Hz, 1H), 4.14-3.63 (m, 3H), 3.55-3.36* (m, 1H), 2.99-2.83 (m, 1H), 2.76-2.59* (m, 1H), 2.47-2.35 (m, 1H), 2.27-1.90 (m, 1H), 1.20 (d, J=7.0, 1.3 Hz, 6H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.24H.sub.27FN.sub.6O.sub.2: 451.2; found 451.3.

[1727] The following compounds in Table T-2 were synthesized using procedures similar to Compound 244 using the appropriate starting materials.

TABLE-US-00016 TABLE T-2 LCMS, Compound Exact mass Found No. Structure IUPAC (g/mol) [M + H].sup.+ 245 [01343] embedded image (2S)-1-acetyl-N- [(S)-phenyl[5- (propan-2- yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 365.2 366.3 246 [01344] (2S,4R)-1-[2-(3,5- dimethyl-1H- pyrazol-4- yl)acetyl]-4- fluoro-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 477.3 478.1 247 [01345] (2S,4R)-4-fluoro- N-[(S)-phenyl[5- (propan-2- yl)pyridin-2- yl]methyl]-1-[2- (quinolin-5-yl) acetyl]pyrrolidine- 2-carboxamide 510.2 511.2 248 [01346] embedded image (2S,4R)-1- [2-(1H-1,3- benzodiazol- 1-yl)acetyl]- 4-fluoro-N- [(S)- phenyl[5- (propan-2- yl)pyridin-2- yl]methyl] pyrrolidine-2- carboxamide 499.2 500.1 249 [01347] (2S,4R)-4-fluoro- 1-[2-(5-methyl- 2,4-dioxo-1,2,3,4- tetrahydropyrimidin- 1-yl)acetyl]-N- [(S)-phenyl[5- (propan-2- yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 507.2 508.2 250 [01348] embedded image (2S,4R)-1-{2- [(dimethylcarbamoyl) amino]acetyl}- 4-fluoro-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 469.2 470.3 251 [01349] 2-[(2S,4R)-4- fluoro-2-{[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]carbamoyl} pyrrolidin-1- yl]-2-oxoethyl N,N- dimethylcarbamate 470.2 471.1 252 [01350] embedded image (2S,4R)-4-fluoro- N-[(S)-phenyl[5- (propan-2- yl)pyridin-2- yl]methyl]-1-[2- (1H-1,2,3,4- tetrazol-1-yl) acetyl]pyrrolidine- 2-carboxamide 451.2 452.2 253 [01351] (2S,4R)-1-{2-[5- (difluoromethyl)- 1,3,4-oxadiazol-2- yl]acetyl}-4- fluoro-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 501.2 502.1 254 [01352] embedded image (2S,4R)-1-{2-[5- (difluoromethyl)- 1H-1,2,3,4- tetrazol-1- yl]acetyl}-4- fluoro-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 501.2 502.3 255 [01353] (2S,4R)-4-fluoro- N-[(S)-phenyl[5- (propan-2- yl)pyridin-2- yl]methyl]-1-{2- (trifluoromethyl)- 2H-1,2,3,4- tetrazol-2-yl] acetyl}pyrrolidine- 2-carboxamide 519.2 520.2 256 [01354] embedded image (2S,4R)-1-{2-[5- (difluoromethyl)- 2H-1,2,3,4- tetrazol-2- yl]acetyl}-4- fluoro-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 501.2 502.2 257 [01355] (2S,4R)-4-fluoro- 1-[2-(2- methylquinolin-5- yl)acetyl]-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 524.3 525.3 258 [01356] embedded image (2S,4R)-4-fluoro- 1-(2-{3-oxo- 2H,3H- [1,2,4]triazolo[4,3- a]pyridin-8- yl}acetyl)-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 516.2 517.3 259 [01357] (2S,4R)-1-{2-[4- (dimethylamino)- 2H-1,2,3-triazol-2- yl]acetyl}-4- fluoro-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 493.3 494.3 260 [01358] embedded image (2S,4R)-1-{2-{4- (dimethylamino)- 1H-1,2,3-triazol-1- yl]acetyl}-4- fluoro-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 493.3 494.2 261 [01359] (2S,4R)-4-fluoro- 1-{2- [(methylcarbamoyl) amino]acetyl}-N- [(S)-phenyl[5- (propan-2- yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 455.2 456.2 262 [01360] embedded image (2S,4R)-1-[2- (carbamoylamino) acetyl]-4-fluoro-N- [(S)-phenyl[5- (propan-2- yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 441.2 442.1 263 [01361] (2S,4R)-4-fluoro- 1-[2-(1-methyl-5- oxo-4,5-dihydro- 1H-1,2,4-triazol-3- yl)acetyl]-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 480.2 481.3 264 [01362] embedded image (2S,4R)-4-fluoro- 1-[2-(4-methyl-5- oxo-4,5-dihydro- 1H-1,2,4-triazol-3- yl)acetyl]-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 480.2 481.2 265 [01363] (2S,4R)-1-{2- [(azetidine-1- carbonyl)amino] acetyl}-4-fluoro- N-[(S)-phenyl[5- (propan-2- yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 481.2 482.2 266 [01364] embedded image (2S,4R)-4-fluoro- 1-[2-(4-methyl-5- oxo-4,5-dihydro- 1,3,4-oxadiazol-2- yl)acetyl]-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 481.2 482.3 267 [01365] (2S,4R)-4-fluoro- 1-[2-(4-methyl-5- oxo-4,5-dihydro- 1,2,4-oxadiazol-3- yl)acetyl]-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 481.2 482.3 268 [01366] embedded image (2S,4R)-4-fluoro- N-[(S)-phenyl[5- (propan-2- yl)pyridin-2- yl]methyl]-1-{2- [4- (trifluoromethyl)- 1H-1,2,3-triazol-5-yl] acetyl}pyrrolidine- 2-carboxamide 518.2 519.3 269 [01367] (2S,4R)-4-fluoro- 1-{2-[(2- methylpyrimidin- 4- yl)amino]acetyl}- N-[(S)-phenyl[5- (propan-2- yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 490.2 491.2 270 [01368] embedded image (2S,4R)-4-fluoro- 1-[2-(1,3-oxazol- 2-yl)acetyl]-N- [(S)-phenyl[5- (propan-2- yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 450.2 451.3 271 [01369] (2S,4R)-4-fluoro- 1-[2-(5-methyl- 1,3-oxazol-2- yl)acetyl]-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 464.2 465.2 272 [01370] embedded image (2S,4R)-4-fluoro- 1-[2-(4-methyl- 1,3-oxazol-2- yl)acetyl]-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 464.2 465.2 273 [01371] (2S,4R)-1- [(2S)-2- [(dimethylcarbamoyl) amino]propanoyl]- 4-fluoro-N- [(S)- phenyl[5- (propan-2- yl)pyridin-2- yl]methyl] pyrrolidine-2- carboxamide 483.3 484.3 274 [01372] embedded image (2S,4R)-1- [(2R)-2- [(dimethylcarbamoyl) amino]propanoyl]- 4-fluoro-N- [(S)- phenyl[5- (propan-2- yl)pyridin-2- yl]methyl] pyrrolidine-2- carboxamide 483.3 484.3 275 [01373] (2S,4R)-4-fluoro- 1-[2-(5-methyl-2- oxo-2,3-dihydro- 1,3,4-oxadiazol-3- yl)acetyl]-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 481.2 482.3 276 [01374] embedded image (2S,4R)-1-{2-[4- (azetidin-1-yl)-2H- 1,2,3-triazol-2 -yl]acetyl}-4- fluoro-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 505.3 506.3 277 [01375] (2S,4R)-1- {2-[4-(3,3- difluoroazetidin- 1-yl)- 2H-1,2,3- triazol-2- yl]acetyl}-4- fluoro-N- phenyl[5- (propan-2- yl)pyridin-2- yl]methyl] pyrrolidine-2- carboxamide 541.2 542.3 278 [01376] embedded image (2S,4R)-1-{2-[4- (diethylamino)- 2H-1,2,3-triazol-2- yl]acetyl}-4- fluoro-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 521.3 522.5 279 [01377] (1S,2S,5R)-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2- yl]methyl]-3-[2- (1H-1,2,3-triazol- 5-yl)acetyl]-3- azabicyclo[3.1.0] hexane-2- carboxamide 444.2 445.4 280 [01378] embedded image (2S,5S)-5-methyl- N-[(S)-phenyl[5- (propan-2- yl)pyridin-2- yl]methyl]-1-[2- (1H-1,2,3-triazol- 5-yl) acetyl]pyrrolidine- 2-carboxamide 446.2 447.3 281 [01379] N-{2-[(2S,4R)-4- fluoro-2-{[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]carbamoyl} pyrrolidin-1- yl]-2-oxoethyl}-4- (2,2,2-trifluoroethyl) piperazine-1- carboxamide 592.3 593.2 282 [01380] embedded image 4- (cyclopropyl methyl)-N- {2-[(2S,4R)- 4-fluoro-2- phenyl[5- (propan-2- yl)pyridin-2- yl]methyl] carbamoyl} pyrrolidin-1-yl]- 2-oxoethyl} piperazine-1- carboxamide 564.3 565.5 283 [01381] N-{2-[(2S,4R)-4- fluoro-2-{[(S)- phenyl[5-(propan- 2-yl)pyridin-2- yl}pyrrolidin-1- yl]-2-oxoethyl}-4- methylpiperazine- 1-carboxamide 524.3 525.3 284 [01382] embedded image (2S,4R)-4-fluoro- 1-[2-(5-oxo-4,5- dihydro-1H-1,2,4- triazol-3- yl)acetyl]-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 466.2 467.0 285 [01383] (2S,4R)-4-fluoro- N-[(S)-phenyl[5- (propan-2- yl)pyridin-2- yl]methyl]-1-[2- (4H-1,2,4-triazol- 4-yl) acetyl]pyrrolidine- 2-carboxamide 450.2 451.3 286 [01384] embedded image (2S,4R)-4-fluoro- 1-[2-(5-oxo-4,5- dihydro-1,2,4- oxadiazol-3- yl)acetyl]-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 467.2 468.2 287 [01385] (2S,4R)-4-fluoro- 1-[3-(5-oxo-4,5- dihydro-1H-1,2,4- triazol-3- yl)propanoyl]-N- [(S)-phenyl[5- (propan-2- yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 480.2 481.0 288 [01386] embedded image (2S,4R)-4-fluoro- 1-[2-(5-oxo-4,5- dihydro-1H-1,2,4- triazol-4- yl)acetyl]-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 466.2 467.2 289 [01387] (2S,4R)-4-fluoro- 1-(3-{3-oxo- 2H,3H- [1,2,4]triazolo[4,3- a]pyridin-2- propanoyl)-N- [(S)-phenyl[5- (propan-2- yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 530.2 531.2 290 [01388] embedded image (2S,4R)-1- {2-[(3,3- difluoroazetidine- 1- carbonyl)amino] acetyl}-4- fluoro-N- [(S)- phenyl[5- (propan-2- yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 517.2 517.2 291 [01389] (2S,4R)-4-fluoro- N-[(S)-phenyl[5- (propan-2- yl)pyridin-2- yl]methyl]-1-(2- {[3- (trifluoromethyl) azetidine-1- carbonyl]amino} acetyl)pyrrolidine- 2-carboxamide 549.2 549.2 292 [01390] embedded image (2S,4R)-4-fluoro- N-[(S)-phenyl[5- (propan-2- yl)pyridin-2- yl]methyl]-1-[2- (1H-pyrazol-1-yl) acetyl]pyrrolidine- 2-carboxamide 449.2 449.2 710 [01391] (2S,4R)-1-[2-(1,4- dimethyl-5-oxo- 4,5-dihydro-1H- 1,2,4-triazol-3- yl)acetyl]-4- fluoro-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 494.2 495.3 711 [01392] embedded image (2S,4R)-1-{2-[4- (azetidin-1-yl)-1H- 1,2,3-triazol-1- yl]acetyl}-4- fluoro-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 505.3 506.3 712 [01393] (2S,4R)-4-fluoro- 1-[2-(5-methoxy- 1-methyl-1H- 1,2,4-triazol-3- yl)acetyl]-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 494.2 495.3 713 [01394] embedded image (2S,4R)-1-{2-[5- (diethylamino)- 1H-1,2,3-triazol-1- yl]acetyl}-4- fluoro-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 521.3 522.3 714 [01395] (2S,4R)-1-{2-[5- (3,3- difluoroazetidin-1- yl)-1H-1,2,3- triazol-1- yl]acetyl}-4- fluoro-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 541.2 542.3 715 [01396] embedded image (2S,4R)-1-{2-[5- (azetidin-1-yl)-1H- 1,2,3-triazol-1- yl]acetyl}-4- fluoro-N-[(S)- phenyl[5-(propan- 2-yl)pyridin-2-yl] methyl]pyrrolidine- 2-carboxamide 505.2 506.3

Example S-3: Synthesis of (2S,4R)—N—((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-1-(2-(5-(difluoromethyl)-1H-tetrazol-1-yl)acetyl)-4-fluoropyrrolidine-2-carboxamide

Compound 293

[1728] ##STR01397## ##STR01398##

[1729] Step a: In four parallel reactions, 6-fluoropyridin-2-amine (125 g, 1.11 mol, 1 eq) in MeCN (1.2 L) at 0° C. under N.sub.2 was treated with NBS (209 g, 1.17 mmol, 1.05 eq) in MeCN (1.2 L). The reaction mixtures were stirred at 20° C. for 2 h. The four parallel reactions were combined, and the resulting mixture was concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give 5-bromo-6-fluoropyridin-2-amine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.5H.sub.4BrFN.sub.2: 190.9; found 191.0.

[1730] Step b: To a mixture of 5-bromo-6-fluoropyridin-2-amine (200 g, 1.04 mol, 1 eq) and cyclopropylboronic acid (226 g, 2.63 mol, 2.5 eq) in 1,4-dioxane (2 L) and H.sub.2O (200 mL) under N.sub.2 were added K.sub.3PO.sub.4 (666 g, 3.14 mol, 3 eq), PCy.sub.3 (58.6 g, 209 mmol, 0.2 eq), and Pd(OAc).sub.2 (11.7 g, 52.3 mmol, 0.05 eq). The system was then degassed and charged with nitrogen three times. The reaction mixture was warmed to 100° C. and stirred for 12 h. The reaction mixture was then cooled to room temperature and filtered through Celite. The resulting filtrate was diluted with H.sub.2O (2 L) and then extracted with EtOAc (3×500 mL). The combined organic extracts were washed with brine (2×300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 5-cyclopropyl-6-fluoropyridin-2-amine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.9FN.sub.2: 153.1; found 153.0.

[1731] Step c: To a mixture of 5-cyclopropyl-6-fluoropyridin-2-amine (120 g, 788 mmol, 1 eq) in dibromomethane (564 mL) under N.sub.2 was added isopentyl nitrite (110 g, 946 mmol, 127 mL, 1.2 eq). To the resulting mixture was added CuBr.sub.2 (211 g, 946 mmol, 44.3 mL, 1.2 eq) over 0.5 h. The final mixture was then degassed and charged with nitrogen three times before stirring at 20° C. for 16 h. The reaction mixture was then filtered, and the filtrate was diluted with H.sub.2O (500 mL) and extracted with EtOAc (3×300 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 6-bromo-3-cyclopropyl-2-fluoropyridine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.7BrFN: 216.0; found 216.1.

[1732] Step d: To a mixture of 6-bromo-3-cyclopropyl-2-fluoropyridine (90 g, 416 mmol, 1 eq) and trifluoro(vinyl)-λ4-borane, potassium salt (83.7 g, 624 mmol, 1.5 eq) in i-PrOH (900 mL) at 20° C. under N.sub.2 was added TEA (126 g, 1.25 mol, 3 eq) and Pd(dppf)Cl.sub.2DCM (17 g, 20.8 mmol, 0.05 eq). The resulting mixture was degassed and charged with nitrogen three times. The reaction mixture was then warmed to 100° C. and stirred for 2 h. The reaction mixture was then cooled to room temperature and filtered. The filtrate was diluted with H.sub.2O (500 mL) and extracted with EtOAc (3×300 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was then purified by column chromatography to give 3-cyclopropyl-2-fluoro-6-vinylpyridine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.10FN: 164.1; found 164.1.

[1733] Step e: To a mixture of 3-cyclopropyl-2-fluoro-6-vinylpyridine (47 g, 288 mmol, 1 eq) in THF (800 mL) and H.sub.2O (160 mL) at 20° C. under N.sub.2 was added NaIO.sub.4 (246 g, 1.15 mol, 4 eq) and K.sub.2OsO.sub.4.2H.sub.2O (2.12 g, 5.76 mmol, 0.02 eq). The resulting mixture was degassed and charged with nitrogen three times before stirring for 2 h. The reaction mixture was then filtered, and the filtrate was diluted with H.sub.2O (500 mL), and extracted with EtOAc (3×300 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give 5-cyclopropyl-6-fluoropicolinaldehyde. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.9H.sub.8FNO: 166.1; found 166.2.

[1734] Step f: To a mixture of 5-cyclopropyl-6-fluoropicolinaldehyde (38 g, 230 mmol, 1 eq) and (S)-2-methylpropane-2-sulfinamide (30.6 g, 253 mmol, 1.1 eq) in DCM (200 mL) at 20° C. under N.sub.2 was added Cs.sub.2CO.sub.3 (82.4 g, 253 mmol, 1.1 eq). The system was then degassed and charged with nitrogen three times. The resulting mixture was then warmed to 40° C. and stirred for 12 h. The reaction solution was then diluted with H.sub.2O (300 mL) and extracted with DCM (3×200 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was then purified by column chromatography to give (S,E)-N-((5-cyclopropyl-6-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.13H.sub.17FN.sub.2OS: 269.1; found 269.2.

[1735] Step g: To a solution of (S,E)-N-((5-cyclopropyl-6-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (58 g, 216 mmol, 1 eq) in dry DCM (600 mL) at −70° C. under nitrogen was added PhMgBr (3 M in Et.sub.2O, 93.6 mL, 281 mmol, 1.3 eq) in a dropwise manner. The resulting reaction mixture was stirred at −70° C. for 1 h. The reaction mixture was then quenched with saturated aqueous NH.sub.4Cl solution (500 mL), warmed to room temperature, and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (S)—N—((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.19H.sub.23FN.sub.2OS: 347.2; found 347.3.

[1736] Step h: To a solution of (S)—N—((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (74 g, 213 mmol, 1 eq) in EtOAc (100 mL) at 0° C. under N.sub.2 was added HCl/EtOAc (4 M, 740 mL, 2940 mmol, 13.8 eq). The resulting mixture was then warmed 20° C. and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure, and the crude residue obtained was triturated with MTBE (500 mL). The resulting solid was collected by filtration and dried under reduced pressure to give (S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methanaminium chloride. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.15H.sub.15FN.sub.2: 243.1; found 243.2.

[1737] Step i: To a mixture of (S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methanaminium chloride (56 g, 200 mmol, 1 eq) and (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (60.9 g, 261 mmol, 1.3 eq) in DMF (500 mL) at 0° C. under N2 was added N-methylmorpholine (NMM, 101 g, 1.00 mol, 110 mL, 5 eq) and T3P (50% in ethyl acetate, 166 g, 261 mmol, 155 mL, 1.3 eq). The resulting mixture was degassed and charged with nitrogen three times, warmed to 20° C. and stirred 1 h. The reaction mixture was then diluted with H.sub.2O (200 mL) and extracted with EtOAc (3×300 mL). The combined organic extracts were washed with brine (500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (2S,4R)-2-(((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.25H.sub.29F.sub.2N.sub.3O.sub.3: 458.2; found 458.2.

[1738] Step j: To a solution of tert-butyl (2S,4R)-2-(((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (90 g, 196 mmol, 1 eq) in EtOAc (100 mL) at 0° C. under N.sub.2 was added HCl/EtOAc (4 M, 900 mL, 18.3 eq). The resulting mixture was warmed to 20° C. and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure, and the resulting crude residue was added to H.sub.2O (100 mL). The resulting mixture was cooled to 0° C., adjusted to pH=7-8 with saturated aqueous NaHCO.sub.3 and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with brine (100 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude material was then triturated with i-PrOH (500 mL), and the resulting solid was isolated via filtration. The solid obtained was dried under reduced pressure to give (2S,4R)—N—((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.20H.sub.21F.sub.2N.sub.3O: 358.2; found 358.3.

[1739] Step k: To a mixture of 2-(5-(difluoromethyl)-1H-tetrazol-1-yl)acetic acid (Intermediate A-2, 4.53 g, 25.5 mmol, 1.30 eq) and (2S,4R)—N—((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide (7 g, 19.6 mmol, 1.00 eq) in DMF (70 mL) at −20° C. was added N-methylmorpholine (11.2 g, 117 mmol, 6 eq) and T3P (50% in ethyl acetate, 25.0 g, 39.1 mmol, 2.00 eq). The reaction mixture was then warmed to −10° C. and stirred for 2 h. The reaction mixture was then quenched with water (100 mL) and extracted with dichloromethane (2×100 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue was purified by prep-HPLC to give (2S,4R)—N—((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-1-(2-(5-(difluoromethyl)-1H-tetrazol-1-yl)acetyl)-4-fluoropyrrolidine-2-carboxamide. .sup.1H NMR (4.2:1 rotamer ratio, asterisk denotes distinct minor rotamer peaks, obscured peaks not reported, 400 MHz, DMSO-d6) δ 9.29* (d, J=7.7 Hz, 1H), 8.92 (d, J=8.0 Hz, 1H), 7.65-7.17 (m, 8H), 6.11* (d, J=7.7 Hz, 1H), 6.03-5.66 (m, 3H), 5.60-5.23 (m, 1H), 5.10-4.92* (m, 2H), 4.65 (t, J=8.4 Hz, 1H), 4.17-3.76 (m, 2H), 3.61-3.40* (m, 1H), 2.92-2.75* (m, 1H), 2.15-1.89 (m, 2H), 1.03-0.91 (m, 2H), 0.82-0.69 (m, 2H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.24H.sub.23F.sub.4N.sub.7O.sub.2: 518.2; found 518.1.

[1740] The following compounds in Table T-3 were synthesized using procedures similar to Compound 293 using the appropriate starting materials.

TABLE-US-00017 TABLE T-3 Exact LCMS, Compound mass Found No. Structure IUPAC (g/mol) [M + H].sup.+ 294 [01399] embedded image (2S,4R)-1-[2-(1H-1,3- benzodiazol-1-yl)acetyl]- N-[(S)-(5-cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoropyrrolidine-2- carboxamide 515.2 516.2 295 [01400] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-[2-(5-methyl- 2,4-dioxo-1,2,3,4- tetrahydropyrimidin-1- yl)acetyl]pyrrolidine-2- carboxamide 523.2 524.3 296 [01401] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-[2-(4H-1,2,4- triazol-4- yl)acetyl]pyrrolidine-2- carboxamide 466.2 467.2 297 [01402] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-(2-{3-oxo- 2H,3H- [1,2,4]triazolo[4,3- a]pyridin-8- yl}acetyl)pyrrolidine-2- carboxamide 532.2 533.3 298 [01403] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [5-(dimethylamino)-1H- 1,2,3-triazol-1- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 509.2 510.2 299 [01404] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [4-(dimethylamino)-1H- 1,2,3-triazol-1- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 509.2 510.2 300 [01405] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [(dimethylcarbamoyl) amino]acetyl}-4- fluoropyrrolidine-2- carboxamide 485.2 486.2 301 [01406] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-{2- [(methylcarbamoyl)amino] acetyl}pyrrolidine-2- carboxamide 471.2 472.2 302 [01407] embedded image (2S,4R)-1-[2- (carbamoylamino)acetyl]- N-[(S)-(5-cyclopropyl- 6-fluoropyridin-2- yl)(phenyl)methyl]-4- fluoropyrrolidine-2- carboxamide 457.2 458.3 303 [01408] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-[2-(1-methyl-5- oxo-4,5-dihydro-1H- 1,2,4-triazol-3- yl)acetyl]pyrrolidine-2- carboxamide 496.2 497.3 304 [01409] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-[2-(4-methyl-5- oxo-4,5-dihydro-1H- 1,2,4-triazol-3- yl)acetyl]pyrrolidine-2- carboxamide 496.2 497.1 305 [01410] (2S,4R)-1-{2-[(azetidine- 1- carbonyl)amino]acetyl}- N-[(S)-(5-cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoropyrrolidine-2- carboxamide 497.2 498.2 306 [01411] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-[2-(4-methyl-5- oxo-4,5-dihydro-1,3,4- oxadiazol-2- yl)acetyl]pyrrolidine-2- carboxamide 497.2 498.2 307 [01412] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-{2-[4- (trifluoromethyl)-1H- 1,2,3-triazol-5- yl]acetyl}pyrrolidine-2- carboxamide 534.2 535.1 308 [01413] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-{2-[(2- methylpyrimidin-4- yl)amino]acetyl}pyrrolidine- 2-carboxamide 506.2 507.3 309 [01414] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-{2-[(1,3-oxazol- 2- yl)amino]acetyl}pyrrolidine- 2-carboxamide 481.2 482.4 310 [01415] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1- [(2S)-2- [(dimethylcarbamoyl) amino]propanoyl]-4- fluoropyrrolidine-2- carboxamide 499.2 500.3 311 [01416] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1- [(2R)-2- [(dimethylcarbamoyl) amino]propanoyl]-4- fluoropyrrolidine-2- carboxamide 499.2 500.3 312 [01417] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-[2-(1,3-oxazol- 2-yl)acetyl]pyrrolidine- 2-carboxamide 466.2 467.2 313 [01418] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-[2-(5-methyl- 1,3-oxazol-2- yl)acetyl]pyrrolidine-2- carboxamide 480.2 481.3 314 [01419] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-[2-(4-methyl- 1,3-oxazol-2- yl)acetyl]pyrrolidine-2- carboxamide 480.2 481.2 315 [01420] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [(3,3-difluoroazetidine- 1- carbonyl)amino]acetyl}- 4-fluoropyrrolidine-2- carboxamide 533.2 534.3 316 [01421] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-[2-(5-methyl-2- oxo-2,3-dihydro-1,3,4- oxadiazol-3- yl)acetyl]pyrrolidine-2- carboxamide 497.2 498.2 317 [01422] (2S,4R)-1-{2-[4- (azetidin-1-yl)-2H-1,2,3- triazol-2-yl]acetyl}-N- [(S)-(5-cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoropyrrolidine-2- carboxamide 521.2 522.3 318 [01423] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [4-(3,3-difluoroazetidin- 1-yl)-2H-1,2,3-triazol-2- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 557.2 558.2 319 [01424] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [4-(diethylamino)-2H- 1,2,3-triazol-2- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 537.3 538.4 320 [01425] embedded image (1S,2S,5R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-3-[2- (1H-1,2,3-triazol-5- yl)acetyl]-3- azabicyclo[3.1.0]hexane- 2-carboxamide 460.2 461.3 321 [01426] (2S,5S)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-5- methyl-1-[2-(1H-1,2,3- triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 462.2 463.1 716 [01427] embedded image (2S,4R)-1-[2-(1H-1,3- benzodiazol-1-yl)acetyl]- N-[(R)-(5-cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoropyrrolidine-2- carboxamide 515.2 516.3 717 [01428] (2S,4R)-N-[(R)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [4-(dimethylamino)-2H- 1,2,3-triazol-2- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 509.2 510.2 718 [01429] embedded image (2S,4R)-N-[(R)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-(2-{3-oxo- 2H,3H- [1,2,4]triazolo[4,3- a]pyridin-8- yl}acetyl)pyrrolidine-2- carboxamide 532.2 533.2 719 [01430] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-[2-(4-methyl-5- oxo-4,5-dihydro-1,2,4- oxadiazol-3- yl)acetyl]pyrrolidine-2- carboxamide 497.2 498.2 720 [01431] embedded image (2S,4R)-N-[(R)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-{2-[(2- methylpyrimidin-4- yl)amino]acetyl}pyrrolidine- 2-carboxamide 506.2 507.3 721 [01432] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-[2-(1H-1,2,3- triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 466.2 467.1 722 [01433] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-[2- (1,4-dimethyl-5-oxo-4,5- dihydro-1H-1,2,4-triazol- 3-yl)acetyl]-4- fluoropyrrolidine-2- carboxamide 510.2 511.3 723 [01434] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-[2-(1H-pyrazol- 1-yl)acetyl]pyrrolidine- 2-carboxamide 465.2 466.1 724 [01435] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-[2-(5-methyl- 1H-pyrazol-1- yl)acetyl]pyrrolidine-2- carboxamide 479.2 480.1 725 [01436] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [5-(difluoromethyl)-1H- pyrazol-1-yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 515.2 516.3 726 [01437] embedded image (2S,4R)-1-{2-[4- (azetidin-1-yl)-1H-1,2,3- triazol-1-yl]acetyl}-N- [(S)-(5-cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoropyrrolidine-2- carboxamide 521.2 522.3 727 [01438] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-[2- (2,4-dioxo-1,2,3,4- tetrahydropyrimidin-1- yl)acetyl]-4- fluoropyrrolidine-2- carboxamide 509.2 510.1 728 [01439] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-{2-[4- (trifluoromethyl)-1H- pyrazol-1- yl]acetyl}pyrrolidine-2- carboxamide 533.2 534.1 729 [01440] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [3-(difluoromethyl)-1H- pyrazol-1-yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 515.2 516.1 730 [01441] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-{2-[3- (trifluoromethyl)-1H- pyrazol-1- yl]acetyl}pyrrolidine-2- carboxamide 533.2 534.3 731 [01442] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-[2-(2-oxo-1,2- dihydropyridin-3- yl)acetyl]pyrrolidine-2- carboxamide 492.2 515.3 732 [01443] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-[2-(5-methyl-6- oxo-1,6-dihydropyridin- 3-yl)acetyl]pyrrolidine- 2-carboxamide 506.2 507.1 733 [01444] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-[2- (3-ethyl-5-methyl-2,4- dioxo-1,2,3,4- tetrahydropyrimidin-1- yl)acetyl]-4- fluoropyrrolidine-2- carboxamide 551.2 552.1 734 [01445] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-[2-(6-oxo-1,6- dihydropyridin-3- yl)acetyl]pyrrolidine-2- carboxamide 492.2 493.2 735 [01446] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-[2- (3-ethyl-2,4-dioxo- 1,2,3,4- tetrahydropyrimidin-1 yl)acetyl]-4- fluoropyrrolidine-2- carboxamide 537.2 538.1 736 [01447] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-[2- (1-ethyl-6-oxo-1,6- dihydropyridin-3- yl)acetyl]-4- fluoropyrrolidine-2- carboxamide 520.2 521.4 737 [01448] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-[2- (6-ethoxy-5- methylpyridin-3- yl)acetyl]-4- fluoropyrrolidine-2- carboxamide 534.2 535.2 738 [01449] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-{2-[4- (trifluoromethyl)-1,3- oxazol-2- yl]acetyl}pyrrolidine-2- carboxamide 534.2 535.1 739 [01450] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-[2- (1-ethyl-5-methyl-6-oxo- 1,6-dihydropyridin-3- yl)acetyl]-4- fluoropyrrolidine-2- carboxamide 534.2 535.2 740 [01451] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-[2- (1-ethyl-5-methyl-2-oxo- 1,2-dihydropyridin-3- yl)acetyl]-4- fluoropyrrolidine-2- carboxamide 534.2 535.2 741 [01452] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-[2- (1-ethyl-2-oxo-1,2- dihydropyridin-3- yl)acetyl]-4- fluoropyrrolidine-2- carboxamide 520.2 521.2 742 [01453] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-[2- (4-ethyl-5-oxo-4,5- dihydropyrazin-2- yl)acetyl]-4- fluoropyrrolidine-2- carboxamide 521.2 522.2 743 [01454] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-[2-(5-methoxy- 1-methyl-1H-1,2,4- triazol-3- yl)acetyl]pyrrolidine-2- carboxamide 510.2 511.3 744 [01455] embedded image (2S,4R)-1-(2- {[benzyl(trifluoromethyl) carbamoyl]amino}acetyl)- N-[(S)-(5-cyclopropyl- 6-fluoropyridin-2- yl)(phenyl)methyl]-4- fluoropyrrolidine-2- carboxamide 615.2 616.3 745 [01456] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-{2-[5- (trifluoromethyl)-1H- 1,2,3-triazol-1- yl]acetyl}pyrrolidine-2- carboxamide 534.2 535.1 746 [01457] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-[2-(5-oxo-4,5- dihydropyrazin-2- yl)acetyl]pyrrolidine-2- carboxamide 493.2 494.3 747 [01458] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [5-(difluoromethyl)-1H- 1,2,3-triazol-1- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 516.2 517.3 748 [01459] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [5-(diethylamino)-1H- 1,2,3-triazol-1- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 537.3 538.3 749 [01460] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [3-(difluoromethyl)-1- methyl-1H-pyrazol-4- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 529.2 530.3 750 [01461] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [5-(difluoromethyl)-3- methyl-1H-pyrazol-1- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 529.2 530.2 751 [01462] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [5-(difluoromethyl)-1- methyl-1H-pyrazol-4- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 529.2 530.3 752 [01463] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [3-(difluoromethyl)-5- methyl-1H-pyrazol-1- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 529.2 530.3 753 [01464] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-[2- (4-ethyl-3-oxo-3,4- dihydropyrazin-2- yl)acetyl]-4- fluoropyrrolidine-2- carboxamide 521.2 522.2 754 [01465] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [4-(difluoromethyl)-1- methyl-1H-pyrazol-5- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 529.2 530.2 755 [01466] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-{2-[5- (trifluoromethyl)-1H- 1,2,3,4-tetrazol-1- yl]acetyl}pyrrolidine-2- carboxamide 535.2 536.1 756 [01467] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [4-(difluoromethyl)-1H- 1,2,3-triazol-5- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 516.2 517.2 757 [01468] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [4-(difluoromethyl)-1- methyl-1H-pyrazol-3- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 529.2 530.2 758 [01469] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [5-(3,3-difluoroazetidin- 1-yl)-1H-1,2,3-triazol-1- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 557.2 558.3 759 [01470] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [3-(difluoromethyl)-4H- 1,2,4-triazol-4- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 516.2 517.2 760 [01471] embedded image (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoro-1-{2-[5- (trifluoromethyl)-1H- pyrazol-1- yl]acetyl}pyrrolidine-2- carboxamide 533.2 534.2 761 [01472] (2S,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-[2- (4,5-dimethyl-1,3- oxazol-2-yl)acetyl]-4- fluoropyrrolidine-2- carboxamide 494.2 495.1 762 [01473] embedded image (2S,4R)-1-{2-[5- (azetidin-1-yl)-1H-1,2,3- triazol-1-yl]acetyl}-N- [(S)-(5-cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-4- fluoropyrrolidine-2- carboxamide 521.2 522.3 763 [01474] (2S,3R,4R)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [5-(difluoromethyl)-1H- 1,2,3,4-tetrazol-1- yl]acetyl}-4-fluoro-3- hydroxypyrrolidine-2- carboxamide 533.2 534.2 764 [01475] embedded image (2S,3S,4S)-N-[(S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl]-1-{2- [5-(difluoromethyl)-1H- 1,2,3,4-tetrazol-1- yl]acetyl}-4-fluoro-3- hydroxypyrrolidine-2- carboxamide 533.2 534.1

Example S-4: Synthesis of (2S,4R)-4-fluoro-N—((S)-(3-fluoro-4-isopropylphenyl)(phenyl)methyl)-1-(2-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)acetyl)pyrrolidine-2-carboxamide

Compound 322

[1741] ##STR01476## ##STR01477##

[1742] Step a: To a mixture of 4-bromo-3-fluoro-benzaldehyde (200 g, 985 mmol, 1.00 eq) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (215 g, 1.28 mol, 1.30 eq) in toluene (3.70 L) and H.sub.2O (410 mL) at 25° C. under N.sub.2 was added Pd(dppf)Cl.sub.2 (36.0 g, 49.3 mmol, 0.05 eq) and K.sub.3PO.sub.4 (418 g, 1.97 mol, 2.00 eq). The mixture was warmed to 90° C. and stirred for 12 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give 3-fluoro-4-isopropenyl-benzaldehyde. The compound was carried forward to the next step without further characterization.

[1743] Step b: To a solution of 3-fluoro-4-isopropenyl-benzaldehyde (124 g, 755 mmol, 1.00 eq) in EtOAc (1.20 L) under N.sub.2 was added Pd/C (85.0 g, 10 wt. %). The suspension was degassed and purged with H.sub.2 several times. The mixture was stirred at 25° C. under H.sub.2 (15 psi) for 1 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give 3-fluoro-4-isopropyl-benzaldehyde. The compound was carried forward to the next step without further characterization.

[1744] Step c: To a mixture of 3-fluoro-4-isopropyl-benzaldehyde (80.0 g, 481 mmol, 1.00 eq) and (R)-2-methylpropane-2-sulfinamide (64.2 g, 523 mmol, 1.10 eq) in DCM (450 mL) at 25° C. was added Cs.sub.2CO.sub.3 (173 g, 530 mmol, 1.10 eq). The mixture was warmed to 40° C. and stirred for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain (R,E)-N-(3-fluoro-4-isopropylbenzylidene)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.14H.sub.20FNOS: 270.1; found 270.0.

[1745] Step d: To a solution of (R,E)-N-(3-fluoro-4-isopropylbenzylidene)-2-methylpropane-2-sulfinamide (30.0 g, 111 mmol, 1.00 eq) in DCM (400 mL) −65° C. under N.sub.2 was added, dropwise, a solution of phenylmagnesium bromide (3 M in Et.sub.2O, 55.7 mL, 1.50 eq) over a period of 30 min. The reaction mixture was stirred at −65° C. for 6 h, then warmed to 25° C. and stirred for an additional 6 h. The reaction mixture was quenched with saturated aqueous NH.sub.4Cl (50 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with water (3×30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to obtain (R)—N—((S)-(3-fluoro-4-isopropylphenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide. The compound was carried forward to the next step without further characterization.

[1746] Step e: To a mixture of (R)—N—((S)-(3-fluoro-4-isopropylphenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (35.0 g, 101 mmol, 1.00 eq) in DCM (300 mL) at 25° C. was added HCl/EtOAc (4 M, 50.4 mL, 2.00 eq), and the mixture was stirred for 2 h. The reaction mixture was filtered and the solid so obtained was set aside. The filtrate was concentrated under reduced pressure and the resulting residue was combined with the previously obtained solid. The mixture was dissolved in MTBE (200 mL) and filtered, and the filtrate was concentrated under reduced pressure to give (S)-(3-fluoro-4-isopropylphenyl)(phenyl)methanaminium chloride. The compound was carried forward to the next step without further characterization.

[1747] Step f: To a solution of (S)-(3-fluoro-4-isopropylphenyl)(phenyl)methanaminium chloride (600 mg, 2.14 mmol, 1 eq), and 1-methylimidazole (880 mg, 10.7 mmol, 5 eq) in CH.sub.3CN (10 mL) at −20° C. was added (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (600 mg, 2.57 mmol, 1.2 eq). After 10 min, chloro-N,N,N,N-tetramethylformamidinium hexafluorophosphate (TCFH, 722 mg, 2.57 mmol, 1.2 eq) was added at −20° C., and the resulting mixture was stirred for 2 h. The reaction mixture was warmed to 25° C., quenched with H.sub.2O (30 mL), and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to afford tert-butyl (2S,4R)-4-fluoro-2-(((S)-(3-fluoro-4-isopropylphenyl)(phenyl)methyl)carbamoyl)pyrrolidine-1-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.26H.sub.32F.sub.2N.sub.2O.sub.3: 459.2; found 459.1.

[1748] Step g: To a mixture of tert-butyl (2S,4R)-4-fluoro-2-(((S)-(3-fluoro-4-isopropylphenyl)(phenyl)methyl)carbamoyl)pyrrolidine-1-carboxylate (0.8 g, 1.74 mmol, 1 eq) in EtOAc (3 mL) at 0° C. was added 4M HCl/EtOAc (10 mL). The resulting mixture was stirred at 0° C. for 2 h. The reaction was then concentrated directly at low temperature under reduced pressure. The solid so obtained was washed with MTBE (3×10 mL), filtered, and dried under reduced pressure to give (2S,4R)-4-fluoro-N—((S)-(3-fluoro-4-isopropylphenyl)(phenyl)methyl)pyrrolidine-2-carboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.21H.sub.24F.sub.2N.sub.2O: 359.2; found 359.1.

[1749] Step h: To a mixture of (2S,4R)-4-fluoro-N—((S)-(3-fluoro-4-isopropylphenyl)(phenyl)methyl)pyrrolidine-2-carboxamide (50 mg, 139 μmol, 1 eq), 4-methylmorpholine (28.22 mg, 279 μmol, 2 eq) and 2-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)acetic acid (Intermediate A-3, 32.8 mg, 167 μmol, 1.2 eq) in DMF (3 mL) was added T3P (267 mg, 418 μmol, 50% in EtOAc, 3 eq) at −20° C. The mixture was stirred at −20° C. for 2 h under N2 atmosphere. The reaction mixture was then quenched with H.sub.2O (20 mL) at 0° C. and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give (2S,4R)-4-fluoro-N—((S)-(3-fluoro-4-isopropylphenyl)(phenyl)methyl)-1-(2-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)acetyl)pyrrolidine-2-carboxamide. .sup.1H NMR (3.9:1 rotamer ratios, asterisk denotes minor rotamer peaks, obscured peaks not reported, 400 MHz, DMSO-d6) δ 9.25* (d, J=8.0 Hz, 1H), 8.89 (d, J=8.2 Hz, 1H), 8.51-8.44 (m, 1H), 7.38-7.18 (m, 6H), 7.15-6.93 (m, 2H), 6.14* (d, J=8.0 Hz, 1H), 6.01 (d, J=8.2 Hz, 1H), 5.88-5.79 (m, 1H), 5.79-5.70* (m, 1H), 5.64-5.55 (m, 1H), 5.56-5.24 (m, 1H), 4.97-4.81* (m, 1H), 4.57 (t, J=8.4 Hz, 1H), 4.22-4.09 (m, 1H), 4.00-3.76 (m, 1H), 3.58-3.40* (m, 1H), 3.18-3.05 (m, 1H), 2.92-2.77* (m, 1H), 2.30-1.91 (m, 1H), 1.22-1.15 (m, 6H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.26H.sub.26F.sub.5N.sub.5O.sub.2: 536.2; found 536.2.

[1750] The following compounds in Table T-4 were synthesized using procedures similar to Compound 322 using the appropriate starting materials.

TABLE-US-00018 TABLE T-4 Exact LCMS, Compound mass Found No. Structure IUPAC (g/mol) [M + H].sup.+ 323 [01478] embedded image (2S,5S)-N-[(S)-[3- fluoro-4-(propan-2- yl)phenyl](phenyl)methyl]- 5-methyl-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 463.2 464.2 324 [01479] (1S,3S,5S)-N-[(S)-[3- fluoro-4-(propan-2- yl)phenyl](phenyl)methyl]- 2-[2-(1H-1,2,3- triazol-5-yl)acetyl]-2- azabicyclo[3.1.0]hexane- 3-carboxamide 461.2 462.1 325 [01480] embedded image (1S,2S,5R)-N-[(S)-[3- fluoro-4-(propan-2- yl)phenyl](phenyl)methyl]- 3-[2-(1H-1,2,3- triazol-5-yl)acetyl]-3- azabicyclo[3.1.0]hexane- 2-carboxamide 461.2 462.1 326 [01481] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(1H-1,2,3- triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 467.2 468.1 327 [01482] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-(2-hydroxy-2- methylpropanoyl)pyrrolidine- 2-carboxamide 444.2 445.1 328 [01483] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(1H-1,2,3,4- tetrazol-5- yl)acetyl]pyrrolidine-2- carboxamide 468.2 469.1 329 [01484] embedded image (2S,4R)-4-fluoro-N- [(R)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(1H-1,2,3,4- tetrazol-5- yl)acetyl]pyrrolidine-2- carboxamide 468.2 469.1 330 [01485] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(1H-1,2,3,4- tetrazol-1- yl)acetyl]pyrrolidine-2- carboxamide 468.2 469.1 331 [01486] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(1H-1,2,3- triazol-1- yl)acetyl]pyrrolidine-2- carboxamide 467.2 468.1 332 [01487] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(5-methyl- 1,3,4-oxadiazol-2- yl)acetyl]pyrrolidine-2- carboxamide 482.2 493.1 333 [01488] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[1-(1,3,4- oxadiazol-2- yl)cyclopropanecarbonyl] pyrrolidine-2- carboxamide 494.2 495.1 334 [01489] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl[(phenyl)methyl]- 1-[2-methyl-2- (1,3,4-oxadiazol-2- yl)propanoyl]pyrrolidine- 2-carboxamide 496.2 497.1 335 [01490] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(1-methyl-1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 481.2 480.1 336 [01491] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl[(phenyl)methyl]- 1-[2-(1-methyl-1H- 1,2,3-triazol-4- yl)acetyl]pyrrolidine-2- carboxamide 481.2 482.1 337 [01492] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(1-methyl-1H- pyrazol-5- yl)acetyl]pyrrolidine-2- carboxamide 480.2 481.3 338 [01493] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(1,2-oxazol-5- yl)acetyl]pyrrolidine-2- carboxamide 467.2 468.1 339 [01494] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(4-methyl-2,5- dioxopiperazin-1- yl)acetyl]pyrrolidine-2- carboxamide 526.2 527.1 340 [01495] (2S,4R,5S)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 5-methyl-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 481.2 482.2 341 [01496] embedded image (5S)-N-[(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 4-[2-(1H-1,2,3- triazol-5-yl)acetyl]-4- azaspiro[2.4]heptane-5- carboxamide 475.2 476.1 342 [01497] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(pyridazin-4- yl)acetyl]pyrrolidine-2- carboxamide 478.2 479.3 343 [01498] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- yl]-1-[2-(pyridazin-3- yl)acetyl]pyrrolidine-2- carboxamide 478.2 479.1 344 [01499] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl[(phenyl)methyl]- 1-[2-(pyrazin-2- yl)acetyl]pyrrolidine-2- carboxamide 478.2 479.2 345 [01500] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(pyrimidin-5- yl)acetyl]pyrrolidine-2- carboxamide 478.2 479.1 346 [01501] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(pyrimidin-4- yl)acetyl]pyrrolidine-2- carboxamide 478.2 479.2 347 [01502] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(pyridin-4- yl)acetyl]pyrrolidine-2- carboxamide 477.2 478.2 348 [01503] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(pyridin-3- yl)acetyl]pyrrolidine-2- carboxamide 477.2 478.2 349 [01504] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(pyridin-2- yl)acetyl]pyrrolidine-2- carboxamide 477.2 478.1 350 [01505] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- [2-(1-methyl-1H- pyrazol-3- yl)acetyl]pyrrolidine-2- carboxamide 480.2 481.3 351 [01506] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(1,3,5- trimethyl-1H-pyrazol-4- yl)acetyl]pyrrolidine-2- carboxamide 508.3 509.3 352 [01507] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(5-methyl-2,4- dioxo-1,2,3,4- tetrahydropyrimidin-1- yl)acetyl]pyrrolidine-2- carboxamide 524.2 525.0 353 [01508] embedded image (2S,4R)-1-[2-(3,5- dimethyl-2,4-dioxo- 1,2,3,4- tetrahydropyrimidin-1- yl)acetyl]-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl] pyrrolidine-2- carboxamide 538.2 539.1 354 [01509] (2S,4R)-1-[2-(1H-1,3- benzodiazol-1- yl)acetyl]-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl] pyrrolidine-2- carboxamide 516.2 517.2 355 [01510] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(1-methyl-1H- pyrazol-4- yl)acetyl]pyrrolidine-2- carboxamide 480.2 481.1 356 [01511] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-(2-{imidazo[1,2- a]pyridin-3- yl}acetyl)pyrrolidine-2- carboxamide 516.2 517.1 357 [01512] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(quinolin-6- yl)acetyl]pyrrolidine-2- carboxamide 527.2 528.1 358 [01513] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-(2- {[1,2,4]triazolo[1,5- a]pyridin-6- yl}acetyl)pyrrolidine-2- carboxamide 517.2 518.1 359 [01514] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl[(phenyl)methyl]- 1-{2-[5- (trifluoromethyl)-1H- 1,2,3,4-tetrazol-1- yl]acetyl}pyrrolidine-2- carboxamide 536.2 559.2 [M + Na].sup.+ 360 [01515] 2-[(2S,4R)-4-fluoro-2- {[(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl] carbamoyl}pyrrolidin- 1-yl]-2-oxoethyl N,N- dimethylcarbamate 487.2 488.1 361 [01516] embedded image (2S,4R)-1-{2- [(dimethylcarbamoyl) amino]acetyl}-4-fluoro- N-[(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl] pyrrolidine-2- carboxamide 486.2 487.1 362 [01517] (2S,4R)-1-{2- [(dimethylcarbamoyl) (methyl)amino]acetyl}-4- fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl] pyrrolidine-2- carboxamide 500.3 501.2 363 [01518] embedded image 2-[(2S,4R)-4-fluoro-2- {[(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl] carbamoyl}pyrrolidin- 1-yl]-2-oxoethyl piperazine-1- carboxylate 528.3 529.3 364 [01519] 1-tert-butyl 4-{2- [(2S,4R)-4-fluoro-2- {[(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl] carbamoyl}pyrrolidin- 1-yl]-2-oxoethyl} piperazine-1,4- dicarboxylate 628.3 529.3 [M − Boc + 1].sup.+ 365 [01520] embedded image N-{2-[(2S,4R)-4-fluoro- 2-{[(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl] carbamoyl}pyrrolidin- 1-yl]-2- oxoethyl}piperazine-1- carboxamide 527.3 528.1 366 [01521] tert-butyl 4-({2- [(2S,4R)-4-fluoro-2- {[(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl] carbamoyl}pyrrolidin- 1-yl]-2- oxoethyl}carbamoyl) piperazine-1-carboxylate 627.3 628.3 367 [01522] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(4-methyl-1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine-2- carboxamide 481.2 482.2 368 [01523] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-{2-[4- (trifluoromethyl)-1H- 1,2,3-triazol-5- yl]acetyl}pyrrolidine-2- carboxamide 535.2 536.3 369 [01524] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-{2-[4-(piperazin- 1-yl)-1H-1,2,3-triazol-5- yl]acetyl}pyrrolidine-2- carboxamide 551.3 552.3 370 [01525] tert-butyl 4-(5-{2- [(2S,4R)-4-fluoro-2- {[(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl] carbamoyl}pyrrolidin- 1-yl]-2-oxoethyl}-1H- 1,2,3-triazol-4- yl)piperazine-1- carboxylate 651.3 652.4 371 [01526] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-{2-[4-(morpholin- 4-yl)-1H-1,2,3-triazol-5- yl]acetyl}pyrrolidine-2- carboxamide 552.3 553.3 372 [01527] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-{2-[4- (trifluoromethyl)-1H- 1,2,3-triazol-1- yl]acetyl}pyrrolidine-2- carboxamide 535.2 558.0 [M + Na].sup.+ 373 [01528] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(4-methyl-1H- 1,2,3-triazol-1- yl)acetyl]pyrrolidine-2- carboxamide 481.2 482.2 374 [01529] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(5-methyl-1H- 1,2,3-triazol-1- yl)acetyl]pyrrolidine-2- carboxamide 481.2 482.2 375 [01530] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-{2-[4-(piperazin- 1-yl)-1H-1,2,3-triazol-1- yl]acetyl}pyrrolidine-2- carboxamide 551.3 552.3 376 [01531] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-{2-[4-(piperazin- 1-yl)-2H-1,2,3-triazol-2- yl]acetyl}pyrrolidine-2- carboxamide 551.3 552.3 377 [01532] embedded image (2S,4R)-1-{2-[4- (dimethylamino)-1H- 1,2,3-triazol-1- yl]acetyl}-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl] pyrrolidine-2- carboxamide 510.3 511.2 378 [01533] (2S,4R)-1-{2-[4- (dimethylamino)-2H- 1,2,3-triazol-2- yl]acetyl}-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl] pyrrolidine-2- carboxamide 510.3 511.2 379 [01534] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-(2-{3-oxo-2H,3H- [1,2,4]triazolo[4,3- a]pyridin-8- yl}acetyl)pyrrolidine-2- carboxamide 533.2 534.2 380 [01535] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(1H-imidazol- 1-yl)acetyl]pyrrolidine- 2-carboxamide 466.2 467.2 381 [01536] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[(5S)-2-oxo-1,3- oxazolidine-5- carbonyl]pyrrolidine-2- carboxamide 471.2 489.2 [M + NH.sub.4].sup.+ 382 [01537] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[(5R)-2-oxo-1,3- oxazolidine-5- carbonyl]pyrrolidine-2- carboxamide 471.2 472.2 383 [01538] embedded image (2S,4R)-1-{2-[5- (difluoromethyl)-1,3,4- oxadiazol-2-yl]acetyl}- 4-fluoro-N-[(S)-[3- fluoro-4-(propan-2- yl)phenyl](phenyl)methyl] pyrrolidine-2- carboxamide 518.2 519.1 384 [01539] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[2-(4H-1,2,4- triazol-4- yl)acetyl]pyrrolidine-2- carboxamide 467.2 467.9 765 [01540] embedded image (2S,4R)-1-[(2S)-3- carbamoyl-2- acetamidopropanoyl]-4- fluoro-N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](phenyl)methyl] pyrrolidine-2- carboxamide 514.2 515.2 766 [01541] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[(2R) or (2S)-2- (1H-1,2,3,4-tetrazol-1- yl)propanoyl]pyrrolidine- 2-carboxamide (column: DAICEL CHIRALPAK AD-3, second-eluting isomer) 482.2 483.2 767 [01542] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[(2S) or (2R)-2- (1H-1,2,3,4-tetrazol-1- yl)propanoyl]pyrrolidine- 2-carboxamide (column: DAICEL CHIRALPAK AD-3, first-eluting isomer) 482.2 483.2 768 [01543] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[(2R) or (2S)-2- (1H-imidazol-1- yl)propanoyl]pyrrolidine- 2-carboxamide (column: DAICEL CHIRALPAK IG-3, first-eluting isomer) 480.2 481.2 769 [01544] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[(2R) or (2S)-2- (1H-1,2,3-triazol-5- yl)propanoyl]pyrrolidine- 2-carboxamide (column: Phenomenex Luna C18, first-eluting isomer) 481.2 482.1 770 [01545] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[(2S) or (2R)-2- (1H-1,2,3-triazol-5- yl)propanoyl]pyrrolidine- 2-carboxamide (column: Phenomenex Luna C18, second- eluting isomer) 481.2 482.1 771 [01546] embedded image (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[(2S) or (2R)-2- (1H-imidazol-1- yl)propanoyl]pyrrolidine- 2-carboxamide (column: DAICEL CHIRALPAK IG-3, second-eluting isomer) 480.2 481.2 772 [01547] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[(1H-1,2,3-triazol- 5- yl)methanesulfonyl] pyrrolidine-2-carboxamide 503.2 504.1 773 [01548] embedded image (2S,4R)-4-fluoro-N -[(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[(2R) or (2S)-2- hydroxy-2-(1H-1,2,3- triazol-5- yl)acetyl]pyrrolidine-2- carboxamide (column: DAICEL CHIRALPAK AD-3, first-eluting isomer) 483.2 484.2 774 [01549] (2S,4R)-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl]- 1-[(2S) or (2R)-2- hydroxy-2-(1H-1,2,3- triazol-5- yl)acetyl]pyrrolidine-2- carboxamide (column: DAICEL CHIRALPAK AD-3, second-eluting isomer) 483.2 484.2 775 [01550] embedded image (2S,4R)-1-{2-[4- (dimethylamino)-1H- 1,2,3-triazol-5- yl]acetyl}-4-fluoro-N- [(S)-[3-fluoro-4- (propan-2- yl)phenyl](phenyl)methyl] pyrrolidine-2- carboxamide 510.3 511.3

Example S-5: Synthesis of (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoro-N—((S)-(6-fluoro-5-isopropylpyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide

Compound 385

[1751] ##STR01551##

[1752] Step a: To a solution of 2-bromo-6-fluoropyridine (50 g, 284 mmol, 1 eq) in THF (500 mL) at −78° C. was added LDA (2 M in THF, 142 mL, 1 eq) in a dropwise manner. The resulting mixture was stirred at −78° C. for 30 min. To this mixture was added acetone (24.7 g, 426 mmol, 1.5 eq) in a dropwise manner, and the resulting reaction mixture was stirred at −78° C. for 1.5 h. The reaction mixture was then cooled to 0° C. and quenched by dropwise addition of water (500 mL), and the resulting mixture was extracted with EtOAc (2×500 mL). The combined organic extracts were washed with brine (2×200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give 2-(6-bromo-2-fluoropyridin-3-yl)propan-2-ol. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.9BrFNO: 234.0; found 234.0.

[1753] Step b: To a solution of 2-(6-bromo-2-fluoropyridin-3-yl)propan-2-ol (60 g, 256 mmol, 1 eq) in DCE (500 mL) at 25° C. was added Et.sub.3SiH (149 g, 1.28 mol, 5 eq) and TFA (292 g, 2.56 mol, 10 eq). The reaction mixture was then warmed to 60° C. and stirred for 15 h. After cooling, the mixture was concentrated under reduced pressure. The resulting residue was poured into ice-water (300 mL) and adjusted to pH=7 by addition of saturated aqueous Na.sub.2CO.sub.3 solution. The resulting biphasic mixture was extracted with EtOAc (3×500 mL). The combined organic extracts were washed with brine (3×300 mL), dried over anhydrous Na.sub.2SO.sub.4, and filtered. The filtrate was then concentrated under reduced pressure, and the resulting crude residue was purified by column chromatography to give a mixture of 6-bromo-2-fluoro-3-isopropylpyridine and 6-bromo-2-fluoro-3-(prop-1-en-2-yl)pyridine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.9BrFN: 218.0; found 218.1. [M+H].sup.+ calculated for C.sub.8H.sub.7BrFN: 216.0; found 215.9.

[1754] Step c: To a solution of 6-bromo-2-fluoro-3-isopropylpyridine and 6-bromo-2-fluoro-3-(prop-1-en-2-yl)pyridine (58 g, crude) in MeOH (500 mL) at 25° C. was added PtO.sub.2 (4.17 g, 18.3 mmol). The resulting mixture was degassed and purged with H.sub.2. The reaction mixture was then stirred at 25° C. under H.sub.2 atmosphere (50 psi) for 12 h. The reaction mixture was then filtered through a pad of Celite, and the filter cake was washed with MeOH (2×200 mL). The combined filtrate was concentrated under reduced pressure, and the resulting crude residue was purified by column chromatography to give 6-bromo-2-fluoro-3-isopropylpyridine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.9BrFN: 218.0; found 218.1.

[1755] Step d: To a solution of 6-bromo-2-fluoro-3-isopropylpyridine (32.0 g, 146 mmol, 1 eq) in THF (250 mL) at −78° C. was added n-BuLi (2.5 M in hexane, 88.0 mL, 1.5 eq) in a dropwise manner. The resulting mixture was stirred at −78° C. for 30 min. To this mixture was added (R,E)-N-benzylidene-2-methylpropane-2-sulfinamide (30.7 g, 146 mmol, 1 eq) as a solution in THF (250 mL) in a dropwise manner. The resulting mixture was then stirred at −78° C. for 4 h. The reaction mixture was then poured into ice-water (500 mL) and extracted with EtOAc (3×500 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography followed by prep-HPLC to give (R)—N—((S)-(6-fluoro-5-isopropylpyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.19H.sub.25FN.sub.2OS: 349.2; found 349.2.

[1756] Step e: To a solution of (R)—N—((S)-(6-fluoro-5-isopropylpyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (12.0 g, 34.4 mmol, 1 eq) in dioxane (10 mL) at 0° C. was added HCl/dioxane (4 M, 500 mL). The reaction mixture was warmed to 25° C. and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give (S)-(6-fluoro-5-isopropylpyridin-2-yl)(phenyl)methanaminium chloride, which was used in the next step without further purification. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.15H.sub.17FN.sub.2: 245.1; found 245.2.

[1757] Step f: To a mixture of (S)-(6-fluoro-5-isopropylpyridin-2-yl)(phenyl)methanaminium chloride (11 g, crude, 1 eq) and (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (10.0 g, 43.1 mmol, 1.1 eq) in CH.sub.3CN (200 mL) at −20° C. was added 1-methylimidazole (NMI, 48.2 g, 587 mmol, 46.8 mL, 15 eq) and chloro-N,N,N,N-tetramethylformamidinium hexafluorophosphate (TCFH, 12.1 g, 43.1 mmol, 1.1 eq). The reaction mixture was then stirred at −20° C. for 2 h. The reaction mixture was then poured into H.sub.2O (500 mL) and extracted with EtOAc (3×500 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give tert-butyl (2S,4R)-4-fluoro-2-(((S)-(6-fluoro-5-isopropylpyridin-2-yl)(phenyl)methyl)carbamoyl)pyrrolidine-1-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.25H.sub.31F.sub.2N.sub.3O.sub.3: 460.2; found 460.2.

[1758] Step g: To a solution of tert-butyl (2S,4R)-4-fluoro-2-(((S)-(6-fluoro-5-isopropylpyridin-2-yl)(phenyl)methyl)carbamoyl)pyrrolidine-1-carboxylate (14.0 g, 30.4 mmol, 1 eq) in dioxane (50 mL) at 25° C. was added HCl/dioxane (4 M, 300 mL, 45.9 eq), and the resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was then concentrated under reduced pressure to give (2S,4R)-4-fluoro-N—((S)-(6-fluoro-5-isopropylpyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide hydrochloride. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.20H.sub.23F.sub.2N.sub.3O: 360.2; found 360.1.

[1759] Step h: To a mixture of (2S,4R)-4-fluoro-N—((S)-(6-fluoro-5-isopropylpyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide hydrochloride (8 g, 22.2 mmol, 1 eq) and 2-(1H-1,2,3-triazol-5-yl)acetic acid (Intermediate A-1, 3.39 g, 26.7 mmol, 1.2 eq) in DCM (200 mL) at 0° C. was added 1-methylimidazole (NMI, 27.4 g, 333 mmol, 15 eq) and T3P (17.0 g, 26.7 mmol, 15.8 mL, 50% in EtOAc, 1.2 eq). The reaction mixture was then warmed to 25° C. and stirred for 12 h. The reaction mixture was then poured into H.sub.2O (200 mL) and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography followed by prep-HPLC to give (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoro-N—((S)-(6-fluoro-5-isopropylpyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide. .sup.1H NMR (3:1 rotamer ratio, asterisk denotes distinct minor rotamer peaks, obscured peaks not reported, 400 MHz, DMSO-d6) δ 14.71 (br s, 1H), 9.30* (d, J=7.8 Hz, 1H), 8.92 (d, J=8.1 Hz, 1H), 7.92-7.80 (m, 1H), 7.67 (s, 1H), 7.54* (s, 1H), 7.40-7.18 (m, 6H), 6.09* (d, J=7.8 Hz, 1H), 5.98 (d, J=8.1 Hz, 1H), 5.48-5.20 (m, 1H), 4.90* (t, J=8.0 Hz, 1H), 4.62 (t, J=8.3 Hz, 1H), 4.12-3.63 (m, 3H), 3.12-2.95 (m, 1H), 2.79-2.61* (m, 1H), 2.28-1.91 (m, 1H), 1.24-1.16 (m, 6H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.24H.sub.26F.sub.2N.sub.6O.sub.2: 469.2; found 469.3.

[1760] The following compounds in Table T-5 were synthesized using procedures similar to Compound 385 using the appropriate starting materials.

TABLE-US-00019 TABLE T-5 Exact LCMS, Compound mass Found No. Structure IUPAC (g/mol) [M + H].sup.+ 386 [01552] embedded image (2S,4R)-1-[2-(3,5- dimethyl-2,4-dioxo- 1,2,3,4- tetrahydropyrimidin- 1-yl)acetyl]-4-fluoro- N-[(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 539.2 540.1 387 [01553] (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-[2-(2- methylquinolin-5- yl)acetyl]pyrrolidine- 2-carboxamide 542.2 543.2 388 [01554] embedded image (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-[2-(5-methyl-2,4- dioxo-1,2,3,4- tetrahydropyrimidin- 1-yl)acetyl]pyrrolidine- 2-carboxamide 525.2 526.3 389 [01555] (2S,4R)-1-[2-(1H-1,3- benzodiazol-1-yl) acetyl]-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 517.2 518.3 390 [01556] embedded image (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-[2-(4H-1,2,4- triazol-4-yl)acetyl] pyrrolidine- 2-carboxamide 468.2 469.2 391 [01557] (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-(2-{3-oxo-2H,3H- [1,2,4]triazolo[4,3-a] pyridin-8-yl}acetyl) pyrrolidine- 2-carboxamide 534.2 535.2 392 [01558] embedded image (2S,4R)-1-{2-[4- (dimethylamino)-2H- 1,2,3-triazol-2- yl]acetyl}-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 511.3 512.3 393 [01559] (2S,4R)-1-{2-[4- (dimethylamino)-1H- 1,2,3-triazol-1-yl] acetyl}-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 511.3 512.2 394 [01560] embedded image (2S,4R)-1-{2- [(dimethylcarbamoyl) amino]acetyl}-4- fluoro-N-[(S)-[6- fluoro-5-(propan-2- yl)pyridin-2- yl](phenyl)methyl] pyrrolidine-2- carboxamide 487.2 488.3 395 [01561] (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-{2-[(methylcarbamoyl) amino]acetyl}pyrrolidine- 2-carboxamide 473.2 474.2 396 [01562] embedded image (2S,4R)-1-[2- (carbamoylamino) acetyl]-4-fluoro-N-[(S)- [6-fluoro-5-(propan- 2-yl)pyridin-2- yl](phenyl)methyl] pyrrolidine-2- carboxamide 459.2 460.1 397 [01563] (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-[2-(1-methyl-5-oxo- 4,5-dihydro-1H-1,2,4- triazol-3-yl)acetyl] pyrrolidine- 2-carboxamide 498.2 499.4 398 [01564] embedded image (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-[2-(4-methyl-5-oxo- 4,5-dihydro-1H-1,2,4- triazol-3-yl)acetyl] pyrrolidine- 2-carboxamide 498.2 499.2 399 [01565] (2S,4R)-1-{2- [(azetidine-1- carbonyl)amino] acetyl}-4-fluoro- N-[(S)-[6-fluoro- 5-(propan-2- yl)pyridin-2- yl](phenyl)methyl] pyrrolidine-2- carboxamide 499.2 500.3 400 [01566] embedded image (2S,4R)-1-{2-[5- (difluoromethyl)-1H- 1,2,3,4-tetrazol-1- yl]acetyl}-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 519.2 520.1 401 [01567] (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-[2-(4-methyl-5-oxo- 4,5-dihydro-1,3,4- oxadiazol-2- yl)acetyl]pyrrolidine- 2-carboxamide 499.2 500.3 402 [01568] embedded image (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-[2-(4-methyl-5-oxo- 4,5-dihydro-1,2,4- oxadiazol-3- yl)acetyl]pyrrolidine- 2-carboxamide 499.2 500.2 403 [01569] (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- l-{2-[4- (trifluoromethyl)-1H- 1,2,3-triazol-5- yl]acetyl}pyrrolidine- 2-carboxamide 536.2 537.1 404 [01570] embedded image (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-{2-[(2- methylpyrimidin-4- yl)amino]acetyl} pyrrolidine- 2-carboxamide 508.2 509.3 405 [01571] (2S,4R)-1-[(2S)-2- [(dimethylcarbamoyl) amino]propanoyl]-4- fluoro-N-[(S)-[6- fluoro-5-(propan-2- yl)pyridin-2- yl](phenyl)methyl] pyrrolidine-2- carboxamide 501.3 502.4 406 [01572] embedded image (2S,4R)-1-[(2R)-2- [(dimethylcarbamoyl) amino]propanoyl]-4- fluoro-N-[(S)-[6- fluoro-5-(propan-2- yl)pyridin-2- yl](phenyl)methyl] pyrrolidine-2- carboxamide 501.3 502.4 407 [01573] (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-[2-(1,3-oxazol-2- yl)acetyl]pyrrolidine- 2-carboxamide 468.2 469.2 408 [01574] embedded image (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-[2-(5-methyl-1,3- oxazol-2-yl)acetyl] pyrrolidine- 2-carboxamide 482.2 483.1 409 [01575] (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-[2-(4-methyl-1,3- oxazol-2-yl)acetyl] pyrrolidine- 2-carboxamide 482.2 483.3 410 [01576] embedded image (2S,4R)-1-{2-[(3,3- difluoroazetidine-1- carbonyl)amino] acetyl}-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl) pyridin-2-yl](phenyl) methyl]pyrrolidine-2- carboxamide 535.2 536.2 411 [01577] (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl)- 1-[2-(5-methyl-2-oxo- 2,3-dihydro-1,3,4- oxadiazol-3- yl)acetyl]pyrrolidine- 2-carboxamide 499.2 500.2 412 [01578] embedded image (2S,4R)-1-{2-[4- (azetidin-1-yl)-2H- 1,2,3-triazol-2- yl]acetyl}-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 523.3 524.3 413 [01579] (2S,4R)-1-{2-[4-(3,3- difluoroazetidin-1- yl)-2H-1,2,3-triazol- 2-yl]acetyl}-4-fluoro- N-[(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 559.2 560.3 414 [01580] embedded image (2S,4R)-1-{2-[4- (diethylamino)-2H- 1,2,3-triazol-2- yl]acetyl(-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 539.3 540.4 415 [01581] (1S,2S,5R)-N-[(S)-[6- fluoro-5-(propan-2- yl)pyridin-2- yl](phenyl)methyl]-3- [2-(1H-1,2,3-triazol- 5-yl)acetyl]-3- azabicyclo[3.1.0] hexane-2-carboxamide 462.2 463.4 416 [01582] embedded image (2S,5S)-N-[(S)-[6- fluoro-5-(propan-2- yl)pyridin-2- yl](phenyl)methyl]-5- methyl-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 464.2 465.4 776 [01583] (2S,4R)-4-fluoro-N- [(R*)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-[2-(1H-1,2,3- triazol-5-yl)acetyl] pyrrolidine- 2-carboxamide 468.2 469.2 777 [01584] embedded image (2S,4R)-1-[2-(3,5- dimethyl-2,4-dioxo- 1,2,3,4- tetrahydropyrimidin- 1-yl)acetyl]-4-fluoro- N-[(R*)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 539.2 540.1 778 [01585] (2S,4R)-4-fluoro-N- [(R*)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-[2-(5-methyl-2,4- dioxo-1,2,3,4- tetrahydropyrimidin- 1-yl)acetyl]pyrrolidine- 2-carboxamide 525.2 526.3 779 [01586] embedded image (2S,4R)-1-[2-(1,4- dimethyl-5-oxo-4,5- dihydro-1H-1,2,4- triazol-3-yl)acetyl]-4- fluoro-N-[(S)-[6- fluoro-5-(propan-2- yl)pyridin-2- yl](phenyl)methyl] pyrrolidine-2- carboxamide 512.2 513.3 780 [01587] (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-{3-{3-oxo-2H,3H- [1,2,4]triazolo[4,3-a] pyridin-2-yl} propanoyl)pyrrolidine- 2-carboxamide 548.2 549.2 781 [01588] embedded image (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-[2-(1H-pyrazol-1- yl)acetyl]pyrrolidine- 2-carboxamide 467.2 468.1 782 [01589] (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-[2-(5-methyl-1H- pyrazol-1-yl)acetyl] pyrrolidine- 2-carboxamide 481.2 482.2 783 [01590] embedded image (2S,4R)-1-{2-[5- (difluoromethyl)-1H- pyrazol-1-yl]acetyl}- 4-fluoro-N-[(S)-[6- fluoro-5-(propan-2- yl)pyridin-2- yl](phenyl)methyl] pyrrolidine-2- carboxamide 517.2 518.2 784 [01591] (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-[2-(5-methyl-6-oxo- 1,6-dihydropyridin-3- yl)acetyl]pyrrolidine- 2-carboxamide 508.2 509.1 785 [01592] embedded image (2S,4R)-1-[2-(2,4- dioxo-1,2,3,4- tetrahydropyrimidin- 1-yl)acetyl]-4-fluoro- N-[(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 511.2 512.1 786 [01593] (2S,4R)-1-[2-(3-ethyl- 2,4-dioxo-1,2,3,4- tetrahydropyrimidin- 1-yl)acetyl]-4-fluoro- N-[(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 539.2 540.2 787 [01594] embedded image (2S,4R)-1-{2-[4- (azetidin-1-yl)-1H- 1,2,3-triazol-1- yl]acetyl}-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 523.3 524.3 788 [01595] (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](pheny])methyl]- 1-{2-[4- (trifluoromethyl)-1H- pyrazol-1-yl]acetyl} pyrrolidine- 2-carboxamide 535.2 536.2 789 [01596] embedded image (2S,4R)-1-{2-[3- (difluoromethyl)-1H- pyrazol-1-yl]acetyl}- 4-fluoro-N-[(S)-[6- fluoro-5-(propan-2- yl)pyridin-2- yl](phenyl)methyl] pyrrolidine-2- carboxamide 517.2 518.2 790 [01597] (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-{2-[3- (trifluoromethyl)-1H- pyrazol-1-yl]acetyl} pyrrolidine- 2-carboxamide 535.2 559.1 [M + Na] 791 [01598] embedded image (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-[2-(6-oxo-1,6- dihydropyridin-3- yl)acetyl]pyrrolidine- 2-carboxamide 494.2 495.2 792 [01599] (2S,4R)-1-[2-(1-ethyl- 6-oxo-1,6- dihydropyridin-3- yl)acetyl]-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 522.2 523.4 793 [01600] embedded image (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-[2-(2-oxo-1,2- dihydropyridin-3- yl)acetyl]pyrrolidine- 2-carboxamide 494.2 495.3 794 [01601] (2S,4R)-1-[2-(3-ethyl- 5-methyl-2,4-dioxo- 1,2,3,4- tetrahydropyrimidin- 1-yl)acetyl]-4-fluoro- N-[(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 553.3 554.2 795 [01602] embedded image (2S,4R)-1-[2-(1-ethyl- 2-oxo-1,2- dihydropyridin-3- yl)acetyl]-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 522.2 523.3 796 [01603] (2S,4R)-1-[2-(1-ethyl- 5-methyl-6-oxo-1,6- dihydropyridin-3- yl)acetyl]-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 536.3 537.2 797 [01604] embedded image (2S,4R)-1-[2-(4-ethyl- 5-oxo-4,5- dihydropyrazin-2- yl)acetyl]-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 523.2 524.3 798 [01605] (2S,4R)-1-[2-(6- ethoxy-5- methylpyridin-3- yl)acetyl]-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 536.3 537.2 799 [01606] embedded image (2S,4R)-1-[2-(1-ethyl- 5-methyl-2-oxo-1,2- dihydropyridin-3- yl)acetyl]-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 536.3 537.2 800 [01607] (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-[2-(5-methoxy-1- methyl-1H-1,2,4- triazol-3-yl)acetyl] pyrrolidine- 2-carboxamide 512.2 513.4 801 [01608] embedded image (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-{2-[4- (trifluoromethyl)-1,3- oxazol-2-yl]acetyl} pyrrolidine- 2-carboxamide 536.2 537.3 802 [01609] (2S,4R)-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl]- 1-[2-(5-oxo-4,5- dihydropyrazin-2- yl)acetyl]pyrrolidine- 2-carboxamide 495.2 496.3 803 [01610] embedded image (2S,4R)-1-{2-[5- (difluoromethyl)-3- methyl-1H-pyrazol-1- yl]acetyl}-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 531.2 532.3 804 [01611] (2S,4R)-1-{2-[3- (difluoromethyl)-5- methyl-1H-pyrazol-1- yl]acetyl}-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 531.2 532.3 805 [01612] embedded image (2S,4R)-1-{2-[5- (diethylamino)-1H- 1,2,3-triazol-1- yl]acetyl}-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 539.3 540.2 806 [01613] (2S,4R)-1-[2-(4-ethyl- 3-oxo-3,4- dihydropyrazin-2- yl)acetyl]-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 523.2 524.3 807 [01614] embedded image (2S,4R)-1-{2-[5-(3,3- difluoroazetidin-1- yl)-1H-1,2,3-triazol- 1-yl]acetyl}-4-fluoro- N-[(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 559.2 560.3 808 [01615] (2S,4R)-1-{2-[5- (azetidin-1-yl)-1H- 1,2,3-triazol-1- yl]acetyl}-4-fluoro-N- [(S)-[6-fluoro-5- (propan-2-yl)pyridin- 2-yl](phenyl)methyl] pyrrolidine-2- carboxamide 523.2 524.1

Example S-6: Synthesis of (2S,4R)-1-(2-(1H-benzo[d]imidazol-1-yl)acetyl)-N—((S)-(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide

Compound 417

[1761] ##STR01616##

[1762] Step a: To a solution of 4-bromo-3-fluorobenzaldehyde (150 g, 738 mmol, 1.00 eq) in toluene (2.00 L) and H.sub.2O (240 mL) under nitrogen atmosphere was added cyclopropylboronic acid (82.5 g, 960 mmol, 1.30 eq), K.sub.3PO.sub.4 (360 g, 1.70 mol, 2.30 eq) and Pd(dppf)Cl.sub.2 (27.0 g, 36.9 mmol, 0.05 eq). The resulting mixture was degassed and purged with N.sub.2, warmed to 90° C., and stirred for 16 h. The reaction mixture was then filtered through Celite, and the solvent was removed under reduced pressure. The resulting crude material was purified by column chromatography to give 4-cyclopropyl-3-fluorobenzaldehyde, which was carried forward to the next step without further characterization.

[1763] Step b: To a solution of 4-cyclopropyl-3-fluorobenzaldehyde (146 g, 889 mmol, 1.00 eq) in DCM (1320 mL) under nitrogen atmosphere was added (R)-2-methylpropane-2-sulfinamide (118 g, 978 mmol, 1.10 eq), and Cs.sub.2CO.sub.3 (318 g, 978 mmol, 1.10 eq). The resulting mixture was warmed to 40° C. and stirred for 16 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting crude material was purified by column chromatography to give (R,E)-N-(4-cyclopropyl-3-fluorobenzylidene)-2-methylpropane-2-sulfinamide, which was carried forward to the next step without further characterization.

[1764] Step c: To a solution of (R,E)-N-(4-cyclopropyl-3-fluorobenzylidene)-2-methylpropane-2-sulfinamide (47.7 g, 178 mmol, 1.00 eq) in DCM (477 mL) at −65° C. under N2 was added phenylmagnesium bromide (3 M in Et.sub.2O, 77.3 mL, 1.30 eq) in a dropwise manner. The resulting mixture was stirred while warming to 25° C. over 4 h. The reaction mixture was then quenched with saturated aqueous NH.sub.4Cl (500 mL). The resulting biphasic mixture was extracted with EtOAc (3×500 mL). The organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by column chromatography to give (R)—N—((S)-(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide, which was carried forward to the next step without further characterization.

[1765] Step d: To a solution of (R)—N—((S)-(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (81.6 g, 236 mmol, 1.00 eq) in DCM (1632 mL) at 25° C. was added HCl/EtOAc (4 M, 147 mL, 2.50 eq) in one portion. The resulting mixture was stirred for 2 h. The mixture was then filtered, and the solid obtained was set aside. The filtrate was then concentrated under reduced pressure, and the resulting material was suspended in MTBE (800 mL) and filtered. The solids obtained from both filtrations were combined and dissolved in aqueous Na.sub.2CO.sub.3 (0.5 N, 1.00 L) and DCM (1.00 L). The isolated organic layer was washed with water (500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give (S)-(4-cyclopropyl-3-fluorophenyl)(phenyl)methanaminium chloride, which was carried forward to the next step without further characterization.

[1766] Step e: To a mixture of (S)-(4-cyclopropyl-3-fluorophenyl)(phenyl)methanaminium chloride (12.5 g, 51.8 mmol, 1 eq) and (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (13.2 g, 56.9 mmol, 1.1 eq) in MeCN (125 mL) at 0° C. was added 1-methylimidazole (NMI, 12.7 g, 155 mmol, 12.3 mL, 3 eq) and chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH, 17.4 g, 62.1 mmol, 1.2 eq). The resulting mixture was warmed to 25° C. and stirred for 2 h under N.sub.2 atmosphere. The reaction mixture was then quenched with H.sub.2O (50 mL) and extracted with EtOAc (200 mL). The combined organic extracts were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give tert-butyl (2S,4R)-2-(((S)-(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.26H.sub.30F.sub.2N.sub.2O.sub.3: 457.2; found 457.1.

[1767] Step f: To a solution of tert-butyl (2S,4R)-2-(((S)-(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (15.0 g, 32.8 mmol, 1 eq) in EtOAc (50 mL) was added HCl/EtOAc (4 M, 50 mL, 6.09 eq), and the resulting mixture was stirred at 25° C. for 2 h under N.sub.2 atmosphere. MTBE (50 mL) was then added to the reaction mixture, which was then stirred for 10 min. The reaction mixture was then filtered and the filter cake was dried under reduced pressure to give (2S,4R)—N—((S)-(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide hydrochloride. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.21H.sub.22F.sub.2N.sub.2O: 357.2; found 357.2.

[1768] Step g: To a mixture of (2S,4R)—N—((S)-(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide hydrochloride (3.50 g, 8.91 mmol, 1 eq) and 2-(1H-benzo[d]imidazol-1-yl)acetic acid (Intermediate A-4, 2.46 g, 11.6 mmol, 1.3 eq) in MeCN (35 mL) at −20° C. was added 1-methylimidazole (NMI, 5.85 g, 71.3 mmol, 8 eq), and chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH, 3.25 g, 11.6 mmol, 1.3 eq). The resulting mixture was then warmed to 0° C. and stirred for 2 h. The reaction mixture was then quenched by addition of H.sub.2O (100 mL), and the resulting biphasic mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography followed by prep-HPLC to give (2S,4R)-1-(2-(1H-benzo[d]imidazol-1-yl)acetyl)-N—((S)-(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide (5.16 g). .sup.1H NMR (6.4:1 rotamer ratio, asterisk denotes distinct minor rotamer peaks, obscured peaks not reported, 400 MHz, methanol-d4) δ 8.09 (s, 1H), 7.91* (s, 1H), 7.73-7.61 (m, 1H), 7.51-7.42 (m, 1H), 7.37-7.05 (m, 7H), 7.03-6.83 (m, 3H), 6.27* (s, 1H), 6.06 (s, 1H), 5.52-5.03 (m, 3H), 4.74-4.65 (m, 1H), 4.62-4.48* (m, 1H), 4.23-3.82 (m, 2H), 3.61* (ddd, J=37.1, 13.8, 3.2 Hz, OH), 2.97-2.81* (m, 1H), 2.67-2.49 (m, 1H), 2.46-2.26* (m, 1H), 2.25-1.96 (m, 2H), 0.99-0.92 (m, 2H), 0.72-0.65 (m, 2H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.30H.sub.28F.sub.2N.sub.4O.sub.2: 515.2; found 515.4.

[1769] The following compounds in Table T-6 were synthesized using procedures similar to Compound 417 using the appropriate starting materials.

TABLE-US-00020 TABLE T-6 Exact LCMS, Compound mass Found No. Structure IUPAC (g/mol) [M + H].sup.+ 418 [01617] embedded image (2S,4R)-1-acetyl-N- [(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4- fluoropyrrolidine-2- carboxamide 398.2 399.2 419 [01618] (2S,5S)-1-acetyl-N- [(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl) methyl]-5- methylpyrrolidine- 2-carboxamide 394.2 395.2 420 [01619] (1S,3S,5S)-2- acetyl-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-2- azabicyclo[3.1.0] hexane-3-carboxamide 392.2 393.1 421 [01620] embedded image (2S)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-1-(2- acetamidoacetyl) pyrrolidine-2- carboxamide 437.2 438.1 422 [01621] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [3-(1,3-oxazol-2- yl)propanoyl]pyrrolidine- 2-carboxamide 479.2 480.1 423 [01622] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(3-oxomorpholin-4- yl)acetyl]pyrrolidine- 2-carboxamide 497.2 498.1 424 [01623] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(2-oxo-1,3- oxazolidin-3-yl)acetyl] pyrrolidine- 2-carboxamide 483.2 484.1 425 [01624] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(3-methyl-2- oxoimidazolidin-1- yl)acetyl]pyrrolidine- 2-carboxamide 496.2 497.1 426 [01625] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(1,3,4-oxadiazol-2- yl)acetyl]pyrrolidine- 2-carboxamide 466.2 467.1 427 [01626] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-1-{2-[5- (difluoromethyl)- 1,3,4-oxadiazol-2- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 516.2 517.1 428 [01627] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- {2-[5-(trifluoromethyl)- 1,3,4-oxadiazol-2- yl]acetyl}pyrrolidine- 2-carboxamide 534.2 535.2 429 [01628] embedded image (2S,4R)-1-[2-(5- cyclopropyl-1,3,4- oxadiazol-2- yl)acetyl]-N-[(S)- (4-cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4- fluoropyrrolidine-2- carboxamide 506.2 507.1 430 [01629] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4- fluoro-1-[2-(1H- 1,2,3,4-tetrazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 466.2 467.1 431 [01630] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4- fluoro-1-[2-(1H- 1,2,3,4-tetrazol-1- yl)acetyl]pyrrolidine- 2-carboxamide 466.2 467.2 432 [01631] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(5-methyl-1H- 1,2,3,4-tetrazol-1- yl)acetyl]pyrrolidine- 2-carboxamide 480.2 481.2 433 [01632] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(5-methyl-2H- 1,2,3,4-tetrazol-2- yl)acetyl]pyrrolidine- 2-carboxamide 480.2 481.1 434 [01633] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(5-methyl-4H- 1,2,4-triazol-3- yl)acetyl]pyrrolidine- 2-carboxamide 479.2 480.1 435 [01634] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(1H-pyrazol-1- yl)acetyl]pyrrolidine- 2-carboxamide 464.2 465.1 436 [01635] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(1H-pyrazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 464.2 465.3 437 [01636] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(1H-pyrazol-4- yl)acetyl]pyrrolidine- 2-carboxamide 464.2 465.1 438 [01637] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(1,2-oxazol-3- yl)acetyl]pyrrolidine- 2-carboxamide 465.2 466.1 439 [01638] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 465.2 466.1 440 [01639] (1S,2S,5R)-N-[(S)- (4-cyclopropyl-3- fluorophenyl)(phenyl) methyl]-3-[2- (1H-1,2,3-triazol-5- yl)acetyl]-3- azabicyclo[3.1.0] hexane-2-carboxamide 459.2 460.1 441 [01640] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-1-{2- [(dimethylcarbamoyl) amino]acetyl}-4- fluoropyrrolidine-2- carboxamide 484.2 485.1 442 [01641] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1-[2-(5- methyl-2,4-dioxo- 1,2,3,4- tetrahydropyrimidin-1- yl)acetyl]pyrrolidine- 2-carboxamide 522.2 523.2 443 [01642] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1-[2- (quinolin-5- yl)acetyl]pyrrolidine- 2-carboxamide 525.2 526.2 444 [01643] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-1-[2- (3,5-dimethyl-1H- pyrazol-4-yl)acetyl]-4- fluoropyrrolidine-2- carboxamide 492.2 493.2 445 [01644] embedded image 2-[(2S,4R)-2-{[(S)- (4-cyclopropyl-3- fluorophenyl)(phenyl) methyl]carbamoyl}-4- fluoropyrrolidin-1- yl]-2-oxoethyl 4- methylpiperazine- 1-carboxylate 540.3 541.3 446 [01645] 2-[(2S,4R)-2-{[(S)- (4-cyclopropyl-3- fluorophenyl)(phenyl) methyl]carbamoyl}-4- fluoropyrrolidin-1- yl]-2-oxoethyl 4-(2,2,2- trifluoroethyl)piperazine- 1-carboxylate 608.2 609.2 447 [01646] embedded image 2-[(2S,4R)-2-{[(S)- (4-cyclopropyl-3- fluorophenyl)(phenyl) methyl]carbamoyl}-4- fluoropyrrolidin-1- yl]-2-oxoethyl 4- (cyclopropylmethyl) piperazine-1-carboxylate 580.3 591.3 448 [01647] 2-[(2S,4R)-2-{[(S)- (4-cyclopropyl-3- fluorophenyl)(phenyl) methyl]carbamoyl}-4- fluoropyrrolidin-1- yl]-2-oxoethyl 4-(2- methoxyethyl)piperazine- 1-carboxylate 584.3 585.3 449 [01648] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1-[2-(3- methyl-2,4-dioxo- 1,2,3,4- tetrahydropyrimidin-1- yl)acetyl]pyrrolidine- 2-carboxamide 522.2 523.2 450 [01649] (2S,4R)-1-[2-(1H- 1,2,3-benzotriazol- 1-yl)acetyl]-N-[(S)- (4-cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4- fluoropyrrolidine-2- carboxamide 515.2 516.3 451 [01650] embedded image 2-[(2S,4R)-2-{[(S)- (4-cyclopropyl-3- fluorophenyl)(phenyl) methyl]carbamoyl}-4- fluoropyrrolidin-1- yl]-2-oxoethyl azetidine-1-carboxylate 497.2 498.3 452 [01651] N-{2-[(2S,4R)-2- {[(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl) methyl]carbamoyl}-4- fluoropyrrolidin-1- yl]-2-oxoethyl} morpholine-4- carboxamide 526.2 527.3 453 [01652] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(1-oxo-2,3-dihydro- 1H-isoindol-2-yl)acetyl] pyrrolidine-2- carboxamide 529.2 530.2 454 [01653] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(2-oxo-2,3-dihydro- 1H-indol-1- yl)acetyl]pyrrolidine- 2-carboxamide 529.2 530.1 455 [01654] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(1-methyl-2-oxo-2,3- dihydro-1H-indol- 3-yl)acetyl]pyrrolidine- 2-carboxamide 543.2 544.3 456 [01655] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(2-oxo-2,3- dihydro-1H- 1,3-benzodiazol-1- yl)acetyl]pyrrolidine- 2-carboxamide 530.2 531.2 457 [01656] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1-[2- (3-methyl-2-oxo-2,3- dihydro-1H-1,3- benzodiazol-1-yl)acetyl] pyrrolidine-2- carboxamide 544.2 545.2 458 [01657] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(1H-indazol-3- yl)acetyl]pyrrolidine- 2-carboxamide 514.2 515.1 459 [01658] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(1-methyl-1H-indazol- 3-yl)acetyl]pyrrolidine- 2-carboxamide 528.2 529.2 460 [01659] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1-[2- (1H-indol-2-yl)acetyl] pyrrolidine- 2-carboxamide 513.2 514.3 461 [01660] embedded image tert-butyl 2-{2- [(2S,4R)-2-{[(S)- (4-cyclopropyl-3- fluorophenyl)(phenyl) methyl]carbamoyl}-4- fluoropyrrolidin-1- yl]-2-oxoethyl}-1H- indole-1-carboxylate 613.3 514.3 [M − Boc + H].sup.+ 462 [01661] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1-[2-(1- methyl-1H-indol-2- yl)acetyl]pyrrolidine- 2-carboxamide 527.2 528.3 463 [01662] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1-[2-(1- methyl-1H-indol-3- yl)acetyl]pyrrolidine- 2-carboxamide 527.2 528.2 464 [01663] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1-[2-(2- methyl-1H-1,3- benzodiazol-1- yl)acetyl]pyrrolidine- 2-carboxamide 528.2 529.3 465 [01664] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1-[2-(2- oxopiperazin-1- yl)acetyl]pyrrolidine- 2-carboxamide 496.2 497.2 466 [01665] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- {2-[2-oxo-4-(2,2,2- trifluoroethyl)piperazin- 1-yl]acetyl}pyrrolidine- 2-carboxamide 578.2 579.2 467 [01666] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(2-oxo-2,3- dihydro-1H-indol-3- yl)acetyl]pyrrolidine- 2-carboxamide 529.2 530.2 468 [01667] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1-[2-(4- methyl-1H-imidazol-1- yl)acetyl]pyrrolidine- 2-carboxamide 478.2 479.2 469 [01668] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-1-{2- [(1-ethyl-1H-1,2,3- triazol-4- yl)amino]acetyl}-4- fluoropyrrolidine-2- carboxamide 508.2 509.3 470 [01669] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-1-{2- [(2-ethyl-2H-1,2,3- triazol-4- yl)amino]acetyl}-4- fluoropyrrolidine-2- carboxamide 508.2 509.3 471 [01670] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1-{2- [(pyrazin-2-yl)amino] acetyl}pyrrolidine-2- carboxamide 491.2 492.2 472 [01671] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- {2-[(2-methylpyrimidin- 4-yl)amino]acetyl} pyrrolidine-2- carboxamide 505.2 506.3 473 [01672] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-1-{2- [(1-ethyl-1H-1,2,3- triazol-4-yl)(methyl) amino]acetyl}-4- fluoropyrrolidine-2- carboxamide 522.3 523.2 474 [01673] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-1-{2- [(2-ethyl-2H-1,2,3- triazol-4-yl)(methyl) amino]acetyl}-4- fluoropyrrolidine-2- carboxamide 522.3 523.2 475 [01674] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1-{2- [methyl(pyrazin-2- yl)amino]acetyl} pyrrolidine-2- carboxamide 505.2 506.1 476 [01675] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1-{2- [methyl(2- methylpyrimidin-4- yl)amino]acetyl} pyrrolidine-2- carboxamide 519.2 520.3 477 [01676] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1-[2- (2-methylquinolin-5- yl)acetyl]pyrrolidine- 2-carboxamide 539.2 540.2 478 [01677] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1-(2- {[1,2,4]triazolo[1,5-a] pyridin-6-yl}acetyl) pyrrolidine-2- carboxamide 515.2 516.3 479 [01678] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1-(2- {imidazo[1,2-a]pyridin- 3-yl}acetyl)pyrrolidine- 2-carboxamide 514.2 515.3 480 [01679] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1-[2- (2-methylquinolin-6- yl)acetyl]pyrrolidine- 2-carboxamide 539.2 540.2 481 [01680] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [2-(4H-1,2,4-triazol-4- yl)acetyl]pyrrolidine- 2-carboxamide 465.2 466.3 482 [01681] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- (2-{3-oxo-2H,3H- [1,2,4]triazolo[4,3-a] pyridin-8-yl}acetyl) pyrrolidine-2- carboxamide 531.2 532.2 483 [01682] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-1-{2-[4- (dimethylamino)- 2H-1,2,3-triazol-2- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 508.2 509.2 484 [01683] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-1-{2-[4- (dimethylamino)- 1H-1,2,3-triazol-1- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide 508.2 509.2 485 [01684] embedded image tert-butyl N-[(5-{2- [(2S,4R)-2-{[(S)- (4-cyclopropyl-3- fluorophenyl)(phenyl) methyl]carbamoyl}-4- fluoropyrrolidin-1- yl]-2-oxoethyl}- 1,3,4-oxadiazol-2- yl)methyl]carbamate 595.3 596.3 486 [01685] N-{2-[(2S,4R)-2- {[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]carbamoyl}- 4-fluoropyrrolidin-1- yl]-2-oxoethyl}-4- methylpiperazine- 1-carboxamide 539.3 540.3 487 [01686] embedded image N-{2-[(2S,4R)-2- {[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]carbamoyl}-4- fluoropyrrolidin-1- yl]-2-oxoethyl}-4- (2,2,2-trifluoroethyl) piperazine-1- carboxamide 607.3 608.2 488 [01687] N-{2-[(2S,4R)-2- {[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]carbamoyl}-4- fluoropyrrolidin-1- yl]-2-oxoethyl}-4- (2-methoxyethyl) piperazine-1- carboxamide 583.3 584.2 489 [01688] embedded image (2S,4R)-1-{2-[5- (aminomethyl)- 1,3,4-oxadiazol-2- yl]acetyl}-N-[(S)- (4-cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4- fluoropyrrolidine-2- carboxamide 495.2 496.1 490 [01689] N-{2-[(2S,4R)-2- {[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]carbamoyl}-4- fluoropyrrolidin-1- yl]-2-oxoethyl}-4- (cyclopropylmethyl) piperazine-1- carboxamide 579.3 580.2 491 [01690] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4- fluoro-1-[2-(5-oxo- 4,5-dihydro-1H- 1,2,4-triazol-3- yl)acetyl]pyrrolidine- 2-carboxamide 481.2 482.3 492 [01691] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4- fluoro-1-[2-(5-oxo- 4,5-dihydro-1,2,4- oxadiazol-3- yl)acetyl]pyrrolidine- 2-carboxamide 482.2 483.1 493 [01692] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1- [3-(5-oxo-4,5-dihydro- 1H-1,2,4-triazol-3- yl)propanoyl]pyrrolidine- 2-carboxamide 495.2 496.2 494 [01693] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1-[2-(4- methyl-5-oxo-4,5- dihydro-1,2,4-oxadiazol- 3-yl)acetyl]pyrrolidine- 2-carboxamide 496.2 497.1 495 [01694] embedded image (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-1-{2-[(3,3- difluoroazetidine-1- carbonyl)amino] acetyl}-4- fluoropyrrolidine-2- carboxamide 532.2 533.1 496 [01695] (2S,4R)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4-fluoro-1-(2- {[3-(trifluoromethyl) azetidine-1-carbonyl] amino}acetyl) pyrrolidine-2- carboxamide 564.2 565.2 809 [01696] embedded image (2S,4R)-1-[(2S) or (2R)-2-(1H-1,3- benzodiazol-1- yl)propanoyl]-N- [(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4- fluoropyrrolidine-2- carboxamide (column: DAICEL CHIRALPAK AD, second-eluting isomer) 528.2 529.2 810 [01697] (2S,4R)-1-[(2R) or (2S)-2-(1H-1,3- benzodiazol-1- yl)propanoyl]-N- [(S)-(4-cyclopropyl-3- fluorophenyl)(phenyl) methyl]-4- fluoropyrrolidine-2- carboxamide (column: DAICEL CHIRALPAK AD, first-eluting isomer) 528.2 529.3

Example S-7: Synthesis of (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-N—((S) or (R)-(5-cyclopropylpyridin-2-yl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide and (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-N—((R) or (S)-(5-cyclopropylpyridin-2-yl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide

Compound 497 & Compound 498

[1770] ##STR01698##

[1771] Step a: To a solution of 5-bromopicolinaldehyde (5.00 g 26.9 mmol, 1 eq) in DCM (50 mL) at 25° C. was added 2-methylpropane-2-sulfinamide (3.58 g 29.6 mmol, 1.1 eq) and Cs.sub.2CO.sub.3 (9.63 g 29.6 mmol, 1.1 eq). The system was degassed and charged with nitrogen, and the reaction mixture was warmed to 40° C. and stirred for 2 h under N.sub.2 atmosphere. After cooling, the reaction solution was filtered and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give (E)-N-((5-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.13BrN.sub.2OS: 289.0; found 289.1.

[1772] Step b: A solution of (E)-N-((5-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (7.5 g, 25.9 mmol, 1 eq) in DCM (80 mL) was degassed and charged with nitrogen three times and cooled to −70° C. To the cooled solution was added PhMgBr (3 M in Et.sub.2O, 10.4 mL, 1.2 eq) in a dropwise manner under N.sub.2 atmosphere. The reaction mixture was then stirred at −70° C. for 2 h, warmed to room temperature, and stirred for another 1 h under N.sub.2 atmosphere. The reaction mixture was then quenched with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (3×50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give N-((5-bromopyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.16H.sub.19BrN.sub.2OS: 367.0; found 367.1.

[1773] Step c: To a solution of N-((5-bromopyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (9.00 g, 24.5 mmol, 1 eq) in toluene (200 mL) and H.sub.2O (20 mL) at 25° C. was added cyclopropylboronic acid (16.8 g, 196 mmol, 8 eq), K.sub.3PO.sub.4 (15.6 g, 73.5 mmol, 3 eq) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (2.00 g, 2.45 mmol, 0.1 eq). The reaction mixture was degassed and purged with nitrogen three times, warmed to 110° C., and stirred for 16 h under N.sub.2 atmosphere. After cooling, the reaction mixture was concentrated under reduced pressure. To the resulting residue was added water (150 mL), and the biphasic mixture was extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with brine (3×100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give N-((5-cyclopropylpyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.19H.sub.24N.sub.20S: 329.2; found 329.2.

[1774] Step d: To a solution of N-((5-cyclopropylpyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (5 g, 15.2 mmol, 1 eq) in ethyl acetate (10 mL) at 0° C. under N2 atmosphere was added HCl in ethyl acetate (4 M, 20 mL). The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was then filtered, and the solid obtained was dried under reduced pressure to give (5-cyclopropylpyridin-2-yl)(phenyl)methanamine hydrochloride, which was used without further purification. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.15H.sub.16N.sub.2: 225.1; found 225.2.

[1775] Step e: To a solution of (5-cyclopropylpyridin-2-yl)(phenyl)methanamine hydrochloride (3.50 g, 13.4 mmol, 1 eq) in CH.sub.3CN (30 mL) at −20° C. under N.sub.2 atmosphere was added 1-methyl-1H-imidazole (NMI, 4.69 g, 57.1 mmol, 3 eq) and (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (3.76 g, 16.1 mmol, 1.2 eq). After stirring for 10 min, N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate (4.52 g, 16.1 mmol, 1.2 eq) was added in portions. The reaction mixture was then stirred at −20° C. for 2 h under N.sub.2 atmosphere. The reaction mixture was then quenched with H.sub.2O (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (3×30 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give tert-butyl (2S,4R)-2-(((5-cyclopropylpyridin-2-yl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.25H.sub.30FN.sub.3O.sub.3: 440.2; found 440.3.

[1776] Step f: To a solution of tert-butyl (2S,4R)-2-(((5-cyclopropylpyridin-2-yl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (7 g, crude) in 1,4-dioxane (5 mL) at 0° C. was added HCl/dioxane (4 M, 50 mL). The resulting mixture was stirred at 0° C. for 4 h. The reaction was then concentrated under reduced pressure. The resulting solid was washed with MTBE (3×10 mL) and dried under reduced pressure to give (2S,4R)—N-((5-cyclopropylpyridin-2-yl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide hydrochloride (6.5 g). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.20H.sub.22FN.sub.3O: 340.2; found 340.2.

[1777] Step g: To a solution of (2S,4R)—N-((5-cyclopropylpyridin-2-yl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide hydrochloride (6.50 g, 17.3 mmol, 1 eq) in DMF (50 mL) at 0° C. was added 4-methylmorpholine (NMM, 7.00 g, 69.2 mmol, 4 eq), 2-(1H-1,2,3-triazol-5-yl)acetic acid (2.63 g, 20.8 mmol, 1.2 eq), and T3P (27.5 g, 43.2 mmol, 50% in ethyl acetate, 2.5 eq). The reaction mixture was then stirred at 0° C. for 2 h under N.sub.2 atmosphere. The reaction mixture was then quenched with H.sub.2O (60 mL) at 0° C. and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (70 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography and chiral SFC (column: REGIS (s,s) WHELK-01 (250 mm×50 mm, 10 μm); mobile phase: [Phase A: CO.sub.2, Phase B: 0.1% NH.sub.3(aq) in EtOH]; isocratic at 40% B, 3.4 min) to give (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-N—((S) or (R)-(5-cyclopropylpyridin-2-yl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide (Compound 497; first-eluting isomer) and (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-N—((R) or (S)-(5-cyclopropylpyridin-2-yl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide (Compound 498; second-eluting isomer).

[1778] First-eluting isomer (Compound 497): .sup.1H NMR (4.4:1 rotamer ratio, asterisk denotes distinct minor rotamer peaks, obscured peaks not reported, 400 MHz, methanol-d4) δ 8.30-8.21 (m, 1H), 7.55-7.39 (m, 2H), 7.38-7.14 (m, 5H), 6.18* (s, 1H), 6.09 (s, 1H), 5.44-5.18 (m, 1H), 4.70 (t, 1H), 4.15-4.02 (m, 1H), 3.97-3.75 (m, 3H), 3.70-3.50* (m, 2H), 2.85-2.70* (m, 1H), 2.65-2.50 (m, 1H), 2.37-2.06 (m, 1H), 2.00-1.84 (m, 1H), 1.08-0.95 (m, 2H), 0.75-0.62 (m, 2H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.26H.sub.25FN.sub.6O.sub.2: 449.2; found 449.2.

[1779] Second-eluting isomer (Compound 498): .sup.1H NMR (4.4:1 rotamer ratio, asterisk denotes distinct minor rotamer peaks, obscured peaks not reported, 400 MHz, methanol-d4) δ 8.30-8.21 (m, 1H), 7.53-7.39 (m, 2H), 7.38-7.17 (m, 6H), 6.18* (s, 1H), 6.09 (s, 1H), 5.44-5.18 (m, 1H), 4.70 (t, J=9.3, 7.7 Hz, 1H), 4.15-4.02 (m, 1H), 3.98-3.75 (m, 3H), 3.68-3.51* (m, 2H), 2.85-2.69* (m, 1H), 2.65-2.50 (m, 1H), 2.38-2.05 (m, 1H), 2.00-1.83 (m, 1H), 1.08-0.95 (m, 2H), 0.79-0.60 (m, 2H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.26H.sub.25FN.sub.6O.sub.2: 449.2; found 449.1.

[1780] The following compounds in Table T-7 were synthesized using procedures similar to Compound 497 and Compound 498 using the appropriate starting materials.

TABLE-US-00021 TABLE T-7 Exact LCMS, Compound mass Found No. Structure IUPAC (g/mol) [M + H].sup.+ 499 [01699] embedded image (2S,4R)-1-acetyl- N-[(S) or (R)-(5- cyclopropylpyridin-2- yl)(phenyl)methyl]-4- fluoropyrrolidine- 2-carboxamide (column: REGIS (s, s) WHELK-O1, first-eluting isomer) 381.2 382.2 500 [01700] (2S,4R)-1-acetyl- N-[(R) or (S)-(5- cyclopropylpyridin-2- yl)(phenyl)methyl]-4- fluoropyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, second-eluting isomer) 381.2 382.4

Example S-8: Synthesis of (2S,4R)—N—((S)-(5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl)(phenyl)methyl)-1-(2-(3-ethyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-4-fluoropyrrolidine-2-carboxamide

Compound 501

[1781] ##STR01701##

[1782] Step a: To a solution of 3-bromo-2-fluoro-6-methylpyridine (9.00 g, 47.3 mmol, 1.00 eq) in CHCl.sub.3 (90 mL) at 25° C. under N.sub.2 was added N-bromosuccinimide (NBS, 10.1 g, 56.8 mmol, 1.20 eq) and azodiisobutyronitrile (AIBN, 777 mg, 4.74 mmol, 0.1 eq). The resulting mixture was warmed to 80° C. and stirred for 5 h. At this time, the reaction mixture was cooled to room temperature and poured into water (200 mL). The resulting biphasic mixture was extracted with dichloromethane (2×100 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to obtain 3-bromo-6-(bromomethyl)-2-fluoropyridine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.6H.sub.4Br.sub.2FN: 267.9; found 267.9.

[1783] Step b: To a solution of 3-bromo-6-(bromomethyl)-2-fluoropyridine (13.0 g, 38.6 mmol, 80% purity, 1.00 eq) in MeCN (130 mL) at 20° C. under N.sub.2 was added N-methylmorpholine N-oxide (NMMO, 9.06 g, 77.3 mmol, 8.16 mL, 2.00 eq). The resulting mixture was stirred at 20° C. for 2 h. The reaction mixture was then poured into water (200 mL) and extracted with dichloromethane (2×100 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to obtain 5-bromo-6-fluoropicolinaldehyde.

[1784] Step c: To a mixture of 5-bromo-6-fluoropicolinaldehyde (5.00 g, 24.5 mmol, 1.00 eq) and (S)-2-methylpropane-2-sulfinamide (3.27 g, 26.9 mmol, 1.10 eq) in DCM (50 mL) at 20° C. under N.sub.2 was added Cs.sub.2CO.sub.3 (8.78 g, 26.9 mmol, 1.10 eq). The resulting mixture was stirred for 10 min before it was warmed 40° C. and stirred for 2 h. The reaction mixture was then cooled to room temperature and poured into water (50 mL). The resulting biphasic mixture was extracted with dichloromethane (2×50 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to obtain (S,E)-N-((5-bromo-6-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide.

[1785] Step d: To a solution of (S,E)-N-((5-bromo-6-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (7.04 g, 22.9 mmol, 1.00 eq) in DCM (70 mL) −65° C. under N.sub.2 was added in a dropwise manner phenylmagnesium bromide (5.41 g, 29.8 mmol, 1.30 eq). The resulting mixture was stirred at −65° C. for 1 h. The reaction mixture was then poured into water (100 mL) at room temperature. The resulting biphasic mixture was extracted with dichloromethane (2×100). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to obtain (S)—N—((S)-(5-bromo-6-fluoropyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide, which was carried forward to the next step without further characterization.

[1786] Step e: To a solution of (S)—N—((S)-(5-bromo-6-fluoropyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (7.50 g, 19.4 mmol, 1.00 eq) in EtOAc (30 mL) at 0° C. was added HCl/EtOAc (30 mL). The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was then concentrated under reduce pressure to obtain (S)-(5-bromo-6-fluoropyridin-2-yl)(phenyl)methanamine hydrochloride (6.18 g). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.12H.sub.10BrFN.sub.2: 281.0; found: 281.0.

[1787] Step f: To a mixture of (S)-(5-bromo-6-fluoropyridin-2-yl)(phenyl)methanamine hydrochloride (0.5 g, 1.78 mmol, 1.00 eq) and (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (456 mg, 1.96 mmol, 1.10 eq) in DMF (5 mL) at −20° C. was added N-methylmorpholine (NMM, 5.34 mmol, 3.00 eq) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P, 3.56 mmol, 2.12 mL, 50% purity, 2.00 eq). The resulting mixture was allowed to warm to 0° C. and stirred for 1 h. The reaction mixture was then poured into water (20 mL) at room temperature. The resulting biphasic mixture was extracted with dichloromethane (2×50 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (2S,4R)-2-(((S)-(5-bromo-6-fluoropyridin-2-yl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (0.7 g). LC-MS (ESI): m/z: [M−t-Bu+H+H].sup.+ calculated for C.sub.22H.sub.24BrF.sub.2N.sub.3O.sub.3: 440.0; found: 440.1.

[1788] Step g: To a solution of tert-butyl (2S,4R)-2-(((S)-(5-bromo-6-fluoropyridin-2-yl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (700 mg, 1.41 mmol, 1.00 eq) and 3-bromo-1,1-difluorocyclobutane (482 mg, 2.82 mmol, 2.00 eq) in 1,2-Dimethoxyethane (DME, 12 mL) at 25° C. under N.sub.2 was added nickel(II) chloride ethylene glycol dimethyl ether complex (NiCl.sub.2.glyme, 3.1 mg, 14.1 μmol, 0.01 eq), 4,4-di-tert-butyl-2,2-bipyridyl (dtbpy, 3.79 mg, 14.1 μmol, 0.01 eq), Na.sub.2CO.sub.3 (298 mg, 2.82 mmol, 2.00 eq), tris(trimethylsilyl)silane (TTMSS, 350 mg, 1.41 mmol, 1 eq) and (Ir[dF(CF.sub.3)ppy].sub.2(dtbpy))PF.sub.6 (CAS: 870987-63-6, 15.8 mg, 14.1 μmol, 0.01 eq) in one portion. The resulting mixture was stirred for 16 h under N.sub.2 at 25° C. under a 34 W blue LED. The reaction mixture was then filtered and concentrated under reduced pressure to give a crude residue that was purified by column chromatography to give tert-butyl (2S,4R)-2-(((S)-(5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate. LC-MS (ESI): m/z: [M−t-Bu+H+H].sup.+ calculated for C.sub.26H.sub.29F.sub.4N.sub.3O.sub.3: 452.1; found: 452.1.

[1789] Step h: To a solution of tert-butyl (2S,4R)-2-(((S)-(5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (173 mg, 341 μmol, 1.00 eq) in EtOAc (1 mL) at 0° C. was added HCl/EtOAc (4 M, 2 mL). The resulting mixture was stirred at 0° C. for 2 h. The reaction mixture was then concentrated under reduced pressure to give a crude residue. This residue was diluted in DCM (20 mL) and adjusted to pH=7 with saturated aqueous NaHCO.sub.3 solution. The reaction mixture was then extracted with DCM (3×45 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give (2S,4R)—N—((S)-(5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.21H.sub.21F.sub.4N.sub.3O: 408.2; found: 408.2.

[1790] Step i: To a mixture of (2S,4R)—N—((S)-(5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide (80.0 mg, 196 μmol, 1 eq) and 2-(3-ethyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid (62.5 mg, 295 μmol, 1.5 eq) in DMF (3 mL) at 0° C. under N.sub.2 was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P, 250 mg, 393 μmol, 50% purity, 2 eq) and N-methylmorpholine (NMM, 79.5 mg, 785 μmol, 4 eq) in one portion. The resulting mixture was stirred at 0° C. for 1 h. The reaction was then allowed to warm to 20° C. and stirred 1 h. The reaction mixture was then diluted with H.sub.2O (20 mL) at 20° C. and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to obtain (2S,4R)—N—((S)-(5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl)(phenyl)methyl)-1-(2-(3-ethyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-4-fluoropyrrolidine-2-carboxamide. .sup.1H NMR (4.3:1 rotamer ratio, asterisk denotes distinct minor rotamer peaks, obscured peaks not reported, 400 MHz, methanol-d4) δ 7.88-7.78 (m, 1H), 7.44-7.37* (in, 2H), 7.37-7.18 (m, 7H), 7.06* (d, J=1.3 Hz, 1H), 6.19* (s, 1H), 6.08 (s, 1H), 5.50-5.18 (m, 1H), 4.92-4.77 (m, 1H), 4.76-4.68 (m, 1H), 4.58* (d, J=16.3 Hz, 1H), 4.48 (d, J=16.7 Hz, 1H), 4.15-3.77 (m, 4H), 3.53-3.43 (m, 1H), 3.06-2.91 (m, 2H), 2.86-2.55 (m, 3H), 2.27-2.07 (m, 1H), 1.92-1.84 (m, 3H), 1.16 (t, J=7.0 Hz, 3H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.30H.sub.31F.sub.4N.sub.5O.sub.4: 602.2; found: 602.3.

[1791] The following compounds in Table T-8 were synthesized using procedures similar to Compound 501 using the appropriate starting materials.

TABLE-US-00022 TABLE T-8 Exact LCMS, Compound mass Found No. Structure IUPAC (g/mol) [M + H].sup.+ 502 [01702] embedded image (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 4-fluoro-1-[2-(5- methyl-2-oxo-2,3- dihydro-1,3,4- oxadiazol-3-yl) acetyl]pyrrolidine- 2-carboxamide 547.2 548.30 503 [01703] (2S,4R)-1-{2- [(azetidine-1- carbonyl)amino] acetyl}-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 4-fluoropyrrolidine- 2-carboxamide 547.2 548.30 504 [01704] embedded image (2S,4R)-1-[2-(1H- 1,3-benzodiazol- 1-yl)acetyl]-N- [(S)-[5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 4-fluoropyrrolidine- 2-carboxamide 565.2 566.20 505 [01705] (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 4-fluoro-1-[2- (1,3-oxazol-2-yl) acetyl]pyrrolidine- 2-carboxamide 516.2 517.10 506 [01706] embedded image (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 4-fluoro-1-[2-(5- methyl-2,4-dioxo- 1,2,3,4- tetrahydropyrimidin- 1-yl)acetyl] pyrrolidine- 2-carboxamide 573.2 574.1 507 [01707] (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 1-{2- [(dimethylcarbamoyl) amino]acetyl}-4- fluoropyrrolidine- 2-carboxamide 535.2 536.3 508 [01708] embedded image (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 4-fluoro-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 516.2 517.2 509 [01709] (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 4-fluoro-1-[2-(5- methyl-1,3- oxazol-2-yl) acetyl]pyrrolidine- 2-carboxamide 530.2 531.2 510 [01710] embedded image (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 4-fluoro-1-{2-[4- (trifluoromethyl)- 1H-1,2,3-triazol-5- yl]acetyl} pyrrolidine-2- carboxamide 584.2 585.2 511 [01711] (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 4-fluoro-1-[2-(4- methyl-1,3- oxazol-2-yl) acetyl]pyrrolidine- 2-carboxamide 530.2 531.2 512 [01712] embedded image (2S,4R)-1-{2- [(3,3- difluoroazetidine-1- carbonyl)amino] acetyl}-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 4-fluoropyrrolidine- 2-carboxamide 583.2 584.3 513 [01713] (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 1-{2-[5- (difluoromethyl)- 1H-1,2,3,4- tetrazol-1- yl]acetyl}-4- fluoropyrrolidine- 2-carboxamide 567.2 568.1 514 [01714] embedded image (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 1-[2-(2,4-dioxo- 1,2,3,4- tetrahydropyrimid in-1-yl)acetyl]-4- fluoropyrrolidine- 2-carboxamide 559.2 560.1 515 [01715] (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 1-[2-(3-ethyl- 2,4-dioxo-l,2,3,4- tetrahydropyrimid in-1-yl)acetyl]-4- fluoropyrrolidine- 2-carboxamide 587.2 588.2 516 [01716] embedded image (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 4-fluoro-1-[2-(6- oxo-1,6- dihydropyridin-3- yl)acetyl]pyrrolidine- 2-carboxamide 542.2 543.3 517 [01717] (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 4-fluoro-1-[2-(2- oxo-1,2- dihydropyridin-3-yl) acetyl]pyrrolidine- 2-carboxamide 542.2 543.3 518 [01718] embedded image (2S,4R)-N-[(R)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin- 2-yl](phenyl)methyl]- 1-[2-(3-ethyl-5- methyl-2,4-dioxo- 1,2,3,4- tetrahydropyrimidin- 1-yl)acetyl]-4- fluoropyrrolidine- 2-carboxamide 601.2 602.3 519 [01719] (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin- 2-yl](phenyl)methyl]- 1-[2-(1-ethyl-6- oxo-1,6- dihydropyridin-3- yl)acetyl]-4- fluoropyrrolidine- 2-carboxamide 570.2 571.3 520 [01720] embedded image (2S,4R)-N-[(R)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 4-fluoro-1-[2-(6- oxo-1,6- dihydropyridin-3-yl) acetyl]pyrrolidine- 2-carboxamide 542.2 543.3 521 [01721] (2S,4R)-N-[(R)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 4-fluoro-1-[2-(2- oxo-1,2- dihydropyridin-3- yl)acetyl]pyrrolidine- 2-carboxamide 542.2 543.3 522 [01722] embedded image (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 4-fluoro-1-[2-(5- methyl-6-oxo-1,6- dihydropyridin-3- yl)acetyl]pyrrolidine- 2-carboxamide 556.2 557.2 523 [01723] (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 1-[2-(1-ethyl-5- methyl-6-oxo-1,6- dihydropyridin-3- yl)acetyl]-4- fluoropyrrolidine- 2-carboxamide 584.2 585.2 524 [01724] embedded image (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 1-[2-(6-ethoxy- 5-methylpyridin- 3-yl)acetyl]-4- fluoropyrrolidine- 2-carboxamide 584.2 585.2 525 [01725] (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 1-[2-(1-ethyl-5- methyl-2-oxo-1,2- dihydropyrdin-3- yl)acetyl]-4- fluoropyrrolidine- 2-carboxamide 584.2 585.2 526 [01726] embedded image (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 1-[2-(1-ethyl-2- oxo-1,2- dihydropyridin-3- yl)acetyl]-4- fluoropyrrolidine- 2-carboxamide 570.2 571.2 527 [01727] (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 1-[2-(4-ethyl-5- oxo-4,5- dihydropyrazin-2- yl)acetyl]-4- fluoropyrrolidine- 2-carboxamide 571.2 572.3 528 [01728] embedded image (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 4-fluoro-1-{2-[4- (trifluoromethyl)- 1,3-oxazol-2- yl]acetyl}pyrrolidine- 2-carboxamide 584.2 585.1 529 [01729] (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 4-fluoro-1-[2-(3- oxo-3,4- dihydropyrazin-2-yl) acetyl]pyrrolidine- 2-carboxamide 543.2 544.3 530 [01730] embedded image (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 4-fluoro-l-[2-(5- oxo-4,5- dihydropyrazin-2- yl)acetyl]pyrrolidine- 2-carboxamide 543.3 544.3 531 [01731] (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl)- 6-fluoropyridin-2- yl](phenyl)methyl]- 1-[2-(4-ethyl-3- oxo-3,4- dihydropyrazin-2- yl)acetyl]-4- fluoropyrrolidine- 2-carboxamide 571.2 572.3

Example S-9: Synthesis of (2S,4R)—N—((S)-(5-(3,3-difluorocyclobutyl)pyridin-2-yl)(phenyl)methyl)-1-((dimethylcarbamoyl)glycyl)-4-fluoropyrrolidine-2-carboxamide

Compound 532

[1792] ##STR01732##

[1793] Step a: To a solution of 6-bromonicotinic acid (40 g, 198 mmol, 1 eq) in THF (400 mL) at 0° C. under N.sub.2 was added BH.sub.3.Me.sub.2S (10 M, 59.40 mL, 3 eq). The mixture was then warmed to 20° C. and stirred for 3 h. The reaction mixture was then cooled to 0° C., quenched with MeOH (200 mL), H.sub.2O (100 mL), and saturated aqueous K.sub.2CO.sub.3 (100 mL), sequentially. The resulting biphasic mixture was then extracted with EtOAc (3×200 mL), and the combined organic extracts were washed with water, dried over anhydrous Na.sub.2SO.sub.4, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (6-bromopyridin-3-yl)methanol. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.6H.sub.6BrNO: 188.0; found: 188.0.

[1794] Step b: To a solution of (6-bromopyridin-3-yl)methanol (16.2 g, 86.3 mmol, 1 eq) and PPh.sub.3 (26.0 g, 99.7 mmol, 1.15 eq) in DCM (150 mL) at 0° C. was added N-bromosuccinimide (NBS, 17.7 g, 99.7 mmol, 1.15 eq). The resulting mixture was then allowed to warm to 20° C. and stirred for 3 h. The reaction mixture was then quenched by addition H.sub.2O (200 mL) at 20° C., and the resulting biphasic mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 2-bromo-5-(bromomethyl)pyridine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.6H.sub.5Br.sub.2N: 249.9; found: 249.9.

[1795] Step c: To a solution of trimethylsilyl cyanide (TMSCN, 12.5 g, 126 mmol, 15.7 mL, 1 eq) in CH.sub.3CN (30 mL) at 0° C. was added tetrabutylammonium fluoride (TBAF, 1 M, 126 mL, 1.5 eq), and the resulting mixture was stirred for 0.5 h at 0° C. 2-bromo-5-(bromomethyl)pyridine (21.1 g, 84.9 mmol, 1 eq) in CH.sub.3CN (100 mL) was then added to the reaction mixture, and the resulting mixture was warmed to 20° C. and stirred for 0.5 h. The reaction mixture was then cooled to 0° C. and quenched by addition H.sub.2O (150 mL). The resulting biphasic mixture was then extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 2-(6-bromopyridin-3-yl)acetonitrile. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.7H.sub.5BrN.sub.2: 197.0; found: 197.0.

[1796] Step d: To a solution of 2-(6-bromopyridin-3-yl)acetonitrile (13.5 g, 68.5 mmol, 1 eq) in dimethylacetamide (DMA, 130 mL) at 0° C. under N.sub.2 was added NaH (5.48 g, 137 mmol, 60% purity, 2 eq). The resulting mixture was stirred at 0° C. for 30 min, and then [2,2-difluoro-3-(trifluoromethylsulfonyloxy)propyl] trifluoromethanesulfonate (30.9 g, 82.2 mmol, 1.2 eq) was added to the reaction mixture. The resulting mixture was then stirred at 0° C. for 1 h. The reaction mixture was then quenched by addition ice-water (100 mL) at 0° C. The resulting biphasic mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 1-(6-bromopyridin-3-yl)-3,3-difluorocyclobutane-1-carbonitrile. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.7BrF.sub.2N.sub.2: 273.0; found: 273.0.

[1797] Step e: A mixture of 1-(6-bromopyridin-3-yl)-3,3-difluorocyclobutane-1-carbonitrile (2.34 g, 8.57 mmol, 1 eq) in aqueous H.sub.2SO.sub.4 (40 mL, 50%) was warmed to 100° C. and stirred 16 h. The reaction mixture was then cooled to 0° C. and adjusted to pH=6 with saturated aqueous K.sub.2CO.sub.3 at 0° C. The resulting mixture was then extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 1-(6-bromopyridin-3-yl)-3,3-difluorocyclobutane-1-carboxylic acid. The crude residue obtained was used for next step without further purification. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.8BrF.sub.2NO.sub.2: 292.0; found: 292.0.

[1798] Step f: A mixture of 1-(6-bromopyridin-3-yl)-3,3-difluorocyclobutane-1-carboxylic acid (2.30 g, 7.87 mmol, 1 eq) and KF (2.29 g, 39.4 mmol, 5 eq) in DMSO (10 mL) was warmed to 140° C. and stirred for 3 h. The mixture was then cooled to room temperature and poured into ice-water (50 mL). The resulting biphasic mixture was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 2-bromo-5-(3,3-difluorocyclobutyl)pyridine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.9H.sub.8BrF.sub.2N: 248.0; found: 248.1.

[1799] Step g: A mixture of 2-bromo-5-(3,3-difluorocyclobutyl)pyridine (6 g, 24.1 mmol, 1 eq), potassium vinyltrifluoroborate (4.86 g, 36.2 mmol, 1.5 eq), Cs.sub.2CO.sub.3 (15.7 g, 48.3 mmol, 2 eq), and Pd(PPh.sub.3).sub.4 (2 g, 1.73 mmol, 0.07 eq) in dioxane (100 mL) and H.sub.2O (10 mL) was de-gassed, placed under N.sub.2, warmed to 100° C., and stirred for 16 h. The reaction mixture was concentrated in vacuum to obtain 5-(3,3-difluorocyclobutyl)-2-vinylpyridine, which was used directly in the next step without further purification or characterization.

[1800] Step h: To a solution of 5-(3,3-difluorocyclobutyl)-2-vinylpyridine (4 g, 20.4 mmol, 1 eq) in THF (100 mL) and H.sub.2O (30 mL) at 0° C. was added NaIO.sub.4 (17.5 g, 81.9 mmol, 4 eq) and K.sub.2OsO.sub.4.2H.sub.2O (377 mg, 1.02 mmol, 0.05 eq). The mixture was allowed to warm to 20° C. and stirred at 20° C. for 16 h. The reaction mixture was then filtered, and the biphasic mixture was extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 5-(3,3-difluorocyclobutyl)picolinaldehyde. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.9F.sub.2NO: 198.0; found: 198.0.

[1801] Step i: A mixture of 5-(3,3-difluorocyclobutyl)picolinaldehyde (2.5 g, 12.6 mmol, 1 eq), (S)-2-methylpropane-2-sulfinamide (1.69 g, 13.9 mmol, 1.1 eq), and Cs.sub.2CO.sub.3 (6.20 g, 19.0 mmol, 1.5 eq) in DCM (50 mL) was warmed to 40° C. and stirred for 1 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to obtain (S,E)-N-((5-(3,3-difluorocyclobutyl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.14H.sub.18F.sub.2N.sub.2OS: 301.1; found: 301.1.

[1802] Step j: To a stirring solution of (S,E)-N-((5-(3,3-difluorocyclobutyl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (3.50 g, 11.6 mmol, 1 eq) in DCM (50 mL) at −60° C. was added phenylmagnesium bromide (3 M, 5.83 mL, 1.5 eq) in a dropwise manner. The mixture was then allowed to warm to 0° C. and stirred for 2 h. The reaction mixture was then quenched with saturated aqueous NH.sub.4Cl (30 mL) at 0° C. The resulting biphasic mixture was then extracted with DCM (2×30 mL). The combined organic extracts were washed with brine (80 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to obtain (S)—N—[(S)-[5-(3,3-difluorocyclobutyl)-2-pyridyl]-phenyl-methyl]-2-methyl-propane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.20H.sub.24F.sub.2N.sub.2OS: 379.2; found: 379.2.

[1803] Step k: To a mixture of (S)—N—[(S)-[5-(3,3-difluorocyclobutyl)-2-pyridyl]-phenyl-methyl]-2-methyl-propane-2-sulfinamide (4.0 g, 10.5 mmol, 1 eq) in dioxane (20 mL) at 0° C. was added HCl/dioxane (4 M, 30 mL, 11.3 eq). The resulting mixture was stirred at 0° C. for 1 h The reaction mixture was then concentrated under reduced pressure to give (S)-(5-(3,3-difluorocyclobutyl)pyridin-2-yl)(phenyl)methanaminium chloride, which was used in the next step without further purification. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.16H.sub.16F.sub.2N.sub.2: 275.1; found: 275.2.

[1804] Step l: To a mixture of (S)-(5-(3,3-difluorocyclobutyl)pyridin-2-yl)(phenyl)methanaminium chloride (3.09 g, 10.3 mmol, 1 eq) and (2S,4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid (2.88 g, 12.3 mmol, 1.2 eq) in MeCN (50 mL) at −20° C. under N.sub.2 was added 1-methylimidazole (NMI, 2.54 g, 30.8 mmol, 3 eq) and chloro-N,N,N′,N-tetramethylformamidinium hexafluorophosphate (TCFH, 3.47 g, 12.3 mmol, 1.2 eq). The resulting mixture was stirred at −20° C. for 1 h. The reaction was then quenched with H.sub.2O (100 mL), and the resulting biphasic mixture was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (2S,4R)-2-(((S)-(5-(3,3-difluorocyclobutyl)pyridin-2-yl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.26H.sub.30F.sub.3N.sub.3O.sub.3: 490.2; found: 490.3.

[1805] Step m: To a solution of tert-butyl (2S,4R)-2-(((S)-(5-(3,3-difluorocyclobutyl)pyridin-2-yl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (5.00 g, 10.2 mmol, 1 eq) in EtOAc (30 mL) at 0° C. was added HCl/EtOAc (4 M, 30 mL) in a dropwise manner. The reaction was then allowed to warm to 25° C. and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure. The crude residue obtained was triturated with i-PrOH/EtOH (ratio=4:1, 150 mL) to give (2S,4R)-2-(((S)-(5-(3,3-difluorocyclobutyl)pyridin-2-yl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidin-1-ium chloride. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.21H.sub.22F.sub.3N.sub.3O: 390.2; found: 390.3.

[1806] Step n: To a solution of (2S,4R)-2-(((S)-(5-(3,3-difluorocyclobutyl)pyridin-2-yl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidin-1-ium chloride (80 mg, 205 μmol, 1 eq) and (dimethylcarbamoyl)glycine (36.0 mg, 246 μmol, 1.2 eq) in DCM (3 mL) at 0° C. was added N-methylmorpholine (NMM, 104 mg, 1.03 mmol, 5 eq) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P, 196 mg, 308 μmol, 50% purity, 1.5 eq). The resulting mixture was stirred at 0° C. for 2 h. The reaction mixture was then poured into water (10 mL) at 0° C. and stirred for 10 min. The biphasic mixture was then extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine (10 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give (2S,4R)—N—((S)-(5-(3,3-difluorocyclobutyl)pyridin-2-yl)(phenyl)methyl)-1-((dimethylcarbamoyl)glycyl)-4-fluoropyrrolidine-2-carboxamide. .sup.1H NMR (2.3:1 rotamer ratio, asterisk denotes minor rotamer peaks, obscured peaks not reported, 400 MHz, DMSO-d6) δ 9.27* (d, J=7.9 Hz, 1H), 8.88 (d, J=8.4 Hz, 1H), 8.50-8.41 (m, 1H), 7.80-7.71 (m, 1H), 7.48-7.40 (m, 1H), 7.37-7.18 (m, 4H), 6.46 (t, J=5.5 Hz, 1H), 6.35* (t, J=5.6 Hz, 1H), 6.16-6.05 (m, 1H), 5.46-5.18 (m, 1H), 4.85* (t, J=8.0 Hz, 1H), 4.60 (t, J=8.3 Hz, 1H), 4.03-3.83 (m, 2H), 3.75-3.57 (m, 2H), 3.51-3.22 (m, 4H), 3.06-2.91 (m, 2H), 2.84-2.68 (m, 4H), 2.23-1.85 (m, 2H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.26H.sub.30F.sub.3N.sub.5O.sub.3: 518.2; found: 518.4.

[1807] The following compounds in Table T-9 were synthesized using procedures similar to Compound 532 using the appropriate starting materials.

TABLE-US-00023 TABLE T-9 Exact LCMS, Compound mass Found No. Structure IUPAC (g/mol) [M + H].sup.+ 533 [01733] embedded image (2S,4R)-1-{2- [(azetidine-1- carbonyl)amino] acetyl}-N-[(S)- [5-(3,3- difluorocyclobutyl) pyridin-2- yl](phenyl)methyl]- 4-fluoropyrrolidine- 2-carboxamide 529.2 530.2 534 [01734] (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl) pyridin-2- yl](phenyl)methyl]- 4-fluoro-1-[2-(1H- 1,2,3-triazol-5-yl) acetyl]pyrrolidine- 2-carboxamide 498.2 499.3 535 [01735] embedded image (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl) pyridin-2- yl](phenyl)methyl]- 4-fluoro-1-[2-(5- methyl-2,4-dioxo- 1,2,3,4- tetrahydropyrimidin- 1-yl)acetyl] pyrrolidine- 2-carboxamide 555.2 556.4 536 [01736] (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl) pyridin-2- yl](phenyl)methyl]- 4-fluoro-1-[2-(5- methyl-1,3- oxazol-2-yl) acetyl]pyrrolidine- 2-carboxamide 512.2 513.1 537 [01737] embedded image (2S,4R)-1-[2-(1H- 1,3-benzodiazol- 1-yl)acetyl]-N- [(S)-[5-(3,3- difluorocyclobutyl) pyridin-2-yl] (phenyl)methyl]-4- fluoropyrrolidine- 2-carboxamide 547.2 548.1 538 [01738] (2S,4R)-1-{2- [(3,3- difluoroazetidine-1- carbonyl)amino] acetyl}-N-[(S)-[5- (3,3- difluorocyclobutyl) pyridin-2- yl](phenyl)methyl]- 4-fluoropyrrolidine- 2-carboxamide 565.2 566.2 539 [01739] embedded image (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl) pyridin-2-yl] (phenyl)methyl]- 4-fluoro-1-[2- (1,3-oxazol-2- yl)acetyl] pyrrolidine-2- carboxamide 498.2 499.4 540 [01740] (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl) pyridin-2-yl] (phenyl)methyl]- 4-fluoro-1-[2-(4- methyl-1,3- oxazol-2- yl)acetyl] pyrrolidine-2- carboxamide 512.2 513.4 541 [01741] embedded image (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl) pyridin-2- yl](phenyl)methyl]- 4-fluoro-1-[2-(5- methyl-2-oxo-2,3- dihydro-1,3,4- oxadiazol-3-yl) acetyl]pyrrolidine- 2-carboxamide 529.2 530.2 542 [01742] (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl) pyridin-2-yl] (phenyl)methyl]- 4-fluoro-1-{2-[4- (trifluoromethyl)- 1H-1,2,3-triazol-5- yl]acetyl} pyrrolidine-2- carboxamide 566.2 567.1 543 [01743] embedded image (2S,4R)-N-[(S)- [5-(3,3- difluorocyclobutyl) pyridin-2- yl](phenyl)methyl]- 4-fluoro-1-{2-[4- (trifluoromethyl)- 1,3-oxazol-2-yl] acetyl}pyrrolidine- 2-carboxamide 566.2 567.1

Example S-10: Synthesis of (2S,4R)-1-((azetidine-1-carbonyl)glycyl)-N—((S)-(4-(3,3-difluorocyclobutyl)-3-fluorophenyl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide and (2S,4R)-1-((azetidine-1-carbonyl)glycyl)-N—((R)-(4-(3,3-difluorocyclobutyl)-3-fluorophenyl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide

Compounds 544 and 545

[1808] ##STR01744##

[1809] Step a: A mixture of 4-bromo-3-fluorobenzaldehyde (25 g, 123 mmol, 1 eq), (R)-2-methylpropane-2-sulfinamide (16.4 g, 135 mmol, 1.1 eq) and Cs.sub.2CO.sub.3 (60.1 g, 184 mmol, 1.5 eq) in DCM (150 mL) at 40° C. was stirred for 1 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (R,E)-N-(4-bromo-3-fluorobenzylidene)-2-methylpropane-2-sulfinamide (37 g). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.13BrFNOS: 306.0; found: 305.9.

[1810] Step b: To a solution of (R,E)-N-(4-bromo-3-fluorobenzylidene)-2-methylpropane-2-sulfinamide (37 g, 120 mmol, 1 eq) in DCM (150 mL) at −60° C. was added phenylmagnesium bromide (3 M, 48.3 mL, 1.2 eq) in a dropwise manner. The resulting mixture was and stirred at −60° C. for 1 h before it was warmed to 0° C. and stirred for 1 h. The reaction mixture was then quenched by addition of saturated aqueous NH.sub.4Cl (300 mL) at 0° C. The resulting biphasic mixture was extracted with EtOAc (3×150 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to obtain (R)—N—((S)-(4-bromo-3-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.17H.sub.19BrFNOS: 384.0; found: 383.9.

[1811] Step c: To a mixture of (R)—N—((S)-(4-bromo-3-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (45 g, 117 mmol, 1 eq) in dioxane (200 mL) at 0° C. was added HCl/dioxane (4 M, 500 mL). The resulting mixture was stirred at 0° C. for 2 h. The reaction mixture was then filtered, and the white solid was washed with petroleum ether (3×50 mL). The washed solid was then dried under reduced pressure. The residue obtained was triturated with 2-methoxy-2-methylpropane to obtain (S)-(4-bromo-3-fluorophenyl)(phenyl)methanaminium chloride. LC-MS (ESI): m/z: [M−NH.sub.2].sup.+ calculated for C.sub.13H.sub.11BrFN: 263.0; found: 263.0.

[1812] Step d: To a solution of (S)-(4-bromo-3-fluorophenyl)(phenyl)methanaminium chloride (20 g, 63.1 mmol, 1 eq), (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (17.6 g, 75.8 mmol, 1.2 eq) in CH.sub.3CN (300 mL) at −20° C. was added N-methylimidazole (NMI, 25.9 g, 315 mmol, 5 eq) and chloro-N,N,N,N-tetramethylformamidinium hexafluorophosphate (TCFH, 19.5 g, 69.4 mmol, 1.1 eq). The resulting mixture was then stirred at −20° C. for 1 h. The reaction mixture was then quenched by addition H.sub.2O (500 mL) at 20° C. and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to obtain tert-butyl (2S,4R)-2-(((S)-(4-bromo-3-fluorophenyl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.23H.sub.25BrF.sub.2N.sub.2O.sub.3: 495.1; found: 495.0.

[1813] Step e: To a solution of tert-butyl (2S,4R)-2-(((S)-(4-bromo-3-fluorophenyl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (5 g, 10.0 mmol, 1 eq) in dimethylacetamide (DME, 10 mL) at 25° C. under N.sub.2 was added 3-bromo-1,1-difluorocyclobutane (2.59 g, 15.1 mmol, 1.5 eq), nickel(II) chloride ethylene glycol dimethyl ether complex (NiCl.sub.2.glyme, 11.0 mg, 50.4 μmol, 0.005 eq), 4,4-di-tert-butyl-2,2-bipyridyl (dtbpy, 13.5 mg, 50.4 μmol, 0.005 eq), Na.sub.2CO.sub.3 (2.14 g, 20.1 mmol, 2 eq), tris(trimethylsilyl)silane (TTMSS, 2.51 g, 10.0 mmol, 3.11 mL, 1 eq) and (Ir[dF(CF.sub.3)ppy].sub.2(dtbpy))PF.sub.6 (113 mg, 100 μmol, 0.01 eq). The resulting mixture was stirred under N.sub.2 at 25° C. under 34 W blue LED for 16 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (2S,4R)-2-(((S)-(4-(3,3-difluorocyclobutyl)-3-fluorophenyl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.27H.sub.30F.sub.4N.sub.2O.sub.3: 507.2; found: 507.2.

[1814] Step f: To a mixture of tert-butyl (2S,4R)-2-(((S)-(4-(3,3-difluorocyclobutyl)-3-fluorophenyl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (2.5 g, 4.94 mmol, 1 eq) in dioxane (20 mL) at 0° C. was added HCl/dioxane (4 M, 20 mL), and the resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was then concentrated under reduced pressure, and the crude residue obtained was recrystallized from isopropanol (20 mL) to give (2S,4R)-2-(((S)-(4-(3,3-difluorocyclobutyl)-3-fluorophenyl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidin-1-ium chloride. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.22H.sub.22F.sub.4N.sub.2O: 407.2; found: 407.1.

[1815] Step g: To a solution of (2S,4R)-2-(((S)-(4-(3,3-difluorocyclobutyl)-3-fluorophenyl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidin-1-ium chloride (130 mg, 294 μmol, 1 eq) in DMF (1 mL) at 0° C. was added 2-(azetidine-1-carboxamido)acetic acid (68.6 mg, 352 μmol, 1.2 eq, HCl salt), N-methylmorpholine (NMM, 178 mg, 1.76 mmol, 6 eq) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P, 374 mg, 587 μmol, 50% purity, 2 eq). The resulting mixture was stirred at 0° C. for 2 h. The reaction mixture was then quenched by addition of H.sub.2O (10 mL). The resulting biphasic mixture was then extracted with EtOAc (3×10 mL). The combined organic layers were washed with saturated aqueous NaCl (3×10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give a mixture of (2S,4R)-1-((azetidine-1-carbonyl)glycyl)-N—((S)-(4-(3,3-difluorocyclobutyl)-3-fluorophenyl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide and (2S,4R)-1-((azetidine-1-carbonyl)glycyl)-N—((R)-(4-(3,3-difluorocyclobutyl)-3-fluorophenyl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide. This purified mixture was then separated using chiral SFC to give (2S,4R)-1-((azetidine-1-carbonyl)glycyl)-N—((S)-(4-(3,3-difluorocyclobutyl)-3-fluorophenyl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide (major isomer, Compound 544) and (2S,4R)-1-((azetidine-1-carbonyl)glycyl)-N—((R)-(4-(3,3-difluorocyclobutyl)-3-fluorophenyl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide (minor isomer, Compound 545).

[1816] Major isomer (Compound 544): .sup.1H NMR (3:1 rotamer ratio, asterisk denotes minor rotamer peaks, obscured peaks not reported, 400 MHz, DMSO-d6) δ 9.22 (d, J=8.1 Hz, OH), 8.85 (d, J=8.5 Hz, 1H), 7.42-7.21 (m, 7H), 7.18-7.04 (m, 3H), 6.40 (t, J=5.7 Hz, 1H), 6.28 (t, J=5.8 Hz, OH), 6.14-6.03 (m, 1H), 5.47-5.19 (m, 2H), 4.72 (t, J=8.1 Hz, OH), 4.52 (t, J=8.4 Hz, 1H), 4.02-3.58 (m, 11H), 3.55-3.43 (m, 1H), 3.05-2.90 (m, 2H), 2.83-2.64 (m, 2H), 2.48-2.36 (m, 1H), 2.18-2.05 (m, 3H), 2.04-1.83 (m, 1H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.28H.sub.30F.sub.4N.sub.4O.sub.3: 547.2; found 547.3.

[1817] Minor isomer (Compound 545): .sup.1H NMR (2.6:1 rotamer ratio, asterisk denotes minor rotamer peaks, obscured peaks not reported, 400 MHz, DMSO-d6) δ 9.22* (d, J=8.2 Hz, 1H), 8.89 (d, J=8.6 Hz, 1H), 7.41-7.08 (m, 7H), 6.38 (t, J=5.7 Hz, 1H), 6.28* (t, J=5.8 Hz, 1H), 6.14-6.03 (m, 1H), 5.48-5.20 (m, 1H), 4.72* (t, J=8.1 Hz, 1H), 4.53 (t, J=8.4 Hz, 1H), 4.01-3.70 (m, 5H), 3.69-3.59 (m, 1H), 3.55-3.43 (m, 1H), 3.05-2.90 (m, 2H), 2.83-2.67 (m, 2H), 2.46-2.35 (m, 1H), 2.18-2.06 (m, 2H), 2.07-1.85 (in, 1H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.28H.sub.30F.sub.4N.sub.4O.sub.3: 547.2; found 547.3.

[1818] The following compounds in Table T-10 were synthesized using procedures similar to Compounds 544 and 545 using the appropriate starting materials.

TABLE-US-00024 TABLE T-10 Com- Exact LCMS, pound mass Found No. Structure IUPAC (g/mol) [M + H].sup.+ 546 [01745] embedded image (2S,4R)-N-[(S)- [4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl) methyl]-4- fluoro-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 515.2 516.3 547 [01746] (2S,4R)-N-[(S)- [4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl) methyl]-1-{2- [(dimethylcarbamoyl) amino]acetyl}-4- fluoropyrrolidine- 2-carboxamide 534.2 535.2 548 [01747] embedded image (2S,4R)-N-[(R)- [4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl) methyl]-1-{2- [(dimethylcarbamoyl) amino]acetyl}-4- fluoropyrrolidine- 2-carboxamide 534.2 535.2 549 [01748] (2S,4R)-1-[2-(1H- 1,3-benzodiazol- 1-yl)acetyl]-N- [(S)-[4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl) methyl]-4- fluoropyrrolidine- 2-carboxamide 564.2 565.1 550 [01749] embedded image (2S,4R)-N-[(S)- [4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl) methyl]-4- fluoro-1-[2-(5- methyl-1,3- oxazol-2-yl) acetyl]pyrrolidine- 2-carboxamide 529.2 530.1 551 [01750] (2S,4R)-N-[(S)- [4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl) methyl]-4- fluoro-1-[2-(5- methyl-2,4-dioxo- 1,2,3,4- tetrahydropyrimidin-1- yl)acetyl]pyrrolidine- 2-carboxamide 572.2 488.3 552 [01751] embedded image (2S,4R)-N-[(S)- [4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl) methyl]-4- fluoro-1-[2-(1,3- oxazol-2- yl)acetyl]pyrrolidine- 2-carboxamide 515.2 516.4 553 [01752] (2S,4R)-N-[(S)- [4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl) methyl]-4- fluoro-1-{2-[4- (trifluoromethyl)- 1H-1,2,3-triazol-5- yl]acetyl}pyrrolidine- 2-carboxamide 583.2 584.2 554 [01753] embedded image (2S,4R)-N-[(S)- [4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl) methyl]-4- fluoro-1-[2-(4- methyl-1,3- oxazol-2- yl)acetyl]pyrrolidine- 2-carboxamide 529.2 530.2 555 [01754] (2S,4R)-N-[(S)- [4-(3,3- difluorocyclobutyl)-3- fluorophenyl](phenyl) methyl]-4- fluoro-1-{2-[4- (trifluoromethyl)- 1,3-oxazol-2- yl]acetyl}pyrrolidine- 2-carboxamide 583.2 584.1

Example S-11: Synthesis of (2S,4R)-4-fluoro-N—((S)-(3-fluoro-4-(1-methylcyclopropyl)phenyl)(phenyl)methyl)-1-(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)pyrrolidine-2-carboxamide and (2S,4R)-4-fluoro-N—((R)-(3-fluoro-4-(1-methylcyclopropyl)phenyl)(phenyl)methyl)-1-(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)pyrrolidine-2-carboxamide

Compounds 556 and 557

[1819] ##STR01755##

[1820] Step a: To a solution of methyl 4-bromo-3-fluoro-benzoate (25.0 g, 107 mmol, 1 eq) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (36.0 g, 214 mmol, 2 eq) in dioxane (200 mL) and H.sub.2O (10 mL) under N.sub.2 was added K.sub.2CO.sub.3 (44.4 g, 321 mmol, 3 eq) and Pd(dppf)Cl.sub.2 (3.15 g, 4.30 mmol, 0.04 eq). The reaction was then warmed to 100° C. and stirred for 16 h under N.sub.2. The reaction mixture was then cooled to 0° C. and quenched by addition H.sub.2O (100 mL). The resulting biphasic mixture was then extracted with EtOAc (3×100 mL). The combined organic extracts were washed with H.sub.2O (2×50 mL) and brine (2×50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 3-fluoro-4-(prop-1-en-2-yl)benzoate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.11FO.sub.2: 195.1; found: 195.1.

[1821] Step b: To a solution of ZnEt.sub.2 (1 M in hexane, 154 mL, 2.50 eq) in DCM (100 mL) at 0° C. was dropwise added TFA (18.3 g, 160 mmol, 2.61 eq) in DCM (30 ml) over 15 min. Diiodomethane (41.3 g, 154 mmol, 12.4 mL, 2.50 eq) in DCM (30 mL) was then dropwise added at 0° C. After 15 min, methyl 3-fluoro-4-(prop-1-en-2-yl)benzoate (12 g, 61.7 mmol, 1 eq) in DCM (30 mL) was added dropwise at 0° C. The reaction mixture was then allowed to warm to 20° C. and stirred for 16 h. The reaction was then poured into saturated aqueous NH.sub.4Cl (200 mL) at 0° C. and stirred for 10 min. The biphasic mixture was then extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 3-fluoro-4-(1-methylcyclopropyl)benzoate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.12H.sub.13FO.sub.2: 209.1; found: 209.1.

[1822] Step c: To a solution of methyl 3-fluoro-4-(1-methylcyclopropyl)benzoate (12 g, 46.1 mmol, 18.1 mL, 80% purity, 1 eq) in THF (100 mL) at 0° C. was added diisobutylaluminum hydride (DIBAL-H, 1 M in THF, 138 mL, 3 eq). The reaction was then allowed to warm to 20° C. and stirred for 2 h. The reaction mixture was then poured into saturated aqueous NH.sub.4Cl (100 mL) at 0° C. and stirred for 10 min. The biphasic mixture was then extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give (3-fluoro-4-(1-methylcyclopropyl)phenyl)methanol, which was carried into the next step without further purification. LC-MS (ESI): m/z: [M−H.sub.2O].sup.+ calculated for C.sub.11H.sub.13FO: 163.1; found: 163.1.

[1823] Step d: To a solution of (3-fluoro-4-(1-methylcyclopropyl)phenyl)methanol (8 g, 44.3 mmol, 1 eq) in DCM (150 mL) at 25° C. was added MnO.sub.2 (57.8 g, 665 mmol, 15 eq). The resulting mixture was warmed to 50° C. and stirred for 16 h. The reaction mixture was then poured into H.sub.2O (100 mL) at 0° C., and the resulting biphasic mixture was extracted with DCM (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 3-fluoro-4-(1-methylcyclopropyl)benzaldehyde, which was carried into the next step without further purification. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.11FO: 179.1; found: 179.1.

[1824] Step e: To a mixture of 3-fluoro-4-(1-methylcyclopropyl)benzaldehyde (10 g, 56.1 mmol, 1 eq) and (R)-2-methylpropane-2-sulfinamide (7.48 g, 61.7 mmol, 1.1 eq) in DCM (150 mL) at 25° C. was added Cs.sub.2CO.sub.3 (27.4 g, 84.1 mmol, 1.5 eq). The resulting mixture was warmed to 40° C. and stirred for 1 h. The reaction mixture was then poured into H.sub.2O (50 mL) at 0° C., and the resulting biphasic mixture was extracted with DCM (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (R,E)-N-(3-fluoro-4-(1-methylcyclopropyl)benzylidene)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.15H.sub.20FNOS: 282.1; found: 282.0.

[1825] Step f: To a solution of (R,E)-N-(3-fluoro-4-(1-methylcyclopropyl)benzylidene)-2-methylpropane-2-sulfinamide (13 g, 46.2 mmol, 1 eq) in DCM (150 mL) at −60° C. was added phenylmagnesium bromide (3 M, 18.4 mL, 1.2 eq) in a dropwise manner. The resulting mixture was stirred at −60° C. for 1 h. The reaction mixture was then allowed to warm to 0° C. and stirred for 1 h. The reaction mixture was then quenched by addition of saturated aqueous NH.sub.4Cl (100 mL) at 0° C., and the resulting biphasic mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (R)—N—((S)-(3-fluoro-4-(1-methylcyclopropyl)phenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.21H.sub.26FNOS: 360.2; found: 360.1.

[1826] Step g: To a mixture of (R)—N—((S)-(3-fluoro-4-(1-methylcyclopropyl)phenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (15 g, 41.7 mmol, 1 eq) in dioxane (100 mL) at 0° C. was added HCl/dioxane (4 M, 150 mL), and the resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was filtered and the filter cake was washed with petroleum ether (3×50 mL). The filter cake was then added to saturated aqueous NaHCO.sub.3 (200 mL) and stirred for 20 min. The resulting biphasic mixture was then extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure obtain (S)-(3-fluoro-4-(1-methylcyclopropyl)phenyl)(phenyl)methanamine. LC-MS (ESI): m/z: [M−NH.sub.2].sup.+ calculated for C.sub.17H.sub.18FN: 240.1; found: 240.0.

[1827] Step h: To a solution of (S)-(3-fluoro-4-(1-methylcyclopropyl)phenyl)(phenyl)methanamine (1.2 g, 4.70 mmol, 1 eq) and (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1.32 g, 5.64 mmol, 1.2 eq) in CH.sub.3CN (20 mL) at −20° C. was added N-methylimidazole (NMI, 1.93 g, 23.5 mmol, 1.87 mL, 5 eq) and chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH, 1.58 g, 5.64 mmol, 1.2 eq). The resulting mixture was stirred at −20° C. for 1 h. The reaction mixture was then warmed to 0° C. and quenched with H.sub.2O (50 mL). The resulting biphasic mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (2S,4R)-4-fluoro-2-(((S)-(3-fluoro-4-(1-methylcyclopropyl)phenyl)(phenyl)methyl)carbamoyl)pyrrolidine-1-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.27H.sub.32F.sub.2N.sub.2O.sub.3: 471.2; found: 471.1.

[1828] Step i: To a solution of tert-butyl (2S,4R)-4-fluoro-2-(((S)-(3-fluoro-4-(1-methylcyclopropyl)phenyl)(phenyl)methyl)carbamoyl)pyrrolidine-1-carboxylate (2 g, 4.25 mmol, 1 eq) in dioxane (10 mL) at 0° C. was added HCl/dioxane (4M, 20 mL). The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was then concentrated under reduced pressure to give (2S,4R)-4-fluoro-2-(((S)-(3-fluoro-4-(1-methylcyclopropyl)phenyl)(phenyl)methyl)carbamoyl)pyrrolidin-1-ium chloride. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.22H.sub.24F.sub.2N.sub.2O: 371.2; found: 371.1.

[1829] Step j: To a solution of (2S,4R)-4-fluoro-2-(((S)-(3-fluoro-4-(1-methylcyclopropyl)phenyl)(phenyl)methyl)carbamoyl)pyrrolidin-1-ium chloride (100 mg, 270 μmol, 1 eq) in DMF (1.00 mL) at 0° C. was added 2-(5-methyl-2,4-dioxo-pyrimidin-1-yl)acetic acid (64.6 mg, 351 μmol, 1.3 eq), N-methylmorpholine (NMM, 149 mg, 1.47 mmol, 6 eq) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P, 344 mg, 540 μmol, 50% purity, 2 eq), and the resulting mixture was stirred at 0° C. for 1 h. The reaction was then allowed to warm to 20° C. and for 15 h. The reaction mixture was then quenched by addition of H.sub.2O (10 mL), and the resulting biphasic mixture was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with saturated aqueous NaCl (2×10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained residue was purified by prep-HPLC to give (2S,4R)-4-fluoro-N—((S)-(3-fluoro-4-(1-methylcyclopropyl)phenyl)(phenyl)methyl)-1-(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)pyrrolidine-2-carboxamide (major isomer, Compound 556) and (2S,4R)-4-fluoro-N—((R)-(3-fluoro-4-(1-methylcyclopropyl)phenyl)(phenyl)methyl)-1-(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)pyrrolidine-2-carboxamide (minor isomer, compound 557).

[1830] Major isomer (Compound 556): .sup.1H NMR (3.1:1 rotamer ratio, asterisk denotes minor rotamer peaks, obscured peaks not reported, 400 MHz, DMSO-d6) δ 11.30 (br s, 1H), 9.26* (d, J=8.0 Hz, 1H), 8.86 (d, J=8.2 Hz, 1H), 7.38-7.20 (m, 7H), 7.11-7.02* (m, 2H), 7.02-6.93 (m, 2H), 6.10* (d, J=7.9 Hz, 1H), 6.01 (d, J=8.2 Hz, 1H), 5.52-5.22 (m, 1H), 4.77* (t, J=8.2 Hz, 1H), 4.66 (d, J=16.8 Hz, 1H), 4.58-4.41 (m, 2H), 4.06-3.89 (m, 1H), 3.82-3.65 (m, 1H), 3.53-3.36* (m, 1H), 2.82-2.68* (m, 1H), 2.27-2.09* (m, 1H), 2.09-1.88 (m, 1H), 1.78-1.70 (m, 3H), 1.31-1.25 (m, 3H), 0.77-0.63 (m, 4H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.29H.sub.30F.sub.2N.sub.4O.sub.4: 537.2; found 537.3.

[1831] Minor isomer (compound 557): .sup.1H NMR (3.3:1 rotamer ratio, asterisk denotes minor rotamer peaks, obscured peaks not reported, 400 MHz, DMSO-d6) δ 11.30 (br s, 1H), 9.27* (d, J=8.1 Hz, 1H), 8.89 (d, J=8.3 Hz, 1H), 7.41-7.20 (m, 6H), 7.17-6.94 (m, 2H), 6.11* (d, J=8.0 Hz, 1H), 6.01 (d, J=8.2 Hz, 1H), 5.54-5.21 (m, 1H), 4.77* (t, J=8.2 Hz, 1H), 4.68 (d, J=16.8 Hz, 1H), 4.54 (t, J=8.1 Hz, 1H), 4.45 (d, J=16.9 Hz, 1H), 4.05-3.86 (m, 1H), 3.83-3.65 (m, 1H), 3.53-3.36* (in, 1H), 2.25-1.87 (m, 1H), 1.78-1.70 (m, 3H), 1.30-1.21 (m, 3H), 0.75-0.62 (in, 4H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.29H.sub.30F.sub.2N.sub.4O.sub.4: 537.2; found 537.3.

[1832] The following compounds in Table T-11 were synthesized using procedures similar to Compounds 556 and 557 using the appropriate starting materials.

TABLE-US-00025 TABLE T-11 Com- Exact LCMS, pound mass Found No. Structure IUPAC (g/mol) [M + H].sup.+ 558 [01756] embedded image (2S,4R)-4-fluoro- N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl) phenyl](phenyl) methyl]-1-[2-(1H- 1,2,3-triazol-5-yl) acetyl]pyrrolidine- 2-carboxamide 479.2 480.2 559 [01757] (2S,4R)-4-fluoro- N-[(R)-[3-fluoro- 4-(1- methylcyclopropyl) phenyl](pyridin- 3-yl)methyl]-1-[2- (1H-1,2,3-triazol-5-yl) acetyl]pyrrolidine- 2-carboxamide 480.2 481.3 560 [01758] embedded image 2-[(2S,4R)-4- fluoro-2-{[(S)-[3- fluoro-4-(1- methylcyclopropyl) phenyl](phenyl) methyl]carbamoyl} pyrrolidin-1-yl]- 2-oxoethyl azetidine-1- carboxylate 511.2 512.3 561 [01759] (2S,4R)-4-fluoro- N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl) phenyl](phenyl) methyl]-1-[2-(1- methyl-1H-indol-2- yl)acetyl]pyrrolidine- 2-carboxamide 541.3 542.3 562 [01760] embedded image (2S,4R)-4-fluoro- N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl) phenyl](phenyl) methyl]-1-[2-(2- oxopiperazin-1- yl)acetyl]pyrrolidine- 2-carboxamide 510.2 511.3 563 [01761] (2S,4R)-4-fluoro- N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl) phenyl](phenyl) methyl]-1-[2-(1- methyl-1H-indol-3- yl)acetyl]pyrrolidine- 2-carboxamide 541.3 542.3 564 [01762] embedded image (2S,4R)-4-fluoro- N-[(S)-[3-fluoro-4-(1- methylcyclopropyl) phenyl](phenyl) methyl]-1-[2-(1- methyl-1H-indazol-3- yl)acetyl]pyrrolidine- 2-carboxamide 542.2 543.1 565 [01763] N-{2-[(2S,4R)-4- fluoro-2-{[(S)-[3- fluoro-4-(1- methylcyclopropyl) phenyl](phenyl) methyl]carbamoyl} pyrrolidin-1-yl]-2- oxoethyl}morpholine- 4-carboxamide 540.3 541.3 566 [01764] embedded image (2S,4R)-4-fluoro- N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl) phenyl](phenyl) methyl]-1-[2-(2- methyl-1H-1,3- benzodiazol-1-yl) acetyl]pyrrolidine- 2-carboxamide 542.2 543.3 567 [01765] (2S,4R)-1-[(2R) or (2S)-2-(1H-1,3- benzodiazol-1- yl)propanoyl]-4- fluoro-N-[(S)-[3- fluoro-4-(1- methylcyclopropyl) phenyl](phenyl) methyl]pyrrolidine- 2-carboxamide (column: DAICEL CHIRALPAK IG-3, first-eluting isomer) 542.2 543.3 568 [01766] embedded image (2S,4R)-4-fluoro- N-[(S)-[3-fluoro- 4-(1- methyl cyclopropyl) phenyl](phenyl) methyl]-1-[2-(3- methyl-2-oxo-2,3- dihydro-1H-1,3- benzodiazol-1- yl)acetyl]pyrrolidine- 2-carboxamide 558.2 559.3 569 [01767] (2S,4R)-4-fluoro- N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl) phenyl](phenyl) methyl]-1-[2-(3- methyl-2,4-dioxo- 1,2,3,4- tetrahydropyrimidin- 1-yl) acetyl]pyrrolidine- 2-carboxamide 536.2 537.2 570 [01768] embedded image (2S,4R)-4-fluoro- N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl) phenyl](phenyl) methyl]-1-[2-(2- oxo-2,3-dihydro- 1H-1,3- benzodiazol-1- yl)acetyl]pyrrolidine- 2-carboxamide 544.2 545.3 571 [01769] (2S,4R)-4-fluoro- N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl) phenyl](phenyl) methyl]-1-[2-(1H- indazol-3- yl)acetyl]pyrrolidine- 2-carboxamide 528.2 529.1 572 [01770] embedded image (2S,4R)-1-[2-(2,5- dioxopiperazin-1- yl)acetyl]-4- fluoro-N-[(S)-[3- fluoro-4-(1- methylcyclopropyl) phenyl](phenyl) methyl]pyrrolidine- 2-carboxamide 524.2 525.2 573 [01771] (2S,4R)-4-fluoro- N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl) phenyl](phenyl) methyl]-1-[2-(1- oxo-2,3-dihydro- 1H-isoindol-2- yl)acetyl]pyrrolidine- 2-carboxamide 543.2 544.1 574 [01772] embedded image (2S,4R)-1-[(2S) or 2R)-2-(1H-1,3- benzodiazol-1- yl)propanoyl]-4- fluoro-N-[(S)-[3- fluoro-4-(1- methylcyclopropyl) phenyl](phenyl) methyl]pyrrolidine- 2-carboxamide (column: DAICEL CHIRALPAK IG-3, second-eluting isomer) 542.2 543.3 575 [01773] (2S,4R)-1-[2-(1H- 1,2,3- benzotriazol-1- yl)acetyl]-4- fluoro-N-[(S)-[3- fluoro-4-(1- methylcyclopropyl) phenyl](phenyl) methyl]pyrrolidine- 2-carboxamide 529.2 530.1 576 [01774] embedded image (2S,4R)-4-fluoro- N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl) phenyl](phenyl) methyl]-1-[2-(2- oxo-2,3-dihydro- 1H-indol-1- yl)acetyl]pyrrolidine- 2-carboxamide 543.2 544.2 577 [01775] (2S,4R)-4-fluoro- N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl) phenyl](phenyl) methyl]-1-[2-(1- methyl-2-oxo-2,3- dihydro-1H-indol-3- yl)acetyl]pyrrolidine- 2-carboxamide 557.2 558.3 578 [01776] embedded image 2,2,2- trifluoroethyl 4- {2-[(2S,4R)-4- fluoro-2-{[(S)-[3- fluoro-4-(1- methylcyclopropyl) phenyl](phenyl) methyl]carbamoyl} pyrrolidin-1-yl]- 2-oxoethyl}-3- oxopiperazine-1- carboxylate 636.2 637.2 579 [01777] 2-[(2S,4R)-4- fluoro-2-{[(S)-[3- fluoro-4-(1- methylcyclopropyl) phenyl](phenyl) methyl]carbamoyl} pyrrolidin-1-yl]- 2-oxoethyl 4-(2- methoxyethyl) piperazine-1- carboxylate 598.3 599.2 580 [01778] embedded image (2S,4R)-4-fluoro- N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl) phenyl](phenyl) methyl]-1-{2-[2- oxo-4-(2,2,2- trifluoroethyl)piperazin- 1-yl]acetyl}pyrrolidine- 2-carboxamide 592.2 593.2 581 [01779] (2S,4R)-4-fluoro- N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl) phenyl](phenyl) methyl]-1-[2-(2- oxo-2,3-dihydro- 1H-indol-3- yl)acetyl]pyrrolidine- 2-carboxamide 543.2 544.2 582 [01780] embedded image (2S,4R)-4-fluoro- N-[(S)-[3-fluoro- 4-(1- methylcyclopropyl) phenyl](phenyl) methyl]-1-[2-(4H- 1,2,4-triazol-4- yl)acetyl]pyrrolidine- 2-carboxamide 479.2 480.3 583 [01781] 2-[(2S,4R)-4- fluoro-2-{[(S)-[3- fluoro-4-(1- methylcyclopropyl) phenyl](phenyl) methyl]carbamoyl} pyrrolidin-1-yl]- 2-oxoethyl 4- methylpiperazine- 1-carboxylate 554.3 555.3 584 [01782] embedded image 2-[(2S,4R)-4- fluoro-2-{[(S)-[3- fluoro-4-(1- methylcyclopropyl) phenyl](phenyl) methyl]carbamoyl} pyrrolidin-1-yl]- 2-oxoethyl 4- (cyclopropylmethyl) piperazine-1- carboxylate 594.3 595.3 585 [01783] 2-[(2S,4R)-4- fluoro-2-{[(S)-[3- fluoro-4-(1- methylcyclopropyl) phenyl](phenyl) methyl]carbamoyl} pyrrolidin-1-yl]- 2-oxoethyl 4- (2,2,2- trifluoroethyl) piperazine-1- carboxylate 622.3 623.3

Example S-12: Synthesis of (2S,4R)-1-((S) or (R)-2-(1H-benzo[d]imidazol-1-yl)propanoyl)-4-fluoro-N—((S)-(6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide and (2S,4R)-1-((R) or (S)-2-(1H-benzo[d]imidazol-1-yl)propanoyl)-4-fluoro-N—((S)-(6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide

Compounds 586 and 587

[1833] ##STR01784##

[1834] Step a: To a solution of 2-bromo-6-fluoropyridine (12.5 g, 71.0 mmol, 1.00 eq) in THF (125 mL) at −60° C. under N.sub.2 was added lithium diisopropylamide (LDA, 2 M in THF, 35.5 mL, 1.00 eq) in a dropwise manner. The resulting mixture was stirred at −60° C. for 0.5 h. Acetone (6.19 g, 106 mmol, 1.50 eq) was then added in a dropwise manner at −60° C. The resulting mixture was then stirred at −60° C. for 0.5 h. The reaction was then allowed to warm to 0° C., quenched by addition of H.sub.2O (60 mL), and stirred for 10 min. The resulting biphasic mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 2-(6-bromo-2-fluoropyridin-3-yl)propan-2-ol. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.9BrFNO: 234.0; found: 234.0.

[1835] Step b: To a solution of 2-(6-bromo-2-fluoropyridin-3-yl)propan-2-ol (13.5 g, 57.7 mmol, 1.00 eq) in toluene (135 mL) at 25° C. was added TsOH (1.99 g, 11.5 mmol, 0.20 eq) in a dropwise manner. The reaction mixture was the warmed to 125° C. and stirred for 16 h. The reaction mixture was then cooled to 0° C. and quenched by addition of H.sub.2O (50 mL). The resulting biphasic mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 6-bromo-2-fluoro-3-(prop-1-en-2-yl)pyridine. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.8H.sub.7BrFN: 216.0; found: 216.0.

[1836] Step c: To a solution of 6-bromo-2-fluoro-3-(prop-1-en-2-yl)pyridine (6.5 g, 30.1 mmol, 1.00 eq) in MeOH (65 mL) was added TEA (6.09 g, 60.17 mmol, 2.00 eq) and Pd(dppf)Cl.sub.2 (2.46 g, 3.01 mmol, 0.10 eq). The reaction mixture was then placed under an atmosphere of CO (50 psi), warmed to 60° C., and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 6-fluoro-5-(prop-1-en-2-yl)picolinate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.10FNO.sub.2: 196.1; found: 196.1.

[1837] Step d: To a solution of ZnEt.sub.2 (1 M in hexane, 102 mL, 5.00 eq) at 0° C. was added TFA (102 mmol, 7.6 mL, 5.00 eq) in DCM (24 mL) in a dropwise manner. The resulting mixture was stirred at 0° C. for 0.5 h. CH.sub.2I.sub.2 (27.4 g, 102 mmol, 5.00 eq) in DCM (22 mL) was then added in a dropwise manner at 0° C., and the resulting mixture was stirred at 0° C. for 0.5 h. Methyl 6-fluoro-5-(prop-1-en-2-yl)picolinate (4 g, 20 mmol, 1.00 eq) in DCM (12 mL) was then added in a dropwise manner at 0° C. The resulting mixture was then allowed to warm to 20° C. and stirred for 15 h. The reaction mixture was then quenched by addition of saturated aqueous NH.sub.4Cl (100 ml) at 0° C., and the resulting biphasic mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue was obtained was purified by column chromatography and prep-HPLC to give methyl 6-fluoro-5-(1-methylcyclopropyl)picolinate (2.56 g). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.11H.sub.12FNO.sub.2: 210.1; found: 210.1.

[1838] Step e: A solution of 6-fluoro-5-(1-methylcyclopropyl)picolinate (1.25 g, 5.97 mmol, 1 eq) in THF (12.5 mL) was degassed and purged with N.sub.2 and cooled to −65° C. To this solution was added diisobutylaluminium hydride (DIBAL-H, 1 M in THF, 11.9 mL, 2 eq) in a dropwise manner. The resulting mixture was stirred at −65° C. for 2 h. The reaction mixture was then warmed to 0° C. and quenched by addition water (50 mL). The resulting biphasic mixture was then filtered and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (2×50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 6-fluoro-5-(1-methylcyclopropyl)picolinaldehyde. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.10H.sub.10FNO: 180.1; found: 180.1.

[1839] Step f: To a mixture of 6-fluoro-5-(1-methylcyclopropyl)picolinaldehyde (0.8 g, 4.46 mmol, 1 eq) and 2-methylpropane-2-sulfinamide (1.08 g, 8.93 mmol, 2 eq) in THF (8 mL) at 25° C. under N.sub.2 was added Ti(Oi-Pr).sub.4 (2.54 g, 8.93 mmol, 2.64 mL, 2 eq). The resulting mixture was warmed to 80° C. and stirred for 2 h. The reaction mixture was then poured into ice-water (15 mL) and stirred for 10 min. The resulting biphasic mixture was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (2×30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (E)-N-((6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.14H.sub.19FN.sub.2OS: 283.1; found: 283.1.

[1840] Step g: To a solution of (E)-N-((6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.15 g, 4.07 mmol, 1 eq) in DCM (11.5 mL) at −60° C. was added phenylmagnesium bromide (3 M in diethyl ether, 2.04 mL, 1.5 eq) in a dropwise manner. The resulting mixture was stirred at −60° C. for 1 h before it was warmed to 10° C. and stirred for 1 h. The reaction mixture was then poured into saturated aqueous NH.sub.4Cl (30 mL) and stirred for 10 min. The resulting biphasic mixture was then extracted with DCM (2×50 mL). The combined organic extracts were washed with brine (2×30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give N-((6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.20H.sub.25FN.sub.2OS: 361.2; found: 361.2.

[1841] Step h: To a solution of N-((6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (1.45 g, 4.02 mmol, 1 eq) in dioxane (3 mL) at 0° C. was added HCl/dioxane (4 M, 6.44 mL, 6.41 eq), and the resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was then concentrated under reduced pressure. The crude residue was then triturated with methyl tert-butyl ether (10 mL) at 25° C. for 10 min and filtered. The filter cake was dried under reduced pressure to give (6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl)(phenyl)methanaminium chloride. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.16H.sub.17FN.sub.2: 257.1; found: 257.2.

[1842] Step i: To a mixture of (6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl)(phenyl)methanaminium chloride (1.20 g, 4.1 mmol, 1 eq) and (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1.15 g, 4.92 mmol, 1.2 eq) in DCM (20 mL) at 25° C. under N.sub.2 was added N-methylmorpholine (NMM, 1.24 g, 12.3 mmol, 1.35 mL, 3 eq). The resulting mixture was cooled to −20° C. before 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P, 5.22 g, 8.20 mmol, 4.88 mL, 50% purity, 2 eq) was added in a dropwise manner. The resulting mixture was stirred at −20° C. for 1 h before the reaction mixture was poured into ice-water (15 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (3×15 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (2S,4R)-4-fluoro-2-(((6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl)(phenyl)methyl)carbamoyl)pyrrolidine-1-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.26H.sub.31F.sub.2N.sub.3O.sub.3: 472.2; found: 472.2.

[1843] Step j: To a solution of tert-butyl (2S,4R)-4-fluoro-2-(((6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl)(phenyl)methyl)carbamoyl)pyrrolidine-1-carboxylate (3.8 g, 8.06 mmol, 1 eq) in dioxane (20 mL) at 0° C. was added HCl/dioxane (4 M, 20 mL). The resulting mixture was then stirred at 0° C. for 1 h. The reaction mixture was then concentrated under reduced pressure. The crude product was added diluted with saturated aqueous NaHCO.sub.3, and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (2×30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by SFC (column: REGIS(S,S)WHELK-O1) to give (2S,4R)-4-fluoro-N—((S)-(6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide and (2S,4R)-4-fluoro-N—((R)-(6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide as separate diastereomers. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.21H.sub.23F.sub.2N.sub.3O: 372.2; found: 372.2.

[1844] Step k: To a mixture of 2-(1H-benzo[d]imidazol-1-yl)propanoic acid (80.0 mg, 421 μmol, 1.00 eq) and (2S,4R)-4-fluoro-N—((S)-(6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide (156 mg, 421 μmol, 1.00 eq) in DCM (2 mL) at −20° C. under N.sub.2 was added N-methylmorpholine (NMM, 421 μmol, 46.2 μL, 1.00 eq) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P, 841 μmol, 500 μL, 50% purity, 2.00 eq). The resulting mixture was warmed to 0° C. and stirred for 1 h. The reaction was then quenched by addition H.sub.2O (10 mL) at 0° C. The resulting biphasic mixture was then extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC followed by SCF (column: REGIS (R,R)WHELK-O1) to give (2S,4R)-1-((R) or (S)-2-(1H-benzo[d]imidazol-1-yl)propanoyl)-4-fluoro-N—((S)-(6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide (Compound 587; first-eluting isomer) and (2S,4R)-1-((S) or (R)-2-(1H-benzo[d]imidazol-1-yl)propanoyl)-4-fluoro-N—((S)-(6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide (Compound 586; second-eluting isomer).

[1845] First-eluting isomer (Compound 587): .sup.1H NMR (4:1 rotamer ratio, asterisk denotes minor rotamer peaks, obscured peaks not reported, 400 MHz, DMSO-d6) δ 9.61* (d, J=8.3 Hz, 1H), 8.94 (d, J=7.8 Hz, 1H), 8.25 (s, 1H), 7.90-7.81* (m, 1H), 7.81-7.70 (m, 1H), 7.70-7.55 (m, 2H), 7.52-7.42 (m, 1H), 7.39-7.11 (m, 7H), 6.19* (d, J=8.0 Hz, 1H), 5.95 (d, J=7.7 Hz, 1H), 5.72-5.66 (m, 1H), 5.43-5.17 (m, 1H), 5.12-5.02* (m, 1H), 4.71 (t, J=8.4 Hz, 1H), 4.09-3.97 (m, 1H), 2.03-1.79 (m, 2H), 1.59-1.53 (m, 3H), 1.32-1.22 (m, 3H), 0.83-0.62 (m, 4H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.31H.sub.31F.sub.2N.sub.5O.sub.2: 544.2; found 544.2.

[1846] Second-eluting isomer (Compound 586): .sup.1H NMR (4.4:1 rotamer ratio, asterisk denotes minor rotamer peaks, obscured peaks not reported, 400 MHz, DMSO-d6) δ 9.55* (d, J=8.0 Hz, 1H), 8.90 (d, J=8.0 Hz, 1H), 8.34 (s, 1H), 8.23* (s, 1H), 7.84 (dd, J=10.1, 7.5 Hz, 1H), 7.69-7.62 (m, 1H), 7.57* (d, J=8.0 Hz, 1H), 7.52-7.43 (m, 1H), 7.39-7.15 (m, 7H), 7.14-7.07* (m, 1H), 6.95* (d, J=4.1 Hz, 1H), 6.17* (d, J=8.0 Hz, 1H), 6.00 (d, J=7.9 Hz, 1H), 5.70 (q, J=7.0 Hz, 1H), 5.54-5.24 (m, 1H), 5.08* (t, J=7.9 Hz, 1H), 4.88* (q, J=7.1 Hz, 1H), 4.62 (t, J=8.4 Hz, 1H), 4.27 (dd, J=20.4, 12.6 Hz, 1H), 3.97-3.74 (m, 1H), 3.57-3.39* (m, 1H), 2.87-2.71* (m, 1H), 2.14-1.92 (m, 1H), 1.79-1.68 (m, 3H), 1.30-1.26 (m, 3H), 0.81-0.67 (m, 4H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.31H.sub.31F.sub.2N.sub.5O.sub.2: 544.2; found 544.2.

[1847] The following compounds in Table T-12 were synthesized using procedures similar to Compound 586 and Compound 587 using the appropriate starting materials.

TABLE-US-00026 TABLE T-12 Com- Exact LCMS, pound mass Found No. Structure IUPAC (g/mol) [M + H].sup.+ 588 [01785] embedded image (2S,4R)-4-fluoro- N-[(S)-[6-fluoro- 5-(1- methylcyclopropyl) pyridin-2-yl] (phenyl)methyl]-1- [2-(1H-indazol-3- yl)acetyl]pyrrolidine- 2-carboxamide 529.2 530.3 589 [01786] N-{2-[(2S,4R)-4- fluoro-2-{[(S)-[6- fluoro-5-(1- methylcyclopropyl) pyridin-2- yl](phenyl)methyl] carbamoyl}pyrrolidin- 1-yl]-2-oxoethyl} morpholine-4- carboxamide 541.3 542.3 590 [01787] embedded image (2S,4R)-4-fluoro- N-[(R)-[6-fluoro- 5-(1- methylcyclopropyl) pyridin-2- yl](phenyl)methyl]- 1-[2-(1H-indazol-3- yl)acetyl]pyrrolidine- 2-carboxamide 529.2 530.3 591 [01788] (2S,4R)-4-fluoro- N-[(S)-[6-fluoro- 5-(1- methylcyclopropyl) pyridin-2- yl](phenyl)methyl]- 1-[2-(1-methyl- 1H-indol-2- yl)acetyl]pyrrolidine- 2-carboxamide 542.2 543.2 592 [01789] embedded image (2S,4R)-4-fluoro- N-[(S)-[6-fluoro- 5-(1- methylcyclopropyl) pyridin-2- yl](phenyl)methyl]- 1-[2-(1-methyl- 1H-indol-3- yl)acetyl]pyrrolidine- 2-carboxamide 542.2 543.2 593 [01790] (2S,4R)-4-fluoro- N-[(S)-[6-fluoro- 5-(1- methylcyclopropyl) pyridin-2- yl](phenyl)methyl]- 1-[2-(2-methyl- 1H-1,3- benzodiazol-1- yl)acetyl]pyrrolidine- 2-carboxamide 543.2 544.3 594 [01791] embedded image (2S,4R)-1-[2-(1H- 1,2,3- benzotriazol-1- yl)acetyl]-4- fluoro-N-[(S)-[6- fluoro-5-(1- methylcyclopropyl) pyridin-2- yl](phenyl)methyl] pyrrolidine-2- carboxamide 530.2 531.3 595 [01792] (2S,4R)-1-[2-(1H- 1,3-benzodiazol- 1-yl)acetyl]-4- fluoro-N-[(S)-[6- fluoro-5-(1- methylcyclopropyl) pyridin-2- yl](phenyl)methyl] pyrrolidine-2- carboxamide 529.2 530.2 596 [01793] embedded image (2S,4R)-4-fluoro- N-[(S)-[6-fluoro- 5-(1- methylcyclopropyl) pyridin-2- yl](phenyl)methyl]- 1-[2-(1-methyl- 1H-indazol-3- yl)acetyl]pyrrolidine- 2-carboxamide 543.2 544.2 597 [01794] (2S,4R)-4-fluoro- N-[(S)-[6-fluoro- 5-(1- methylcyclopropyl) pyridin-2- yl](phenyl)methyl]- 1-[2-(1-methyl- 2-oxo-2,3- dihydro-1H-indol-3- yl)acetyl]pyrrolidine- 2-carboxamide 558.2 559.2 598 [01795] embedded image (2S,4R)-4-fluoro- N-[(S)-[6-fluoro- 5-(1- methylcyclopropyl) pyridin-2- yl](phenyl)methyl]- 1-[2-(1H-indol-2- yl)acetyl]pyrrolidine- 2-carboxamide 528.2 529.2 599 [01796] (2S,4R)-4-fluoro- N-[(S)-[6-fluoro- 5-(1- methylcyclopropyl) pyridin-2- yl](phenyl)methyl]- 1-[2-(2-oxo-2,3- dihydro-1H-1,3- benzodiazol-1- yl)acetyl]pyrrolidine- 2-carboxamide 545.2 546.2 600 [01797] embedded image (2S,4R)-4-fluoro- N-[(S)-[6-fluoro- 5-(1- methylcyclopropyl) pyridin-2- yl](phenyl)methyl]- 1-[2-(3-methyl- 2-oxo-2,3- dihydro-1H-1,3- benzodiazol-1- yl)acetyl]pyrrolidine- 2-carboxamide 559.2 560.2 601 [01798] tert-butyl 2-{2- [(2S,4R)-4-fluoro- 2-{[(S)-[6-fluoro- 5-(1- methylcyclopropyl) pyridin-2- yl](phenyl)methyl] carbamoyl}pyrrolidin- 1-yl]-2-oxoethyl}-1H- indole-1- carboxylate 628.3 629.3

##STR01799##

[1848] Step a: To a mixture of 5-isopropyl-4-methylpicolinaldehyde (3 g, 18.4 mmol, 1 eq) and (R)-2-methylpropane-2-sulfinamide (2.90 g, 23.9 mmol, 1.3 eq) in THF (5 mL) at 25° C. under N.sub.2 was added Ti(Oi-Pr).sub.4 (10.4 g, 36.7 mmol, 2 eq). The resulting mixture was warmed to 80° C. and stirred for 1 h. The reaction mixture was then quenched with H.sub.2O (30 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (R,E)-N-((5-isopropyl-4-methylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.14H.sub.22N.sub.2OS: 267.1; found: 267.1.

[1849] Step b: To a mixture of (R,E)-N-((5-isopropyl-4-methylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (850 mg, 3.19 mmol, 1 eq) in DCM (5 mL) at 0° C. under N.sub.2 was added PhLi (1 M in Et.sub.2O, 8.0 mL, 2.5 eq). The resulting mixture was warmed to 25° C. and stirred for 16 h. The reaction mixture was then quenched with aq. NH.sub.4Cl solution (10 mL), and the resulting biphasic mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give (R)—N—((S)-(5-isopropyl-4-methylpyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.20H.sub.28N.sub.2OS: 345.2; found: 345.1.

[1850] Step c: To a solution of (R)—N—((S)-(5-isopropyl-4-methylpyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (75 mg, 217 μmol, 1 eq) in EtOAc (2 mL) at 0° C. was added HCl/EtOAc (4 M, 5 mL), and the resulting mixture was warmed to 25° C. and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure to give (S)-(5-isopropyl-4-methylpyridin-2-yl)(phenyl)methanaminium chloride. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.16H.sub.20N.sub.2: 241.2; found: 241.1.

[1851] Step d: To a mixture of (S)-(5-isopropyl-4-methylpyridin-2-yl)(phenyl)methanaminium chloride (65 mg, 234 μmol, 1 eq) and (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (71.2 mg, 305 μmol, 1.3 eq) in MeCN (3 mL) at −20° C. under N.sub.2 was added N-methylimidazole (57.8 mg, 704 μmol, 56.1 μL, 3 eq) and chloro-N,N,N,N-tetramethylformamidinium hexafluorophosphate (TCFH, 85.7 mg, 305 μmol, 1.3 eq), and the resulting mixture was warmed to 0° C. and stirred for 1 h. The reaction mixture was then quenched with H.sub.2O (10 mL), and the resulting biphasic mixture was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-TLC to give tert-butyl (2S,4R)-4-fluoro-2-(((S)-(5-isopropyl-4-methylpyridin-2-yl)(phenyl)methyl)carbamoyl)pyrrolidine-1-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.26H.sub.34FN.sub.3O.sub.3: 456.3; found: 456.1.

[1852] Step e: To a solution of tert-butyl (2S,4R)-4-fluoro-2-(((S)-(5-isopropyl-4-methylpyridin-2-yl)(phenyl)methyl)carbamoyl)pyrrolidine-1-carboxylate (35 mg, 76.8 μmol, 1 eq) in EtOAc (2 mL) at 25° C. under N.sub.2 was added HCl/EtOAc (4 M, 2 mL). The resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was then concentrated under reduced pressure to give (2S,4R)-4-fluoro-2-(((S)-(5-isopropyl-4-methylpyridin-2-yl)(phenyl)methyl)carbamoyl)pyrrolidin-1-ium chloride. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.21H.sub.26FN.sub.3O: 356.2; found: 356.1.

[1853] Step f: To a mixture of (2S,4R)-4-fluoro-2-(((S)-(5-isopropyl-4-methylpyridin-2-yl)(phenyl)methyl)carbamoyl)pyrrolidin-1-ium chloride (45.3 mg, 127 μmol, 1 eq) and 2-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)acetic acid (34.1 mg, 191 μmol, 1.5 eq) in MeCN (3 mL) at −20° C. under N.sub.2 was added chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH, 53.7 mg, 191 μmol, 1.5 eq) and N-methylimidazole (31.4 mg, 382 μmol, 3 eq). The resulting mixture was warmed to 0° C. and stirred for 1 h. The reaction mixture was then diluted with H.sub.2O (10 mL), and the resulting biphasic mixture was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give (2S,4R)-1-(2-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)acetyl)-4-fluoro-N—((S)-(5-isopropyl-4-methylpyridin-2-yl)(phenyl)methyl)pyrrolidine-2-carboxamide. .sup.1H NMR (4.7:1 rotamer ratio, asterisk denotes distinct minor rotamer peaks, obscured peaks not reported, 400 MHz, methanol-d4) δ 8.39* (s, 1H), 8.32 (s, 1H), 7.38-7.19 (m, 5H), 7.16-7.12 (m, 1H), 7.09* (s, 1H), 7.01* (s, 1H), 6.15* (s, 1H), 6.11 (s, 1H), 5.48-5.20 (m, 1H), 4.74-4.67 (m, 1H), 4.23* (s, 1H), 4.16-4.03 (m, 1H), 3.99-3.81 (m, 1H), 3.24-3.13 (m, 1H), 2.70-2.56 (m, 1H), 2.37-2.32 (m, 3H), 2.28-2.07 (m, 1H), 1.32-1.25 (m, 6H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.26H.sub.28F.sub.3N.sub.5O.sub.3: 516.2; found 516.2.

[1854] The following compounds in Table T-13 were synthesized using procedures similar to Compound 602 using the appropriate starting materials.

TABLE-US-00027 TABLE T-13 Com- Exact LCMS, pound mass Found No. Structure IUPAC (g/mol) [M + H].sup.+ 603 [01800] embedded image (2S,4R)-1-acetyl- N-[(S) or (R)-(5- cyclobutylpyridin- 2-yl) (phenyl)methyl]-4- fluoropyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 395.2 396.2 604 [01801] (2S,4R)-4-fluoro- N-[(S) or (R)-[4- methyl-5-(propan- 2-yl)pyridin-2- yl](phenyl)methyl]- 1-[2-(1H-1,2,3- triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 464.2 465.2 605 [01802] embedded image (2S,4R)-4-fluoro- N-[(S) or (R)-[4- fluoro-5-(propan- 2-yl)pyridin-2-yl] (phenyl)methyl]- 1-[2-(1H-1,2,3- triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 468.2 469.1 606 [01803] (2S,4R)-N-[(S) or (R)-[4- (difluoromethyl)- 5-(propan-2- yl)pyridin-2- yl](phenyl)methyl]- 4-fluoro-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 500.2 501.2 607 [01804] embedded image (2S,4R)-4-fluoro- N-[(S) or (R)-[6- methyl-5-(propan- 2-yl)pyridin-2- yl](phenyl)methyl]- 1-[2-(1H-1,2,3- triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 464.2 465.2 608 [01805] (2S,4R)-4-fluoro- N-[(S) or (R)- phenyl[5-(propan- 2-yl)-4- (trifluoromethyl) pyridin-2- yl]methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 518.2 519.2 609 [01806] embedded image (2S,4R)-1-{2-[5- (difluoromethyl)- 1,3,4-oxadiazol-2- yl]acetyl}-4- fluoro-N-[(S) or (R)-[6-methyl-5- (propan-2- yl)pyridin-2- yl](phenyl)methyl] pyrrolidine-2- carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 515.2 516.2 610 [01807] (2S,4R)-N-[(S) or (R)-(5- cyclobutylpyridin-2- yl)(phenyl)methyl]- 4-fluoro-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 462.2 463.2 611 [01808] embedded image (2S,4R)-N-[(S) or (R)-(5-tert- butylpyridin-2- yl)(phenyl)methyl]- 4-fluoro-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 464.2 465.1 612 [01809] (2S,4R)-4-fluoro- N-[(S) or (R)-[6- methoxy-5- (propan-2- yl)pyridin-2-yl] (phenyl)methyl]- 1-[2-(1H-1,2,3- triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 480.2 481.1

Example S-14: Synthesis of (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-N—((R)-(2-aminopyridin-3-yl)(3-fluoro-4-isopropylphenyl)methyl)-4-fluoropyrrolidine-2-carboxamide

Compound 613

[1855] ##STR01810##

[1856] Step a: To a solution of 3-iodopyridin-2-amine (9.00 g, 40.9 mmol, 1 eq) in DCM (200 mL) was added TEA (102 mmol, 14.2 mL, 2.5 eq) and Boc.sub.2O (49.1 mmol, 11.3 mL, 1.2 eq), DMAP (500 mg, 4.09 mmol, 0.1 eq). The resulting mixture was stirred at 25° C. for 15 h. The reaction mixture was then cooled to 0° C. and quenched by addition of water (100 mL), and the resulting biphasic mixture was adjusted to pH=6 using aq. HCl solution (4 N). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (2×100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was triturated with petroleum ether to give tert-butyl (tert-butoxycarbonyl)(3-iodopyridin-2-yl)carbamate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.15H.sub.21IN.sub.2O.sub.4: 421.0; found 421.1.

[1857] Step b: To a solution of tert-butyl (tert-butoxycarbonyl)(3-iodopyridin-2-yl)carbamate (15.0 g, 35.7 mmol, 1 eq) in DCM (100 mL) was added bis(trifluoromethylsulfonyloxy)copper (12.9 g, 35.7 mmol, 1 eq). The resulting mixture was stirred at 25° C. for 20 min. The reaction mixture was then cooled to 0° C. and quenched by addition of water (100 mL). The resulting biphasic mixture was then extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine (2×100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give tert-butyl (3-iodopyridin-2-yl)carbamate, which was carried forward to the next step without further purification or characterization.

[1858] Step c: To a solution of tert-butyl (3-iodopyridin-2-yl)carbamate (7.13 g, 22.3 mmol, 3 eq) in THF (45 mL) at 0° C. was added i-PrMgCl.LiCl (1.3 M in THF, 28.6 mL, 5 eq), and the resulting mixture was stirred at 0° C. for 2 h. Then, (E)-N-(3-fluoro-4-isopropylbenzylidene)-2-methylpropane-2-sulfinamide (2 g, 7.42 mmol, 1 eq) in THF (0.5 mL) was added dropwise. The resulting mixture was allowed to warm to 25° C. and stirred for 2 h. The reaction mixture was then cooled to 0° C. and quenched by addition of saturated aq. NH.sub.4Cl solution (50 mL). The resulting biphasic mixture was then extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (2×50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (3-(((tert-butylsulfinyl)amino)(3-fluoro-4-isopropylphenyl)methyl)pyridin-2-yl)carbamate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.24H.sub.34FN.sub.3O.sub.3S: 464.2; found 464.1.

[1859] Step d: To a solution of tert-butyl (3-(((tert-butylsulfinyl)amino)(3-fluoro-4-isopropylphenyl)methyl)pyridin-2-yl)carbamate (3.3 g, 7.12 mmol, 1 eq) in THF (25 mL) and H.sub.2O (5 mL) was added I2 (4.52 g, 17.8 mmol, 2.5 eq). The resulting mixture was warmed to 50° C. and stirred for 1 h. The reaction mixture was then cooled to 0° C. and quenched by addition of saturated aq. Na.sub.2S203 solution (30 mL), and the resulting biphasic mixture was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (2×50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give tert-butyl (3-(amino(3-fluoro-4-isopropylphenyl)methyl)pyridin-2-yl)carbamate, which was carried forward to the next step without further purification. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.20H.sub.26FN.sub.3O.sub.2: 360.2; found 360.1.

[1860] Step e: To a solution of tert-butyl (3-(amino(3-fluoro-4-isopropylphenyl)methyl)pyridin-2-yl)carbamate (2.4 g, 6.68 mmol, 1 eq) and (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1.87 g, 8.01 mmol, 1.2 eq) in MeCN (25 mL) at −20° C. was added N-methylimidazole (NMI, 2.74 g, 33.4 mmol, 2.6 mL, 5 eq) and chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH, 2.06 g, 7.34 mmol, 1.1 eq). The resulting mixture was stirred at −20° C. for 0.5 h. The reaction mixture was then warmed to 0° C. and quenched by addition of water (20 mL), and the resulting biphasic mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (2×50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (2S,4R)-2-(((R)-(2-((tert-butoxycarbonyl)amino)pyridin-3-yl)(3-fluoro-4-isopropylphenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (first-eluting isomer) and tert-butyl (2S,4R)-2-(((S)-(2-((tert-butoxycarbonyl)amino)pyridin-3-yl)(3-fluoro-4-isopropylphenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (second-eluting isomer) as separate diastereomers that were carried forward individually. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.30H.sub.40F.sub.2N.sub.4O.sub.5: 575.3; found 575.2.

[1861] Step f: To a solution of tert-butyl (2S,4R)-2-(((R)-(2-((tert-butoxycarbonyl)amino)pyridin-3-yl)(3-fluoro-4-isopropylphenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (700 mg, 1.22 mmol, 1 eq) in EtOAc (10 mL) was added HCl/EtOAc (4 M, 20 mL). The resulting mixture was stirred at 25° C. for 15 h. The reaction mixture was then concentrated under reduced pressure to give (2S,4R)-2-(((R)-(2-aminopyridin-3-yl)(3-fluoro-4-isopropylphenyl)methyl)carbamoyl)-4-fluoropyrrolidin-1-ium chloride, which was carried forward to the next step without additional purification. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.20H.sub.24F.sub.2N.sub.4O: 375.2; found 375.1.

[1862] Step g: To a solution of (2S,4R)-2-(((R)-(2-aminopyridin-3-yl)(3-fluoro-4-isopropylphenyl)methyl)carbamoyl)-4-fluoropyrrolidin-1-ium chloride (200 mg, 487 μmol, 1 eq) and 2-(1H-1,2,3-triazol-5-yl)acetic acid (61.9 mg, 487 μmol, 1 eq) in DCM (5 mL) and DMF (0.5 mL) at −20° C. was added N-methylimidazole (NMI, 400 mg, 4.87 mmol, 10 eq) and T3P (633 μmol, 370 μL, 50% purity, 1.3 eq). The resulting mixture was stirred at −20° C. for 1 h. The reaction mixture was then warmed to 0° C. and quenched by addition of water (10 mL), and the resulting biphasic mixture was extracted with EtOAc (2×15 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-N—((R)-(2-aminopyridin-3-yl)(3-fluoro-4-isopropylphenyl)methyl)-4-fluoropyrrolidine-2-carboxamide. .sup.1H NMR (4.3:1 rotamer ratio, asterisk denotes distinct minor rotamer peaks, obscured peaks not reported, 400 MHz, DMSO-d6) δ 14.69 (br s, 1H), 9.16* (d, J=8.1 Hz, 1H), 8.87 (d, J=8.1 Hz, 1H), 7.90-7.83 (m, 1H), 7.65 (br s, 1H), 7.37-7.24 (m, 1H), 7.18-6.93 (m, 3H), 6.55-6.44 (m, 1H), 6.12* (d, J=8.1 Hz, 1H), 5.94 (d, J=7.9 Hz, 1H), 5.77* (s, 2H), 5.62 (s, 2H), 5.49-5.19 (m, 1H), 4.83-4.73* (m, 1H), 4.48 (t, J=8.5 Hz, 1H), 4.09-3.96 (m, 1H), 3.88-3.67 (m, 2H), 3.19-3.09 (m, 1H), 2.09-1.86 (m, 1H), 1.20 (d, J=6.9 Hz, 6H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.24H.sub.27F.sub.2N.sub.7O.sub.2: 484.2; found 484.1.

[1863] The following compounds in Table T-14 were synthesized using procedures similar to Compound 613 using the appropriate starting materials.

TABLE-US-00028 TABLE T-14 Com- Exact LCMS, pound mass Found No. Structure IUPAC (g/mol) [M + H].sup.+ 614 [01811] embedded image (2S,4R)-1-acetyl- 4-fluoro-N-[(S)- [4-(propan-2- yl)phenyl](1H- pyrazol-5-yl) methyl]pyrrolidine- 2-carboxamide 372.2 373.2 615 [01812] (2S)-N-[(R) or (S)-(4- cyclopropyl-3- fluorophenyl)(1H- pyrazol-5- yl)methyl]-1-(2- acetamidoacetyl) pyrrolidine-2- carboxamide (column: REGIS (s,s) WHELK-O1, second-eluting isomer) 427.2 428.1 616 [01813] embedded image (2S,4R)-4-fluoro- N-[(R) or (S)-[3- fluoro-4-(propan- 2-yl)phenyl](5- fluoropyridin-2- yl)methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 486.2 487.1 617 [01814] (2S,4R)-4-fluoro- N-[(R) or (S)-[3- fluoro-4-(propan- 2-yl)phenyl](5- fluoropyridin-3- yl)methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 486.2 487.1 618 [01815] embedded image (2S,4R)-N-[(S) or (R)-(2- aminopyridin-4- yl)[3-fluoro-4- (propan-2- yl)phenyl]methyl]- 4-fluoro-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 483.2 484.1 619 [01816] (2S,4R)-4-fluoro- N-[(R) or (S)-[3- fluoro-4-(propan- 2-yl)phenyl](3- fluoropyridin-4- yl)methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 486.2 487.1 620 [01817] embedded image (2S,4R)-N-[(R) or (S)-(6- aminopyridin-3- yl)[3-fluoro-4- (propan-2- yl)phenyl]methyl]- 4-fluoro-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: DAICEL CHIRALPAK IG-3, first-eluting isomer) 483.2 484.1 621 [01818] (2S,4R)-N-[(R) or (S)-(6- aminopyridin-2- yl)[3-fluoro-4- (propan-2- yl)phenyl]methyl]- 4-fluoro-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, second-eluting isomer) 483.2 484.1 622 [01819] embedded image (2S,4R)-N-[(R) or (S)-(2- aminopyridin-3- yl)[3-methyl-4- (propan-2- yl)phenyl]methyl]- 1-{2- [(dimethylcarbamoyl) amino]acetyl}-4- fluoropyrrolidine- 2-carboxamide (column: Waters Xbridge BEH C18, second- eluting isomer) 498.3 499.2 623 [01820] (2S,4R)-4-fluoro- N-[(R) or (S)-[3- fluoro-4-(propan- 2-yl)phenyl](1H- pyrazol-5- yl)methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, second-eluting isomer) 457.2 458.1 624 [01821] embedded image (2S,4R)-N-[(R) or (S)-(2- aminopyridin-3- yl)[3-methyl-4- (propan-2- yl)phenyl]methyl]- 4-fluoro-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: Lux Cellulose-2, second-eluting isomer) 479.2 480.1 625 [01822] (2S,4R)-N-[(R) or (S)-(2- aminopyridin-3- yl)[3-methyl-4- (propan-2- yl)phenyl]methyl]- 4-fluoro-1-[2- (1,3,5-trimethyl- 1H-pyrazol-4- yl)acetyl]pyrrolidine- 2-carboxamide (column: DAICEL CHIRALPAK AD-3, first-eluting isomer) 520.3 521.2 626 [01823] embedded image (2S,4R)-4-fluoro- N-[(R) or (S)-[3- fluoro-4-(1- methylcyclopropyl) phenyl](2- methoxypyridin- 3-yl)methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: DAICEL CHIRALPAK AD-3, second- eluting isomer) 510.2 511.3 627 [01824] (2S,4R)-4-fluoro- N-[(R) or (S)-[3- fluoro-4-(1- methylcyclopropyl) phenyl](2- methylpyridin-3- yl)methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 494.2 495.2 628 [01825] embedded image (2S,4R)-4-fluoro- N-[(R) or (S)-[6- fluoro-5-(propan- 2-yl)pyridin-2- yl]({imidazo[1,5- a]pyridin-3- yl})methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: DAICEL CHIRALPAK AD-3, first-eluting isomer) 508.2 509.2 629 [01826] (2S,4R)-4-fluoro- N-[(S) or (R)-[6- fluoro-5-(propan- 2-yl)pyridin-2- yl]({imidazo[1,5- a]pyridin-1- yl})methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: DAICEL CHIRALPAK AD-3, first-eluting isomer) 508.2 509.1 630 [01827] embedded image (2S,4R)-4-fluoro- N-[(S) or (R)-[6- fluoro-5-(propan- 2-yl)pyridin-2- yl](1H-pyrazol-5- yl)methyl]-1-[2- (1,3-oxazol-2- yl)acetyl]pyrrolidine- 2-carboxamide (column: DAICEL CHIRALPAK AD-3, second- eluting isomer) 458.2 459.1 631 [01828] (2S,4R)-4-fluoro- N-[(S) or (R)-[6- fluoro-5-(propan- 2-yl)pyridin-2- yl]({imidazo[1,5- a]pyridin-7- yl})methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 508.2 509.2 632 [01829] embedded image (2S,4R)-4-fluoro- N-[(S) or (R)-[6- fluoro-5-(propan- 2-yl)pyridin-2- yl](1H-indazol-6- yl)methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 508.2 509.1 633 [01830] (2S,4R)-4-fluoro- N-[(R) or (S)-[6- fluoro-5-(propan- 2-yl)pyridin-2- yl](1H-indazol-6- yl)methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, second-eluting isomer) 508.2 509.3 634 [01831] embedded image (2S,4R)-1-acetyl- 4-fluoro-N-[(S) or (R)-[6-fluoro-5- (propan-2- yl)pyridin-2- yl](1H-indazol-6- yl)methyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 441.2 442.1 635 [01832] (2S,4R)-1-acetyl- 4-fluoro-N-[(S) or (R)-[6-fluoro-5- (propan-2- yl)pyridin-2-yl](1- methyl-1H- indazol-6- yl)methyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 455.2 456.2 636 [01833] embedded image (2S,4R)-1-acetyl- 4-fluoro-N-[(S) or (R)-[6-fluoro-5- (propan-2- yl)pyridin-2-yl](2- methyl-2H- indazol-6- yl)methyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 455.2 456.1 637 [01834] (2S,4R)-1-acetyl- N-[(S) or (R)-(5- cyclopropyl-6- fluoropyridin-2- yl)(1H-indazol-6- yl)methyl]-4- fluoropyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, second-eluting isomer) 439.1 440.1

Example S-15: Synthesis of methyl (3-((S)-((2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoropyrrolidine-2-carboxamido)(6-fluoro-5-isopropylpyridin-2-yl)methyl)benzyl)carbamate

Compound 638

[1864] ##STR01835##

[1865] Step a: To a solution of tert-butyl (3-bromobenzyl)carbamate (7.94 g, 27.7 mmol, 1.5 eq) in THF (30 mL) at −78° C. under N.sub.2 was added n-BuLi (2.5 M in hexane, 18.5 mL, 2.5 eq), and the resulting mixture was stirred at −78° C. for 0.5 h. (E)-N-((6-fluoro-5-isopropylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (5 g, 18.5 mmol, 1 eq) in THF (20 mL) was then added at −78° C. The resulting mixture was stirred at −78° C. for 1.5 h. The reaction was then quenched by addition of saturated aq. NH.sub.4Cl solution (20 mL), and the resulting biphasic mixture was extracted with ethyl acetate (3×30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (3-(((tert-butylsulfinyl)amino)(6-fluoro-5-isopropylpyridin-2-yl)methyl)benzyl)carbamate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.25H.sub.36FN.sub.3O.sub.3S: 478.3; found 478.3.

[1866] Step b: To a solution of tert-butyl (3-(((tert-butylsulfinyl)amino)(6-fluoro-5-isopropylpyridin-2-yl)methyl)benzyl)carbamate (6 g, 12.5 mmol, 1 eq) in THF: H.sub.2O (5:1, 60 mL) was added I2 (2.55 g, 10.1 mmol, 0.8 eq). The resulting mixture was warmed to 50° C. and stirred for 1 h. The reaction was then quenched with saturated aq. Na.sub.2S.sub.2O.sub.3 solution (100 mL), and the resulting biphasic mixture was extracted with ethyl acetate (3×50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give tert-butyl (3-(amino(6-fluoro-5-isopropylpyridin-2-yl)methyl)benzyl)carbamate, which was carried forward to the next step without additional purification. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.21H.sub.28FN.sub.3O.sub.2: 374.2; found 374.2.

[1867] Step c: To a solution of tert-butyl (3-(amino(6-fluoro-5-isopropylpyridin-2-yl)methyl)benzyl)carbamate (2 g, 5.36 mmol, 1 eq) in DMF (20 mL) at 0° C. was added (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoropyrrolidine-2-carboxylic acid (2.94 g, 8.04 mmol, 80% purity, 1.3 eq), N-methylmorpholine (NMM, 16.1 mmol, 1.7 mL, 3 eq), and T3P (10.7 mmol, 6.3 mL, 50% purity, 2 eq), sequentially. The resulting mixture was warmed to 20° C. and stirred for 16 h. The reaction mixture was then quenched with H.sub.2O (50 mL), and the resulting biphasic mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (3-(((2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoropyrrolidine-2-carboxamido)(6-fluoro-5-isopropylpyridin-2-yl)methyl)benzyl)carbamate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.30H.sub.37F.sub.2N.sub.7O.sub.4: 598.3; found 598.4.

[1868] Step d: To a solution of tert-butyl (3-(((2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoropyrrolidine-2-carboxamido)(6-fluoro-5-isopropylpyridin-2-yl)methyl)benzyl)carbamate (1.2 g, 2.00 mmol, 1 eq) in DCM (12 mL) was added TFA (6.75 mmol, 3 mL, 40 eq). The resulting mixture was stirred at 20° C. for 1 h. The reaction mixture was then adjusted to pH to 5-6 using saturated aq. NaHCO.sub.3 solution, and the resulting biphasic mixture was extracted with ethyl acetate (3×50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC (column: Phenomenex Luna C.sub.18) to give (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-N—((R)-(3-(aminomethyl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-4-fluoropyrrolidine-2-carboxamide (first-eluting isomer) and (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-N—((S)-(3-(aminomethyl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-4-fluoropyrrolidine-2-carboxamide (second-eluting isomer) as separated diastereomers that were carried forward individually. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.25H.sub.29F.sub.2N.sub.7O.sub.2: 498.2; found 498.2.

[1869] Step e: To a solution of (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-N—((S)-(3-(aminomethyl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-4-fluoropyrrolidine-2-carboxamide (35 mg, 65.5 μmol, 1 eq) in DCM (1 mL) at −20° C. was added N-methylimidazole (NMI, 262 μmol, 20.9 μL, 4 eq), methyl chloroformate (190 mg, 2.01 mmol, 30.7 eq). The resulting mixture was warmed to 25° C. and stirred for 3 h. The reaction was then quenched with H.sub.2O (10 mL), and the resulting biphasic mixture was extracted with ethyl acetate (3×15 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give methyl 5-(2-((2S,4R)-4-fluoro-2-(((S)-(6-fluoro-5-isopropylpyridin-2-yl)(3-(((methoxycarbonyl)amino)methyl)phenyl)methyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-1,2,3-triazole-1-carboxylate, which was carried forward to the next step without further purification. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.29H.sub.33F.sub.2N.sub.7O.sub.6: 614.3 found 614.3.

[1870] Step f: To a solution of methyl 5-(2-((2S,4R)-4-fluoro-2-(((S)-(6-fluoro-5-isopropylpyridin-2-yl)(3-(((methoxycarbonyl)amino)methyl)phenyl)methyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-1,2,3-triazole-1-carboxylate (36 mg, 58.7 μmol, 1 eq) in MeOH (0.5 mL) was added K.sub.2CO.sub.3 (16.2 mg, 117 μmol, 2 eq). The resulting mixture was warmed to 70° C. and stirred at for 1 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give methyl (3-((S)-((2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoropyrrolidine-2-carboxamido)(6-fluoro-5-isopropylpyridin-2-yl)methyl)benzyl)carbamate. .sup.1H NMR (2.9:1 rotamer ratio, asterisk denotes distinct minor rotamer peaks, obscured peaks not reported, 400 MHz, DMSO-d6) δ 14.75 (br s, 1H), 9.28* (d, J=7.9 Hz, 1H), 8.90 (d, J=8.1 Hz, 1H), 7.92-7.80 (m, 1H), 7.62 (s, 1H), 7.41-7.05 (m, 5H), 6.07* (d, J=7.6 Hz, 1H), 5.95 (d, J=7.8 Hz, 1H), 5.49-5.19 (m, 1H), 4.90* (t, J=8.0 Hz, 1H), 4.62 (t, J=8.3 Hz, 1H), 4.22-3.62 (m, 5H), 3.54-3.49 (m, 3H), 3.09-2.99 (m, 1H), 2.16-1.91 (m, 1H), 1.24-1.12 (m, 6H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.27H.sub.31F.sub.2N.sub.7O.sub.4: 556.2; found 556.3.

[1871] The following compounds in Table T-15 were synthesized using procedures similar to Compound 638 using the appropriate starting materials.

TABLE-US-00029 TABLE T-15 Com- Exact LCMS, pound mass Found No. Structure IUPAC (g/mol) [M + H].sup.+ 639 [01836] embedded image (2S)-1-acetyl-N- [(R)-(2- methoxyphenyl)[4- (propan-2- yl)phenyl]methyl] pyrrolidine-2- carboxamide 394.2 395.3 640 [01837] (2S)-1-acetyl-N- [(R)-(2- methylphenyl)[4- (propan-2- yl)phenyl]methyl] pyrrolidine-2- carboxamide 378.2 379.3 641 [01838] (2S)-1-acetyl-N- [(S) or (R)-(2- methylphenyl)[5- (propan-2- yl)pyridin-2-yl] methyl]pyrrolidine-2- carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 379.2 380.2 642 [01839] embedded image (2S,4R)-1-acetyl- N-[(R) or (S)-(2- aminophenyl)[4- (propan-2- yl)phenyl]methyl]-4- fluoropyrrolidine- 2-carboxamide (column: DAICEL CHIRALPAK AD-3, first-eluting isomer) 397.2 398.1 643 [01840] (2S)-N-[(R) or (S)-(4- cyclopropyl-3- fluorophenyl)(2- oxo-2,3-dihydro- 1,3-benzoxazol-7- yl)methyl]-1-(2- acetamidoacetyl) pyrrolidine-2- carboxamide (column: REGIS (s,s) WHELK-O1, second-eluting isomer) 494.2 495.2 644 [01841] embedded image (2S)-N-[(R)-(2- oxo-2,3-dihydro- 1H-1,3- benzodiazol-4- yl)[4-(propan-2- yl)phenyl]methyl]- 1-[2-(1H-1,2,3- triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 487.2 488.1 645 [01842] (2S,4R)-4-fluoro- N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](3- fluoropheny)methyl]- 1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 485.2 486.1 646 [01843] embedded image (2S,4R)-4-fluoro- N-[(S)-[3-fluoro- 4-(propan-2- yl)phenyl](4- fluorophenyl)methyl]- 1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 485.2 486.1 647 [01844] (2S,4R)-4-fluoro- N-[(R)-[3-fluoro- 4-(propan-2- yl)phenyl](3- fluorophenyl)methyl]- 1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 485.2 486.1 648 [01845] embedded image (2S)-N-[(S)-(4- cyclopropyl-3- fluorophenyl)(2- oxo-2,3-dihydro- 1H-1,3- benzodiazol-4- yl)methyl]-1-[2- (1H-1,2,3-triazol- 5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, second-eluting isomer) 503.2 504.1 649 [01846] (2S,4R)-N-[(R)- (3- acetamidophenyl) [4-(propan-2- yl)phenyl]methyl]- 4-fluoro-1-[2-(1- methyl-1H-1,2,3- triazol-4- yl)acetyl]pyrrolidine- 2-carboxamide 520.3 521.2 650 [01847] embedded image (2S,4R)-N-[(R) or (S)-(4- cyclopropyl-3- fluorophenyl)(1- methyl-2-oxo-2,3- dihydro-1H-1,3- benzodiazol-4- yl)methyl]-4- fluoro-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, second-eluting isomer) 535.2 536.1 651 [01848] (2S,4R)-4-fluoro- N-[(S) or (R)-[6- fluoro-5-(propan- 2-yl)pyridin-2- yl](3- methoxyphenyl) methyl]-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 498.2 499.1 652 [01849] embedded image (2S,4R)-N-[(S) or (R)- cyclopropyl[3- fluoro-4-(propan-2- yl)phenyl]methyl]- 4-fluoro-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: DAICEL CHIRALPAK IC-3, second-eluting isomer) 431.2 432.3 653 [01850] (2S,4R)-N-[(1S) or (1R)-2- cyclopropyl-1-[3- fluoro-4-(propan-2- yl)phenyl]ethyl]- 4-fluoro-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, second-eluting isomer) 445.2 446.1 654 [01851] embedded image (2S,4R)-1-acetyl- 4-fluoro-N-[(S) or (R)-[6-fluoro-5- (propan-2- yl)pyridin-2-yl](3- methoxyphenyl) methyl]pyrrolidine- 2-carboxamide (column: DAICEL CHIRALPAK IC-3, first-eluting isomer) 431.2 432.1 655 [01852] (2S,4R)-N-[(S)-[3- (acetamidomethyl) phenyl][6-fluoro- 5-(propan-2- yl)pyridin-2- yl]methyl]-4- fluoro-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 539.2 540.3 656 [01853] embedded image (2S,4R)-4-fluoro- N-[(S)-[6-fluoro- 5-(propan-2- yl)pyridin-2-yl](3- {[(methylcarbamoyl) amino]methyl} phenyl)methyl]-1- [2-(1H-1,2,3- triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 554.3 555.2 657 [01854] (2S,4R)-N-[(S) or (R)-(5- cyclopropyl-6- fluoropyridin-2- yl)(2- fluorophenyl)methyl]- 1-{2-[5- (difluoromethyl)- 1H-1,2,3,4- tetrazol-1- yl]acetyl}-4- fluoropyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 535.2 536.3 658 [01855] embedded image (2S,4R)-N-[(S) or (R)-(5- cyclopropyl-6- fluoropyridin-2- yl)(4- fluorophenyl)methyl]- 1-{2-[5- (difluoromethyl)- 1H-1,2,3,4- tetrazol-1- yl]acetyl}-4- fluoropyrrolidine-2- carboxamide (column: DAICEL CHIRALPAK AD-3, second- eluting isomer) 535.2 536.2

Example S-16: Synthesis of (2S,4R)-1-(((1H-1,2,3-triazol-5-yl)methyl)sulfonyl)-N—((S)-(3,5-difluoro-4-isopropylphenyl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide

Compound 659

[1872] ##STR01856##

[1873] Step a: To a solution of 3,5-difluoro-4-isopropylbenzaldehyde (1.05 g, 5.70 mmol, 1 eq) and (R)-2-methylpropane-2-sulfinamide (1.04 g, 8.55 mmol, 1.5 eq) in THF (20 mL) was added Ti(Oi-Pr).sub.4 (3.24 g, 11.4 mmol, 3.37 mL, 2 eq). The resulting mixture was stirred at 25° C. for 15 h. The reaction mixture was then quenched with water (20 mL). The resulting biphasic mixture was filtered, and the filtrate was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (2×30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (R,E)-N-(3,5-difluoro-4-isopropylbenzylidene)-2-methylpropane-2-sulfinamide, which was carried forward to the next step without further purification or characterization.

[1874] Step b: To a solution of (R,E)-N-(3,5-difluoro-4-isopropylbenzylidene)-2-methylpropane-2-sulfinamide (1.4 g, 4.87 mmol, 1 eq) in THF (15 mL) at 0° C. was added phenylmagnesium bromide (3 M in diethyl ether, 2.44 mL, 1.5 eq). The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was then quenched by addition of saturated aq. NH.sub.4C.sub.1 solution (15 mL), and the resulting biphasic mixture was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (2×20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (R)—N—((S)-(3,5-difluoro-4-isopropylphenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.20H.sub.25F.sub.2NOS: 366.2; found 366.1.

[1875] Step c: To a solution of (R)—N—((S)-(3,5-difluoro-4-isopropylphenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (540 mg, 1.48 mmol, 1 eq) in EtOAc (10 mL) was added HCl/EtOAc (4 M, 10 mL). The resulting mixture was stirred at 25° C. for 0.5 h. The reaction mixture was then filtered, and the solid was washed with petroleum ether to give (S)-(3,5-difluoro-4-isopropylphenyl)(phenyl)methanaminium chloride, which was carried forward to the next step without further purification or characterization.

[1876] Step d: To a solution of (S)-(3,5-difluoro-4-isopropylphenyl)(phenyl)methanaminium chloride (0.22 g, 739 μmol, 1 eq) and (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (190 mg, 813 μmol, 1.1 eq) in MeCN (10 mL) at −20° C. was added N-methylimidazole (NMI, 303 mg, 3.69 mmol, 294 μL, 5 eq) and chloro-N,N,N,N′-tetramethylformamidinium hexafluorophosphate (TCFH, 228 mg, 813 μmol, 1.1 eq). The resulting mixture was stirred at −20° C. for 1 h. The reaction mixture was then quenched by addition of ice-water (5 mL) at −20° C., and the resulting biphasic mixture was adjusted to pH=5 with aqueous HCl (4 N). The resulting biphasic mixture was then extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (2×10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (2S,4R)-2-(((S)-(3,5-difluoro-4-isopropylphenyl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.26H.sub.31F.sub.3N.sub.2O.sub.3: 477.2; found 477.3.

[1877] Step e: To a solution of tert-butyl (2S,4R)-2-(((S)-(3,5-difluoro-4-isopropylphenyl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (0.35 g, 734 μmol, 1 eq) in DCM (10 mL) was added TFA (3.08 g, 27.0 mmol, 2 mL, 36.8 eq). The mixture was stirred at 25° C. for 1 h. The mixture was then concentrated under reduced pressure to give (2S,4R)-2-(((S)-(3,5-difluoro-4-isopropylphenyl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidin-1-ium 2,2,2-trifluoroacetate. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.21H.sub.23F.sub.3N.sub.2O: 377.2; found 377.1.

[1878] Step f: To a mixture of (2S,4R)-2-(((S)-(3,5-difluoro-4-isopropylphenyl)(phenyl)methyl)carbamoyl)-4-fluoropyrrolidin-1-ium 2,2,2-trifluoroacetate (100 mg, 265 μmol, 1 eq) and DIPEA (343 mg, 2.66 mmol, 10 eq) in DCM (5 mL) at 0° C. was added (1-benzyl-1H-1,2,3-triazol-4-yl)methanesulfonyl chloride (216 mg, 797 μmol, 3 eq) in portions. The resulting mixture was warmed to 20° C. and stirred for 3 h. The reaction mixture was then poured into ice-water (30 mL) and stirred for 10 min. The resulting biphasic mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give (2S,4R)-1-(((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)sulfonyl)-N—((S)-(3,5-difluoro-4-isopropylphenyl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.31H.sub.32F.sub.3N.sub.5O.sub.3S: 612.2; found 612.3.

[1879] Step g: To a solution of (2S,4R)-1-(((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)sulfonyl)-N—((S)-(3,5-difluoro-4-isopropylphenyl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide (20 mg, 32.7 μmol, 1 eq) in MeOH (50 mL) was added Pd/C (100 mg, 10% purity). The resulting suspension was degassed under vacuum and purged with H.sub.2. The resulting mixture was stirred under H.sub.2 (50 psi) at 20° C. for 16 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give (2S,4R)-1-(((1H-1,2,3-triazol-5-yl)methyl)sulfonyl)-N—((S)-(3,5-difluoro-4-isopropylphenyl)(phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 15.04 (br s, 1H), 9.05 (d, J=8.1 Hz, 1H), 7.79 (br s, 1H), 7.40-7.23 (m, 5H), 6.96 (d, J=9.4 Hz, 2H), 6.11 (d, J=8.0 Hz, 1H), 5.32 (d, J=52.6 Hz, 1H), 4.68-4.48 (m, 3H), 3.79-3.66 (m, 1H), 3.51 (dd, J=39.0, 12.6 Hz, 1H), 3.29-3.19 (m, 1H), 2.75-2.54 (m, 1H), 2.18-1.97 (m, 1H), 1.25 (d, J=7.1 Hz, 6H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.24H.sub.26F.sub.3N.sub.5O.sub.3S: 522.2; found 522.1.

[1880] The following compounds in Table T-16 were synthesized using procedures similar to Compound 659 using the appropriate starting materials.

TABLE-US-00030 TABLE T-16 Com- Exact LCMS, pound mass Found No. Structure IUPAC (g/mol) [M + H].sup.+ 660 [01857] embedded image (2S,4R)-1-acetyl- N-[(S) or (R)-(4- cyclobutyl-3- fluorophenyl)(phenyl) methyl]-4- fluoropyrrolidine- 2-carboxamide (column: DAICEL CHIRALPAK AS-3, first-eluting isomer) 412.2 413.2 661 [01858] (2S,4R)-N-[(S) or (R)-[3,5-difluoro- 4-(propan-2- yl)phenyl](phenyl) methyl]-4-fluoro- 1-[2-(1,3-oxazol-2- yl)acetyl]pyrrolidine- 2-carboxamide (column: CHIRALCEL OD-3, first-eluting isomer) 485.2 486.1 662 [01859] embedded image (2S,4R)-N-[(S)- (4-cyclopropyl- 3,5- difluorophenyl) (phenyl)methyl]- 4-fluoro-1-[2-(1,3- oxazol-2- yl)acetyl]pyrrolidine- 2-carboxamide (column: CHIRALCEL OD-3, first-eluting isomer) 483.2 484.1 663 [01860] (2S,4R)-4-fluoro- N-[(S)-[2-methyl- 4-(propan-2- yl)phenyl](phenyl) methyl]-1-[2- (1,3-oxazol-2- yl)acetyl]pyrrolidine- 2-carboxamide 463.2 486.1 (M + Na) 664 [01861] embedded image (2S,4R)-N-[(S)- (3-chloro-4- cyclopropylphenyl) (phenyl)methyl]- 4-fluoro-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 481.2 482.2 665 [01862] (2S,4R)-N-[(S)- (4-cyclopropyl-3- methylphenyl) (phenyl)methyl]- 4-fluoro-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 461.2 462.3 666 [01863] embedded image (2S,4R)-N-[(R) or (S)-[3,5-difluoro- 4-(propan-2- yl)phenyl](phenyl) methyl]-4-fluoro- 1-[2-(1H-1,2,3- triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 485.2 486.1 667 [01864] (2S,4R)-N-[(S) or (R)-[3,5-difluoro- 4-(propan-2- yl)phenyl](phenyl) methyl]-4-fluoro- 1-[2-(1H-1,2,3- triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 485.2 486.1 668 [01865] embedded image (2S,4R)-N-[(S) or (R)-[3,5-difluoro- 4-(propan-2- yl)phenyl](phenyl) methyl]-4-fluoro- 1-[2-(1H-1,2,3- triazol-1- yl)acetyl]pyrrolidine- 2-carboxamide (column: CHIRALCEL OD-3, first-eluting isomer) 485.2 486.1 669 [01866] (2S,4R)-N-[(S)- [3,5-difluoro-4- (propan-2- yl)phenyl](phenyl) methyl]-4-fluoro- 1-[2-(1H-1,2,3,4- tetrazol-1- yl)acetyl]pyrrolidine- 2-carboxamide 486.2 487.1 670 [01867] embedded image (2S,4R)-4-fluoro- N-[(S)-[3-methyl- 4-(propan-2- yl)phenyl](phenyl) methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 463.2 464.1 671 [01868] (2S,4R)-N-[(R)- [3-chloro-4- (propan-2- yl)phenyl](phenyl) methyl]-4-fluoro- 1-[2-(1H-1,2,3- triazol-5-yl) acetyl]pyrrolidine- 2-carboxamide 483.2 484.2 672 [01869] embedded image (2S,4R)-N-[(S)- [3-chloro-4- (propan-2- yl)phenyl](phenyl) methyl]-4-fluoro- 1-[2-(1H-1,2,3- triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 483.2 484.2 673 [01870] (2S,4R)-N-[(R) or (S)-(4-cyclobutyl-3- fluorophenyl)(phenyl) methyl]-4- fluoro-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: CHIRALCEL OD-3, second- eluting isomer) 479.2 480.2 674 [01871] embedded image (2S,4R)-N-[(S) or (R)-(4-cyclobutyl-3- fluorophenyl) (phenyl)methyl]-4- fluoro-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: CHIRALCEL OD-3, first-eluting isomer) 479.2 480.2 675 [01872] (2S,4R)-N-[(S) or (R)-(4-cyclobutyl- 3- fluorophenyl) (phenyl)methyl]-4- fluoro-1-[2-(1H- 1,2,3,4-tetrazol-1- yl)acetyl]pyrrolidine- 2-carboxamide (column: CHIRALCEL AD-3, first-eluting isomer) 480.2 481.2 676 [01873] embedded image (2S,4R)-N-[(R) or (S)-{4-[(2R) or (2S)-butan-2-yl]-3- fluorophenyl}(phenyl) methyl]-4- fluoro-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, second-eluting isomer) 481.2 482.1 677 [01874] (2S,4R)-N-[(S) or (R)-{4-[(2R) or (2S)-butan-2-yl]-3- fluorophenyl} (phenyl)methyl]-4- fluoro-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 481.2 482.1 678 [01875] embedded image (2S,4R)-4-fluoro- N-[(R) or (S)-[3- fluoro-5-methyl- 4-(propan-2- yl)phenyl](phenyl) methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: CHIRALCEL IC-3, second-eluting isomer) 481.2 482.3 679 [01876] (2S,4R)-N-[(S)- [3- (difluoromethyl)- 4-(propan-2- yl)phenyl](phenyl) methyl]-4-fluoro- 1-[2-(1H-1,2,3- triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 499.2 500.2 680 [01877] embedded image (2S,4R)-4-fluoro- N-[(S) or (R)-[3- fluoro-5-methyl- 4-(propan-2- yl)phenyl](phenyl) methyl]-1-[2- (1H-1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: CHIRALCEL IC-3, first-eluting isomer) 481.2 482.3 681 [01878] (2S,4R)-4-fluoro- N-[(S)-[3-fluoro- 4-(1- methylcyclobutyl) phenyl](phenyl)methyl]- 1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 493.2 494.3 682 [01879] embedded image (2S,4R)-N-[(S) or (R)-(4- cyclopropyl-3- fluoro-5- methylphenyl) (phenyl)methyl]- 4-fluoro-1-[2-(5- methyl-2H- 1,2,3,4-tetrazol-2- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, second-eluting isomer) 494.2 512.2 683 [01880] (2S,4R)-4-fluoro- N-[(S) or (R)- phenyl[4-(propan- 2-yl)-3- (trifluoromethyl) phenyl]methyl]-1- [2-(1H-1,2,3- triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: CHIRALCEL IC-3, first-eluting isomer) 517.2 518.1 684 [01881] embedded image (2S,4R)-4-fluoro- N-[(R)-[3-fluoro-4-(1- methylcyclobutyl) phenyl](phenyl) methyl]-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 493.2 494.3 685 [01882] (2S,4R)-N-[(S)- (4-tert-butyl-3- fluorophenyl)(phenyl) methyl]-4- fluoro-1-[2-(1H- 1,2,3-triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide 481.2 482.3

Example S-17: Synthesis of (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-N—((S) or (R)-(3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-4-fluoropyrrolidine-2-carboxamide and (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-N—((R) or (S)-(3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-4-fluoropyrrolidine-2-carboxamide

Compounds 686 and 687

[1881] ##STR01883##

[1882] Step a: To a solution of 5-(3-bromophenyl)-1H-pyrazole (619 mg, 2.77 mmol, 1.5 eq) in THF (5 mL) at −78° C. under N.sub.2 was added n-BuLi (2.5 M in hexane, 1.85 mL, 2.5 eq), and the resulting mixture was stirred at −78° C. for 0.5 h. (E)-N-((6-fluoro-5-isopropylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (0.5 g, 1.85 mmol, 1 eq) in THF (1 mL) was then added dropwise at −78° C. The resulting mixture was allowed to warm to 20° C. and stirred for 2 h. The reaction was then quenched with saturated aq. NH.sub.4Cl (10 mL), and the resulting biphasic mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give N-((3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.22H.sub.27FN.sub.4OS: 415.2; found 415.2.

[1883] Step b: To a solution of N-((3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (0.5 g, 1.21 mmol, 1 eq) in dioxane (5 mL) was added HCl/dioxane (4 M, 5 mL). The resulting mixture was stirred at 20° C. for 2 h. The mixture was then concentrated under reduced pressure. The crude residue obtained was triturated with MTBE (5 mL) to give (3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methanaminium chloride. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.18H.sub.19FN.sub.4: 311.2; found 311.2.

[1884] Step c: To a solution of (3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methanaminium chloride (0.15 g, 432 μmol, 1 eq) and (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoropyrrolidine-2-carboxylic acid (136 mg, 562 μmol, 1.3 eq) in DMF (2 mL) at 0° C. was added N-methylmorpholine (NMM, 175 mg, 1.73 mmol, 190 μL, 4 eq) and T3P (550 mg, 865 μmol, 50% purity, 2 eq). The resulting mixture was warmed to 20° C. and stirred for 16 h. The reaction mixture was then diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC (column: Phenomenex C.sub.18) to give (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-N—((R)-(3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-4-fluoropyrrolidine-2-carboxamide (Compound 687; first-eluting isomer) and (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-N—((S)-(3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-4-fluoropyrrolidine-2-carboxamide (Compound 686; second-eluting isomer).

[1885] First-eluting isomer (Compound 687): .sup.1H NMR (2.9:1 rotamer ratio, asterisk denotes minor rotamer peaks, obscured peaks not reported, 400 MHz, DMSO-d6) δ 12.89 (s, 1H), 9.41* (d, J=7.8 Hz, 1H), 9.06 (d, J=8.3 Hz, 1H), 7.86 (t, J=8.9 Hz, 1H), 7.82-7.59 (m, 3H), 7.54 (d, J=7.6 Hz, 1H), 7.44-7.26 (m, 2H), 7.26-7.14 (m, 1H), 6.67 (s, 1H), 6.15* (d, J=7.9 Hz, 1H), 6.03 (d, J=8.1 Hz, 1H), 5.48-5.19 (m, 1H), 4.96-4.85* (m, 1H), 4.65 (t, J=8.3 Hz, 1H), 4.14-3.62 (m, 3H), 3.11-2.92 (m, 1H), 2.10-1.89 (m, 1H), 1.23-1.17 (m, 6H), 1.17-1.12* (m, 6H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.27H.sub.28F.sub.2N.sub.8O.sub.2: 535.2; found 535.2.

[1886] Second-eluting isomer (Compound 686): .sup.1H NMR (3.3:1 rotamer ratio, asterisk denotes minor rotamer peaks, obscured peaks not reported, 400 MHz, DMSO-d6) δ 14.77 (br s, 1H), 13.24* (br s, 1H), 12.85 (br s, 1H), 9.35* (d, J=7.8 Hz, 1H), 9.01 (d, J=8.1 Hz, 1H), 7.93-7.77 (m, 2H), 7.77-7.56 (m, 3H), 7.41-7.25 (m, 2H), 7.16 (d, J=7.7 Hz, 1H), 6.75-6.70 (m, 1H), 6.61* (s, 1H), 6.13* (d, J=7.8 Hz, 1H), 6.03 (d, J=8.0 Hz, 1H), 5.50-5.21 (m, 1H), 4.92* (t, J=8.0 Hz, 1H), 4.66 (t, J=8.3 Hz, 1H), 4.13-3.65 (m, 4H), 3.05 (hept, J=6.9 Hz, 1H), 2.14-1.93 (m, 1H), 1.24-1.17 (m, 6H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.27H.sub.28F.sub.2N.sub.8O.sub.2: 535.2; found 535.2.

Example S-18: Synthesis of (2S,4R)—N—((S) or (R)-(3-(4H-1,2,4-triazol-3-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-1-acetyl-4-fluoropyrrolidine-2-carboxamide and (2S,4R)—N—((R) or (S)-(3-(4H-1,2,4-triazol-3-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-1-acetyl-4-fluoropyrrolidine-2-carboxamide

Compounds 688 and 689

[1887] ##STR01884##

[1888] Step a: To a solution of 1-bromo-3-iodobenzene (8.06 g, 28.4 mmol, 1.1 eq) in THF (40 mL) at 0° C. under N.sub.2 was added i-PrMgCl.LiCl (1.3 M in THF, 21.9 mL, 1.1 eq) in a dropwise manner. The resulting mixture was stirred at 0° C. for 2 h before (E)-N-((6-fluoro-5-isopropylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (7 g, 25.8 mmol, 1 eq) in THF (20 mL) was added in a dropwise manner at 0° C. The resulting mixture was allowed to warm to 20° C. and stirred for 1 h. The reaction was then quenched with saturated aq. NH.sub.4Cl solution (20 mL), and the resulting biphasic mixture was extracted with ethyl acetate (3×40 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give N-((3-bromophenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.19H.sub.24BrFN.sub.2OS: 427.1; found 427.1.

[1889] Step b: To a solution of N-((3-bromophenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (6 g, 14.0 mmol, 1 eq) in dioxane (20 mL) at 25° C. was added HCl/dioxane (50 mL). The resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was then filtered to give (3-bromophenyl)(6-fluoro-5-isopropylpyridin-2-yl)methanaminium chloride. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.15H.sub.16BrFN.sub.2: 323.0; found 323.0.

[1890] Step c: To a solution of (3-bromophenyl)(6-fluoro-5-isopropylpyridin-2-yl)methanaminium chloride (5.8 g, 16.1 mmol, 1 eq) in DMF (30 mL) at 0° C. was added NMM (64.5 mmol, 7 mL, 4 eq), (2S,4R)-1-acetyl-4-fluoropyrrolidine-2-carboxylic acid (4.24 g, 24.2 mmol, 1.5 eq), and T3P (32.3 mmol, 19 mL, 50% purity, 2 eq), sequentially. The resulting mixture was warmed to 15° C. and stirred for 1 h. The reaction mixture was then poured into ice-water (50 mL) and stirred for 5 min. The resulting biphasic mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (2S,4R)-1-acetyl-N-((3-bromophenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-4-fluoropyrrolidine-2-carboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.22H.sub.24BrF.sub.2N.sub.3O.sub.2: 480.1; found 480.0.

[1891] Step d: To a mixture of (2S,4R)-1-acetyl-N-((3-bromophenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-4-fluoropyrrolidine-2-carboxamide (2 g, 4.16 mmol, 1 eq) and bis(pinacolato)diboron (1.16 g, 4.58 mmol, 1.1 eq) in DMSO (20 mL) was added potassium acetate (1.02 g, 10.4 mmol, 2.5 eq). The resulting mixture was then degassed and purged with N.sub.2. To this mixture added Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (340 mg, 416 μmol, 0.1 eq), and the resulting mixture was degassed and purged with N.sub.2. The reaction mixture was then warmed to 120° C. and stirred for 2 h under N.sub.2 atmosphere. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (2S,4R)-1-acetyl-4-fluoro-N-((6-fluoro-5-isopropylpyridin-2-yl)(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)pyrrolidine-2-carboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.28H.sub.36BF.sub.2N.sub.3O.sub.4: 528.3; found 528.4.

[1892] Step e: To a mixture of (2S,4R)-1-acetyl-4-fluoro-N-((6-fluoro-5-isopropylpyridin-2-yl)(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)pyrrolidine-2-carboxamide (1 g, 1.90 mmol, 1 eq) and 3-bromo-4-trityl-4H-1,2,4-triazole (888 mg, 2.28 mmol, 1.2 eq) in dioxane (7 mL) and H.sub.2O (0.5 mL) was added Cs.sub.2CO.sub.3 (1.24 g, 3.79 mmol, 2 eq). The resulting mixture was degassed and purged with N.sub.2, and then Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (310 mg, 379 μmol, 0.2 eq) was added in one portion. The resulting mixture was degassed and purged with N.sub.2. The reaction mixture was then warmed to 120° C. and stirred for 1 h under N.sub.2 atmosphere. The reaction solution was then filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (2S,4R)-1-acetyl-4-fluoro-N-((6-fluoro-5-isopropylpyridin-2-yl)(3-(4-trityl-4H-1,2,4-triazol-3-yl)phenyl)methyl)pyrrolidine-2-carboxamide. LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.43H.sub.40F.sub.2N.sub.6O.sub.2: 711.3; found 711.3.

[1893] Step f: To a solution of (2S,4R)-1-acetyl-4-fluoro-N-((6-fluoro-5-isopropylpyridin-2-yl)(3-(4-trityl-4H-1,2,4-triazol-3-yl)phenyl)methyl)pyrrolidine-2-carboxamide (0.7 g, 984 μmol, 1 eq) in MeOH (5 mL) at 0° C. was added HCl/dioxane (4M, 10 mL). The resulting mixture was allowed to warm to 20° C. and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure. The crude residue obtained was purified by prep-TLC to give (2S,4R)—N—((S)-(3-(4H-1,2,4-triazol-3-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-1-acetyl-4-fluoropyrrolidine-2-carboxamide. This mixture of diastereomers was then purified by prep-HPLC (column: Phenomenex Luna C.sub.18) to give (2S,4R)—N—((R) or (S)-(3-(4H-1,2,4-triazol-3-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-1-acetyl-4-fluoropyrrolidine-2-carboxamide (Compound 689, first-eluting isomer) and (2S,4R)—N—((S) or (R)-(3-(4H-1,2,4-triazol-3-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-1-acetyl-4-fluoropyrrolidine-2-carboxamide (Compound 688, second-eluting isomer).

[1894] First-eluting isomer (Compound 689): .sup.1H NMR (2:1 rotamer ratio, asterisk denotes minor rotamer peaks, obscured peaks not reported, 400 MHz, DMSO-d6) δ 9.34* (d, J=7.9 Hz, 1H), 9.09 (d, J=8.1 Hz, 1H), 8.52-8.39 (m, 1H), 8.04-7.99* (m, 1H), 7.97-7.85 (m, 3H), 7.64-7.58 (m, 1H), 7.50-7.31 (m, 2H), 6.15* (d, J=7.8 Hz, 1H), 6.03 (d, J=8.0 Hz, 1H), 5.46-5.17 (m, 1H), 4.73* (t, J=8.0 Hz, 1H), 4.60 (t, J=8.3 Hz, 1H), 3.96-3.60 (m, 2H), 3.12-2.98 (m, 1H), 2.47-2.37 (m, 1H), 2.12-1.89 (m, 4H), 1.81* (s, 3H), 1.25-1.16 (m, 6H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.24H.sub.26F.sub.2N.sub.6O.sub.2: 469.2; found 469.2.

[1895] Second-eluting isomer (Compound 688): .sup.1H NMR (2:1 rotamer ratio, asterisk denotes minor rotamer peaks, obscured peaks not reported, 400 MHz, DMSO-d6) δ 14.20 (br s, 1H), 9.32* (d, J=8.0 Hz, 1H), 9.02 (d, J=8.1 Hz, 1H), 8.47 (br s, 1H), 8.07-7.82 (m, 3H), 7.49-7.35 (m, 3H), 6.15* (d, J=8.0 Hz, 1H), 6.06 (d, J=8.0 Hz, 1H), 5.48-5.17 (m, 1H), 4.75* (t, J=8.1 Hz, 1H), 4.62 (t, J=8.4 Hz, 1H), 3.96-3.62 (m, 2H), 3.12-3.00 (m, 1H), 2.24-1.92 (m, 4H), 1.77* (s, 3H), 1.24-1.17 (m, 6H). LC-MS (ESI): m/z: [M+H].sup.+ calculated for C.sub.24H.sub.26F.sub.2N.sub.6O.sub.2: 469.2; found 469.2.

[1896] The following compounds in Table T-17 were synthesized using procedures similar to Compound 686, 687, 688 and 689 using the appropriate starting materials.

TABLE-US-00031 TABLE T-17 Com- Exact LCMS, pound mass Found No. Structure IUPAC (g/mol) [M + H].sup.+ 690 [01885] embedded image (2S,4R)-1-acetyl- 4-fluoro-N-[(S) or (R)-[6-fluoro-5- (propan-2- yl)pyridin-2-yl][3- (1H-pyrazol-5- yl)phenyl]methyl] pyrrolidine-2- carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 467.2 468.2 691 [01886] (2S,4R)-1-(2- acetamidoacetyl)- 4-fluoro-N-[(S) or (R)-[6-fluoro-5- (propan-2- yl)pyridin-2-yl][3- (1H-pyrazol-5- yl)phenyl]methyl] pyrrolidine-2- carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 524.2 525.1 692 [01887] embedded image (2S,4R)-4-fluoro- N-[(R) or (S)-[6- fluoro-5-(propan- 2-yl)pyridin-2- yl][3-(1,3-oxazol-5- yl)phenyl]methyl]- 1-[2-(1H-1,2,3- triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, second-eluting isomer) 535.2 536.1 693 [01888] (2S,4R)-4-fluoro- N-[(S) or (R)-[6- fluoro-5-(propan- 2-yl)pyridin-2- yl][3-(1,3-oxazol-5- yl)phenyl]methyl]- 1-[2-(1H-1,2,3- triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 535.2 536.1 694 [01889] embedded image (2S,4R)-4-fluoro- N-[(S) or (R)-[6- fluoro-5-(propan- 2-yl)pyridin-2- yl][3-(1,2-oxazol-5- yl)phenyl]methyl]- 1-[2-(1H-1,2,3- triazol-5- yl)acetyl]pyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 535.2 536.2 695 [01890] (2S,4R)-1-acetyl- 4-fluoro-N-[(S) or (R)-[6-fluoro-5- (propan-2- yl)pyridin-2-yl][3- (1-methyl-1H- pyrazol-5- yl)phenyl]methyl] pyrrolidine-2- carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 481.2 482.1 696 [01891] embedded image (2S,4R)-1-acetyl- 4-fluoro-N-[(S) or (R)-[6-fluoro-5- (propan-2- yl)pyridin-2-yl][3- (3-methyl-1H- pyrazol-5- yl)phenyl]methyl] pyrrolidine-2- carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 481.2 482.2 697 [01892] (2S,4R)-1-acetyl- N-[(S) or (R)-[3- (1,3-dimethyl-1H- pyrazol-5- yl)phenyl][6- fluoro-5-(propan- 2-yl)pyridin-2- yl]methyl]-4- fluoropyrrolidine- 2-carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 495.2 496.2 698 [01893] embedded image (2S,4R)-1-acetyl- 4-fluoro-N-[(S) or (R)-[6-fluoro-5- (propan-2- yl)pyridin-2-yl][3- (1,2-oxazol-5- yl)phenyl]methyl] pyrrolidine-2- carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 468.2 469.1 699 [01894] (2S,4R)-1-acetyl- 4-fluoro-N-[(S) or (R)-[6-fluoro-5- (propan-2- yl)pyridin-2-yl][3- (1H-pyrazol-1- yl)phenyl]methyl] pyrrolidine-2- carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 467.2 468.1 700 [01895] embedded image (2S,4R)-1-acetyl- 4-fluoro-N-[(S) or (R)-[6-fluoro-5- (propan-2- yl)pyridin-2-yl][3- (1,3,4-oxadiazol-2- yl)phenyl]methyl] pyrrolidine-2- carboxamide (column: REGIS (s,s) WHELK-O1, first-eluting isomer) 469.1 470.2

BIOLOGICAL EXAMPLES

Example B-1

[1897] The GYS1 coupled enzyme assay is a kinetic biochemical assay that indirectly quantifies the rate of glycogen synthesis by coupling the conversion of GYS1 substrate UDP-glucose into UDP with downstream enzymatic reactions. UDP is released from UDP-glucose as glucose monomers are linked into the growing glycogen strand by GYS1. The coupled assay then proceeds with pyruvate kinase utilizing UDP and phospho(enol)pyruvate (PEP) to form pyruvate. Lactate dehydrogenase then converts pyruvate and NADH into lactate and NAD+. Oxidation of NADH to NAD+ can be measured continuously with a plate reader by quantifying the decrease in NADH absorbance at 340 nm over time.

[1898] Compounds that inhibit the hGYS1 enzyme and, subsequently, the downstream conversion of NADH to NAD+, were tested using assay ready plates (black, clear bottom 384 well plates) in a final DMSO reaction volume of 2.5% DMSO. The Assay Buffer contained 50 mM Tris pH 7.5, 2 mM MgCl2, and 100 mM KCl. Fresh stocks of BSA at a final concentration of 0.02% and TCEP at 1 mM were added before splitting buffer into hGYS1 buffer and substrate buffer. To the hGYS1 buffer, rabbit liver glycogen was added at a final concentration of 0.2% glycogen. Glucose-6-Phosphate was added at 1 mM, recombinant hGYS1/GN1 protein was added at 50 nM to the substrate buffer, phosphoenolpyruvate (PEP) was added at 2 mM, UDP-Glucose was added at 0.8 mM, NADH) was added at 0.6 mM, and Pyruvate Kinase/Lactate Dehydrogenase was added at 20 units/mL. The reaction was initiated by mixing hGYS1 buffer and substrate buffer at a 1:1 ratio. Both buffers were plated using a liquid dispensing device with hGYS1 buffer plated first followed by the substrate buffer. Plates were spun briefly to eliminate air bubbles and are immediately read in continuous mode at an absorbance of 340 nm, for 10 time points in one-minute increments, for a total of 10 minutes. The slope from these 10 time points was normalized to the positive and negative control wells. The duplicate % inhibition values are then averaged and fit to a Hill equation for dose response according to the Levenberg-Marquardt algorithm with the Hill equation maximum set to 100 and the minimum set to 0.

[1899] The results are shown in Table 2 below, which reports the IC.sub.50 of each compound. Unless otherwise specified, IC.sub.50 values are reported as the geometric mean of at least 2 assay runs on separate days. Each run represents the average of a technical replicate, where each compound was assayed twice in the same plate. As shown in the table below, the compounds of the present invention are potent inhibitors of human GYS1. A superscript “#” symbol in Table 2 indicates results from a single assay run.

[1900] Note that, in Table 2, the compounds are referred to by the corresponding Compound No. in Table 1, which is also referred to in the synthetic examples. When one or more of the numbered compounds are identified by stereochemistry (for example, (R)- or (S)-), the specific stereoisomer for which data is provided in Table 2 may be identified by the elution order of such compound as described in the synthetic examples. To illustrate, Compound 497 is the first-eluting isomer in step g of Example S-7 and Compound 498 is the second-eluting isomer in step g of Example S-7.

TABLE-US-00032 TABLE 2 Compound PK/LDH No. IC.sub.50 (μM) 1 0.033 2 0.059 3 0.168 4 0.998 5 0.353 6 0.211 7 0.113 8 0.042 9 0.059 10 0.050 11 0.091 12 0.415 13 0.147 14 0.129 15 0.048 16 0.033 17 0.034 18 0.045 19 0.047 20 0.046 21 0.027 22 0.043 23 0.070 24 0.050 25 0.235 26 0.036 27 0.023 28 0.060 29 0.070 30 0.947 31 0.048 32 0.023 33 0.106 34 0.075 35 0.185 36 0.073 37 0.045 38 0.051 39 0.050 40 0.026 41 0.031 42 0.495 43 0.091 44 0.106 45 0.058 46 0.136 47 0.138 48 0.044 49 0.039 50 0.017 51 0.019 52 0.037 53 0.789 54 0.047 55 0.043 56 0.041 57 0.231 58 0.145 59 0.085 60 0.188 61 0.243 62 0.064 63 0.015 64 0.081 65 0.076 66 0.082 67 0.010 68 0.034 69 0.036 70 0.050 71 0.375 72 0.472 73 0.105 74 0.705 75 0.224 76 0.106 77 0.008 78 0.953 79 0.313 80 0.318 81 0.025 82 0.504 83 0.015 84 0.010 85 0.154 86 0.012 87 0.028 88 0.049 89 0.060 90 0.032 91 0.047 92 0.439 93 0.108 94 0.188 95 0.130 96 0.021 97 0.712 98 0.244 99 0.065 100 0.073 101 0.054 102 0.058 103 0.162 104 0.061 105 0.249 106 0.186 107 0.019 108 0.077 109 0.041 110 0.033 111 1.085 112 0.854 113 1.042 114 0.208 115 0.493 116 0.121 117 0.049 118 0.020 119 0.109 120 0.343 121 0.015 122 0.989 123 1.001 124 0.078 125 0.023 126 0.011 127 0.318 128 0.056 129 0.217 130 0.007 131 0.563 132 0.099 133 0.010 134 0.041 135 0.044 136 0.009 137 0.017 138 0.012 139 0.357 140 0.067 141 0.181 142 0.077 143 0.323 144 0.168 145 0.915 146 0.206 147 0.127 148 0.344 149 0.332 150 0.554 151 0.241 152 0.132 153 0.412 154 0.285 155 0.206 156 0.304 157 0.392 158 0.070 159 0.740 160 0.069 161 0.374 162 0.136 163 0.135 164 0.467 165 0.361 166 0.056 167 0.116 168 0.439 169 0.091 170 0.306 171 0.097 172 0.255 173 0.844 174 0.179 175 0.582 176 0.410 177 0.349 178 0.038 179 0.031 180 0.235 181 0.449 182 0.748 183 0.041 184 0.075 185 0.026 186 0.097 187 0.073 188 0.237 189 0.095 190 0.220 191 0.131 192 0.076 193 0.303 194 0.027 195 0.044 196 0.143 197 0.128 198 0.031 199 1.190 200 4.419 201 0.461 202 0.071 203 0.862 204 3.527 205 3.737 206 2.484 207 0.387 208 0.113 209 0.091 210 0.107 211 0.469 212 0.095 213 0.282 214 0.853 215 3.772 216 0.247 217 0.096 218 0.293 219 0.101 220 0.038 221 0.043 222 0.040 223 0.062 224 0.070 225 0.044 226 0.083 227 0.076 228 0.077 229 0.025 230 0.117 231 0.105 232 0.025 233 0.252 234 0.695 235 0.342 236 0.058 237 0.054 238 0.046 239 0.067 240 0.060 241 0.082 242 0.079 243 0.086 244 0.077 245 1.312 246 0.033 247 0.010 248 0.012 249 0.021 250 0.043 251 0.053 252 0.186 253 0.067 254 0.075 255 0.088 256 0.039 257 0.007 258 0.026 259 0.015 260 0.035 261 0.059 262 0.062 263 0.080 264 0.130 265 0.041 266 0.089 267 0.464 268 0.018 269 0.014 270 0.096 271 0.036 272 0.054 273 0.149 274 0.264 275 0.076 276 0.020 277 0.031 278 0.011 279 0.234 280 0.149 281 0.059 282 0.049 283 0.058 284 0.090 285 0.149 286 0.147 287 0.124 288 0.109 289 0.056 290 0.056 291 0.053 292 0.1109 293 0.038 294 0.006 295 0.013 296 0.087 297 0.015 298 0.012 299 0.022 300 0.028 301 0.046 302 0.067 303 0.036 304 0.073 305 0.024 306 0.078 307 0.010 308 0.011 309 0.055 310 0.075 311 0.127 312 0.097 313 0.039 314 0.063 315 0.023 316 0.037 317 0.017 318 0.020 319 0.007 320 0.197 321 0.124 322 0.013 323 0.074 324 0.142 325 0.075 326 0.020 327 0.121 328 0.016 329 0.336 330 0.021 331 0.023 332 0.025 333 0.165 334 0.145 335 0.037 336 0.015 337 0.027 338 0.034 339 0.018 340 0.018 341 0.780 342 0.034 343 0.027 344 0.013 345 0.032 346 0.024 347 0.030 348 0.024 349 0.025 350 0.020 351 0.008 352 0.005 353 0.007 354 0.005 355 0.018 356 0.013 357 0.021 358 0.011 359 0.063 360 0.019 361 0.010 362 0.090 363 0.019 364 0.080 365 0.007 366 0.020 367 0.016 368 0.005 369 0.537 370 0.569 371 0.343 372 0.036 373 0.014 374 0.022 375 0.006 376 0.008 377 0.012 378 0.006 379 0.008 380 0.047 381 0.058 382 0.034 383 0.027 384 0.033 385 0.017 386 0.005 387 0.005 388 0.005 389 0.004 390 0.027 391 0.006 392 0.005 393 0.008 394 0.007 395 0.008 396 0.013 397 0.009 398 0.009 399 0.008 400 0.012 401 0.010 402 0.059 403 0.004 404 0.006 405 0.020 406 0.041 407 0.015 408 0.008 409 0.010 410 0.008 411 0.010 412 0.007 413 0.006 414 0.003 415 0.048 416 0.025 417 0.023 418 0.697 419 2.190 420 3.563 421 0.294 422 0.166 423 0.350 424 0.287 425 0.224 426 0.363 427 0.165 428 0.374 429 0.114 430 0.191 431 0.221 432 0.185 433 0.091 434 0.109 435 0.149 436 0.173 437 0.157 438 0.303 439 0.185 440 0.447 441 0.051 442 0.023 443 0.028 444 0.044 445 0.075 446 0.098 447 0.096 448 0.071 449 0.039 450 0.094 451 0.095 452 0.040 453 0.077 454 0.072 455 0.291 456 0.055 457 0.032 458 0.071 459 0.028 460 0.187 461 0.026 462 0.024 463 0.025 464 0.023 465 0.547 466 0.238 467 0.324 468 0.091 469 0.061 470 0.082 471 0.029 472 0.022 473 0.100 474 0.043 475 0.077 476 0.039 477 0.020 478 0.069 479 0.055 480 0.079 481 0.247 482 0.068 483 0.049 484 0.066 485 0.210 486 0.041 487 0.068 488 0.031 489 0.353 490 0.052 491 0.093 492 0.138 493 0.103 494 0.661 495 0.066 496 0.086 497 0.369 498 >10 499 2.258 500 >100 501 0.003 502 0.01 503 0.008 504 0.003 505 0.02 506 0.004 507 0.022 508 0.021 509 0.008 510 0.009 511 0.012 512 0.015 513 0.014 514 0.007 515 0.004 516 0.008 517 0.008 518 1.498 519 0.008 520 0.557 521 2.606 522 0.005 523 0.005 524 0.006 525 0.004 526 0.011 527 0.007 528 0.015 529 0.016 530 0.012 531 0.008 532 0.065 533 0.043 534 0.057 535 0.012 536 0.024 537 0.011 538 0.048 539 0.068 540 0.047 541 0.055 542 0.011 543 0.049 544 0.011 545 1.68 546 0.027 547 0.016 548 0.328 549 0.006 550 0.042 551 0.007 552 0.082 553 0.008 554 0.034 555 0.097 556 0.027 557 0.424 558 0.136 559 1.58 560 0.144 561 0.036 562 0.685 563 0.063 564 0.056 565 0.048 566 0.046 567 0.642 568 0.089 569 0.066 570 0.082 571 0.075 572 0.205 573 0.178 574 0.022 575 0.119 576 0.085 577 0.478 578 0.613 579 0.059 580 0.249 581 0.269 582 0.319 583 0.105 584 0.104 585 0.202 586 0.010 587 0.109 588 0.036 589 0.101 590 2.553 591 0.032 592 0.01 593 0.019 594 0.05 595 0.025 596 0.02 597 0.064 598 0.153 599 0.04 600 0.036 601 0.034 602 0.092 603 0.602 604 0.176 605 0.168 606 1.125 607 0.333 608 2.856 609 0.225 610 0.107 611 0.547 612 2.182 613 0.130 614 1.149 615 1.578 616 1.324 617 1.644 618 1.515 619 1.157 620 0.142 621 0.555 622 0.443 623 0.111 624 0.408 625 0.139 626 0.805 627 1.618 628 2.778 629 1.483 630 0.092 631 0.176 632 0.013 633 1.598 634 0.043 635 0.082 636 0.071 637 0.453 638 0.399 639 0.921 640 1.445 641 2.95 642 1.333 643 2.185 644 0.273 645 0.1 646 0.048 647 1.643 648 0.616 649 0.483 650 1.436 651 0.077 652 1.203 653 0.262 654 0.252 655 1.008 656 1.301 657 0.127 658 0.099 659 0.331 660 0.309 661 0.043 662 0.227 663 2.022 664 0.115 665 0.099 666 2.273 667 0.023 668 0.025 669 0.04 670 0.071 671 0.849 672 0.082 673 1.74 674 0.096 675 0.101 676 0.554 677 0.051 678 1.065 679 0.577 680 0.015 681 0.03 682 0.116 683 2.362 684 1.332 685 0.204 686 0.013 687 3.82 688 0.106 689 >10.0 690 0.047 691 0.015 692 2.48 693 0.056 694 0.034 695 0.929 696 0.103 697 1.777 698 0.151 699 0.051 700 0.321 701 0.446 702 1.256 703 2.159 704 2.218 705 1.722 707 1.992 708 2.508 709 1.144 710 0.146 711 0.03 712 0.015 713 0.074 714 0.045 715 0.105 716 2.161 717 1.481 718 2.618 719 0.254 720 2.45 721 0.079 722 0.085 723 0.046 724 0.034 725 0.015 726 0.03 727 0.017 728 0.036 729 0.039 730 0.037 731 0.066 732 0.027 733 0.005 734 0.026 735 0.005 736 0.02 737 0.037 738 0.105 739 0.017 740 0.009 741 0.016 742 0.024 743 0.028 744 0.046 745 0.024 746 0.07 747 0.016 748 0.015 749 0.006 750 0.011 751 0.013 752 0.021 753 0.021 754 0.027 755 0.102 756 0.023 757 0.029 758 0.032 759 0.018 760 0.017 761 0.055 762 0.027 763 0.466 764 0.155 765 0.047 766 0.038 767 0.106 768 0.121 769 0.022 770 0.062 771 0.033 772 0.356 773 0.124 774 0.022 775 1.08 776 1.151 777 0.042 778 0.381 779 0.016 780 0.009 781 0.011 782 0.011 783 0.005 784 0.005 785 0.006 786 0.003 787 0.007 788 0.02 789 0.01 790 0.008 791 0.007 792 0.006 793 0.012 794 0.002 795 0.011 796 0.005 797 0.016 798 0.012 799 0.004 800 0.009 801 0.024 802 0.009 803 0.004 804 0.017 805 0.012 806 0.006 807 0.019 808 0.012 809 0.007 810 0.357

Example B-2

[1901] The GYS1 cell based assay is a bioluminescent assay that quantifies the glucose resulting from glycogen digestion; the quantified glucose is an indirect measure of GYS1 glycogen synthesis. Newly synthesized glycogen is digested using Glucoamylase; the resulting glucose is quantified by using the Glucose-glo assay kit from Promega. Glucose-glo works by coupling glucose oxidation and NADH production with a bioluminescent system that is activated with NADH. Glucose is oxidized by Glucose dehydrogenase and the reaction reduces NAD+ to NADH; NADH activates Reductase which reduces a pro-luciferin Reductase Substrate to luciferin. Luciferin is detected in a luciferase reaction using Ultra-Glo rLuciferase and ATP, and the luminesce produced is proportional to the glucose in the sample. The luminescence is measured as a single point read in a plate reader.

[1902] Compounds that inhibit the hGYS1 enzyme and, subsequently, the glycogen synthesis in cells, were tested using assay ready plates (white, clear bottom 384 well plates) in a final DMSO reaction volume of 1% DMSO. Compounds in the assay ready plates were mixed with media with no additives, except for 20 mM glucose prior to cell addition. HeLa cells were starved in media with no additives, except for 1× Glutamax for 24 h. Starved HeLa cells were plated, in a 1:1 ratio to the media in the assay ready plate and incubated for 24 h at 37° C. and 5% C.sub.02. Cells were washed in 1×PBS buffer and lysed in lysis buffer containing 50% 1×PBS and 25% 0.3 N HCl of the final volume in the well or reaction volume; cells were incubated with lysis buffer for 10 minutes and quenched with the remaining 25% of the reaction volume that consisted of 450 mM Tris pH 8.0. Lysates were mixed in a 1:1 ratio with Glucoamylase in 100 mM Sodium Acetate buffer, pH 5.3; the mixture was incubated for 1 h at 37° C. The digested lysate was mixed in a 1:1 ratio with Glucose-glo detection mixture as per vendor recommendations (Luciferase detection buffer, Reductase, Reductase substrate, Glucose dehydrogenase, and NAD) in read-out plates (solid white 384-well plates) and incubated for 1 h at RT. The plates were read using a plate reader with luminescence capabilities. Each compound concentration Relative Luminescence Unit (RLU) was averaged and normalized to the average RLU of the positive and negative controls to obtain a percentage inhibition. The normalized data vs. concentration was plotted; to determine the half-maximal concentration (IC.sub.50), the Levenberg-Marquardt algorithm was used to fit a Hill equation to the dose response data.

[1903] The results are shown in Table 3 below, which reports the IC.sub.50 of each compound. Unless otherwise specified, IC.sub.50 values are reported as the geometric mean of at least 2 assay runs on separate days. As shown in the table below, the compounds of the present invention are potent inhibitors of human GYS1. Unless otherwise specified, IC.sub.50 values are reported as the geometric mean of at least two assay runs on separate days. Each run represents the average of a technical replicate, where each compound was assayed twice in the same plate. A superscript “#” symbol in Table 3 indicates results from a single assay run.

TABLE-US-00033 TABLE 3 Compound Avg IC.sub.50 No. (μM) 1 0.42 2 1.09 17 0.33 21 0.47 49 0.36 77 0.12 126 0.17 136 0.17 138 0.27 145 >10.00 149 >10.00 166 0.78 177 2.09 178 0.41 179 0.4 183 0.93 184 3.03 198 0.39 201 3.7 202 1.86 219 1.41 227 1.31 236 0.81 239 1.56 240 2.09 241 1.14 242 1.14 243 2.25 244 1.8 246 0.62 247 0.18 248 0.2 249 1.15 250 1.27 252 2.48 253 1.09 254 1.23 255 1.01 256 0.99 257 0.24 258 0.74 259 0.28 260 0.53 261 1.8 262 3.63 263 1.95 264 4.29 265 0.83 266 1.22 267 4.3 268 0.83 269 0.24 270 1.4 271 0.87 272 0.71 273 1.79 274 3.23 275 1.05 276 0.4 277 0.65 278 0.23 279 2.31 280 1.53 281 1.56 282 4.18 283 2.4 284 5.19 285 >18.64 286 >30.00 287 11.81 293 0.66 294 0.16 295 0.59 296 4.44 297 0.7 298 0.26 299 0.42 300 0.57 301 0.9 302 1.23 303 1.52 304 2.33 305 0.63 306 0.81 307 0.5 308 0.33 309 0.97 310 1.29 311 2.1 312 0.83 313 0.86 314 1.01 315 0.73 316 0.93 317 0.39 318 0.58 319 0.24 320 1.59 321 1.24 322 0.29 323 0.9 326 0.34 330 0.56 332 0.27 335 0.45 336 0.28 338 0.39 339 0.31 340 0.25 342 0.37 343 0.46 347 0.4 348 0.27 349 0.4 351 0.13 352 0.11 353 0.09 354 0.06 355 0.16 356 0.19 357 0.22 358 0.19 359 0.96 360 0.31 361 0.21 362 1.15 363 0.32 364 0.48 365 1.19 367 0.47 368 0.15 369 >30.00 371 3.88 372 1.1 373 0.21 374 0.36 375 0.57 377 0.14 378 0.17 379 0.19 380 0.45 381 0.44 382 0.52 383 0.41 384 0.7 385 0.39 386 0.08 387 0.03 388 0.12 389 0.05 390 1.03 391 0.15 392 0.1 393 0.12 394 0.15 395 0.24 396 0.33 397 0.4 398 0.28 399 0.15 400 0.17 401 0.29 402 0.85 403 0.14 404 0.07 405 0.49 406 0.76 407 0.42 408 0.35 409 0.29 410 0.13 411 0.22 412 0.12 413 0.16 414 0.06 415 0.71 416 0.47 417 0.45 423 >9.26 425 3.59 427 1.96 431 3.35 433 1.48 442 0.86 445 1.66 446 2.19 447 5.32 448 1.35 449 0.7 450 1.73 451 1.57 452 0.98 453 1.84 454 1.6 455 3.62 456 1.08 457 0.72 458 1.33 459 0.75 460 2.42 461 0.57 462 0.64 463 0.67 464 0.65 465 6.04 466 2.32 467 4.81 468 1.43 469 1.18 470 0.96 471 0.7 472 0.54 473 1.77 474 0.88 475 1.29 476 0.9 477 0.63 478 1.19 479 1.43 480 1.12 481 7.77 482 1.41 483 0.72 484 0.82 485 3.72 486 1.02 487 2.09 488 0.88 490 2.87 491 5.55 492 >30.00 493 15.77 494 12.41 495 1.5 496 1.82 497 >5.67 498 >10.00 501 0.05 502 0.17 503 0.24 504 0.06 505 0.35 506 0.37 507 0.26 508 0.31 509 0.18 510 0.23 511 0.26 512 0.29 513 0.22 514 0.77 515 0.1 516 0.71 517 0.54 518 10.68 519 0.22 520 >30.00 521 >30.00 522 0.45 523 0.08 524 0.19 525 0.05 526 0.13 527 0.25 528 0.33 529 1.04 530 0.91 531 0.06 532 1.18 533 1.21 534 1.28 535 1.22 536 0.35 537 0.16 538 1.22 539 0.96 540 0.59 541 0.65 542 1.48 543 0.61 544 0.26 545 >30.00 546 0.51 547 0.36 548 5.76 549 0.12 550 0.65 551 0.21 552 1.12 553 0.4 554 0.38 555 0.66 556 0.76 557 5.78 558 2.46 559 >22.13 560 1.8 561 0.87 562 7.07 563 0.78 564 0.79 565 1.21 566 0.77 567 11.54 568 0.96 569 0.96 570 1.22 571 0.93 572 3.6 573 1.66 574 0.2 575 2.09 576 1.8 577 3.98 578 6.66 579 1.83 580 4.27 581 3.92 582 8.08 583 1.64 584 4.07 585 3.21 586 0.15 587 2.39 588 0.48 589 1.42 590 23.43 591 0.31 592 0.33 593 0.28 594 0.72 595 0.46 596 0.28 597 1.32 598 2.18 599 0.72 600 0.62 601 0.71 602 0.76 604 1.59 605 2.13 607 3.29 608 >10.00 609 1.65 610 1.01 611 5.32 612 >28.95 622 >10.00 623 4.07 624 5.79 625 1.14 626 >30.00 627 29.51 628 >30.00 629 >23.95 630 2.13 631 13.62 632 0.66 633 >30.00 638 >23.41 650 >10.00 651 1.57 652 21.64 653 3.75 654 3.29 655 >30.00 656 10.85 657 1.5 658 1.66 659 4.35 667 0.29 668 0.32 669 0.47 670 0.66 672 1.22 674 0.71 675 1.13 676 13.99 677 0.99 678 >10.00 679 8.49 680 0.27 681 0.43 682 2.09 683 >30.00 684 13.81 685 2.71 686 0.64 687 >30 690 0.9 691 0.39 692 >30.00 693 1.15 694 1.21 695 >26.28 696 2.71 697 9.2 710 2.34 711 0.63 712 0.33 713 0.86 714 1.39 716 22.26 717 >25.76 718 >30.00 719 2.22 720 >30.00 721 1.09 722 1.45 723 0.72 724 0.63 725 0.31 726 0.54 727 0.91 728 0.79 729 0.71 730 0.76 731 1.62 732 1.37 733 0.15 734 1.73 735 0.27 736 0.78 737 0.55 738 1.21 739 0.34 740 0.32 741 0.71 742 0.63 743 0.48 744 1.52 745 0.51 746 1.62 747 0.42 748 0.53 749 0.25 750 0.26 751 0.47 752 0.64 753 0.32 754 0.42 755 1.06 756 1.7 757 0.4 758 1.16 759 0.59 760 0.37 766 0.35 768 1.23 769 0.29 771 0.54 772 4.53 773 1.2 774 0.19 775 >17.54 776 >9.01 777 0.93 778 7.01 779 0.33 780 0.28 781 0.27 782 0.22 783 0.08 784 0.31 785 0.13 786 0.05 787 0.13 788 0.34 789 0.28 790 0.25 791 0.39 792 0.21 793 0.58 794 0.04 795 0.24 796 0.11 797 0.29 798 0.22 799 0.1 800 0.18 801 0.38 802 0.37 803 0.08 804 0.14 805 0.28 806 0.09 807 0.45 809 0.19 810 5.28

Example B-3

[1904] The GYS2 coupled enzyme assay is a kinetic biochemical assay that indirectly quantifies the rate of glycogen synthesis by coupling the conversion of GYS2 substrate UDP-glucose into UDP with downstream enzymatic reactions. UDP is released from UDP-glucose as glucose monomers are linked into the growing glycogen strand by GYS2. The coupled assay then proceeds with pyruvate kinase utilizing UDP and phospho(enol)pyruvate (PEP) to form pyruvate. Lactate dehydrogenase then converts pyruvate and NADH into lactate and NAD+. Oxidation of NADH to NAD+ can be measured continuously with a plate reader by quantifying the decrease in NADH absorbance at 340 nm over time.

[1905] Compounds that inhibit the hGYS2 enzyme and, subsequently, the downstream conversion of NADH to NAD+, were tested using assay ready plates (black, clear bottom 384 well plates) in a final DMSO reaction volume of 2.5% DMSO. The Assay Buffer contained 50 mM Tris pH 7.5, 2 mM MgCl2, and 100 mM KCl. Fresh stocks of BSA at a final concentration of 0.02% and TCEP 1 mM were added before splitting buffer into hGYS2 buffer and substrate buffer. To the hGYS2 buffer, rabbit liver glycogen was added at a final concentration of 0.2% glycogen. Glucose-6-Phosphate was added at 2 mM, recombinant hGYS2/GN1 protein was added at 200 nM to the substrate buffer, phosphoenolpyruvate (PEP) was added at 2 mM, UDP-Glucose was added at 2 mM, NADH was added at 0.6 mM, and Pyruvate Kinase/Lactate Dehydrogenase was added at 20 units/mL. The reaction was initiated by mixing hGYS2 buffer and substrate buffer at a 1:1 ratio. Both buffers were plated using a liquid dispensing device with hGYS2 buffer plated first followed by the substrate buffer. Plates were spun briefly to eliminate air bubbles and are immediately read in continuous mode at an absorbance of 340 nm, for 10 time points in one-minute increments, for a total of 10 minutes. The slope from these 10 time points was normalized to the positive and negative control wells. The duplicate % inhibition values are then averaged and fit to a Hill equation for dose response according to the Levenberg-Marquardt algorithm with the Hill equation maximum set to 100 and the minimum set to 0.

[1906] The results are shown in Table 4 below, which reports the IC.sub.50 of each compound. Unless otherwise specified, IC.sub.50 values are reported as the geometric mean of at least 2 assay runs on separate days. As shown in the table below, the compounds of the present invention are not potent inhibitors of human GYS2. Unless otherwise specified, IC.sub.50 values are reported as the geometric mean of at least two assay runs on separate days. Each run represents the average of a technical replicate, where each compound was assayed twice in the same plate. A superscript “#” symbol in Table 4 indicates results from a single assay run.

TABLE-US-00034 TABLE 4 Compound Avg_IC50 No. (μM) 1 >100.0 2 >100.0 3 >100.0 6 >100.0 7 >100.0 8 >100.0 9 >100.0 10 >100.0 11 >100.0 13 >100.0 14 >100.0 15 >100.0 16 >100.0 17 >100.0 18 >100.0 21 >100.0 22 >100.0 23 >100.0 24 >100.0 25 >100.0 26 >100.0 27 >100.0 28 >100.0 29 >100.0 31 >100.0 32 >100.0 33 >100.0 34 >100.0 35 >100.0 36 >100.0 37 >100.0 38 >100.0 40 >100.0 41 >100.0 44 >100.0 46 >100.0 48 >100.0 49 >100.0 50 >100.0 51 >100.0 52 >100.0 55 >100.0 56 >100.0 57 >100.0 58 >100.0 59 >100.0 60 >100.0 61 >100.0 62 >100.0 63 >100.0 64 >100.0 65 >100.0 67 >100.0 68 >100.0 69 >100.0 70 >100.0 73 >100.0 75 >100.0 76 >100.0 77 >100.0 81 >100.0 83 >100.0 84 >100.0 85 >100.0 86 >100.0 87 >100.0 88 >100.0 89 >100.0 90 >100.0 91 >100.0 93 >100.0 94 >100.0 95 >100.0 96 >100.0 98 >100.0 99 >100.0 100 >100.0 101 >100.0 102 >100.0 103 >100.0 104 >100.0 105 >100.0 106 >100.0 107 >100.0 108 >100.0 109 >100.0 110 >100.0 114 >100.0 117 >100.0 118 >100.0 119 >100.0 121 >100.0 125 >100.0 126 >100.0 128 >100.0 129 >100.0 130 >100.0 133 >100.0 134 >100.0 135 >100.0 136 >100.0 137 >100.0 138 >100.0 140 >100.0 141 >100.0 142 >100.0 144 >100.0 146 >100.0 147 >100.0 151 >100.0 154 >100.0 155 >100.0 158 >100.0 160 >100.0 162 >100.0 163 >100.0 166 >100.0 167 >100.0 169 >100.0 171 >100.0 172 >100.0 174 >100.0 178 >100.0 179 >100.0 180 >100.0 183 >100.0 184 >100.0 185 >100.0 187 >100.0 188 >100.0 189 >100.0 190 >100.0 191 >100.0 192 >100.0 193 >100.0 194 >100.0 195 >100.0 196 >100.0 197 >100.0 198 >100.0 202 >100.0 203 >100.0 204 >100.0 205 >100.0 206 >100.0 207 >100.0 208 >100.0 209 >100.0 210 >100.0 213 >100.0 214 >100.0 216 >100.0 217 >100.0 218 >100.0 219 >100.0 220 >100.0 221 >100.0 222 >100.0 223 >100.0 224 >100.0 226 >100.0 227 >100.0 228 >100.0 229 >100.0 231 >100.0 232 >100.0 233 >100.0 236 >100.0 237 >100.0 238 >100.0 239 >100.0 240 >100.0 241 >100.0 242 >100.0 243 >100.0 244 >100.0 245 >100.0 246 >100.0 247 >100.0 248 >100.0 249 >100.0 250 >100.0 251 >100.0 252 >100.0 253 >100.0 254 >100.0 255 >100.0 256 >100.0 257 >100.0 258 >100.0 259 >100.0 260 >100.0 261 >100.0 262 >100.0 263 >100.0 264 >100.0 265 >100.0 266 >100.0 268 >100.0 269 >100.0 270 >100.0 271 >100.0 272 >100.0 273 >100.0 274 >100.0 275 >100.0 276 >100.0 277 >100.0 278 >100.0 279 >100.0 280 >100.0 281 >100.0 282 >100.0 283 >100.0 284 >100.0 287 >100.0 288 >100.0 289 >100.0 290 >100.0 291 >100.0 292 >100.0 293 >100.0 294 >100.0 295 >100.0 296 >100.0 298 >100.0 299 >100.0 300 >100.0 301 >100.0 302 >100.0 303 >100.0 304 >100.0 306 >100.0 307 >100.0 308 >100.0 309 >100.0 310 >100.0 311 >100.0 312 >100.0 313 >100.0 314 >100.0 315 >100.0 316 >100.0 317 >100.0 318 >100.0 319 >100.0 320 >100.0 321 >100.0 322 >100.0 323 >100.0 324 >100.0 325 >100.0 326 >100.0 328 >100.0 330 >100.0 331 >100.0 332 >100.0 333 >100.0 334 >100.0 335 >100.0 336 >100.0 337 >100.0 338 >100.0 339 >100.0 340 >100.0 342 >100.0 343 >100.0 344 >100.0 345 >100.0 346 >100.0 347 >100.0 348 >100.0 349 >100.0 350 >100.0 351 >100.0 352 >100.0 353 >100.0 354 >100.0 355 >100.0 356 >100.0 357 >100.0 358 >100.0 359 >100.0 360 >100.0 361 >100.0 362 >100.0 363 >100.0 364 >100.0 365 >100.0 366 >100.0 367 >100.0 368 >82.29 369 >100.0 371 >100.0 372 >100.0 373 >100.0 374 >100.0 375 >77.43 376 >100.0 377 >100.0 378 >100.0 379 >100.0 380 >100.0 381 >100.0 382 >100.0 383 >100.0 384 >100.0 385 >100.0 386 >100.0 387 36.22 388 >100.0 389 >90.29 390 >100.0 391 89.32 392 >100.0 393 >100.0 394 >100.0 395 >100.0 396 >100.0 398 >100.0 399 >100.0 400 >100.0 401 >100.0 402 >100.0 403 >100.0 404 >100.0 405 >100.0 406 >100.0 407 >100.0 408 >100.0 409 >100.0 410 >100.0 411 >100.0 412 >100.0 413 >100.0 414 78.66 415 >100.0 416 >100.0 417 >100.0 418 >100.0 421 >100.0 422 >100.0 424 >100.0 425 >100.0 426 >100.0 427 >100.0 428 >100.0 430 >100.0 431 >100.0 432 >100.0 433 >100.0 434 >100.0 435 >100.0 436 >100.0 437 >100.0 439 >100.0 441 >100.0 442 >100.0 443 >100.0 444 >100.0 445 >100.0 446 >100.0 447 >100.0 448 >100.0 449 >100.0 450 >100.0 451 >100.0 452 >100.0 453 >100.0 454 >100.0 455 >100.0 456 >100.0 457 >100.0 458 >100.0 459 >100.0 462 >100.0 463 >100.0 464 >100.0 465 >100.0 466 >100.0 467 >100.0 468 >100.0 469 >100.0 470 >100.0 471 >100.0 472 >100.0 474 >100.0 475 >100.0 476 >100.0 477 >100.0 478 68.22 479 >100.0 480 >100.0 481 >100.0 482 >100.0 483 >100.0 484 >100.0 485 >100.0 486 >100.0 487 >100.0 488 >100.0 490 >100.0 491 >100.0 492 >100.0 495 >100.0 496 >100.0 497 >100.0 501 >100.0 502 >100.0 503 >100.0 504 >100.0 505 >100.0 506 >100.0 507 >100.0 508 >100.0 509 >100.0 510 >100.0 511 >100.0 512 >100.0 513 >100.0 514 >100.0 515 >100.0 516 >100.0 517 >100.0 518 >100.0 519 >100.0 520 >100.0 522 >100.0 532 >100.0 533 >100.0 534 >100.0 535 >100.0 536 >100.0 537 >100.0 538 >100.0 539 >100.0 540 >100.0 541 >100.0 542 >100.0 544 >100.0 546 >100.0 547 >100.0 548 >100.0 549 >100.0 550 >100.0 551 >100.0 552 >100.0 553 >100.0 554 >100.0 556 >100.0 558 >100.0 560 >100.0 561 >100.0 562 >100.0 563 >100.0 564 >100.0 565 >100.0 566 >100.0 567 >100.0 568 94.24 569 >100.0 570 >100.0 571 >100.0 572 >100.0 573 >100.0 574 >100.0 575 >100.0 576 >100.0 577 41.18 578 79.27 579 >100.0 580 >100.0 581 >100.0 582 >100.0 583 >100.0 584 >91.76 585 >100.0 586 >100.0 587 >100.0 588 >100.0 589 >100.0 590 >100.0 591 >100.0 592 >100.0 593 >100.0 594 >100.0 595 >100.0 596 >96.68 597 >100.0 599 >100.0 600 >100.0 602 >100.0 603 >100.0 604 >100.0 605 >100.0 607 >100.0 609 >100.0 611 >100.0 613 >100.0 620 >100.0 623 >100.0 625 >100.0 630 >100.0 631 >100.0 632 >100.0 639 >100.0 640 >100.0 642 >100.0 644 >100.0 645 >100.0 646 >100.0 651 >100.0 653 >100.0 659 17.53 660 >100.0 661 >100.0 662 >100.0 664 >100.0 665 >100.0 667 >100.0 668 >100.0 669 >100.0 670 >100.0 671 >100.0 672 >100.0 674 >100.0 675 >100.0 676 >100.0 677 >100.0 679 >100 680 93.0 681 >100.0 682 >100.0 685 >100.0 686 >100.0 690 >100.0 710 >100.0 711 >100.0 719 >100.0 722 >100.0 723 >100.0 724 >100.0 725 >100.0 726 >100.0 727 >100.0 728 >100.0 729 >100.0 731 >100.0 732 >100.0 733 >100.0 734 >100.0 735 >100.0 736 >100.0 765 >100.0 766 >100.0 767 >100.0 768 >100.0 769 >100.0 770 >100.0 771 >100.0 772 >100.0 773 >100.0 774 >100.0 777 >100.0 779 >100.0 780 >100.0 781 >100.0 782 >100.0 783 >100.0 784 >100.0 785 >100.0 786 >100.0 787 >100.0 788 >100.0 789 >100.0 790 >100.0 791 >100.0 792 >100.0 793 >100.0 794 >100.0 795 >100.0 809 >100.0 810 >100.0

Example B-4

[1907] Pompe disease is a glycogen storage disease caused by mutations in the enzyme acid alpha-glucosidase resulting in pathological accumulation of glycogen. Glycogen can accumulate in virtually all tissues, but the primary pathology affects skeletal and cardiac muscle. Inhibiting the synthesis of muscle glycogen could reduce the pathologic build-up of glycogen by acting as a substrate reduction therapy. Savage et. al. identified a predicted protein truncating variant (PTV) in the PPP1R3A gene (a regulator of glycogen metabolism) in ˜0.5% of Europeans, which results in ˜65% reduction in muscle glycogen (Savage et. al., A Prevalent Variant in PPP1R3A Impairs Glycogen Synthesis and Reduces Muscle Glycogen Content in Humans and Mice. PLoS Medicine. 2008; herein incorporated by reference in its entirety). PPP1R3A functions as a key activator of muscle glycogen synthase 1 (GYS1) by dephosphorylating the enzyme and maximizing activity. FIG. 1 demonstrates the pathway in which PPP1R3A (loss of function) LoF leads to reduction in muscle glycogen.

[1908] Large biobanks enable investigation of the consequences of genetic variation on many health-related phenotypes. To assess the consequences of a predicted 65% loss of muscle glycogen, association study was performed in the UK Biobank comparing phenotypes between PPP1R3A PTV carriers and non-carriers. Genetic association studies were performed using REGENIE (Mbatchou, J., Barnard, L., Backman, J. et al. Computationally efficient whole-genome regression for quantitative and binary traits. Nat Genet 53, 1097-1103, 2021), adjusted for age, sex, and the first 10 principal components of ancestry. Quantitative traits were normalized using an inverse rank normal transformation.

[1909] With regards to FIGS. 2A-2H, the association between PPP1R3A PTV and the quantitative phenotypes of left ventricular ejection (LVEF) (%) (FIG. 2A), left ventricle wall thickness (mm) (FIG. 2B), exercise output (watts) (FIG. 2C), max heart rate (HR) exercise (bpm) (FIG. 2D), PQ interval (ms) (FIG. 2E), QRS duration (ms) (FIG. 2F), QT interval (ms) (FIG. 2G), and serum glucose (mmol/L) (FIG. 2H), are depicted. Phenotype values are plotted by PPP1R3A dosage for UK Biobank participants. No association between PPP1R3A PTV and the quantitative phenotypes in the UK Biobank was identified.

[1910] Table 5 below lists the P-value and number of participants (N) for the results depicted in FIGS. 2A-H. No associations between PPP1R3A PTV and cardiac parameters, including left ventricular ejection fraction (p=0.871) and wall thickness (p=0.168) were identified. There was no evidence of changes in EKG cardiac conduction intervals nor in any muscle performance measurements (n=49,616), including maximum heart rate (p=0.444) and maximum workload during an exercise test (p=0.100). Further, no changes in serum glucose (p=0.71) or any other members of a panel of −170 serum metabolites were observed.

TABLE-US-00035 TABLE 5 Phenotype P-value N LVEF 0.871 27,716 LV Wall Thickness 0.168 27,579 Exercise Output 0.100 49,616 Max HR Exercise 0.444 49,603 QRS Duration 0.527 29,507 PQ Interval 0.366 16,694 QT Interval 0.222 17,574 Serum Glucose 0.477 294,042

[1911] As shown in Table 6 below, no association between PPP1R3A PTV and key health outcomes was also observed. In addition to the phenotypes in Table 6, no phenome-wide significant associations between PPP1R3A PTV and rates of any ICD10 code with over 100 occurrences in UK Biobank was observed.

TABLE-US-00036 TABLE 6 Effect Disease (SE) P-value N Cases Type 2 Diabetes −0.094 0.200 18,868 (0.073) Liver Cirrhosis −0.041 0.880 1,325 (0.273) Heart Failure −0.061 0.630 6,117 (0.127)

[1912] After performing an extensive Phenome-wide association study in UK Biobank, no significant associations between any key outcomes or phenotypes and loss of function of PPP1R3A were found. The results provided herein demonstrate that loss of function variants in the PPP1R3A gene are not associated with adverse health outcomes in a large biobank population. This suggests that partial reduction in muscle glycogen (˜65%) from birth is well tolerated and supports the potential safety of pharmacologic reduction of muscle glycogen.

[1913] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entireties, to the same extent as if each were incorporated by reference individually.

[1914] It is to be understood that, while the disclosure has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

INHIBITORS OF GLYCOGEN SYNTHASE 1 (GYS1) AND METHODS OF USE THEREOF

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C07D401/06

CHEMISTRY; METALLURGY

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C07D401/12

CHEMISTRY; METALLURGY

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