WO2024059087A1 - 3-(1h-indole-2-carbonyl)-6,6-dimethyl-n-((s)-1-oxo-3-((s)-2-oxopyrrolidin-3-yl)p ropan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide derivatives as mpro inhibitors for the treatment of coronavirus infections - Google Patents

3-(1h-indole-2-carbonyl)-6,6-dimethyl-n-((s)-1-oxo-3-((s)-2-oxopyrrolidin-3-yl)p ropan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide derivatives as mpro inhibitors for the treatment of coronavirus infections Download PDF

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WO2024059087A1
WO2024059087A1 PCT/US2023/032564 US2023032564W WO2024059087A1 WO 2024059087 A1 WO2024059087 A1 WO 2024059087A1 US 2023032564 W US2023032564 W US 2023032564W WO 2024059087 A1 WO2024059087 A1 WO 2024059087A1
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alkyl
compound
cycloalkyl
pharmaceutically acceptable
acceptable salt
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PCT/US2023/032564
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French (fr)
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Daniel Carney
Edcon Chang
Mallareddy Komandla
Leah L. Frye
Abba LEFFLER
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Takeda Pharmaceutical Company Limited
Schrodinger, Inc.
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Publication of WO2024059087A1 publication Critical patent/WO2024059087A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • TECHNICAL FIELD [0002] The present disclosure relates to novel protease inhibitors useful for inhibiting coronavirus replication and methods for treating a subject infected by coronavirus including the SARS-CoV-2 virus.
  • BACKGROUND [0003] Coronaviruses are a family of enveloped, single-stranded, positive-sense, RNA viruses that are known to cause disease in a wide variety of animals.
  • SARS-CoV-2 is responsible for the COVID-19 respiratory illness and the ensuing pandemic, which as of March 2022, has caused more than 6 million deaths worldwide (WHO COVID-19 dashboard https://covid19.who.int/).
  • WHO COVID-19 dashboard https://covid19.who.int/ Although safe and effective vaccines have been developed, global implementation has been hampered by limited access and recipient hesitancy. Furthermore, breakthrough infections and illness in vaccinated individuals have been widely documented. Most experts believe that COVID-19 will become an endemic illness that will persist in humans for many years to come, if not indefinitely. Therapeutic options for COVID-19 are currently limited. There is a clear unmet medical need for targeted antiviral therapeutics for the treatment COVID-19.
  • SARS-CoV-1 Recent history of severe respiratory illnesses cause by coronaviruses (SARS-CoV-1, MERS-CoV, SARS-CoV-2) highlights the importance of pan- coronavirus therapeutics for future pandemic preparedness.
  • SARS-CoV-2 genome contains 13-15 open reading frames that encode for a variety of structural and non-structural proteins (nsp’s).
  • nsp structural and non-structural proteins
  • ORF1ab The largest open reading frame (ORF1ab) encodes for 2 overlapping polyproteins (pp1a, pp1b) that are cleaved at sequence specific sites into 16 distinct nsp’s that are involved in viral replication, viral assembly, and host immune modulation.
  • Mpro main protease
  • Plp papin-like protease
  • the main protease cleaves peptides after a glutamine (P1) that is adjacent to a hydrophobic residue such as leucine, phenylalanine, or valine (P2). Ullrich, S. and Nitsche, C. (2020).
  • P1 glutamine
  • P2 phenylalanine
  • valine valine
  • proteases This substrate recognition is distinct from all known human proteases. Id. Proteolysis is mediated by a cysteine – histidine catalytic diad along with a buried water molecule that is hydrogen bonded to the catalytic histidine.
  • the main protease sequence is well conserved across human coronaviruses, particularly the active site and substrate binding pocket.
  • R 1 is (a) -C 1-6 alkyl, (b) -C 1-6 haloalkyl, (c) -C 1-6 alkylene-NHCO-C 1-6 haloalkyl, (d) -C 0-6 alkylene-(saturated cycloalkyl), (e) -C 0-6 alkylene-heterocycloalkyl, (f) -C 0-6 alkylene-(tricyclic heteroaryl), (g) -heteroarylene-cycloalkyl, (h) -heteroarylene-aryl, (i) -NH2, -NO2, -C 1-6 alkyl, alkenyl, -C 1-6 alkoxy, -C 1-6 haloalkyl, -O-C 0-6 alkylene-aryl, aryl, cycloalkyl,
  • Another aspect of the present disclosure provides compounds selected from any of the compounds prepared in the examples, or a pharmaceutically acceptable salt thereof.
  • a further aspect of the present disclosure provides a pharmaceutical composition comprising the compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • An additional aspect of the present disclosure provides a method of treating a viral infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of the disclosure.
  • Another aspect of the present disclosure provides a compound of the disclosure or a pharmaceutically acceptable salt or ester thereof, for use in treating a coronavirus infection in a human.
  • a further aspect of the present disclosure provides a compound of the disclosure or a pharmaceutically acceptable salt or ester thereof, for use in treating SARS-CoV-2 infection in a human.
  • An additional aspect of the present disclosure relates to a medical use of the compounds or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a coronavirus infection.
  • DETAILED DESCRIPTION [0014] As used herein, all technical and scientific terms have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.
  • disease or “condition” refers to disturbances and/or anomalies that are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and/or malfunctions.
  • compounds of the present disclosure are inhibitors of Mpro and can be used in treating or preventing diseases and conditions wherein inhibition of Mpro provides a benefit.
  • treatment As used herein, the terms “treatment,” “treat,” and “treating” are interchangeable and refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, including but not limited to therapeutic benefit.
  • treatment includes one or more of the following: (a) inhibiting the disorder (for example, decreasing one or more symptoms resulting from the disorder, and/or diminishing the extent of the disorder); (b) slowing or arresting the development of one or more symptoms associated with the disorder (for example, stabilizing the disorder and/or delaying the worsening or progression of the disorder); and/or (c) relieving the disorder (for example, causing the regression of clinical symptoms, ameliorating the disorder, delaying the progression of the disorder, and/or increasing quality of life).
  • Therapeutic benefit includes eradication and/or amelioration of the underlying disorder being treated.
  • prevent, preventing, and prevention refer to a method of preventing or delaying the onset of a disease or condition and/or its attendant symptoms or barring a subject from acquiring a disease.
  • prodrug or other pharmaceutically acceptable derivative thereof may include “prophylactic treatment”, which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition.
  • administering or “administration” of the compound of formula (I) or formula (I-A) or a pharmaceutically acceptable salt thereof encompasses the delivery to a patient a compound or a pharmaceutically acceptable salt thereof, or a prodrug or other pharmaceutically acceptable derivative thereof, using any suitable formulation or route of administration, e.g., as described herein.
  • the term "therapeutically effective amount” or “effective amount” refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disorder, is sufficient to effect such treatment of the disorder.
  • the effective amount will vary depending on the disorder, and its severity, and the age, weight, etc. of the subject to be treated.
  • the effective amount may be in one or more doses (for example, a single dose or multiple doses may be required to achieve the desired treatment endpoint).
  • An effective amount 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.
  • Suitable doses of any co-administered compounds may optionally be lowered due to the combined action, additive or synergistic, of the compound.
  • patient or “subject” refers to human subject of any age groups and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys).
  • pharmaceutically acceptable or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19.
  • the term "pharmaceutically acceptable carrier” is used herein to refer to a material that is compatible with a recipient subject, preferably a mammal, more preferably a human, and is suitable for delivering an active agent to the target site without terminating the activity of the agent.
  • the toxicity or adverse effects, if any, associated with the carrier preferably are commensurate with a reasonable risk/benefit ratio for the intended use of the active agent.
  • the term “orally” refers to administering a composition that is intended to be ingested. Examples of oral forms include, but are not limited to, tablets, pills, capsules, powders, granules, solutions or suspensions, and drops. Such forms may be swallowed whole or may be in chewable form.
  • C 1 -C 10 or C 1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it;
  • C1-C6 or C 1-6 indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it.
  • an alkyl group contains from 1 to about 20 carbon atoms.
  • alkyl groups have 1 to about 10 carbon atoms.
  • alkyl groups (“lower alkyl”) have 1 to 8, 1 to 6, or 1 to 3 carbon atoms in the chain.
  • alkylene as used herein includes an alkyl group that is substituted at two points. An example is methylene (-CH 2 -), propylene (-CH 2 CH 2 CH 2 -), and the like.
  • substituted with 0, 1, 2, 3, or 4 substituents refers to that a group may be unsubstituted when the group is substituted with 0 substituent, or that the group is substituted with 1, 2, 3, or 4 substituents.
  • optionally substituted refers to that a group may be unsubstituted, or substituted with one or more of the indicated substituents.
  • substituted with 0, 1, 2, 3, or 4 substituents has the same meaning and is equivalent to the term “optionally substituted with 1, 2, 3, or 4 substituents”.
  • alkoxy refers to an alkyl group attached to a terminal oxygen atom.
  • Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy.
  • amino protecting group refers to a protecting group that is suitable for preventing undesired reactions at an amino nitrogen.
  • Representative amino-protecting groups include, but are not limited to, formyl; acyl groups, such as acetyl and trifluoroacetyl; alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl (Bn), trityl (Tr), and 1,1-di-(4'-methoxyphenyl)methyl; and the like.
  • cycloalkyl refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic, bicyclic, or tricyclic aliphatic hydrocarbons containing three to twelve carbon atoms, i.e., a C3-12 cycloalkyl, or the number of carbons designated, e.g., a C 3 cycloalkyl such a cyclopropyl, a C 4 cycloalkyl such as cyclobutyl, etc.
  • the cycloalkyl is bicyclic, i.e., it has two rings.
  • the cycloalkyl is monocyclic, i.e., it has one ring.
  • a cycloalkyl group may be unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NO2, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -SO2(C 1-6 alkyl), -CO(C 1-6 alkyl), benzyloxy, cycloalkyl, aryl, and heteroaryl.
  • the benzyloxy, cycloalkyl, aryl, and heteroaryl may be further substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NO2, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -SO2(C1- 6 alkyl), -CO(C 1-6 alkyl), benzyloxy, cycloalkyl, aryl, and heteroaryl.
  • substituents selected from the group consisting of halo, -OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NO2, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -
  • cycloalkylene as used herein includes a cycloalkyl group that is substituted at two points.
  • aryl refers to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyl tetrahydrofluorenyl, tetrahydroanthracenyl, or anthracenyl) ring systems having six to fourteen carbon atoms in which the monocyclic ring system is aromatic or at least one of the rings in a bicyclic or tricyclic ring system is aromatic.
  • the other ring(s) in the bicyclic or tricyclic ring system may be saturated, partially unsaturated, or fully unsaturated.
  • the bicyclic and tricyclic groups include benzofused carbocyclic rings.
  • a benzofused group includes a phenyl group fused with one or two 4 to 8 membered carbocyclic moieties.
  • An aryl group may be unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NO 2 , -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -SO 2 (C 1-6 alkyl), -CO(C 1 - 6alkyl), benzyloxy, cycloalkyl, aryl, and heteroaryl.
  • substituents selected from the group consisting of halo, -OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NO 2 , -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -SO 2 (
  • the benzyloxy, cycloalkyl, aryl, and heteroaryl may be further substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NO2, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -SO2(C 1-6 alkyl), -CO(C 1-6 alkyl), benzyloxy, cycloalkyl, aryl, and heteroaryl.
  • substituents selected from the group consisting of halo, -OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NO2, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy
  • heteroaryl refers to monocyclic, bicyclic, or tricyclic ring systems containing five to fourteen ring atoms including carbon, zero, one, two, three, or four heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen.
  • the monocyclic ring system is aromatic and at least one of the rings in the bicyclic or tricyclic ring systems is aromatic.
  • the other ring(s) in the bicyclic or tricyclic ring system may be saturated, partially unsaturated, or fully unsaturated.
  • the heteroaryl has three heteroatoms.
  • the heteroaryl has two heteroatoms.
  • the heteroaryl has one heteroatom.
  • the heteroaryl has five to twelve ring atoms. In some embodiments, the heteroaryl has eight to twelve ring atoms. In some embodiments, the heteroaryl has eight or nine ring atoms. In some embodiments, the heteroaryl has nine ring atoms.
  • Non-limiting exemplary heteroaryl groups include thienyl (e.g., thien-2-yl and thien-3-yl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyr
  • the heteroaryl group is indolyl. In some embodiments, the heteroaryl group is 1H-indolyl. In some embodiments, the heteroaryl group is 5H-[1,3]dioxolo[4,5-f]indole.
  • the term heteroaryl also includes N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide.
  • a heteroaryl group may be unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NO2, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -SO2(C 1-6 alkyl), -CO(C 1-6 alkyl), benzyloxy, cycloalkyl, aryl, and heteroaryl.
  • substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NO2, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -SO2(C 1-6 alkyl), -CO(C 1-6
  • the benzyloxy, cycloalkyl, aryl, and heteroaryl may be further substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NO2, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -SO 2 (C 1-6 alkyl), -CO(C 1-6 alkyl), benzyloxy, cycloalkyl, aryl, and heteroaryl.
  • substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NO2, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -SO 2 (C
  • heteroarylene as used herein includes a heteroaryl group that is substituted at two points.
  • heterocycloalkyl refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic or bicyclic ring structure containing three to fourteen ring members, in which zero, one, two, or three of the ring atoms is a heteroatom.
  • Each heteroatom is independently oxygen, sulfur, or nitrogen.
  • the heterocycloalkyl has three heteroatoms.
  • the heterocycloalkyl has two heteroatoms.
  • the heterocycloalkyl has one heteroatom.
  • Non-limiting exemplary heterocycloalkyl groups include thiacyclohexanyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl and thietanyl, oxazinyl, oxetanyl, azetidinyl, thietanyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydrothiophenyl, tetrahydro- 2H-pyran, dihydropyranyl, dioxanyl, 1,3-dioxolanyl, 1,4-dithianyl, hexahydropyrimidine, pyrrolidinyl, dihydropyrrolyl, morpholinyl, piperazinyl, piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyr
  • a heterocycloalkyl group may be unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NO 2 , -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -SO 2 (C 1-6 alkyl), - CO(C 1-6 alkyl), benzyloxy, cycloalkyl, aryl, and heteroaryl.
  • substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NO 2 , -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -SO 2 (C 1-6
  • the benzyloxy, cycloalkyl, aryl, and heteroaryl may be further substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NO2, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -SO2(C 1-6 alkyl), -CO(C 1-6 alkyl), benzyloxy, cycloalkyl, aryl, and heteroaryl.
  • haloalkyl refers to an alkyl group where at least one hydrogen has been replaced with a halo group. In certain embodiments, the haloalkyl group has one halo group. In certain embodiments, the haloalkyl group has two or three halo groups. In certain embodiments, the haloalkyl group is a perfluorinated alkyl group. Examples may include, but are not limited to, chloromethyl, trifluoromethyl, and the like.
  • hydroxyalkyl refers to an alkyl group where at least one hydrogen has been replaced with an alcohol (-OH) group. In certain embodiments, the hydroxyalkyl group has one alcohol group.
  • the hydroxyalkyl group has two alcohol groups, each on a different carbon atom. Examples may include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, and 1-hydroxyethyl.
  • the groups may be the same or different. For example, if R a and R b are each independently alkyl, -F, -NH 2 , or -OH, then a molecule with two R a groups and two R b groups could have all groups be an alkyl group (e.g., four different alkyl groups).
  • the first R a could be alkyl
  • the second R a could be -F
  • the first R b could be -OH
  • the second R b could be -NH2 (or any other substituents taken from the group).
  • both R a and the first R b could be -F
  • the second R b could be alkyl (i.e., some pairs of substituent groups may be the same, while other pairs may be different).
  • Compounds of the present disclosure may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure encompasses the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof.
  • the present disclosure provides a compound of formula I: I or a pharmaceutically acceptable salt thereof, wherein: R 1 is (a) -C 1-6 alkyl, (b) -C 1-6 haloalkyl, (c) -C 1-6 alkylene-NHCO-C 1-6 haloalkyl, (d) -C 0-6 alkylene-(saturated cycloalkyl), (e) -C 0-6 alkylene-heterocycloalkyl, (f) -C 0-6 alkylene-(tricyclic heteroaryl), (g) -heteroarylene-cycloalkyl, (h) -heteroarylene-aryl, (i) , , , , , , wherein R A is halo, -OH, -CN, -NH2, -NO2, -C 1-6 alkyl, alkenyl, -C
  • R 1 is (a) -C 1-6 alkyl, (b) -C 1-6 alkylene-NHCO-C 1-6 haloalkyl, (c) -C 0-6 alkylene-(saturated cycloalkyl), (d) -C 0-6 alkylene-heterocycloalkyl, (e) -C 0-6 alkylene-(tricyclic heteroaryl), (f) -heteroarylene-cycloalkyl, ( , , , , , wherein R A is halo, -OH, -CN, -NH2, -NO2, -C 1-6 alkyl, alkenyl, -C 1-6 alkoxy, -C 1-6 haloalkyl, -O-C 0-6 alkylene-aryl, aryl,
  • R 1 is (a) -C 1-6 alkyl, (b) -C 1-6 alkylene-NHCO-C 1-6 haloalkyl, (c) -C 0-6 alkylene-(saturated cycloalkyl), wherein cycloalkyl is substituted with 0 or 1 phenyl, (d) -C 0-6 alkylene-(3-7 membered heterocycloalkyl), (e) -C 0-6 alkylene-(8-12 membered tricyclic heteroaryl), wherein the tricyclic heteroaryl is substituted with 0 or 1 substituents selected from the group consisting of C 3-6 cycloalkyl and phenyl, (f) -(5-12 membered heteroarylene)-C 3-6 cycloalkyl, (g) -(5-12 membered heteroarylene)-phenyl, (h)
  • R 10 is halo, CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -O(C 1-6 branched alkyl), or -SO2(C 1-6 alkyl); and m is 0, 1, or 2; and (j) or , wherein R 11 is halo, CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, or -SO 2 (C 1-6 alkyl); and r is 0 or 1; wherein at each occurrence, the cycloalkyl, heterocycloalkyl, aryl, phenyl, and heteroaryl are each independently substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -SO2(C 1-6 alkyl), and
  • R 1 is -C 0-6 alkylene-(C3-6 saturated cycloalkyl), wherein the cycloalkyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, and -C 1-6 alkoxy.
  • R 1 in embodiment one is selected from .
  • R 1 is [ , wherein R 1 is substituted with 0, 1, or 2 R A substituents independently selected from the group consisting of halo, -OH, -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, and -C 1-6 alkoxy; and p is 0, 1, or 2.
  • R 1 is halo or -C 1-6 alkyl; and P is 0 or 1.
  • R 1 is selected from .
  • R 1 is -C 0-6 alkylene-heterocycloalkyl, wherein the heterocycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo, -OH, -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, and -C 1-6 alkoxy.
  • R 1 is -C 0 - 3 alkylene-(5-7 membered heterocycloalkyl.
  • R 1 is selected from .
  • R 1 is selected from , , , , , or , wherein R A is halo, -OH, -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, or -C 1-6 alkoxy. [0063] In some embodiments of formula I R 1 is selected from .
  • R is (a) -C 0-6 alkylene-(8-12 membered tricyclic heteroaryl), wherein the tricyclic heteroaryl is substituted with 0 or 1 substituents selected from the group consisting of C3-6cycloalkyl and phenyl, (b) -C 0-6 alkylene-(8-12 membered tricyclic heteroaryl), wherein the tricyclic heteroaryl is substituted with 0 or 1 substituents selected from the group consisting of C3-6cycloalkyl and phenyl, or (c) -(5-12 membered heteroarylene)-phenyl.
  • R 1 in formula I is , , , o , wherein R 10 or R 11 is independently halo, -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, or -SO2(C 1-6 alkyl).
  • R 1 is , wherein R 10 is halo, CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, or -SO2(C 1-6 alkyl); and m is 0, 1, or 2.
  • R 1 is a 5 to 12 membered heteroaryl, (5-12 membered heteroarylene)-C 3-6 cycloalkyl, or -(5-12 membered heteroarylene)-phenyl, wherein the heteroaryl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo, -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, and -SO 2 (C 1-6 alkyl).
  • R 1 is a 8 to 12 membered heteroaryl, (8-12 membered heteroarylene)-C3-6cycloalkyl, or -(8-12 membered heteroarylene)-phenyl, wherein the heteroaryl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo, -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, and -SO 2 (C 1-6 alkyl).
  • R 1 is a 8 to 12 membered heteroaryl substituted with 0, 1, or 2 substituents selected from the group consisting of halo, -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, and -SO 2 (C 1-6 alkyl).
  • R 1 is selected from any of the moieties in Table 1. Table 1
  • R 1 is selected from any of the moieties in Table 2.
  • Table 2
  • R 2 is H;
  • R 3 and R 4 are each independently -H, halo, -OH, -CN, -NH2, -NO2, methylenyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-6 haloalkyl, -O-C 0-6 alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl;
  • R 5 is -H, halo, -C 1-6 alkyl, or -C 1-6 haloalkyl; or R 3 and R 4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; or R 3 and R 5 together with the carbon atoms to which they are attached, form a C 3 -C 6 cycloalkyl; or R 4 and R 5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl;
  • R is H;
  • R 3 and R 4 are each independently -H, halo, -OH, -CN, methylenyl, -C 1-6 alkyl, -C 1-6 alkoxy, phenyl, phenoxy, benzyl, C 3 -C 6 cycloalkyl, 5-7 membered heterocycloalkyl, or 5-9 membered heteroaryl;
  • R 5 is -H, halo, -C 1-6 alkyl, or -C 1-6 haloalkyl; or R 3 and R 4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; or R 3 and R 5 together with the carbon atoms to which they are attached, form a C 3 -C 6 cycloalkyl; or R 4 and R 5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R 2 and R 3 together with the
  • R 2 is H; R 3 and R 4 are each independently -H, halo, -OH, -CN, methylenyl, -C 1-6 alkyl, -C 1-6 alkoxy, phenyl, phenoxy, benzyl, or C3-C6cycloalkyl; R 5 is -H, halo, or -C 1-6 alkyl; or R 3 and R 4 together with the carbon atom to which they are attached, form a C 3 -C 6 cycloalkyl; or R 3 and R 5 together with the carbon atoms to which they are attached, form a C 3 -C 6 cycloalkyl; or R 2 and R 3 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R 2 and R 5 together with the pyrrolidine ring to which they are attached form a bridged 6 to 8 membered heterocycloalkyl; wherein at
  • R 3 and R 4 are each independently -H, halo, -OH, -CN, methylenyl, -C 1-6 alkyl, -C 1-6 alkoxy, phenyl, phenoxy, benzyl, or C 3 -C 6 cycloalkyl, wherein the phenyl, phenoxy, and benzyl are each independently substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C 1-6 alkyl.
  • R 3 is -H, halo, -OH, -CN, methylenyl, -C 1-6 alkyl, -C 1-6 alkoxy, phenyl, phenoxy, benzyl, or C 3 -C 6 cycloalkyl, wherein the phenyl, phenoxy, and benzyl are each independently substituted with 0 or 1 substituent selected from the group consisting of halo and -C 1-6 alkyl; and R 4 is -H, halo, or -C 1-6 alkyl.
  • R 3 is -H, -F, -Me, -Et, -OH, -CN, methylenyl, -OMe, phenyl, phenoxy, , , or cyclohexyl; and R 4 is -H, -F, -Me, or –Et.
  • R 2 is H and R 5 is -H or -C 1-6 alkyl.
  • R 2 and R 5 are H.
  • R 3 is -H, halo, -OH, -CN, methylenyl, -C 1-6 alkyl, -C 1-6 alkoxy, phenyl, phenoxy, benzyl, or C 3 -C 6 cycloalkyl, wherein the phenyl, phenoxy, and benzyl are each independently substituted with 0 or 1 substituent selected from the group consisting of halo and -C 1-6 alkyl; R 4 is -H, halo, or -C 1-6 alkyl; R 2 is -H; and R 5 is -H or -C 1-6 alkyl.
  • R 3 in embodiment one is -H, -F, -Me, -Et, -OH, -CN, methylenyl, -OMe, phenyl, phenoxy , , or cyclohexyl;
  • R 4 is -H, -F, -Me, or -Et; and
  • R 2 and R 5 are -H.
  • R 3 and R 4 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C 1-6 alkyl.
  • R and R together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl; R 2 is H; and R 5 is -H or -C 1-6 alkyl.
  • R 3 and R 4 together with the carbon atom to which they are attached form a C3-C4cycloalkyl; and R 2 and R 5 are –H.
  • R 3 and R 5 together with the carbon atoms to which they are attached form a C3-C6cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C 1-6 alkyl.
  • R 3 and R 5 together with the carbon atoms to which they are attached form a C 3 -C 6 cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents which is -C 1-6 alkyl; R 2 is H; and R 4 is -H or -C 1-6 alkyl.
  • R 3 and R 5 together with the carbon atoms to which they are attached form a C 3 -C 5 cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents which is -Me; and R 2 and R 4 are -H.
  • R 4 and R 5 together with the carbon atoms to which they are attached form a C 3 -C 6 cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C 1-6 alkyl.
  • R 4 and R 5 together with the carbon atoms to which they are attached form a C 3 -C 6 cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents which is -C 1-6 alkyl; R 2 is H; and R 3 is -H or -C 1-6 alkyl.
  • R 4 and R 5 together with the carbon atoms to which they are attached form a C 3 -C 5 cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents which is -Me; and R 2 and R 3 are -H.
  • R 2 and R 3 together with the carbon atoms to which they are attached form a C 3 -C 6 cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C 1-6 alkyl.
  • R 2 and R 3 together with the carbon atoms to which they are attached form a C 3 -C 6 cycloalkyl; and R 4 and R 5 are each independently -H or -C 1-6 alkyl.
  • R 2 and R 3 together with the carbon atoms to which they are attached form a C3-C6cycloalkyl; and R 4 and R 5 are -H.
  • R 2 and R 5 together with the pyrrolidine ring to which they are attached form a bridged 6 to 8 membered heterocycloalkyl, wherein the heterocycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C 1-6 alkyl.
  • R 2 and R 5 together with the pyrrolidine ring to which they are attached form a bridged 6 to 7 membered heterocycloalkyl, wherein the heterocycloalkyl is substituted with 0 or 1 substituent selected from the group consisting of halo and -C 1-6 alkyl; and R 3 and R 4 are each independently -H or -C 1-6 alkyl.
  • R 2 and R 5 together with the pyrrolidine ring to which they are attached form a bridged 7 membered heterocycloalkyl, wherein the heterocycloalkyl is substituted with -F; and R 3 and R 4 are -H.
  • R 7 and R 8 are H.
  • n is 1 or 2.
  • n is 1.
  • the compound of formula I is a compound of formula A , A wherein the variables are as defined herein.
  • R 1 is (a) -C 1-6 alkyl, (b) -C 1-6 alkylene-NHCO-C 1-6 haloalkyl, (c) -C 0-6 alkylene-(saturated cycloalkyl), (d) -C 0-6 alkylene-heterocycloalkyl, (e) -heteroarylene-cycloalkyl, or (f) -heteroarylene-aryl; (g) , , , , , wherein R A is halo, -OH, -CN, -NH2, -NO2, -C 1-6 alkyl, alkenyl, -C 1-6 alkoxy, -C 1-6 haloalkyl, -O-C 0-6 alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; p is 0, 1, 2, 3, 4, or 5;
  • R 1 is (a) -C 1-6 alkylene-NHCO-C 1-6 haloalkyl, (b) -C 0-6 alkylene-(saturated cycloalkyl), (c) -C 0-6 alkylene-(tricyclic heteroaryl), (d) -C 0-6 alkylene-heterocycloalkyl, (e) , , , , , ; wherein R A is halo, -OH, -CN, -NH2, -NO2, -C 1-6 alkyl, alkenyl, -C 1-6 alkoxy, -C 1-6 haloalkyl, -O-C 0-6 alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; (f
  • R 1 is selected from any of the moieties in Table 3. Table 3 , .
  • R 3 is -H, -F, -Me, -Et, -OH, -CN, methylenyl, -OMe, phenyl, phenoxy, , , or cyclohexyl;
  • R 4 is -H, -F, -Me, or -Et; and
  • R 2 and R 5 are -H.
  • R 3 and R 4 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl; and R 5 is H [0106] In some embodiments of formula I or formula A, R 3 and R 5 together with the carbon atoms to which they are attached, form a C 3 -C 6 cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C 1-6 alkyl; and R 4 is H.
  • R and R are each independently -H, halo, -OH, -CN, methylenyl, -C 1-6 alkyl, -C 1-6 alkoxy, phenyl, phenoxy, benzyl, or C 3 -C 6 cycloalkyl, wherein the phenyl, phenoxy, and benzyl are each independently substituted with 0 or 1 substituent selected from the group consisting of halo and -C 1-6 alkyl; and R 5 is -H or -C 1-6 alkyl.
  • R 3 and R 4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; and R 5 is H.
  • R 1 and R 6 are as defined herein.
  • B-1 In some embodiments of formula B, which is a compound of formula B-1 O .
  • B-1 In some embodiments of formula I or formula A, which is a compound of formula C , C wherein R 1 and R 6 are as defined herein.
  • formula C which is a compound of formula C-1 .
  • R 1 is (a) -C 1-6 alkylene-NHCO-C 1-6 haloalkyl, (b) -C 0-6 alkylene-(saturated cycloalkyl), (c) -C 0-6 alkylene-heterocycloalkyl, (d) -C 0-6 alkylene-(tricyclic heteroaryl), (e) , , , , or , ;
  • R A is halo, -OH, -CN, -NH2, -NO2, -C 1-6 alkyl, alkenyl, -C 1-6 alkoxy, -C 1-6 haloalkyl, -O-C 0-6 alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl;
  • p is 0, 1, 2, 3, 4, or 5;
  • R 1 is selected from the group consisting of and R 6 .
  • the present disclosure provides a compound of formula II: II or a pharmaceutically acceptable salt thereof, wherein: R 1A is H, -C 1-6 alkylene-NHCONH-C 1-6 alkyl, -C 1-6 alkylene-NHCO(heteroaryl), -C 1-6 alkylene-cycloalkyl, , , wherein R A is halo, -OH, -CN, -NH2, -NO2, -C 1-6 alkyl, alkenyl, -C 1-6 alkoxy, -C 1-6 haloalkyl, -O-C 0-6 alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; p is 0, 1, 2, 3, 4, or 5; , where
  • R 1A is -C 1-6 alkylene-NHCONH-C 1-6 alkyl. [0118] In some embodiments of formula II, R 1A is . [0119] In some embodiments of formula II, R 1A is -C 1-6 alkylene-NHCO(heteroaryl). [0120] In some embodiments of formula II, R 1A is . [0121] In some embodiments of formula II, R 1A is -C 1-6 alkylene-cycloalkyl, wherein the cycloalkyl is optionally substituted by halo, -C 1-6 alkyl, -OH, -CN, -NH2, or -NO2.
  • R 1A is . [0123] In some embodiments of formula II, R 1A is or ; R A is halo, -OH, -CN, -NH2, -NO2, -C 1-6 alkyl, alkenyl, -C 1-6 alkoxy, -C 1-6 haloalkyl, -O-C 0-6 alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; and p is 0, 1, 2, or 3. [0124] In some embodiments of formula II R 1A is or .
  • R is wherein R 10 is halo, CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -O(C 1-6 branched alkyl), or -SO2(C 1-6 alkyl); and m is 0, 1, or 2.
  • R 1A is .
  • R 1A is R 2 is H.
  • R 3 and R 4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; and R 5 is H.
  • R 3 and R 5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C 1-6 alkyl; and R 4 is H.
  • R 6 is O ; and each R 9 is independently H, C 1-6 alkyl, or cycloalkyl
  • R 6 is or .
  • R 6 is .
  • formula II is a compound of formula II-A or II-B: (II-A) or (II-B) [0134] In some embodiments of formula II is a compound of formula II-A or II-B, wherein the compound is of the formula: , or , or a pharmaceutically acceptable salt thereof. [0135] In some embodiments, provided herein in is a pharmaceutical composition for treating a coronavirus infection in a human in need thereof, comprising a compound of formula (I) and formula (II), or a pharmaceutically acceptable salt thereof.
  • a method of treating a viral infection in a patient comprising administering to the patient a therapeutically effective amount of a compound of formlula (I) or formula (II), or a pharmaceutically acceptable salt thereof.
  • the viral infection is caused by a coronavirus.
  • the viral infection is a coronavirus infection caused by SARS-CoV-2, SARS-CoV, MERS-CoV, 229E, NL63, OC43, or HKUl.
  • the coronavirus infection is caused by SARS-CoV-2.
  • the patient is suffering from COVID-19.
  • the coronavirus infection is caused by SARS-CoV.
  • the coronavirus infection is caused by MERS-CoV.
  • the treatment method inhibits Mpro.
  • the treatment method is administered orally.
  • the treatment is administered once a day, twice a day, or three times a day.
  • the therapeutically effective amount of the treatment is from 0.5 mg to 100 mg, 1 mg to 80 mg, or from 1 mg to 60 mg.
  • the compound of formula (I) or (II) is formulated in a solid dosage form.
  • the present disclosure provides a compound selected from any of the compounds 1-138 described in the examples, or a pharmaceutically acceptable salt thereof.
  • PHARMACEUTICALLY ACCEPTABLE SALTS [0149]
  • the present disclosure encompasses the preparation and use of salts of compounds of the present disclosure.
  • the pharmaceutical "pharmaceutically acceptable salt” refers to salts or zwitterionic forms of compounds of the present disclosure. Salts of compounds of the present disclosure can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with a suitable acid.
  • the pharmaceutically acceptable salts can be acid addition salts formed with pharmaceutically acceptable acids.
  • acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
  • Non-limiting examples of salts of compounds of the present disclosure include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2- hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphsphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, pic
  • available amino groups present in the compounds of the present disclosure can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • any reference compounds of the present disclosure appearing herein is intended to include compounds of the present disclosure as well as pharmaceutically acceptable salts, hydrates, or solvates thereof.
  • the present disclosure encompasses the preparation and use of solvates of compounds of the present disclosure.
  • Solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents.
  • the term "solvate” as used herein is a combination, physical association and/or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively.
  • This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding.
  • solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
  • solvate encompasses both solution-phase and isolatable solvates.
  • Compounds of the present disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, and ethanol, and it is intended that the disclosure includes both solvated and unsolvated forms of compounds of the present disclosure.
  • a pharmaceutically acceptable solvent such as water, methanol, and ethanol
  • solvate is a hydrate.
  • a hydrate relates to a particular subgroup of solvates where the solvent molecule is water.
  • Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M.
  • a typical, non-limiting, process of preparing a solvate would involve dissolving a compound of the present disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvate in a crystal of the solvate.
  • a desired solvent organic, water, or a mixture thereof
  • the viral infection is caused by a coronavirus.
  • the coronavirus infection is caused by a coronavirus including SARS-CoV-1, SARS-CoV-2, MERS-CoV, HCoV-229E, HCoV-HKU1, HCoV-NL63 and HCoV-OC43.
  • the coronavirus infection is caused by a coronavirus including SARS-CoV and MERS-CoV.
  • the coronavirus infection is caused by SARS-CoV-2.
  • the patient is suffering from COVID-19.
  • the patient is suffering from upper respiratory illness, severe interstitial pneumonia, and/or acute respiratory distress syndrome, aggravated by thrombosis in the pulmonary microcirculation.
  • the patient is suffering from multi-organ failure.
  • the patient is suffering from fever, cough, tiredness, loss of taste or smell, shortness of breath or difficulty breathing, muscle aches, chills, sore throat, runny nose, headache, chest pain, and/or pink eye.
  • the coronavirus replication is inhibited.
  • the coronavirus polymerase is inhibited.
  • the coronaviral membrane fusion is inhibited.
  • the inhibition is in vitro or in vivo.
  • the present disclosure relates to a method of treating an individual suffering from a disease or condition wherein inhibition of Mpro provides a benefit comprising administering a therapeutically effective amount of a compound of the present disclosure to an individual in need thereof.
  • Compounds of the present disclosure are inhibitors of Mpro protein. Accordingly, diseases and conditions mediated by Mpro can be treated by employing these compounds.
  • the present disclosure is thus directed generally to a method for treating a condition or disorder responsive to Mpro inhibition in a subject, e.g., a human subject, suffering from, or at risk of suffering from, the condition or disorder, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure.
  • a subject e.g., a human subject
  • the present disclosure is directed to a method of inhibiting Mpro in a subject in need thereof, said method comprising administering to the subject an effective amount of at least one compound of the present disclosure.
  • the Mpro is SARS-CoV-2 Mpro.
  • the methods of the present disclosure can be accomplished by administering a compound of the present disclosure as the neat compound or as a pharmaceutical composition.
  • a human subject is treated with a compound of the present disclosure, or a pharmaceutical composition comprising a compound of the present disclosure, wherein the compound is administered in an amount sufficient to inhibit Mpro in the subject.
  • COMBINATION THERAPY [0169]
  • a compound of the present disclosure is administered in conjunction with a second therapeutic agent useful in the treatment of a disease or condition wherein inhibition of Mpro provides a benefit.
  • the second therapeutic agent is different from the compound of the present disclosure.
  • the second therapeutic agent can be an antiviral agent or an anti-inflamatory/host immune modulator.
  • the antiviral agent may include anti-SARS-CoV-2 monoclonal antibodies such as bamlanivimab/etesevimab, casirivimab/imdevimab, and Sotrovimab; RNA-polymerase inhibitors such as molnupiravir and remdesivir; papin-like protease inhibitors; and methyl transferase inhibitors.
  • the anti-inflamatory/host immune modulator may include steroidal such as dexamethasone; JAK inhibitors such as baricitinib and tofacitinib; and IL-6R blocking monoclonal antibodies such as tocilizumab and sarilumab.
  • a compound of the present disclosure and the second therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect.
  • the compound of the present disclosure and second therapeutic agent can be administered from a single composition or two separate compositions.
  • the second therapeutic agent is administered in an amount to provide its desired therapeutic effect.
  • the effective dosage range for each second therapeutic agent is known in the art, and the second therapeutic agent is administered to an individual in need thereof within such established ranges.
  • a compound of the present disclosure and the second therapeutic agent can be administered together as a single-unit dose or separately as multi-unit doses, wherein the compound of the present disclosure is administered before the second therapeutic agent or vice versa.
  • One or more doses of the compound of the present disclosure and/or one or more dose of the second therapeutic agent can be administered.
  • a compound of the present disclosure therefore can be used in conjunction with one or more second therapeutic agents, for example, but not limited to, anticancer agents.
  • ADMINISTRATIONS AND DOSAGE [0174]
  • a compound of the present disclosure can be administered by any suitable route, for example by oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal through lumbar puncture, transurethral, nasal, percutaneous, i.e., transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and/or surgical implantation at a particular site) administration.
  • Parenteral administration can be accomplished using a needle and syringe or using a high pressure technique.
  • the compound or a pharmaceutically acceptable salt thereof is administered orally.
  • Pharmaceutical compositions include those wherein a compound of the present disclosure is administered in an effective amount to achieve its intended purpose. The exact formulation, route of administration, and dosage is determined by an individual physician in view of the diagnosed condition or disease. Dosage amount and interval can be adjusted individually to provide levels of a compound of the present disclosure that is sufficient to maintain therapeutic effects.
  • Toxicity and therapeutic efficacy of the compounds of the present disclosure can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) of a compound, which defines as the highest dose that causes no toxicity in animals.
  • MTD maximum tolerated dose
  • the dose ratio between the maximum tolerated dose and therapeutic effects (e.g. inhibiting of tumor growth) is the therapeutic index.
  • the dosage can vary within this range depending upon the dosage form employed, and the route of administration utilized. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • a therapeutically effective amount of a compound of the present disclosure required for use in therapy varies with the nature of the condition being treated, the length of time that activity is desired, and the age and the condition of the subject, and is ultimately determined by the attendant physician. Dosage amounts and intervals can be adjusted individually to provide plasma levels of the compound of the present disclosure that are sufficient to maintain the desired therapeutic effects.
  • the desired dose can be administered in a single dose, or as multiple doses administered at appropriate intervals, for example as one, two, three, four or more subdoses per day. Multiple doses sometimes are desired, or required.
  • a compound of the present disclosure can be administered at a frequency of: four doses delivered as one dose per day at four-day intervals (q4d x 4); four doses delivered as one dose per day at three-day intervals (q3d x 4); one dose delivered per day at five-day intervals (qd x 5); one dose per week for three weeks (qwk3); five daily doses, with two-day rest, and another five daily doses (5/2/5); or, any dose regimen determined to be appropriate for the circumstance.
  • the compound or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, or three times a day.
  • a compound of the present disclosure used in a method of the present disclosure can be administered in an amount of about 0.005 to about 500 milligrams per dose, about 0.05 to about 250 milligrams per dose, or about 0.5 to about 100 milligrams per dose.
  • a compound of the present disclosure can be administered, per dose, in an amount of about 0.005, about 0.05, about 0.5, about 5, about 10, about 20, about 30, about 40, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 milligrams, including all doses between 0.005 and 500 milligrams.
  • the therapeutically effective amount is from 0.5 mg to 100 mg, 1 mg to 80 mg, or from 1 mg to 60 mg.
  • the dosage of a composition containing a compound of the present disclosure, or a composition containing the same can be from about 1 ⁇ g/kg to about 200 mg/kg, about 1 ⁇ g/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg.
  • the dosage of a composition can be at any dosage including, but not limited to, about 1 ⁇ g/kg.
  • the dosage of a composition may be at any dosage including, but not limited to, about 1 ⁇ g/kg, about 10 ⁇ g/kg, about 25 ⁇ g/kg, about 50 ⁇ g/kg, about 75 ⁇ g/kg, about 100 ⁇ g/kg, about 125 ⁇ g/kg, about 150 ⁇ g/kg, about 175 ⁇ g/kg, about 200 ⁇ g/kg, about 225 ⁇ g/kg, about 250 ⁇ g/kg, about 275 ⁇ g/kg, about 300 ⁇ g/kg, about 325 ⁇ g/kg, about 350 ⁇ g/kg, about 375 ⁇ g/kg, about 400 ⁇ g/kg, about 425 ⁇ g/kg, about 450 ⁇ g/kg, about 475 ⁇ g/kg, about 500 ⁇ g/kg, about 525 ⁇ g/kg, about 550 ⁇ g/kg, about 575 ⁇ g/kg, about 600 ⁇ g/kg, about 625 ⁇ g/kg, about 650 ⁇ g/
  • compositions are exemplary of the average case, but there can be individual instances in which higher or lower dosages are merited, and such are within the scope of this disclosure.
  • physician determines the actual dosing regimen that is most suitable for an individual subject, which can vary with the age, weight, and response of the particular subject.
  • PHARMACEUTICAL COMPOSITIONS [0181]
  • compounds of the present disclosure typically are administered in admixture with a pharmaceutical carrier to give a pharmaceutical composition selected with regard to the intended route of administration and standard pharmaceutical practice.
  • compositions for use in accordance with the present disclosure are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of compound of the present disclosure.
  • These pharmaceutical compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen. When a therapeutically effective amount of the compound of the present disclosure is administered orally, the composition typically is in the form of a tablet, capsule, powder, solution, or elixir.
  • the composition When administered in tablet form, the composition additionally can contain a solid carrier, such as a gelatin or an adjuvant.
  • a solid carrier such as a gelatin or an adjuvant.
  • the tablet, capsule, and powder contain about 0.01% to about 95%, and preferably from about 1% to about 50%, of a compound of the present disclosure.
  • a liquid carrier such as water, petroleum, or oils of animal or plant origin, can be added.
  • the liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solutions, or glycols.
  • the composition When administered in liquid form, the composition contains about 0.1% to about 90%, and preferably about 1% to about 50%, by weight, of a compound of the present disclosure.
  • compositions When a therapeutically effective amount of a compound of the present disclosure is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution.
  • parenterally acceptable solutions having due regard to pH, isotonicity, stability, and the like, is within the skill in the art.
  • a preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains, an isotonic vehicle.
  • Compounds of the present disclosure can be readily combined with pharmaceutically acceptable carriers well-known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed.1995.
  • Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
  • Pharmaceutical preparations for oral use can be obtained by adding the compound of the present disclosure to a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrating agents can be added.
  • Compound of the present disclosure can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.
  • Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Additionally, suspensions of a compound of the present disclosure can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension.
  • the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions.
  • a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • Compounds of the present disclosure also can be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases.
  • the compound of the present disclosure also can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compound of the present disclosure can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins.
  • suitable polymeric or hydrophobic materials for example, as an emulsion in an acceptable oil
  • ion exchange resins for example, ion exchange resins.
  • the compounds of the present disclosure can be administered orally, buccally, or sublingually in the form of tablets containing excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • excipients such as starch or lactose
  • capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspend
  • Compound of the present disclosure also can be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily.
  • the compound of the present disclosure are typically used in the form of a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.
  • MEDICAL KITS [0192]
  • the present disclosure provides kits which comprise a compound of the present disclosure (or a composition comprising a compound of the present disclosure) packaged in a manner that facilitates their use to practice methods of the present disclosure.
  • the kit includes a compound of the present disclosure (or a composition comprising a compound of the present disclosure) packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method of the present disclosure.
  • the kit further can include a device suitable for administering the composition according to the intended route of administration. GENERAL SYNTHETIC METHODS [0194]
  • the compounds of the present disclosure and intermediates can be prepared according to Scheme 1 below.
  • R 10 is alkyl such as C 1-6 alkyl.
  • P refers to H or an amino protecting group such as Boc.
  • R 1 is selected from any of the groups in Table 1, Table 2, or Table 3.
  • Scheme 1 [0195] Steps 1a & 1b: Steps 1a and 1b can be carried out in the presence of a suitable base and solvent.
  • the base may be an inorganic base or an organic base.
  • Non-limiting examples of the inorganic base may include hydroxides such as sodium hydroxide, lithium hydroxide, or potassium hydroxide; bicarbonates; carbonates; phosphates; and acetates.
  • the organic base may include but is not limited to amines, e.g., tertiary amines; pyridine; and piperidine.
  • the suitable solvent includes but is not limited to protic and aprotic solvents such as water, methanol, ethanol, DMF, DCM, EA, THF, DMSO, ether, ketone, 1,4-dioxane, and the like.
  • the suitable solvent may also be a combination of two or three solvents.
  • the hydrolysis product may be acidified to afford the free acid.
  • Steps 2a & 2b can be performed in the presence of a suitable base, a coupling reagent, and a solvent.
  • a suitable base may include bicarbonates, carbonates, phosphates, and acetates.
  • the organic base may include but is not limited to amines, e.g., tertiary amines such as DIEA.
  • the coupling reagent can be a suitable peptide coupling reagent including, without limitation, T 3 P, HOAt, HOBt, HUTA, DCC, EDC, DIC, BOP, PyBOP, HATU, HBTU, TOTU, COMU, and TBTU.
  • the suitable solvent includes but is not limited to DCM, DMF, THF, DMSO, acetonitrile, ethers, ethyl acetate, 1,4-dioxane, and the like.
  • Steps 3a & 3b can be performed in the presence of a suitable acid and a solvent.
  • the acid may be an inorganic acid or an organic acid.
  • Non-limiting examples of the inorganic base may include hydrochloric acid, phosphoric acid, and sulfuric acid.
  • the organic acid may include but is not limited to TFA and p-toluenesulfonic acid.
  • the suitable solvent includes but is not limited to protic and aprotic solvents such as water, methanol, ethanol, DMF, DCM, EA, THF, DMSO, ether, ketone, 1,4-dioxane, and the like.
  • the suitable solvent may also be a combination of two or three solvents.
  • Steps 4a & 4b can be performed in the presence of a suitable base, a coupling reagent, and a solvent.
  • the inorganic base may include bicarbonates, carbonates, phosphates, and acetates.
  • the organic base may include but is not limited to amines, e.g., tertiary amines such as DIEA.
  • the coupling reagent can be a suitable peptide coupling reagent including, without limitation, T 3 P, HOAt, HOBt, HUTA, DCC, EDC, DIC, BOP, PyBOP, HATU, HBTU, TOTU, COMU, and TBTU.
  • the suitable solvent includes but is not limited to DCM, DMF, THF, DMSO, acetonitrile, ethers, ethyl acetate, 1,4-dioxane, and the like.
  • R 6 is –COOR 9 , and the process further comprises the following steps: [0200] Step 5: Step 5 can be performed in the presence of a reducing reagent and a suitable solvent.
  • a suitable solvent includes protic solvents or aprotic solvents.
  • Protic solvents include but is not limited to water and alcohols such as methanol, ethanol, propanol, and the like.
  • Aprotic solvents include but is not limited to solvents such as DCM, THF, DMF, acetonitrile, and the like.
  • the suitable solvent may also be a combination of two or three solvents.
  • the reducing reagent includes but is not limited to a borohydride reagent or a metal hydride reagent. Non-limiting examples are lithium borohydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and lithium aluminium hydride.
  • Step 6 can be performed in the presence of an oxidizing reagent and a suitable solvent.
  • a suitable solvent includes protic solvents or aprotic solvents.
  • Protic solvents include but is not limited to water and alcohols such as methanol, ethanol, propanol, and the like.
  • Aprotic solvents include but is not limited to solvents such as DCM, THF, DMF, acetonitrile, and the like.
  • the suitable solvent may also be a combination of two or three solvents.
  • the oxidizing reagent includes but is not limited to dichromate, Collins reagent, Dess–Martin periodinane, PCC, PDC, and DMSO/oxalyl chloride.
  • the mixture was stirred at 25°C for 10 hours.
  • the reaction mixture was poured into water (50 mL).
  • the aqueous phase was extracted with DCM (20 mL x3).
  • the combined organic phase was washed with brine (20 mL x2), dried with anhydrous Na2SO4, filtered and concentrated in vacuo.
  • the title compound was obtained as yellow oil (3.3 g, 87.74% yield) which was used in the next step without further purification.
  • Step 2 (1R,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid
  • (1R,2S,5S)-3-tert-butyl 2-methyl 6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.50 g, 5.57 mmol) in H2O (4 mL) and THF (12 mL) was added LiOH.H2O (467 mg, 11.14 mmol) in one portion at 25°C. The mixture was stirred at 25°C for 10 hours.
  • the mixture was poured into water (15 mL) and then acidified with 2M HCl (5 mL) to pH ⁇ 6.
  • the aqueous phase was extracted with DCM (20 mL x4).
  • the combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo.
  • the title compound was obtained as yellow oil (1.2 g, 70.05% yield) which was used in the next step without further purification.
  • Step 3 (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0209] To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin- 3-yl)propanoate (1.35 g, 4.72 mmol) in dioxane (10 mL) was added HCl/dioxane (4 M, 14 mL) in one portion at 25°C. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure.
  • Step 4 (1R,2S,5S)-tert-butyl 2-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate
  • (1R,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (1.20 g, 4.70 mmol) and DIEA (2.43 g, 18.80 mmol) in DCM (15 mL) was added T 3 P (4.49 g, 7.05 mmol, 50% purity in EtOAc) drop
  • Step 5 (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0213] To a solution of (1R,2S,5S)-tert-butyl 2-(((S)-1-methoxy-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3- carboxylate (300 mg, 708.38 ⁇ mol) in dioxane (3 mL) was added HCl/dioxane (4 M, 4 mL) in one portion at 25°C.
  • Step 6 (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(1-phenylcyclopropanecarbonyl)- 3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0215] To a solution of 1-phenylcyclopropanecarboxylic acid (114 mg, 708.63 ⁇ mol) and DIEA (366 mg, 2.83 mmol) in DCM (5 mL) was added T3P (676 mg, 1.06 mmol, 50% purity in EtOAc) dropwise at 0°C.
  • Step 7 (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6- dimethyl-3-(1-phenylcyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(1- phenylcyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2- oxopyrrolidin-3-yl)propanoate 130 mg, 278.04 ⁇ mol
  • LiBH 4 (18 mg, 834.12 ⁇ mol) at 0 o C.
  • Step 8 (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-3-(1-phenylcyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Step 3 (S)-methyl 2-((S)-5-(7-chloro-1H-indole-2-carbonyl)-5- azaspiro[2.4]heptane-6-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0226] To a solution of compound (S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-((S)-5- azaspiro[2.4]heptane-6-carboxamido)propanoate (165 mg, 477.13 ⁇ mol, 1 eq, HCl), 7- chloro-1H-indole-2-carboxylic acid (93 mg, 477.13 ⁇ mol) and DIEA (185 mg, 1.43 mmol, 249.31
  • Step 4 (S)-5-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide [0228] To a solution of (S)-methyl 2-((S)-5-(7-chloro-1H-indole-2-carbonyl)-5- azaspiro[2.4]heptane-6-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (105 mg, 215.63 ⁇ mol) in THF (2 mL) was added LiBH4 (19 mg, 862.52 ⁇ mol) at 0°C.
  • Step 5 (S)-5-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide
  • DCM 10 mL
  • DMP 129 mg, 305.05 ⁇ mol
  • Step 2 (S)-5-(4-fluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide [0235] To a solution of (S)-methyl 2-((S)-5-(4-fluoro-1H-indole-2-carbonyl)-5- azaspiro[2.4]heptane-6-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (90 mg, 191.29 ⁇ mol) in THF (6 mL) was added LiBH4 (12.5 mg, 573.87 ⁇ mol) in one portion at 0°C.
  • Step 3 (S)-5-(4-fluoro-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin- 3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide
  • DCM 3 mL
  • DMP 134 mg, 316.40 ⁇ mol
  • Step 2 6,7-difluoro-1H-indole-2-carboxylic acid
  • ethyl 6,7-difluoro-1H-indole-2-carboxylate 170 mg, 0.75 mmol,
  • MeOH 1 mL
  • LiOH.H 2 O 63 mg, 1.51 mmol
  • the reaction mixture was stirred at 50 °C for 3 hr.
  • the reaction mixture was poured into water (20 mL) and then extracted with PE (50 mL x2). The aqueous phase was then adjusted to pH ⁇ 5 by aqueous HCl (1M).
  • Step 3 (S)-methyl-2-((1R,2S,5S)-3-(6,7-difluoro-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0244] To a mixture of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (182 mg, 0.51 mmol,) and 6,7- difluoro-1H-indole-2-carboxylic acid (100 mg, 0.51 mmol) in DCM (3 mL) was added DIEA (197 mg, 1.52 mmol, 0.26 mL).
  • Step 4 (1R,2S,5S)-3-(6,7-difluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)- 2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Step 5 (1R,2S,5S)-3-(6,7-difluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • To a solution of (1R,2S,5S)-3-(6,7-difluoro-1H-indole-2-carbonyl)-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (30 mg, 63.22 ⁇ mol) in DCM (5 mL) was added DMP (81 mg, 189.67 ⁇ mol) at 25°C.
  • HATU (705 mg, 1.86 mmol) was added at 0°C.
  • the mixture was stirred at 25 °C for 12 hr.
  • the reaction mixture was poured into sat.aq NH4Cl (20 mL).
  • the resulting mixture was extracted with EtOAc (20 mL x2).
  • the combined organic phase was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness.
  • the residue was purified by prep-HPLC (column: Xtimate C18 150 ⁇ 40 mm ⁇ 10 ⁇ m; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 25%-55%, 10 min).
  • Step 2 (1R,2S,5S)-3-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • (S)-methyl 2-((1R,2S,5S)-3-(7-chloro-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate 210 mg, 419.18 ⁇ mol
  • THF 8 mL
  • LiBH4 27 mg, 1.26 mmol
  • Step 3 (1R,2S,5S)-3-(7-chloro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1-oxo- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Step 2 (1R,2S,5S)-3-(7-fluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • (S)-methyl 2-((1R,2S,5S)-3-(7-fluoro-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate 160 mg, 330.22 ⁇ mol
  • LiBH 4 (21.6 mg, 990.67 ⁇ mol) in one portion at 0°C.
  • Step 3 (1R,2S,5S)-3-(7-fluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1-oxo- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • DCM 3 mL
  • DMP 15.0 mg, 361.44 ⁇ mol
  • Step 1 (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-((R)-2-(m-tolyl)propanoyl)-3- azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0265] To a mixture of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (255 mg, 788.53 ⁇ mol) and (R)-2- (m-tolyl)propanoic acid (129 mg, 788.53 ⁇ mol) in DCM (5 mL) was added DIEA (305 mg, 2.37 mmol) and HATU (599 mg, 1.58 m
  • Step 3 (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-3-((R)-2-(m-tolyl)propanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Step 2 (1R,2S,5S)-3-(1-(3-chlorophenyl) cyclopropanecarbonyl)-N-((S)-1-hydroxy- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide
  • Step 2 To a solution of (S)-methyl 2-((1R,2S,5S)-3-(1-(3- chlorophenyl)cyclopropanecarbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (60 mg, 119.52 ⁇ mol) in THF (4 mL) was added LiBH 4 (7 mg, 321.40 ⁇ mol) dropwise at 0°C.
  • Step 3 (1R,2S,5S)-3-(1-(3-chlorophenyl)cyclopropanecarbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide
  • Step 5 (S)-methyl 2-((S)-4,4-dimethylpyrrolidine-2-carboxamido)-3-((S)-2- oxopyrrolidin-3-yl)propanoate [0281] To a mixture of (S)-tert-butyl 2-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)carbamoyl)-4,4-dimethylpyrrolidine-1-carboxylate (200 mg, 486.04 ⁇ mol) in dioxane (2 mL) was added HCl/dioxane (4 M, 2 mL).
  • Step 6 (S)-methyl 2-((S)-1-(7-chloro-1H-indole-2-carbonyl)-4,4- dimethylpyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0283] To a solution of (S)-methyl 2-((S)-4,4-dimethylpyrrolidine-2-carboxamido)-3-((S)- 2-oxopyrrolidin-3-yl)propanoate (165 mg, 474.36 ⁇ mol HCl), 7-chloro-1H-indole-2- carboxylic acid (93 mg, 474.36 ⁇ mol) and DIEA (184 mg, 1.42 mmol
  • Step 7 (S)-1-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-4,4-dimethylpyrrolidine-2-carboxamide [0285] To a solution of (S)-methyl 2-((S)-1-(7-chloro-1H-indole-2-carbonyl)-4,4- dimethylpyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (75 mg, 153.39 ⁇ mol) in THF (2 mL) was added LiBH4 (13 mg, 613.54 ⁇ mol) at 0°C.
  • Step 8 (S)-1-(7-chloro-1H-indole-2-carbonyl)-4,4-dimethyl-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide [0287] To a solution of (S)-1-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-4,4-dimethylpyrrolidine-2-carboxamide (50 mg, 108.47 ⁇ mol,) in DCM (2 mL) was added DMP (92 mg, 216.94 ⁇ mol).
  • Step 2 (S)-methyl-3-((S)-2-oxopyrrolidin-3-yl)-2-((S)-6-azaspiro[3.4]octane-7- carboxamido)propanoate [0292] A mixture of (S)-tert-butyl 7-(((S)-1-methoxy-1-oxo-3-(2-oxoimidazolidin-1- yl)propan-2-yl)carbamoyl)-6-azaspiro[3.4]octane-6-carboxylate (700 mg, 1.65 mmol) in HCl/dioxane (4M, 10 mL) was degassed and purged with N 2 for 3 times
  • Step 3 (S)-methyl-2-((S)-6-(1H-indole-2-carbonyl)-6-azaspiro[3.4]octane-7- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0294] To a mixture of (S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-((S)-6- azaspiro[3.4]octane-7-carboxamido)propanoate (590 mg, 1.64 mmol, HCl) and 1H-indole-2- carboxylic acid (264 mg, 1.64 mmol) in DCM (10 mL) were added DIEA (635 mg, 4.92 mmol) and HATU (1.
  • Step 4 (S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6-(1H- indole-2-carbonyl)-6-azaspiro[3.4]octane-7-carboxamide
  • Step 5 (S)-6-(1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-6-azaspiro[3.4]octane-7-carboxamide
  • (S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6- (1H-indole-2-carbonyl)-6-azaspiro[3.4]octane-7-carboxamide 60 mg, 136.82 ⁇ mol
  • DMP 174 mg, 410.47 ⁇ mol
  • Step 2 (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate hydrochloride [0303] A mixture of (1R,2S,5S)-tert-butyl 2-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopiperidin- 3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (416 mg, 950.80 ⁇ mol) in HCl/dioxane (4 M, 10 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 25 °C for 1 hr under N2 atmosphere.
  • Step 3 (S)-methyl 2-((1R,2S,5S)-3-(1H-indole-2-carbonyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate [0305] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate hydrochloride (355 mg, 949.52 ⁇ mol, HCl) in DCM (5 mL) was added 1H-indole-2-carboxylic acid (153 mg,
  • HATU (469 mg, 1.23 mmol) was added slowly at 0°C.
  • the resulting mixture was stirred at 25 °C for 10 h.
  • Water (15 mL) was added to the reaction mixture.
  • the mixture was extracted with DCM (10 mL x3).
  • the combined organic phase was washed with sat.aq.NH4Cl (10 mL x2), dried over anhydrous Na2SO4, filtered and concentrated to dryness.
  • the residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875 ⁇ 30mm ⁇ 3 ⁇ m; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B%: 23%-63%, 11min).
  • Compound 12 was synthesized by the same procedure as Compound 1. 1 H NMR (400 MHz, CD 3 OD) ⁇ ppm 4.53 - 4.41 (m, 1H), 4.38 - 4.26 (m, 1H), 4.08 - 3.72 (m, 3H), 3.29 - 3.12 (m, 2H), 2.73 - 2.49 (m, 1H), 2.43 - 2.24 (m, 1H), 2.11 - 1.90 (m, 1H), 1.83 - 1.67 (m, 1H), 1.65 - 1.37 (m, 3H), 1.16 - 0.85 (m, 15H).
  • Step 2 4, 7-difluoro-1H-indole-2-carboxylic acid
  • ethyl 4,7-difluoro-1H-indole-2-carboxylate 120 mg, 532.88 ⁇ mol
  • MeOH MeOH
  • H 2 O 1 mL
  • LiOH.H 2 O 45 mg, 1.07 mmol
  • the mixture was stirred at 50 °C for 1 hr.
  • Water (10 mL) was added and the reaction mixture was adjusted to pH ⁇ 5 by aq. HCl (1 N).
  • the resulting mixture was extracted with DCM (10 mL x3).
  • Step 3 (S)-methyl 2-((1R,2S,5S)-3-(4,7-difluoro-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0318] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (91 mg, 253.63 ⁇ mol, HCl), 4,7- difluoro-1H-indole-2-carboxylic acid (50 mg, 253.63 ⁇ mol,) and DIEA (98 mg, 760.89 ⁇ mol) in DCM (3 mL) was added slowly
  • Step 4 (1R,2S,5S)-3-(4,7-difluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)- 2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Step 5 (1R,2S,5S)-3-(4,7-difluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Example 14 (1R,2S,5S)-3-(4-ethyl-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 14) [0324]
  • Step 1 methyl 4-vinyl-1H-indole-2-carboxylate [0325] To a solution of methyl 4-bromo-1H-indole-2-carboxylate (2 g, 7.87 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.4 g, 15.74 mmol, 2.67 mL) in dioxane (16 mL) and H 2 O (4 mL) was added Cs 2 CO 3 (7.7 g, 23.61 mmol
  • Step 2 methyl 4-ethyl-1H-indole-2-carboxylate
  • THF methyl 4-vinyl-1H-indole-2-carboxylate
  • Step 3 4-ethyl-1H-indole-2-carboxylic acid [0329] To a solution of methyl 4-ethyl-1H-indole-2-carboxylate (500 mg, 2.46 mmol) in THF (5 mL) and H2O (5 mL) was added LiOH.H2O (206 mg, 4.92 mmol) at 25°C.
  • the mixture was stirred at 25°C for 10 hrs.
  • the reaction was diluted with water (10 mL).
  • the resulting mixture was extracted with DCM (5 mL x3).
  • the aqueous phase was acidified to pH ⁇ 4 with aq. HCl (2M).
  • the resulting suspension was filtered.
  • the filter cake was then dried under vacuum.
  • the title compound (300 mg, 58.00% yield) was obtained as a pink solid which was used in the next step without further purification.
  • Step 4 (S)-methyl 2-((1R,2S,5S)-3-(4-ethyl-1H-indole-2-carbonyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0331] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (150 mg, 416.84 ⁇ mol, HCl) and 4- ethyl-1H-indole-2-carboxylic acid (79 mg, 416.84 ⁇ mol) in DCM (5 mL) was added DIEA (162 mg, 1.25 mmol) at 0°
  • Step 5 (1R,2S,5S)-3-(4-ethyl-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Step 6 (1R,2S,5S)-3-(4-ethyl-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Step 2 (1R,2S,5S)-3-(4-fluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • (S)-methyl 2-((1R,2S,5S)-3-(4-fluoro-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate 160 mg, 330.22 ⁇ mol
  • LiBH 4 22 mg, 990.67 ⁇ mol
  • Step 3 (1R,2S,5S)-3-(4-fluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1-oxo- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Example 16 (1R,2S,5S)-3-(2-(4,4-difluorocyclohexyl)acetyl)-6,6-dimethyl-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 16) [0344] Step 1: (S)-methyl 2-((1R,2S,5S)-3-(2-(4,4-difluorocyclohexyl)acetyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0345] To a solution of 2-(4,4-difluorocyclohexyl)acetic acid (100 mg, 561.24 ⁇ mol) in DCM
  • Step 2 (1R,2S,5S)-3-(2-(4,4-difluorocyclohexyl)acetyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • (S)-methyl 2-((1R,2S,5S)-3-(2-(4,4-difluorocyclohexyl)acetyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate 85 mg, 175.78 ⁇ mol
  • LiBH4 (12 mg, 527.35 ⁇ mol
  • Step 3 (1R,2S,5S)-3-(2-(4,4-difluorocyclohexyl)acetyl)-6,6-dimethyl-N-((S)-1-oxo- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Example 17 (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-(1-phenylcyclopentanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 17) [0351] Step 1: (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(1-phenylcyclopentanecarbonyl)- 3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0352] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-
  • Step 2 (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6- dimethyl-3-(1-phenylcyclopentanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(1- phenylcyclopentanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2- oxopyrrolidin-3-yl)propanoate 40 mg, 80.71 ⁇ mol
  • LiBH 4 5 mg, 242.13 ⁇ mol
  • Step 3 (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-3-(1-phenylcyclopentanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Step 3 To a solution of (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-6,6-dimethyl-3-(1-phenylcyclopentanecarbonyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (40 mg, 85.54 ⁇ mol) in DCM (8 mL) was added DMP (109 mg, 256.63 ⁇ mol).
  • Step 2 (1R,2S,5S)-3-(6,7-dimethyl-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide
  • (S)-methyl 2-((1R,2S,5S)-3-(6,7-dimethyl-1H-indole-2-carbonyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (94 mg, 190.06 ⁇ mol) in THF (2 mL) was added LiBH 4 (9 mg, 433.24 ⁇ mol) at 0°C.
  • Step 2 (1R,2S,5S)-3-(6-fluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • (S)-methyl 2-((1R,2S,5S)-3-(6-fluoro-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate 160 mg, 330.22 ⁇ mol
  • LiBH4 22 mg, 990.67 ⁇ mol
  • Step 3 (1R,2S,5S)-3-(6-fluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1-oxo- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Example 20 (1R,2S,5S)-3-(4,6-difluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 20) [0372] Step 1: (S)-methyl 2-((1R,2S,5S)-3-(4,6-difluoro-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0373] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
  • HATU (355 mg, 933.72 ⁇ mol) was added to the mixture at 0°C.
  • the resulting mixture was stirred at 25°C for 10 h.
  • Water (12 mL) was added and the reaction was extracted with DCM (30 mL x2).
  • the combined organic phase was washed with sat.aq.NH 4 Cl (20 mL x2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo.
  • the residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875 ⁇ 30mm ⁇ 3 ⁇ m; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B%: 24%-64%, 11min).
  • Step 2 (1R,2S,5S)-3-(4,6-difluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide
  • Step 3 (1R,2S,5S)-3-(4,6-difluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Example 21 (1R,2S,5S)-3-(6-chloro-7-fluoro-1H-indole-2-carbonyl)-6,6-dimethyl- N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 21) [0379] Step 1: ethyl 6-chloro-7-fluoro-1H-indole-2-carboxylate [0380] To a solution of (3-chloro-2-fluorophenyl) hydrazine (500 mg, 2.54 mmol, HCl) in toluene (10 mL) was added 4-methylbenzenesulfonic acid (1.31 g, 7.61 mmol) and ethyl 2- oxopropanoate (295 mg, 2.54 mmol) at 25°C.
  • Step 3 (S)-methyl 2-((1R,2S,5S)-3-(6-chloro-7-fluoro-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0384] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (168 mg, 468.18 ⁇ mol, HCl), 6- chloro-7-fluoro-1H-indole-2-carboxylic acid (100 mg, 468.18 ⁇ mol,) and DIEA (182 mg, 1.40 mmol) in DCM (3 mL) was
  • Step 4 (1R,2S,5S)-3-(6-chloro-7-fluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide
  • Step 5 (1R,2S,5S)-3-(6-chloro-7-fluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide
  • To a solution of (1R,2S,5S)-3-(6-chloro-7-fluoro-1H-indole-2-carbonyl)-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (30 mg, 61.11 ⁇ mol) in DCM (6 mL) was added DMP (52 mg, 122.21 ⁇ mol).
  • Step 2 methyl 2-(3,3-difluorocyclohexyl)acetate
  • DCM methyl 2-(3,3-difluorocyclohexyl)acetate
  • Step 3 2-(3,3-difluorocyclohexyl)acetic acid
  • a mixture of methyl 2-(3,3-difluorocyclohexyl)acetate (250 mg, 1.30 mmol) and LiOH.H2O (163 mg, 3.90 mmol) in H2O (2 mL) and THF (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 C for 4 hr under N2 atmosphere. The reaction mixture was concentrated. Water (10 mL) was added and the reaction mixture was then adjusted to pH ⁇ 4 by aqueous HCl (2 N). The resulting mixture was extracted with DCM (30 mL x10).
  • Step 4 (2S)-methyl 2-((1R,2S,5S)-3-(2-(3,3-difluorocyclohexyl)acetyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0397] To a mixture of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (255 mg, 708.63 ⁇ mol, HCl) and 2- (3,3-difluorocyclohexyl)acetic acid (126 mg, 708.63 ⁇ mol) in DCM (5 mL) was added DIEA (366 mg, 2.83 mmol) and HATU (5
  • Step 6 (1R,2S,5S)-3-(2-(3,3-difluorocyclohexyl)acetyl)-6,6-dimethyl-N-((S)-1-oxo- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Compound 22 [0401] A mixture of (1R,2S,5S)-3-(2-(3,3-difluorocyclohexyl)acetyl)-N-((S)-1-hydroxy-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (90 mg, 197.57 ⁇ mol) and DMP (251 mg, 592.71 ⁇ mol) in DCM (2 mL) was degassed and
  • Example 23 (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-(2-phenylacetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 23) [0403] Step 1: (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(2-(4-methylcyclohexyl)acetyl)-3- azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0404] To a mixture of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-(((S)-2
  • Step 2 (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6- dimethyl-3-(2-phenylacetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Step 3 (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-3-(2-phenylacetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Example 24 (1R,2S,5S)-3-(5-fluoro-1H-indole-2-carbonyl)-N-[(1S)-1-formyl-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 24) [0410] Compound 24 was synthesized by the same procedure as Compound 1.
  • Step 3 (1R,2S,5S)-3-(7-chloro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1-oxo- 3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • (1R,2S,5S)-3-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy- 3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide 45 mg, 92.40 ⁇ mol) in DCM (3 mL) was added DMP (118 mg, 277.21 ⁇ mol) at 25°C.
  • Step 3 (S)-methyl 2-((1S,3aR,6aS)-2-(1H-indole-2- carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate [0424] To a mixture of (S)-methyl 2-((1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (130 mg, 402.00 ⁇ mol) and 1H-indole- 2-carboxylic acid (65 mg, 402.00 ⁇ mol) in DCM (2 mL) was added HATU (305 mg, 803.99 ⁇ mol)
  • the mixture was stirred at 25°C for 2 hr.
  • the mixture was diluted with sat.aq. NH4Cl (10 mL), and extracted with DCM (20 mL x3).
  • the combined organic layer was dried over Na2SO4, filtered and concentrated to give crude product.
  • the crude product was purified by prep-HPLC (column: Phenomenex Gemini- NX C1875 ⁇ 30 mm ⁇ 3 ⁇ m; mobile phase: [water (0.05% NH 3 H 2 O+10 mM NH 4 HCO 3 )- ACN]; B%: 21%-51%, 11 min).
  • the title compound (76 mg, 39.31% yield) was obtained as a white solid.
  • Step 4 (1S,3aR,6aS)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2- (1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
  • (S)-methyl 2-((1S,3aR,6aS)-2-(1H-indole-2- carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate 70 mg, 150.04 ⁇ mol
  • LiBH 4 71 mg, 3.26 mmol
  • Step 5 (1S,3aR,6aS)-2-(1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide
  • Step 2 (1R,2S,5S)-3-(5H-[1,3]dioxolo[4,5-f]indole-6-carbonyl)-N-((S)-1-hydroxy- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide
  • Step 3 (1R,2S,5S)-3-(5H-[1,3]dioxolo[4,5-f]indole-6-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide
  • Step 2 ethyl 7-chloro-4-methoxy-1H-indole-2-carboxylate
  • TsOH 2.57 g, 14.95 mmol
  • ethyl 2-oxopropanoate 579 mg, 4.98 mmol
  • Step 3 7-chloro-4-methoxy-1H-indole-2-carboxylic acid
  • ethyl 7-chloro-4-methoxy-1H-indole-2-carboxylate 80 mg, 315.36 ⁇ mol
  • H 2 O 1 mL
  • LiOH.H 2 O 26 mg, 630.71 ⁇ mol
  • the mixture was stirred at 25 °C for 10 hr.
  • Water (10 mL) was added and the reaction mixture was adjusted to pH ⁇ 5 by aq. HCl (1 N).
  • the resulting mixture was extracted with DCM (10 mL x3).
  • Step 4 (S)-methyl 2-((1R,2S,5S)-3-(7-chloro-4-methoxy-1H-indole-2-carbonyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate
  • Step 5 (1R,2S,5S)-3-(7-chloro-4-methoxy-1H-indole-2-carbonyl)-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide
  • Step 6 (1R,2S,5S)-3-(7-chloro-4-methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide
  • To a solution of (1R,2S,5S)-3-(7-chloro-4-methoxy-1H-indole-2-carbonyl)-N-((S)- 1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (30 mg, 59.64 ⁇ mol) in DCM (6 mL) was added DMP (76 mg, 178.93 ⁇ mol).
  • HATU (539 mg, 1.42 mmol) was added in one portion at 0°C. The mixture was stirred at 25°C for 10 hr. The reaction mixture was poured into water (20 mL). The resulting mixture was extracted with DCM (15 mL x3). The combined organic phase was washed with sat.aq.NaHCO3 (15 mL x2) and brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness.
  • Step 2 (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6- dimethyl-3-(7-(trifluoromethyl)-1H-indole-2-carbonyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide
  • Step 3 (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-3-(7-(trifluoromethyl)-1H-indole-2-carbonyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide
  • Example 31 (S)-5-(4-Methoxy-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (Compound 31) [0464] Compound 31 was synthesized by the same procedure as Compound 2.
  • the mixture was stirred at 25°C for 3 hr.
  • the reaction mixture was diluted with 5% H3PO4 (30 mL) and was extracted with DCM (30 mL x2).
  • the combined organic layer was washed with 5% H 3 PO 4 (20 mL x 3), sat.aq.NaHCO3 (20 mL x 4), water (20 mL), and brine (20 mL), and dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness.
  • the residue was purified by prep- HPLC (column: Xtimate C18150 ⁇ 40 mm ⁇ 10 ⁇ m; mobile phase: [water(10 mM NH 4 HCO 3 )- ACN]; B%: 15%-45%, 10 min).
  • Step 2 (1R,2S,5S)-3-(7-cyano-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • (S)-methyl 2-((1R,2S,5S)-3-(7-cyano-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate 145 mg, 294.99 ⁇ mol
  • LiBH4 26 mg, 1.18 mmol
  • Step 3 (1R,2S,5S)-3-(7-cyano-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • DCM DCM
  • DMP 137 mg, 323.61 ⁇ mol
  • Step 2 methyl 4-isopropyl-1H-indole-2-carboxylate
  • Step 4 (S)-methyl 2-((1R,2S,5S)-3-(4-isopropyl-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0482] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (169 mg, 469.64 ⁇ mol, HCl) and 4- isopropyl-1H-indole-2-carboxylic acid (95 mg, 469.64 ⁇ mol) in DCM (5 mL) was added DIPEA (243 mg, 1.88 mmol) dropwise and HA
  • Step 5 (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3- (4-isopropyl-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • (S)-methyl 2-((1R,2S,5S)-3-(4-isopropyl-1H-indole-2-carbonyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate 140 mg, 275.26 ⁇ mol
  • LiBH4 70 mg, 3.21 mmol
  • Step 6 (1R,2S,5S)-3-(4-isopropyl-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Compound 36 was synthesized by the same procedure as Compound 1. 1 H NMR (400 MHz, CD3OD) ⁇ ppm 7.14 - 6.96 (m, 1H), 6.92 - 6.80 (m, 1H), 6.44 - 6.30 (m, 1H), 4.65 - 4.62 (m, 1H), 4.53 - 4.26 (m, 1H), 4.06 - 3.95 (m, 1H), 3.93 - 3.82 (m, 3H), 3.80 - 3.71 (m, 1H), 3.38 - 3.33 (m, 1H), 3.29 - 3.24 (m, 1H), 2.93 - 2.17 (m, 2H), 2.15 - 1.73 (m, 2H), 1.70 - 1.41 (m, 2H), 1.40 - 1.32 (m, 1H), 1.18 - 0.91 (m, 6H).
  • Step 2 (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6- dimethyl-3-((R)-2-phenylpropanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Step 3 (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-3-((R)-2-phenylpropanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • To a mixture of (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-6,6-dimethyl-3-((R)-2-phenylpropanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (30 mg, 70.17 ⁇ mol) in DCM (2 mL) was added DMP (89 mg, 210.51 ⁇ mol).
  • Step 3 (2-fluoro-5-isopropylphenyl)hydrazine
  • 2-fluoro-5-isopropylaniline (1 g, 6.53 mmol) in HCl (12 M, 10 mL) was added a solution of NaNO2 (675 mg, 9.79 mmol) in H2O (10 mL) at 0°C.
  • the mixture was stirred at 0 °C for 0.5 hr.
  • SnCl2.2H2O (2.95 g, 13.1 mmol) was added and the mixture was stirred at 0 C for 2 h.
  • the reaction mixture was adjusted to pH ⁇ 11 by NaOH (6 M).
  • Step 4 ethyl 7-fluoro-4-isopropyl-1H-indole-2-carboxylate
  • ethyl 2-oxopropanoate 926 mg, 7.89 mmol
  • TsOH 2.06 g, 12.0 mmol
  • Step 6 (S)-methyl 2-((1R,2S,5S)-3-(7-fluoro-4-isopropyl-1H-indole-2-carbonyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate [0512] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (163 mg, 452.02 ⁇ mol, HCl), 7- fluoro-4-isopropyl-1H-indole-2-carboxylic acid (100 mg, 452.02 ⁇ mol) and DIEA (175 mg, 1.36 mmol) in DCM (3
  • Step 7 (1R,2S,5S)-3-(7-fluoro-4-isopropyl-1H-indole-2-carbonyl)-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide
  • Step 8 (1R,2S,5S)-3-(7-fluoro-4-isopropyl-1H-indole-2-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide
  • Step 2 (S)-5-(7-cyano-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide
  • (S)-methyl 2-((S)-5-(7-cyano-1H-indole-2-carbonyl)-5- azaspiro[2.4]heptane-6-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate 230 mg, 481.66 ⁇ mol
  • LiBH4 40 mg, 1.84 mmol
  • Step 3 (S)-5-(7-cyano-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin- 3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide
  • DCM dimethyl methacrylate
  • DMP 68 mg, 160.18 ⁇ mol
  • Example 47 (S)-5-(1H-Indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (Compound 47) [0537] Compound 47 was synthesized by the same procedure as Compound 2.
  • Step 2 (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6- dimethyl-3-(2-methyl-2-phenylpropanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(2-methyl-2- phenylpropanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate 60 mg, 127.78 ⁇ mol
  • LiBH4 13 mg, 638.88 ⁇ mol
  • Step 3 (1R,2S,5S)-6,6-dimethyl-3-(2-methyl-2-phenylpropanoyl)-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Step 2 7-chloro-4-fluoro-1H-indole-2-carboxylic acid
  • ethyl 7-chloro-4-fluoro-1H-indole-2-carboxylate 300 mg, 1.24 mmol
  • H2O 5 mL
  • LiOH.H2O 105 mg, 2.48 mmol
  • the reaction mixture was stirred at 50°C for 1 hr.
  • the reaction mixture was adjusted to pH ⁇ 3 with aq. HCl (1 N).
  • H2O (15 mL) was added to the reaction mixture.
  • the resulting mixture was extracted with DCM (20 mL x3).
  • Step 3 (S)-methyl 2-((1R,2S,5S)-3-(7-chloro-4-fluoro-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0551] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (255 mg, 708.63 ⁇ mol, HCl) in DCM (5 mL) was added DIEA (275 mg, 2.13 mmol) and 7-chloro-4-fluoro-1H-indole-2- carboxylic acid (152 mg, 708.63 ⁇ mol) at
  • HATU (539 mg, 1.42 mmol) was added in one portion at 0°C. The mixture was stirred at 25°C for 10 hr. The reaction mixture was poured into water (20 mL). The resulting mixture was extracted with DCM (15 mL x3). The combined organic phase was washed with sat.aq.NaHCO 3 (15 mL x2) and brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: Xtimate C18150 ⁇ 40 mm ⁇ 10 ⁇ m; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 30%-60%, 15 min).
  • Step 4 (1R,2S,5S)-3-(7-chloro-4-fluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide
  • Step 5 (1R,2S,5S)-3-(7-chloro-4-fluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide
  • Step 1 (1R,2S,5S)-methyl 3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate [0558] To a solution of (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid (2 g, 8.68 mmol) in DCM (30 mL) and DIPEA (4.49 g, 34.74 mmol) was added T3P (8.29 g, 13.03 mmol, 7.75 mL, 50% purity in EtOAc) at 0°C.
  • the mixture was stirred at 25 °C for 1 hr.
  • the reaction was extracted with ethyl acetate (5 mL x 2).
  • the resulting mixture was extracted with DCM (10 mL x 3).
  • the combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated.
  • the title compound (1.03 g, 97.31% yield) was obtained as a white solid.
  • Step 4 tert-butyl ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate
  • tert-butyl ((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)carbamate 2.5 g, 9.68 mmol
  • DCM 25 mL
  • Step 5 tert-butyl ((2S)-1-cyano-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)carbamate
  • tert-butyl ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (2.4 g, 9.36 mmol) was dissolved in MeOH (15 mL) and cooled to 0°C. The solution of NaHSO 3 (1.46 g, 14.05 mmol) dissolved in H2O (22 mL) was added to the above mixture. Then the mixture was stirred at 25°C for 5 hrs.
  • Step 7 (3S)-3-amino-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide
  • Step 7 To a solution of tert-butyl N-[(1S)-3-amino-2-hydroxy-3-oxo-1-[[(3S)-2- oxopyrrolidin-3-yl] methyl]propyl]carbamate (150 mg, 497.78 ⁇ mol) in MeOH (4 mL) was added HCl/dioxane (4 M, 124.44 ⁇ L).
  • Step 8 (1R,2S,5S)-N-((2S)-4-amino-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3- yl)butan-2-yl)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide [0572] To a solution of (3S)-3-amino-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide (118 mg, 496.46 ⁇ mol, HCl) in DCM (2
  • Step 9 (1R, 2S, 5S)-N-((S)-4-amino-3, 4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan- 2-yl)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide [0574] To a solution of (1R,2S,5S)-N-((2S)-4-amino-3-hydroxy-4-oxo-1-((S)-2- oxopyrrolidin-3-yl)butan-2-yl)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • Example 51 (S)-1-(4-Fluoro-1H-indole-2-carbonyl)-4,4-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 51) [0576] Compound 51 was synthesized by the same procedure as Compound 1.
  • Step 2 (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6- dimethyl-3-(2-(4-methylcyclohexyl)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(2-(4- methylcyclohexyl)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin- 3-yl)propanoate 260 mg, 563.27 ⁇ mol
  • LiBH4 70 mg, 3.21 mmol
  • Step 3 (1R,2S,5S)-6,6-dimethyl-3-(2-(4-methylcyclohexyl)acetyl)-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-6,6-dimethyl-3-(2-(4-methylcyclohexyl)acetyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (20 mg, 46.13 ⁇ mol) in DCM (4 mL) was added DMP (59 mg, 138.38 ⁇ mol).
  • Step 2 (1R,2S,5S)-3-(2-cyclohexylacetyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • (S)-methyl 2-((1R,2S,5S)-3-(2-cyclohexylacetyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate 85 mg, 189.92 ⁇ mol
  • LiBH4 (12 mg, 569.75 ⁇ mol
  • Step 3 (1R,2S,5S)-3-(2-cyclohexylacetyl)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • (1R,2S,5S)-3-(2-cyclohexylacetyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide 40 mg, 95.34 ⁇ mol
  • DCM 3 mL
  • DMP 81 mg, 190.68 ⁇ mol
  • Example 54 (1R,2S,5S)-3-(2-Cyclohexylacetyl)-6,6-dimethyl-N-((S)-1-oxo-3-((S)- 2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 54) [0592] Compound 54 was synthesized by the same procedure as Compound 1.
  • Example 56 (1R,2S,5S)-3-(6-Methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 56) [0596] Compound 56 was synthesized by the same procedure as Compound 1.
  • Example 57 (S)-1-(1H-Indole-2-carbonyl)-4,4-dimethyl-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamid (Compound 57) [0598] Compound 57 was synthesized by the same procedure as Compound 2.
  • Example 58 (S)-1-(7-Cyano-1H-indole-2-carbonyl)-4,4-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 58) [0600] Compound 58 was synthesized by the same procedure as Compound 2.
  • Example 59 (1R,2S,5S)-3-(4-Cyano-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 59) [0602] Compound 59 was synthesized by the same procedure as Compound 1.
  • Example 60 (1R,2S,5S)-3-(1H-Indole-2-carbonyl)-6,6-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 60) [0604] Compound 60 was synthesized by the same procedure as Compound 1.
  • Example 61 (2S,4S)-4-Cyclohexyl-1-(1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)- 2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 61) [0606] Compound 61 was synthesized by the same procedure as Compound 2.
  • Example 62 (S)-1-(7-Fluoro-1H-indole-2-carbonyl)-4,4-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 62) [0608] Compound 62 was synthesized by the same procedure as Compound 2.
  • Example 64 (1R,2S,5S)-3-(2-(2,2-Difluorocyclohexyl)acetyl)-6,6-dimethyl-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 64) [0612] Compound 64 was synthesized by the same procedure as Compound 1.
  • Example 65 (1R,2S,5S)-3-(4-Methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 65)
  • Example 66 (1R,2S,5S)-3-(4-Isopropoxy-1H-indole-2-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 66) [0616] Compound 66 was synthesized by the same procedure as Compound 1.
  • Example 68 (1R,2S,5S)-3-(5-Methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 68) [0620] Compound 68 was synthesized by the same procedure as Compound 1.
  • Step 1 (2S,4S)-1-tert-butoxycarbonyl-4-cyclohexyl-pyrrolidine-2-carboxylic acid
  • 2S,4S 2-cyclohexylpyrrolidine-2-carboxylic acid
  • K2CO3 4.9 g, 35.49 mmol
  • H2O 15 mL
  • tert-butoxycarbonyl tert-butyl carbonate 4.43 g, 20.28 mmol
  • Step 2 (2S,4S)-tert-butyl 4-cyclohexyl-2-(((S)-1-methoxy-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)pyrrolidine-1-carboxylate
  • (2S,4S)-1-(tert-butoxycarbonyl)-4-cyclohexylpyrrolidine-2- carboxylic acid (1 g, 3.36 mmol) and DIEA (1.74 g, 13.45 mmol) in DCM (10 mL) was added dropwise T 3 P (3.21 g, 5.04 mmol, 50% purity in EtOAc) at 0°C.
  • Step 3 (S)-methyl 2-((2S,4S)-4-cyclohexylpyrrolidine-2-carboxamido)-3-((S)-2- oxopyrrolidin-3-yl)propanoate hydrochloride [0631]
  • Step 7 (2S,4S)-4-cyclohexyl-1-(7-fluoro-1H-indole-2-carbonyl)-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide
  • (2S,4S)-4-cyclohexyl-1-(7-fluoro-1H-indole-2-carbonyl)-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide 50 mg, 100.28 ⁇ mol
  • DCM 2 mL
  • DMP 85 mg, 200.57 ⁇ mol
  • Example 72 (1R,2S,5S)-6,6-Dimethyl-3-(6-methyl-1H-indole-2-carbonyl)-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 72) [0639] Compound 72 was synthesized by the same procedure as Compound 1.
  • Example 73 (1R,2S,5S)-3-(4,4-Dimethylpentanoyl)-6,6-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 73) [0641] Compound 73 was synthesized by the same procedure as Compound 1.
  • Example 74 (1R,2S,5S)-3-(6-Cyano-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 74) [0643] Compound 74 was synthesized by the same procedure as Compound 1.
  • Step 1 methyl 7-bromo-1H-indole-2-carboxylate
  • SOCl2 1.5 g, 12.50 mmol
  • the reaction mixture was concentrated in vacuo. The residue was dissolved in water (20 mL) and then extracted with EtOAc (40 mL x3). The combined organic phase was washed with water (30 mL), dried over anhydrous Na2SO4, filtered and concentrated.
  • Step 2 methyl 7-cyano-1H-indole-2-carboxylate
  • NMP NMP
  • Step 2 methyl 7-cyano-1H-indole-2-carboxylate
  • Step 3 7-cyano-1H-indole-2-carboxylic acid
  • methyl 7-cyano-1H-indole-2-carboxylate 420 mg, 2.10 mmol
  • H2O 4 mL
  • LiOH.H2O 352 mg, 8.39 mmol
  • the mixture was stirred at 25°C for 10 hr.
  • Water (10 mL) was added and the reaction mixture was adjusted to pH ⁇ 5 by aq. HCl (1 N).
  • the resulting mixture was extracted with EtOAc (30 mL x3).
  • the combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated.
  • Step 4 (S)-methyl 2-((2S,4S)-1-(7-cyano-1H-indole-2-carbonyl)-4- cyclohexylpyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0652] To a solution of compound (S)-methyl 2-((2S,4S)-4-cyclohexylpyrrolidine-2- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (648 mg, 1.61 mmol, HCl), 7-cyano- 1H-indole-2-carboxylic acid (300 mg, 1.61 mmol,) and DIEA (625 mg, 4.83 mmol) in DCM (10 mL) was added slowly HATU (1.23 g, 3.22 mmol) at 0°C.
  • Step 5 (2S,4S)-1-(7-cyano-1H-indole-2-carbonyl)-4-cyclohexyl-N-((S)-1-hydroxy- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide
  • (S)-methyl 2-((2S,4S)-1-(7-cyano-1H-indole-2-carbonyl)-4- cyclohexylpyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate 500 mg, 937.00 ⁇ mol
  • THF 5 mL
  • LiBH 4 70 mg, 3.21 mmol
  • Step 6 (2S,4S)-1-(7-cyano-1H-indole-2-carbonyl)-4-cyclohexyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide
  • (2S,4S)-1-(7-cyano-1H-indole-2-carbonyl)-4-cyclohexyl-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (20 mg, 39.56 ⁇ mol) in DCM (4 mL) was added DMP (50 mg, 118.67 ⁇ mol).
  • Example 76 (S)-5-(4-Cyano-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (Compound 76) [0658] Compound 76 was synthesized by the same procedure as Compound 2.
  • Example 77 (1R,2S,5S)-3-(7-Fluoro-4-methyl-1H-indole-2-carbonyl)-6,6- dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane- 2-carboxamide (Compound 77) [0660] Compound 77 was synthesized by the same procedure as Compound 1.
  • Example 78 (1R,2S,5S)-3-(4H-Furo[3,2-b]pyrrole-5-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 78) [0662] Compound 78 was synthesized by the same procedure as Compound 1.
  • Example 79 (1R,2S,5S)-3-(2-Cyclohexylacetyl)-6,6-dimethyl-N-((S)-1-oxo-3-((S)- 2-oxopiperidin-3-yl)propan-2-yl)-3-azabicyclo[310]hexane-2-carboxamide (Compound 79) [0664] Compound 79 was synthesized by the same procedure as Compound 1.
  • Example 80 (1R,2S,5S)-6,6-Dimethyl-3-(5-(methylsulfonyl)-1H-indole-2- carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane- 2-carboxamide (Compound 80) [0666] Compound 80 was synthesized by the same procedure as Compound 1.
  • Step 2 (S)-methyl 2-((2S,4S)-1-(7-chloro-1H-indole-2-carbonyl)-4- cyclohexylpyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
  • Step 3 (2S,4S)-1-(7-chloro-1H-indole-2-carbonyl)-4-cyclohexyl-N-((S)-1-hydroxy- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide
  • (S)-methyl 2-((2S,4S)-1-(7-chloro-1H-indole-2-carbonyl)-4- cyclohexylpyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate 400 mg, 736.58 ⁇ mol
  • LiBH4 140 mg, 6.43 mmol
  • Step 4 (2S,4S)-1-(7-chloro-1H-indole-2-carbonyl)-4-cyclohexyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide
  • (2S,4S)-1-(7-chloro-1H-indole-2-carbonyl)-4-cyclohexyl-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide 100 mg, 194.16 ⁇ mol
  • DCM 5 mL
  • DMP 165 mg, 388.32 ⁇ mol
  • Example 82 (S)-5-(6-Cyano-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (Compound 82) [0677] Compound 82 was synthesized by the same procedure as Compound 2.
  • Step 2 tert-butyl ((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)carbamate [0682] To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3- yl)propanoic acid (5 g, 18.36 mmol) in DCM (40 mL) was added
  • Step 3 (S)-2-amino-N-methoxy-N-methyl-3-((S)-2-oxopyrrolidin-3- yl)propanamide
  • Step 4 (1R,2S,5S)-tert-butyl 2-(((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3- carboxylate [0686] To a mixture of (1R,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (950 mg, 3.72 mmol) in DCM (10 mL) was added T3P (3.55 g, 5.58 mmol, 3.32 mL, 50% purity) and DIEA (1.92 g, 14.88 mmol, 2.59 mL) at 0°C.
  • Step 6 (1R,2S,5S)-N-((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-(1H-pyrrolo[3,2-b]pyridine-2-carbonyl)-3- azabicyclo[3.1.0]hexane-2-carboxamide
  • Example 84 (S)-N-((S)-1-Oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6-(1- phenylcyclopropanecarbonyl)-6-azaspiro[3.4]octane-7-carboxamide (Compound 84) [0694] Compound 84 was synthesized by the same procedure as Compound 2.
  • Example 86 (1R,2S,5S)-6,6-Dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-(2-(tetrahydro-2H-pyran-4-yl)acetyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 86) [0698] Compound 86 was synthesized by the same procedure as Compound 1.
  • Example 87 (S)-5-(7-Fluoro-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (Compound 87) [0700] Compound 87 was synthesized by the same procedure as Compound 2.
  • Example 88 (1R,2S,5S)-3-(7-Chloro-4-isopropyl-1H-indole-2-carbonyl)-6,6- dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane- 2-carboxamide (Compound 88)
  • Example 90 (1R,2S,5S)-3-(5-Chloro-1-methyl-1H-indole-2-carbonyl)-6,6- dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane- 2-carboxamide (Compound 90) [0706] Compound 90 was synthesized by the same procedure as Compound 1.
  • Example 94 (1R,2S,5S)-3-(1-Hydroxycyclohexanecarbonyl)-6,6-dimethyl-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 94) [0714] Compound 94 was synthesized by the same procedure as Compound 1.
  • Example 95 (1R,2S,5S)-3-(3,3-Dimethylbutanoyl)-6,6-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 95) [0717] Compound 95 was synthesized by the same procedure as Compound 1.
  • Example 96 (1R,2S,5S)-3-(1,4-Dimethylindole-2-carbonyl)-N-[(1S)-1-formyl-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 96) [0719] Compound 96 was synthesized by the same procedure as Compound 1.
  • Example 102 (2S,4S)-1-(1H-Indole-2-carbonyl)-4-methoxy-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 102) [0731] Compound 102 was synthesized by the same procedure as Compound 2.
  • Example 103 (2S,4R)-4-cyclohexyl-1-(1H-Indole-2-carbonyl)-N-((S)-1-oxo-3-((S)- 2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 103) [0733] Compound 103 was synthesized by the same procedure as Compound 2.
  • Example 104 (1R,2S,5S)-6,6-Dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-((S)-2-phenylpropanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 104) [0735] Compound 104 was synthesized by the same procedure as Compound 1.
  • Example 105 (1R,2S,5S)-N-((S)-4-(Cyclopropylamino)-3,4-dioxo-1-((S)-2- oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-(2-(4-methylcyclohexyl)acetyl)-3- azabicyclo[3.1.0]hexane-2-carboxamide (Compound 105) [0737] Compound 105 was synthesized by the same procedure as Compound 119.
  • Example 106 (1S,3S,4R,6S)-6-Fluoro-2-(1H-indole-2-carbonyl)-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (Compound 106) [0739] Compound 106 was synthesized by the same procedure as Compound 2.
  • Example 107 (2S,4R)-1-(1H-Indole-2-carbonyl)-4-methyl-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 107) [0741] Compound 107 was synthesized by the same procedure as Compound 2.
  • Example 108 (S)-1-(1H-Indole-2-carbonyl)-4-methylene-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 108) [0743] Compound 108 was synthesized by the same procedure as Compound 2.
  • Example 109 (2S,4R)-4-(2-Chlorobenzyl)-1-(1H-indole-2-carbonyl)-N-((S)-1-oxo- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 109) [0745] Compound 109 was synthesized by the same procedure as Compound 2.
  • Example 111 (1R,2S,5S)-3-(5-Ethoxy-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 111) [0749] Compound 111 was synthesized by the same procedure as Compound 1.
  • Example 112 (2S,4R)-4-Cyano-1-(1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 112) [0751] Compound 112 was synthesized by the same procedure as Compound 2.
  • Example 113 (2S,3aS,7aS)-1-(1H-Indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)octahydro-1H-indole-2-carboxamide (Compound 113) [0753] Compound 113 was synthesized by the same procedure as Compound 2.
  • Example 114 (1R,2S,5S)-3-(5,6-dimethoxy-1H-Indole-2-carbonyl)-6,6-dimethyl- N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- c [0755] Compound 114 was synthesized by the same procedure as Compound 1.
  • Example 115 (S)-4,4-difluoro-1-(1H-Indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 115) [0757] Compound 115 was synthesized by the same procedure as Compound 2.
  • Example 116 N-((S)-1-((1R,2S,5S)-2-(((S)-4-amino-3,4-dioxo-1-((S)-2- oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3- dimethyl-1-oxobutan-2-yl)-1H-indole-2-carboxamide (Compound 116) [0759] Step 1: (1R,2S,5S)-methyl 3-((S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate [0760] To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3,3-
  • Step 2 (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid
  • (1R,2S,5S)-methyl 3-((S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate 630 mg, 1.65 mmol
  • H2O 3 mL
  • LiOH.H2O 138 mg, 3.29 mmol
  • Step 3 tert-butyl ((2S)-1-((1R,2S,5S)-2-(((2S)-4-amino-3-hydroxy-4-oxo-1-((S)-2- oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3- dimethyl-1-oxobutan-2-yl)carbamate [0764] To a solution of (3S)-3-amino-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide hydrochloride (100 mg, 496.96 mmol) in DCM (4 mL) was added DIEA (178 mg, 1.38 mmol, 240 uL) and (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)
  • Step 4 (1R, 2S, 5S)-3-((S)-2-amino-3, 3-dimethylbutanoyl)-N-((2S)-4-amino-3- hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide
  • Step 4 (1R, 2S, 5S)-3-((S)-2-amino-3, hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3- yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (135 mg
  • Step 5 N-((2S)-1-((1R,2S,5S)-2-(((2S)-4-amino-3-hydroxy-4-oxo-1-((S)-2- oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3- dimethyl-1-oxobutan-2-yl)-1H-indole-2-carboxamide [0768] To a solution of (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-N-((2S)-4- amino-3-hydroxy-4-oxo-1-(((2S)-4- amino-3-hydroxy-4-oxo-1-(((2S)-2-amino-3,3-dimethylbutanoyl)-N-((2S)-4- amino-3-hydroxy-4
  • Step 6 N-((S)-1-((1R,2S,5S)-2-(((S)-4-amino-3,4-dioxo-1-((S)-2-oxopyrrolidin-3- yl)butan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1- oxobutan-2-yl)-1H-indole-2-carboxamide [0770] To a solution of N-((2S)-1-((1R,2S,5S)-2-(((2S)-4-amino-3-hydroxy-4-oxo-1-((S)- 2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)- 3,3-dimethyl
  • Example 117 (1R,2S,5S)-3-(5-Chloro-4-fluoro-1H-indole-2-carbonyl)-6,6- dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane- 2-carboxamide (Compound 117) [0772] Compound 117 was synthesized by the same procedure as Compound 1.
  • Example 118 (1R,2S,5S)-3-(1,4-Dimethylindole-2-carbonyl)-N-[(1S)-1-formyl-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 118) [0774] Compound 118 was synthesized by the same procedure as Compound 1.
  • Step 2 tert-butyl ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate
  • tert-butyl ((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)carbamate (2 g, 7.74 mmol) in DCM (30 mL) was added SO 3 .Py (7.39 g, 46.46 mmol), TEA (4.70 g, 46.46 mmol, 6.47 mL) and DMSO (6.05 g, 77.43 mmol, 6.05 mL) at 25°C.
  • Step 3 isocyanocyclopropane
  • Step 5 (3S)-3-amino-1-(cyclopropylamino)-1-oxo-4-((S)-2-oxopyrrolidin-3- yl)butan-2-yl acetate
  • (3S)-3-((tert-butoxycarbonyl)amino)-1-(cyclopropylamino)-1-oxo- 4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl acetate 60 mg, 156.48 ⁇ mol
  • TFA 0.1 mL
  • Step 6 (3S)-1-(cyclopropylamino)-3-((1R,2S,5S)-6,6-dimethyl-3-(1- phenylcyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)-1-oxo-4-((S)-2- oxopyrrolidin-3-yl)butan-2-yl acetate
  • (3S)-3-amino-1-(cyclopropylamino)-1-oxo-4-((S)-2-oxopyrrolidin- 3-yl)butan-2-yl acetate 45.20 mg, 151.00 ⁇ mol
  • Step 7 (1R,2S,5S)-N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2- oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-(1-phenylcyclopropanecarbonyl)-3- azabicyclo[3.1.0]hexane-2-carboxamide
  • Step 2 tert-butyl ((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)carbamate
  • tert-butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)carbamate (1.00 g, 3.69 mmol) in THF (10 mL) was added TEA (372 mg, 3.69 mmol, 513 uL) at 0°C. Then TFAA (774 mg, 3.69 mmol, 512.67 uL) was added dropwise to the mixture.
  • the reaction was stirred at 25°C for 2 hr. The mixture was concentrated under reduced pressure. The residue was poured into ice-water (20 mL). The aqueous phase was extracted with ethyl acetate (50 mL x3). The combined organic phase was washed with sat.aq.NaHCO3 (30 mL) and brine (30 mL), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was triturated with n-hexane (10 mL) at 25 °C for 30 minutes. The solid was filtered and dried under reduced pressure.
  • Step 3 (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanenitrile [0798] To a solution of tert-butyl ((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)carbamate (300 mg, 1.18 mmol) in DCM (6 mL) was added TFA (3 mL) in one portion at 25°C. The mixture was stirred for 1 hr and then concentrated under reduce pressure. The title compound (300 mg, crude, TFA) was obtained as a yellow oil.
  • Step 4 (1R,2S,5S)-tert-butyl 2-(((S)-1-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate
  • Step 5 (1R,2S,5S)-tert-butyl 2-(((S)-1-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate
  • (1R,2S,5S)-tert-butyl 2-(((S)-1-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate 140 mg, 358.54 ⁇ mol
  • DCM 5 mL
  • TFA 0.5 mL
  • Step 6 (1R,2S,5S)-3-(5H-[1,3]dioxolo[4,5-f]indole-6-carbonyl)-N-[(1S)-1-formyl- 2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
  • (R)-2-(m-tolyl)propanoic acid 21 mg, 126.12 ⁇ mol
  • Example 121 (2S,4R)-1-(1H-Indole-2-carbonyl)-4-methoxy-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 121) [0806] Compound 121 was synthesized by the same procedure as Compound 2.
  • Example 123 (1R,2S,5S)-3-(1-(3-Chlorophenyl)cyclopropanecarbonyl)-N-((S)-1- cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 123) [0810] Compound 123 was synthesized by the same procedure as Compound 120.
  • Example 125 (1S,3S,5S)-2-(1H-Indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (Compound 125) [0814] Compound 125 was synthesized by the same procedure as Compound 2.
  • Example 126 (S)-5-(2-Cyclohexylacetyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (Compound 126) [0816] Compound 126 was synthesized by the same procedure as Compound 2.
  • Example 127 (S)-N-((S)-1-(benzo[d]thiazol-2-yl)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-5-(1H-indole-2-carbonyl)-5-azaspiro[2.4]heptane-6-carboxamide (Compound 127) [0818]
  • Example 128 (1R,2S,5S)-3-(7-Chloro-4-fluoro-1H-indole-2-carbonyl)-N-((S)-1- cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 128) [0819]
  • Example 129 (2S,3aS,6aS)-1-(1H-Indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)octahydrocyclopenta[b]pyrrole-2-carboxamide (Compound 129) [0821] Compound 129 was synthesized by the same procedure as Compound 2.
  • Example 130 (1S,2S,5R)-3-(1H-Indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 130) [0823] Compound 130 was synthesized by the same procedure as Compound 2.
  • Example 131 (1R,2S,5S)-N-((S)-1-Cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-(7- fluoro-4-isopropyl-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- c [0825] Compound 131 was synthesized by the same procedure as Compound 120.
  • Example 132 (1R,2S,5S)-3-(7-Chloro-1H-indole-2-carbonyl)-N-((S)-1-cyano-2- ((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 132) [0827] Compound 132 was synthesized by the same procedure as Compound 120.
  • Example 133 (2S,4R)-1-(1H-Indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-4-phenoxypyrrolidine-2-carboxamide (Compound 133) [0829] Compound 133 was synthesized by the same procedure as Compound 2.
  • Example 134 (2S,4S)-1-(1H-Indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-4-phenoxypyrrolidine-2-carboxamide (Compound 134) [0831] Compound 134 was synthesized by the same procedure as Compound 2.
  • Example 135 (1R,2S,5S)-N-((S)-1-Cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6- dimethyl-3-(1-phenylcyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 135) [0833] Compound 135 was synthesized by the same procedure as Compound 120.
  • Example 136 (1R,2S,5S)-N-((S)-1-Cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6- dimethyl-3-(1-phenylcyclopentanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 136) [0835] Compound 136 was synthesized by the same procedure as Compound 120.
  • Example 137 (2S,4R)-4-(3-Chlorobenzyl)-1-(1H-indole-2-carbonyl)-N-((S)-1-oxo- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 137) [0837] Compound 137 was synthesized by the same procedure as Compound 2.
  • Example 138 (S)-1-(3,3-Dimethylbutanoyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin- 3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 138) [0839] Compound 138 was synthesized by the same procedure as Compound 2.
  • Inhibition% [(CPD-BGCPD)-(ZPE -BGZPE)/ (HPE-BGHPE)-(ZPE -BGZPE)] ⁇ 100%
  • CPD Signal of test compounds wells, containing compound + enzyme + substrate.
  • ZPE Average of signals of zero percent effective control wells, containing enzyme + substrate, no compound.

Abstract

Disclosed are compounds represented by formulae (I) and (II): or a pharmaceutically acceptable salt thereof. Compounds of formula (I) and (II) are useful for treating coronavirus infection via inhibition of the protease Mpro.

Description

3- (1 H-INDOLE-2-CARBONYL)-6,6-DIMETHYL-N-((S)-1-OXO-3-((S)-2-OXOPYRROLIDIN-3-YL)P ROPAN-2-YL)-3-AZABICYCLO[3.1 .O]HEXANE-2-CARBOXAMIDE DERIVATIVES AS MPRO INHIBITORS FOR THE TREATMENT OF CORONAVIRUS INFECTIONS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This International PCT Application claims priority to and the benefit of U.S. Provisional Application No.63/406,060 filed on September 13, 2022, the contents of which are herein incorporated by reference in their entirety. TECHNICAL FIELD [0002] The present disclosure relates to novel protease inhibitors useful for inhibiting coronavirus replication and methods for treating a subject infected by coronavirus including the SARS-CoV-2 virus. BACKGROUND [0003] Coronaviruses are a family of enveloped, single-stranded, positive-sense, RNA viruses that are known to cause disease in a wide variety of animals. Zumla, A., et al., “Coronaviruses—drug discovery and therapeutic options,” Nature Reviews Drug Discovery 15(5):327-347 (2016). Seven coronaviruses are known to infect humans: SARS-CoV-1, SARS-CoV-2, MERS-CoV, HCoV-229E, HCoV-HKU1, HCoV-NL63 and HCoV-OC43. Shamsi, A., et al., “Potential drug targets of SARS-CoV-2: From genomics to therapeutics,” International Journal of Biological Macromolecules 177:1-9 (2021); and Ullrich, S. and Nitsche, C., “The SARS-CoV-2 main protease as drug target,” Bioorganic & Medicinal Chemistry Letters 30(17):127377 (2020). Most notably, SARS-CoV-2 is responsible for the COVID-19 respiratory illness and the ensuing pandemic, which as of March 2022, has caused more than 6 million deaths worldwide (WHO COVID-19 dashboard https://covid19.who.int/). Although safe and effective vaccines have been developed, global implementation has been hampered by limited access and recipient hesitancy. Furthermore, breakthrough infections and illness in vaccinated individuals have been widely documented. Most experts believe that COVID-19 will become an endemic illness that will persist in humans for many years to come, if not indefinitely. Therapeutic options for COVID-19 are currently limited. There is a clear unmet medical need for targeted antiviral therapeutics for the treatment COVID-19. Recent history of severe respiratory illnesses cause by coronaviruses (SARS-CoV-1, MERS-CoV, SARS-CoV-2) highlights the importance of pan- coronavirus therapeutics for future pandemic preparedness. [0004] The SARS-CoV-2 genome contains 13-15 open reading frames that encode for a variety of structural and non-structural proteins (nsp’s). Lu, R. et al., “Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding,” The Lancet 395(10224):565-574 (2020). The largest open reading frame (ORF1ab) encodes for 2 overlapping polyproteins (pp1a, pp1b) that are cleaved at sequence specific sites into 16 distinct nsp’s that are involved in viral replication, viral assembly, and host immune modulation. Shamsi, A. et al. (2016). Cleavage of pp1a and pp1b into individual nsp’s is mediated by two viral proteases, the main protease (Mpro) and the papin-like protease (Plp). Shamsi, A. et al. (2016); Ullrich, S. and Nitsche, C. (2020). The function of both of these proteases are necessary for coronavirus replication and pathogenesis. Shamsi, A. et al. (2016); Ullrich, S. and Nitsche, C. (2020). The main protease cleaves peptides after a glutamine (P1) that is adjacent to a hydrophobic residue such as leucine, phenylalanine, or valine (P2). Ullrich, S. and Nitsche, C. (2020). This substrate recognition is distinct from all known human proteases. Id. Proteolysis is mediated by a cysteine – histidine catalytic diad along with a buried water molecule that is hydrogen bonded to the catalytic histidine. The main protease sequence is well conserved across human coronaviruses, particularly the active site and substrate binding pocket. Banerjee, R. et al., “Potential SARS-CoV-2 main protease inhibitors,” Drug Discovery Today 26(3):804-816 (2021). Therefore, the main protease constitutes an attractive drug target for COVID-19 with a high potential for enabling pan-coronavirus therapeutics. Inhibition of the main protease has been demonstrated to block SARS-CoV-2 infection in cells, and reduce lung viral titer in infected mice. Owen, D. R., et al., “An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19,” Science 374(6575):1586-1593 (2021). Recent clinical data indicate that administration of an Mpro inhibitor to COVID-19 patients shortly after symptom onset significantly reduces hospitalization and death (Pfizer press release: https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oral- antiviral-treatment-candidate). [0005] Therefore, there exists a need to develop new compounds for treating coronavirus infection via inhibition of the protease Mpro. [0006] One aspect of the present disclosure provides a compound of formula I:
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein: R1 is (a) -C1-6alkyl, (b) -C1-6haloalkyl, (c) -C1-6alkylene-NHCO-C1-6haloalkyl, (d) -C0-6alkylene-(saturated cycloalkyl), (e) -C0-6alkylene-heterocycloalkyl, (f) -C0-6alkylene-(tricyclic heteroaryl), (g) -heteroarylene-cycloalkyl, (h) -heteroarylene-aryl, (i)
Figure imgf000004_0002
-NH2, -NO2, -C1-6alkyl, alkenyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; p is 0, 1, 2, 3, 4, or 5; and q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; (j)
Figure imgf000004_0003
is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2; or (k)
Figure imgf000005_0001
is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, or -SO2(C1-6alkyl); and r is 0 or 1; R3, R4, and R5 are each independently -H, halo, -OH, -CN, -NH2, -NO2, alkylenyl, -C1-6alkyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; or R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; or R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R4 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; R2 is H; or R2 and R3 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R2 and R5 together with the pyrrolidine ring to which they are attached form a bridged 6 to 8 membered heterocycloalkyl; R6
Figure imgf000005_0002
R7 and R8 are each independently H or C1-6alkyl; and n is 1, 2, or 3; wherein at each occurrence, cycloalkyl, saturated cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl); provided that where n is 1; R2, R7, and R8 are H; R3 and R5 or R4 and R5 together with the carbon atom to which they are attached form a 3 membered or 5 membered-cycloalkyl; then R1 is not
Figure imgf000006_0001
[0007] Another aspect of the present disclosure provides a compound of formula II:
Figure imgf000006_0002
or a pharmaceutically acceptable salt thereof, wherein: R1A is H, -C1-6alkylene-NHCONH-C1-6alkyl, -C1-6alkylene-NHCO(heteroaryl), -C1-6alkylene-cycloalkyl,
Figure imgf000006_0003
, in RA is halo, -OH, -CN, -NH2, -NO2, -C1-6alkyl, alkenyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; p is 0, 1, 2, 3, 4, or 5;
Figure imgf000006_0004
, rein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2; R3, R4, and R5 are each independently -H, halo, -OH, -CN, -NH2, -NO2, alkylenyl, -C1-6alkyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; or R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; or R and R together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R4 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; R2 is H; or R2 and R3 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R6
Figure imgf000007_0001
R7 and R8 are each independently H or C1-6alkyl; each R9 is independently H, C1-6alkyl, cycloalkyl, or heteroaryl; and R12 is heterocyclyl or heteroaryl; wherein at each occurrence, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl). [0008] Another aspect of the present disclosure provides compounds selected from any of the compounds prepared in the examples, or a pharmaceutically acceptable salt thereof. [0009] A further aspect of the present disclosure provides a pharmaceutical composition comprising the compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [0010] An additional aspect of the present disclosure provides a method of treating a viral infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of the disclosure. [0011] Another aspect of the present disclosure provides a compound of the disclosure or a pharmaceutically acceptable salt or ester thereof, for use in treating a coronavirus infection in a human. [0012] A further aspect of the present disclosure provides a compound of the disclosure or a pharmaceutically acceptable salt or ester thereof, for use in treating SARS-CoV-2 infection in a human. [0013] An additional aspect of the present disclosure relates to a medical use of the compounds or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a coronavirus infection. DETAILED DESCRIPTION [0014] As used herein, all technical and scientific terms have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. DEFINITIONS [0015] The term “disease” or “condition” refers to disturbances and/or anomalies that are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and/or malfunctions. As demonstrated below, compounds of the present disclosure are inhibitors of Mpro and can be used in treating or preventing diseases and conditions wherein inhibition of Mpro provides a benefit. [0016] As used herein, the terms "treatment," "treat," and "treating" are interchangeable and refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, including but not limited to therapeutic benefit. [0017] In some embodiments, "treatment" or "treating" includes one or more of the following: (a) inhibiting the disorder (for example, decreasing one or more symptoms resulting from the disorder, and/or diminishing the extent of the disorder); (b) slowing or arresting the development of one or more symptoms associated with the disorder (for example, stabilizing the disorder and/or delaying the worsening or progression of the disorder); and/or (c) relieving the disorder (for example, causing the regression of clinical symptoms, ameliorating the disorder, delaying the progression of the disorder, and/or increasing quality of life). [0018] Therapeutic benefit includes eradication and/or amelioration of the underlying disorder being treated. It also includes the eradication and/or amelioration of one or more of the symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. [0019] The terms prevent, preventing, and prevention refer to a method of preventing or delaying the onset of a disease or condition and/or its attendant symptoms or barring a subject from acquiring a disease. These terms may include “prophylactic treatment”, which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition. [0020] As used herein, "administering" or "administration" of the compound of formula (I) or formula (I-A) or a pharmaceutically acceptable salt thereof encompasses the delivery to a patient a compound or a pharmaceutically acceptable salt thereof, or a prodrug or other pharmaceutically acceptable derivative thereof, using any suitable formulation or route of administration, e.g., as described herein. [0021] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disorder, is sufficient to effect such treatment of the disorder. The effective amount will vary depending on the disorder, and its severity, and the age, weight, etc. of the subject to be treated. The effective amount may be in one or more doses (for example, a single dose or multiple doses may be required to achieve the desired treatment endpoint). An effective amount 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. Suitable doses of any co-administered compounds may optionally be lowered due to the combined action, additive or synergistic, of the compound. [0022] As used herein, "patient" or “subject” refers to human subject of any age groups and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys). [0023] As used herein, "pharmaceutically acceptable" or "physiologically acceptable" refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use. [0024] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19. [0025] The term "pharmaceutically acceptable carrier" is used herein to refer to a material that is compatible with a recipient subject, preferably a mammal, more preferably a human, and is suitable for delivering an active agent to the target site without terminating the activity of the agent. The toxicity or adverse effects, if any, associated with the carrier preferably are commensurate with a reasonable risk/benefit ratio for the intended use of the active agent. [0026] The term “orally” refers to administering a composition that is intended to be ingested. Examples of oral forms include, but are not limited to, tablets, pills, capsules, powders, granules, solutions or suspensions, and drops. Such forms may be swallowed whole or may be in chewable form. [0027] The terms “a,” “an,” and “the” are to be construed to cover both the singular and the plural, unless otherwise indicated. Recitation of ranges of values herein merely are intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended to better illustrate the disclosure and is not a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure. [0028] The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10%. [0029] The term “halo” refers to -Cl, -F, -Br, or -I. [0030] The term “alkyl” refers to a straight- or branched-chain saturated hydrocarbon. The chain may contain an indicated number of carbon atoms. For example, C1-C10 or C1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it; C1-C6 or C1-6 indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it. If not otherwise indicated, an alkyl group contains from 1 to about 20 carbon atoms. In some aspects, alkyl groups have 1 to about 10 carbon atoms. In some aspects, alkyl groups (“lower alkyl”) have 1 to 8, 1 to 6, or 1 to 3 carbon atoms in the chain. Examples may include, but are not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, neopentyl, 2- methylbutyl, 1,1-dimethylpropyl, hexyl, heptyl, octyl, nonyl, decyl, and docecyl. [0031] The term “alkylene” as used herein includes an alkyl group that is substituted at two points. An example is methylene (-CH2-), propylene (-CH2CH2CH2-), and the like. [0032] The term “substituted with 0, 1, 2, 3, or 4 substituents” refers to that a group may be unsubstituted when the group is substituted with 0 substituent, or that the group is substituted with 1, 2, 3, or 4 substituents. [0033] The term “optionally substituted” refers to that a group may be unsubstituted, or substituted with one or more of the indicated substituents. The term “substituted with 0, 1, 2, 3, or 4 substituents” has the same meaning and is equivalent to the term “optionally substituted with 1, 2, 3, or 4 substituents”. [0034] The term “alkoxy” refers to an alkyl group attached to a terminal oxygen atom. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy. [0035] The term “amino protecting group” refers to a protecting group that is suitable for preventing undesired reactions at an amino nitrogen. Representative amino-protecting groups include, but are not limited to, formyl; acyl groups, such as acetyl and trifluoroacetyl; alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl (Bn), trityl (Tr), and 1,1-di-(4'-methoxyphenyl)methyl; and the like. [0036] The term “cycloalkyl” refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic, bicyclic, or tricyclic aliphatic hydrocarbons containing three to twelve carbon atoms, i.e., a C3-12 cycloalkyl, or the number of carbons designated, e.g., a C3 cycloalkyl such a cyclopropyl, a C4 cycloalkyl such as cyclobutyl, etc. In one embodiment, the cycloalkyl is bicyclic, i.e., it has two rings. In another embodiment, the cycloalkyl is monocyclic, i.e., it has one ring. A cycloalkyl group may be unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), -CO(C1-6alkyl), benzyloxy, cycloalkyl, aryl, and heteroaryl. In some embodiments, the benzyloxy, cycloalkyl, aryl, and heteroaryl may be further substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1- 6alkyl), -CO(C1-6alkyl), benzyloxy, cycloalkyl, aryl, and heteroaryl. [0037] The term “cycloalkylene” as used herein includes a cycloalkyl group that is substituted at two points. [0038] The term “aryl” refers to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyl tetrahydrofluorenyl, tetrahydroanthracenyl, or anthracenyl) ring systems having six to fourteen carbon atoms in which the monocyclic ring system is aromatic or at least one of the rings in a bicyclic or tricyclic ring system is aromatic. The other ring(s) in the bicyclic or tricyclic ring system may be saturated, partially unsaturated, or fully unsaturated. The bicyclic and tricyclic groups include benzofused carbocyclic rings. For example, a benzofused group includes a phenyl group fused with one or two 4 to 8 membered carbocyclic moieties. An aryl group may be unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), -CO(C1- 6alkyl), benzyloxy, cycloalkyl, aryl, and heteroaryl. In some embodiments, the benzyloxy, cycloalkyl, aryl, and heteroaryl may be further substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), -CO(C1-6alkyl), benzyloxy, cycloalkyl, aryl, and heteroaryl. [0039] The term “heteroaryl” refers to monocyclic, bicyclic, or tricyclic ring systems containing five to fourteen ring atoms including carbon, zero, one, two, three, or four heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. The monocyclic ring system is aromatic and at least one of the rings in the bicyclic or tricyclic ring systems is aromatic. The other ring(s) in the bicyclic or tricyclic ring system may be saturated, partially unsaturated, or fully unsaturated. In one embodiment, the heteroaryl has three heteroatoms. In another embodiment, the heteroaryl has two heteroatoms. In another embodiment, the heteroaryl has one heteroatom. In some embodiments, the heteroaryl has five to twelve ring atoms. In some embodiments, the heteroaryl has eight to twelve ring atoms. In some embodiments, the heteroaryl has eight or nine ring atoms. In some embodiments, the heteroaryl has nine ring atoms. Non-limiting exemplary heteroaryl groups include thienyl (e.g., thien-2-yl and thien-3-yl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrazinyl, pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), pyridazinyl, isoindolyl, 3H-indolyl, 1H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), phenothiazolyl, oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl), isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl), furazanyl, phenoxazinyl, triazolyl, triazinyl, and tetrazolyl. In some embodiments, the heteroaryl group is indolyl. In some embodiments, the heteroaryl group is 1H-indolyl. In some embodiments, the heteroaryl group is 5H-[1,3]dioxolo[4,5-f]indole. The term heteroaryl also includes N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide. [0040] A heteroaryl group may be unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), -CO(C1-6alkyl), benzyloxy, cycloalkyl, aryl, and heteroaryl. In some embodiments, the benzyloxy, cycloalkyl, aryl, and heteroaryl may be further substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), -CO(C1-6alkyl), benzyloxy, cycloalkyl, aryl, and heteroaryl. [0041] The term “heteroarylene” as used herein includes a heteroaryl group that is substituted at two points. [0042] The term “heterocycloalkyl” refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic or bicyclic ring structure containing three to fourteen ring members, in which zero, one, two, or three of the ring atoms is a heteroatom. Each heteroatom is independently oxygen, sulfur, or nitrogen. In one embodiment, the heterocycloalkyl has three heteroatoms. In another embodiment, the heterocycloalkyl has two heteroatoms. In another embodiment, the heterocycloalkyl has one heteroatom. Non-limiting exemplary heterocycloalkyl groups include thiacyclohexanyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl and thietanyl, oxazinyl, oxetanyl, azetidinyl, thietanyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydrothiophenyl, tetrahydro- 2H-pyran, dihydropyranyl, dioxanyl, 1,3-dioxolanyl, 1,4-dithianyl, hexahydropyrimidine, pyrrolidinyl, dihydropyrrolyl, morpholinyl, piperazinyl, piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl, tetrahydropyridinyl, tetrahydrothiopyranyl, thiomorpholinyl, thioxanyl, trithianyl, bicyclo[1.1.1]pentanyl, imidazolidinyl, dioxolanyl, oxathiolanyl and dithiolanyl, triazolinyl, oxadiazolinyl, thiadiazolinyl, dihydropyridinyl, thianyl, dioxanyl, triazinanyl, azepanyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, and thiocanyl. [0043] A heterocycloalkyl group may be unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), - CO(C1-6alkyl), benzyloxy, cycloalkyl, aryl, and heteroaryl. In some embodiments, the benzyloxy, cycloalkyl, aryl, and heteroaryl may be further substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), -CO(C1-6alkyl), benzyloxy, cycloalkyl, aryl, and heteroaryl. [0044] The term “haloalkyl” refers to an alkyl group where at least one hydrogen has been replaced with a halo group. In certain embodiments, the haloalkyl group has one halo group. In certain embodiments, the haloalkyl group has two or three halo groups. In certain embodiments, the haloalkyl group is a perfluorinated alkyl group. Examples may include, but are not limited to, chloromethyl, trifluoromethyl, and the like. [0045] The term “hydroxyalkyl” refers to an alkyl group where at least one hydrogen has been replaced with an alcohol (-OH) group. In certain embodiments, the hydroxyalkyl group has one alcohol group. In certain embodiments, the hydroxyalkyl group has two alcohol groups, each on a different carbon atom. Examples may include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, and 1-hydroxyethyl. [0046] When any two substituent groups or any two instances of the same substituent group are “independently” selected from a list of alternatives, the groups may be the same or different. For example, if Ra and Rb are each independently alkyl, -F, -NH2, or -OH, then a molecule with two Ra groups and two Rb groups could have all groups be an alkyl group (e.g., four different alkyl groups). Alternatively, the first Ra could be alkyl, the second Ra could be -F, the first Rb could be -OH, and the second Rb could be -NH2 (or any other substituents taken from the group). Alternatively, both Ra and the first Rb could be -F, while the second Rb could be alkyl (i.e., some pairs of substituent groups may be the same, while other pairs may be different). [0047] Compounds of the present disclosure may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure encompasses the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof. The individual enantiomers can be separated according to methods known in the art in view of the present disclosure. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are also encompassed by the present disclosure. [0048] The stereochemical terms and conventions used in the specification are meant to be consistent with those described in Pure & Appl. Chem 68:2193 (1996), unless otherwise indicated. COMPOUNDS OF THE DISCLOSURE [0049] In some embodiments, the present disclosure provides a compound of formula I:
Figure imgf000015_0001
I or a pharmaceutically acceptable salt thereof, wherein: R1 is (a) -C1-6alkyl, (b) -C1-6haloalkyl, (c) -C1-6alkylene-NHCO-C1-6haloalkyl, (d) -C0-6alkylene-(saturated cycloalkyl), (e) -C0-6alkylene-heterocycloalkyl, (f) -C0-6alkylene-(tricyclic heteroaryl), (g) -heteroarylene-cycloalkyl, (h) -heteroarylene-aryl, (i)
Figure imgf000015_0002
, , , ,
Figure imgf000016_0001
, , wherein RA is halo, -OH, -CN, -NH2, -NO2, -C1-6alkyl, alkenyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; p is 0, 1, 2, 3, 4, or 5; and q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; (j)
Figure imgf000016_0003
, wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2; or (k)
Figure imgf000016_0004
or , wherein R11 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, or -SO2(C1-6alkyl); and r is 0 or 1; R3, R4, and R5 are each independently -H, halo, -OH, -CN, -NH2, -NO2, alkylenyl, -C1-6alkyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; or R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; or R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R4 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; R2 is H; or R2 and R3 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R2 and R5 together with the pyrrolidine ring to which they are attached form a bridged 6 to 8 membered heterocycloalkyl;
Figure imgf000016_0002
R6 is ; R and R are each independently H or C1-6alkyl; and n is 1, 2, or 3; wherein at each occurrence, cycloalkyl, saturated cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl); provided that where n is 1; R2, R7, and R8 are H; R3 and R5 or R4 and R5 together with the carbon atom to which they are attached form a 3 membered or 5 membered-cycloalkyl; then R1 is not
Figure imgf000017_0001
or . [0050] In some embodiments of formula I, the compound is not of the formula:
Figure imgf000017_0002
, , or . [0051] In some embodiments of formula I, R1 is (a) -C1-6alkyl, (b) -C1-6alkylene-NHCO-C1-6haloalkyl, (c) -C0-6alkylene-(saturated cycloalkyl), (d) -C0-6alkylene-heterocycloalkyl, (e) -C0-6alkylene-(tricyclic heteroaryl), (f) -heteroarylene-cycloalkyl, (
Figure imgf000017_0003
, , , ,
Figure imgf000018_0001
, , wherein RA is halo, -OH, -CN, -NH2, -NO2, -C1-6alkyl, alkenyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; p is 0, 1, 2, 3, 4, or 5, and q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; (h)
Figure imgf000018_0002
or , wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2; and (i)
Figure imgf000018_0003
or , w ere n s ao, CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, or -SO2(C1-6alkyl); and r is 0 or 1; wherein at each occurrence, cycloalkyl, heterocycloalkyl, aryl, phenyl, and heteroaryl are each independently substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, -CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl). [0052] In some embodiments of formula I, R1 is (a) -C1-6alkyl, (b) -C1-6alkylene-NHCO-C1-6haloalkyl, (c) -C0-6alkylene-(saturated cycloalkyl), wherein cycloalkyl is substituted with 0 or 1 phenyl, (d) -C0-6alkylene-(3-7 membered heterocycloalkyl), (e) -C0-6alkylene-(8-12 membered tricyclic heteroaryl), wherein the tricyclic heteroaryl is substituted with 0 or 1 substituents selected from the group consisting of C3-6cycloalkyl and phenyl, (f) -(5-12 membered heteroarylene)-C3-6cycloalkyl, (g) -(5-12 membered heteroarylene)-phenyl, (h)
Figure imgf000019_0003
()
Figure imgf000019_0004
, wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2; and (j)
Figure imgf000019_0001
or , wherein R11 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, or -SO2(C1-6alkyl); and r is 0 or 1; wherein at each occurrence, the cycloalkyl, heterocycloalkyl, aryl, phenyl, and heteroaryl are each independently substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, -CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl). [0053] In some embodiments of formula I, R1 is -C0-6alkylene-(C3-6 saturated cycloalkyl), wherein the cycloalkyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, -CN, -C1-6alkyl, -C1-6haloalkyl, and -C1-6alkoxy. [0054] In some embodiments, R1 in embodiment one is selected from
Figure imgf000019_0002
. [0055] In some embodiments of formula I, R1 is [
Figure imgf000020_0001
, wherein R1 is substituted with 0, 1, or 2 RA substituents independently selected from the group consisting of halo, -OH, -CN, -C1-6alkyl, -C1-6haloalkyl, and -C1-6alkoxy; and p is 0, 1, or 2. [0057] In some embodiments of formula I, R1 is halo or -C1-6alkyl; and P is 0 or 1. [0058] In some embodiments of formula I, R1 is selected from
Figure imgf000020_0002
. [0059] In some embodiments of formula I, R1 is -C0-6alkylene-heterocycloalkyl, wherein the heterocycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo, -OH, -CN, -C1-6alkyl, -C1-6haloalkyl, and -C1-6alkoxy. [0060] In some embodiments of formula I, R1 is -C0-3alkylene-(5-7 membered heterocycloalkyl. [0061] In some embodiments of formula I, R1 is selected from
Figure imgf000020_0003
. [0062] In some embodiment of formula I, R1 is selected from
Figure imgf000020_0005
, , , ,
Figure imgf000020_0006
, or
Figure imgf000020_0007
, wherein RA is halo, -OH, -CN, -C1-6alkyl, -C1-6haloalkyl, or -C1-6alkoxy. [0063] In some embodiments of formula I R1 is selected from
Figure imgf000020_0004
. [0064] In some embodiments of formula I, R is (a) -C0-6alkylene-(8-12 membered tricyclic heteroaryl), wherein the tricyclic heteroaryl is substituted with 0 or 1 substituents selected from the group consisting of C3-6cycloalkyl and phenyl, (b) -C0-6alkylene-(8-12 membered tricyclic heteroaryl), wherein the tricyclic heteroaryl is substituted with 0 or 1 substituents selected from the group consisting of C3-6cycloalkyl and phenyl, or (c) -(5-12 membered heteroarylene)-phenyl. [0065] In some embodiments, R1 in formula I is
Figure imgf000021_0001
, , , o , wherein R10 or R11 is independently halo, -CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, or -SO2(C1-6alkyl). [0066] In some embodiments of formula I, R1 is
Figure imgf000021_0002
, wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, or -SO2(C1-6alkyl); and m is 0, 1, or 2. [0067] In some embodiments of formula I, R1 is a 5 to 12 membered heteroaryl, (5-12 membered heteroarylene)-C3-6cycloalkyl, or -(5-12 membered heteroarylene)-phenyl, wherein the heteroaryl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo, -CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, and -SO2(C1-6alkyl). [0068] In some embodiments of formula I, R1 is a 8 to 12 membered heteroaryl, (8-12 membered heteroarylene)-C3-6cycloalkyl, or -(8-12 membered heteroarylene)-phenyl, wherein the heteroaryl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo, -CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, and -SO2(C1-6alkyl). [0069] In some embodiments of formula I, R1 is a 8 to 12 membered heteroaryl substituted with 0, 1, or 2 substituents selected from the group consisting of halo, -CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, and -SO2(C1-6alkyl). [0070] In some embodiments of formula I, R1 is selected from any of the moieties in Table 1. Table 1
Figure imgf000022_0001
Figure imgf000023_0001
. [0071] In some embodiments of formula I, R1 is selected from any of the moieties in Table 2. Table 2
Figure imgf000023_0002
Figure imgf000024_0001
Figure imgf000025_0001
. [0072] In some embodiments of formula I, R2 is H; R3 and R4 are each independently -H, halo, -OH, -CN, -NH2, -NO2, methylenyl, -C1-6alkyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; R5 is -H, halo, -C1-6alkyl, or -C1-6haloalkyl; or R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; or R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R4 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R2 and R3 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R2 and R5 together with the pyrrolidine ring to which they are attached form a bridged 6 to 8 membered heterocycloalkyl; wherein at each occurrence, the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, or 3 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl). [0073] In some embodiments of formula I, R is H; R3 and R4 are each independently -H, halo, -OH, -CN, methylenyl, -C1-6alkyl, -C1-6alkoxy, phenyl, phenoxy, benzyl, C3-C6cycloalkyl, 5-7 membered heterocycloalkyl, or 5-9 membered heteroaryl; R5 is -H, halo, -C1-6alkyl, or -C1-6haloalkyl; or R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; or R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R4 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R2 and R3 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R2 and R5 together with the pyrrolidine ring to which they are attached form a bridged 6 to 8 membered heterocycloalkyl; wherein at each occurrence, the cycloalkyl, heterocycloalkyl, phenyl, phenoxy, benzyl, and heteroaryl are each independently substituted with 0, 1, or 2 substituents selected from the group consisting of halo, -OH, -CN, -C1-6alkyl, -C1-6haloalkyl, and -C1-6alkoxy. [0074] In some embodiments of formula I, R2 is H; R3 and R4 are each independently -H, halo, -OH, -CN, methylenyl, -C1-6alkyl, -C1-6alkoxy, phenyl, phenoxy, benzyl, or C3-C6cycloalkyl; R5 is -H, halo, or -C1-6alkyl; or R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; or R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R2 and R3 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R2 and R5 together with the pyrrolidine ring to which they are attached form a bridged 6 to 8 membered heterocycloalkyl; wherein at each occurrence, the cycloalkyl, heterocycloalkyl, phenyl, phenoxy, and benzyl are each independently substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C1-6alkyl. [0075] In some embodiments of formula I, R3 and R4 are each independently -H, halo, -OH, -CN, methylenyl, -C1-6alkyl, -C1-6alkoxy, phenyl, phenoxy, benzyl, or C3-C6cycloalkyl, wherein the phenyl, phenoxy, and benzyl are each independently substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C1-6alkyl. [0076] In some embodiments of formula I, R3 is -H, halo, -OH, -CN, methylenyl, -C1-6alkyl, -C1-6alkoxy, phenyl, phenoxy, benzyl, or C3-C6cycloalkyl, wherein the phenyl, phenoxy, and benzyl are each independently substituted with 0 or 1 substituent selected from the group consisting of halo and -C1-6alkyl; and R4 is -H, halo, or -C1-6alkyl. [0077] In some embodiments of formula I, R3 is -H, -F, -Me, -Et, -OH, -CN, methylenyl, -OMe, phenyl, phenoxy,
Figure imgf000027_0001
, , or cyclohexyl; and R4 is -H, -F, -Me, or –Et. [0078] In some embodiments of formula I, R2 is H and R5 is -H or -C1-6alkyl. [0079] In some embodiments of formula I, R2 and R5 are H. [0080] In some embodiments of formula I, R3 is -H, halo, -OH, -CN, methylenyl, -C1-6alkyl, -C1-6alkoxy, phenyl, phenoxy, benzyl, or C3-C6cycloalkyl, wherein the phenyl, phenoxy, and benzyl are each independently substituted with 0 or 1 substituent selected from the group consisting of halo and -C1-6alkyl; R4 is -H, halo, or -C1-6alkyl; R2 is -H; and R5 is -H or -C1-6alkyl. [0081] In some embodiments of formula I, R3 in embodiment one is -H, -F, -Me, -Et, -OH, -CN, methylenyl, -OMe, phenyl, phenoxy
Figure imgf000027_0002
, , or cyclohexyl; R4 is -H, -F, -Me, or -Et; and R2 and R5 are -H. [0082] In some embodiments of formula I, R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C1-6alkyl. [0083] In some embodiments of formula I, R and R together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; R2 is H; and R5 is -H or -C1-6alkyl. [0084] In some embodiments of formula I, R3 and R4 together with the carbon atom to which they are attached, form a C3-C4cycloalkyl; and R2 and R5 are –H. [0085] In some embodiments of formula I, R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C1-6alkyl. [0086] In some embodiments of formula I, R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents which is -C1-6alkyl; R2 is H; and R4 is -H or -C1-6alkyl. [0087] In some embodiments of formula I, R3 and R5 together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents which is -Me; and R2 and R4 are -H. [0088] In some embodiments of formula I, R4 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C1-6alkyl. [0089] In some embodiments of formula I, R4 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents which is -C1-6alkyl; R2 is H; and R3 is -H or -C1-6alkyl. [0090] In some embodiments of formula I, R4 and R5 together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents which is -Me; and R2 and R3 are -H. [0091] In some embodiments of formula I, R2 and R3 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C1-6alkyl. [0092] In some embodiments of formula I, R2 and R3 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; and R4 and R5 are each independently -H or -C1-6alkyl. [0093] In some embodiments of formula I, R2 and R3 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; and R4 and R5 are -H. [0094] In some embodiments of formula I, R2 and R5 together with the pyrrolidine ring to which they are attached form a bridged 6 to 8 membered heterocycloalkyl, wherein the heterocycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C1-6alkyl. [0095] In some embodiments of formula I, R2 and R5 together with the pyrrolidine ring to which they are attached form a bridged 6 to 7 membered heterocycloalkyl, wherein the heterocycloalkyl is substituted with 0 or 1 substituent selected from the group consisting of halo and -C1-6alkyl; and R3 and R4 are each independently -H or -C1-6alkyl. [0096] In some embodiments of formula I, R2 and R5 together with the pyrrolidine ring to which they are attached form a bridged 7 membered heterocycloalkyl, wherein the heterocycloalkyl is substituted with -F; and R3 and R4 are -H. [0097] In some embodiments of formula I, R7 and R8 are H. [0098] In some embodiments of formula I, n is 1 or 2. [0099] In some embodiments of formula I, n is 1. [0100] In some embodiments, the compound of formula I is a compound of formula A
Figure imgf000029_0001
, A wherein the variables are as defined herein. [0101] In some embodiments of formula I or formula A, R1 is (a) -C1-6alkyl, (b) -C1-6alkylene-NHCO-C1-6haloalkyl, (c) -C0-6alkylene-(saturated cycloalkyl), (d) -C0-6alkylene-heterocycloalkyl, (e) -heteroarylene-cycloalkyl, or (f) -heteroarylene-aryl; (g)
Figure imgf000029_0002
, , , ,
Figure imgf000030_0001
, wherein RA is halo, -OH, -CN, -NH2, -NO2, -C1-6alkyl, alkenyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; p is 0, 1, 2, 3, 4, or 5; and q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; (
Figure imgf000030_0002
, wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2; (i)
Figure imgf000030_0003
or , wherein R11 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, or -SO2(C1-6alkyl); and r is 0 or 1; R3 and R4 are each independently -H, halo, -OH, -CN, -NH2, -NO2, methylenyl, -C1-6alkyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; R5 is -H, halo, -C1-6alkyl, or -C1-6haloalkyl; or R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; or R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R4 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; and
Figure imgf000030_0004
R6 is ; wherein at each occurrence, the cycloalkyl, saturated cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, or 3 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl). [0102] In some embodiments of compounds of formula I or formula A, R1 is (a) -C1-6alkylene-NHCO-C1-6haloalkyl, (b) -C0-6alkylene-(saturated cycloalkyl), (c) -C0-6alkylene-(tricyclic heteroaryl), (d) -C0-6alkylene-heterocycloalkyl, (e)
Figure imgf000031_0003
, , , ,
Figure imgf000031_0004
, ; wherein RA is halo, -OH, -CN, -NH2, -NO2, -C1-6alkyl, alkenyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; (f)
Figure imgf000031_0001
or , wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2; and (
Figure imgf000031_0002
or , wherein R is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, or -SO2(C1-6alkyl); and r is 0 or 1; wherein at each occurrence, the cycloalkyl, saturated cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, or 3 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl). [0103] In some embodiments of formula I or formula A, R1 is selected from any of the moieties in Table 3. Table 3
Figure imgf000032_0001
, . [0104] In some embodiments of formula I or formula A, R3 is -H, -F, -Me, -Et, -OH, -CN, methylenyl, -OMe, phenyl, phenoxy,
Figure imgf000032_0002
, , or cyclohexyl; R4 is -H, -F, -Me, or -Et; and R2 and R5 are -H. [0105] In some embodiments of formula I or formula A, R3 and R4 together with the carbon atom to which they are attached form a C3-C6cycloalkyl; and R5 is H [0106] In some embodiments of formula I or formula A, R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C1-6alkyl; and R4 is H. [0107] In some embodiments of compounds of formula I or formula A, R and R are each independently -H, halo, -OH, -CN, methylenyl, -C1-6alkyl, -C1-6alkoxy, phenyl, phenoxy, benzyl, or C3-C6cycloalkyl, wherein the phenyl, phenoxy, and benzyl are each independently substituted with 0 or 1 substituent selected from the group consisting of halo and -C1-6alkyl; and R5 is -H or -C1-6alkyl. [0108] In some embodiments of formula I or formula A, R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; and R5 is H. [0109] In some embodiments of formula I or formula A, which is a compound of formula B ,
Figure imgf000033_0001
B wherein R1 and R6 are as defined herein. [0110] In some embodiments of formula B, which is a compound of formula B-1
Figure imgf000033_0002
O . B-1 [0111] In some embodiments of formula I or formula A, which is a compound of formula C
Figure imgf000033_0003
, C wherein R1 and R6 are as defined herein. [0112] In some embodiments of formula C, which is a compound of formula C-1
Figure imgf000034_0001
. C-1 [0113] In some embodiments of formula I, formula A, formula B, formula B-1, formula C, or formula C-1, wherein R1 is (a) -C1-6alkylene-NHCO-C1-6haloalkyl, (b) -C0-6alkylene-(saturated cycloalkyl), (c) -C0-6alkylene-heterocycloalkyl, (d) -C0-6alkylene-(tricyclic heteroaryl), (e)
Figure imgf000034_0004
, , , , or
Figure imgf000034_0005
, ; RA is halo, -OH, -CN, -NH2, -NO2, -C1-6alkyl, alkenyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; (f)
Figure imgf000034_0002
or , wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2; or (g)
Figure imgf000034_0003
or , wherein R11 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, or -SO2(C1-6alkyl); and r is 0 or 1; wherein at each occurrence, the cycloalkyl, saturated cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, or 3 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl); and
Figure imgf000035_0004
[0114] In some embodiments of formula I, formula A, formula B, formula B-1, formula C, or formula C-1, wherein R1 is (a) -C1-6alkylene-NHCO-C1-6haloalkyl, (b) -C0-6alkylene-(saturated cycloalkyl), (c) -C0-6alkylene-(tricyclic heteroaryl), (d)
Figure imgf000035_0001
, ; wherein RA is halo, -OH, -CN, -NH2, -NO2, -C1-6alkyl, alkenyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; (e)
Figure imgf000035_0002
or , wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2; or (f)
Figure imgf000035_0003
or , wherein R11 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, or -SO2(C1-6alkyl); and r is 0 or 1; wherein at each occurrence, the cycloalkyl, saturated cycloalkyl, heterocycloalkyl, aryl, phenyl, and heteroaryl are each independently substituted with 0, 1, or 2 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl); and
Figure imgf000036_0003
. [0115] In some embodiments of formula I, formula A, formula B, formula B-1, formula C, or formula C-1, wherein R1 is selected from the group consisting of
Figure imgf000036_0001
and R6 . [0116] In some embodiments, the present disclosure provides a compound of formula II:
Figure imgf000036_0002
II or a pharmaceutically acceptable salt thereof, wherein: R1A is H, -C1-6alkylene-NHCONH-C1-6alkyl, -C1-6alkylene-NHCO(heteroaryl), -C1-6alkylene-cycloalkyl, ,
Figure imgf000037_0001
, wherein RA is halo, -OH, -CN, -NH2, -NO2, -C1-6alkyl, alkenyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; p is 0, 1, 2, 3, 4, or 5;
Figure imgf000037_0002
, wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2; R3, R4, and R5 are each independently -H, halo, -OH, -CN, -NH2, -NO2, alkylenyl, -C1-6alkyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; or R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; or R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R4 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; R2 is H; or R2 and R3 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or
Figure imgf000037_0003
R6 is O or -COR12; R7 and R8 are each independently H or C1-6alkyl; each R is independently H, C1-6alkyl, cycloalkyl, or heteroaryl; R12 is heterocyclyl or heteroaryl; and n is 1, 2, or 3; wherein at each occurrence, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl). [0117] In some embodiments of formula II, R1A is -C1-6alkylene-NHCONH-C1-6alkyl. [0118] In some embodiments of formula II, R1A is
Figure imgf000038_0001
. [0119] In some embodiments of formula II, R1A is -C1-6alkylene-NHCO(heteroaryl). [0120] In some embodiments of formula II, R1A is
Figure imgf000038_0002
. [0121] In some embodiments of formula II, R1A is -C1-6alkylene-cycloalkyl, wherein the cycloalkyl is optionally substituted by halo, -C1-6alkyl, -OH, -CN, -NH2, or -NO2. [0122] In some embodiments of formula II, R1A is
Figure imgf000038_0003
. [0123] In some embodiments of formula II, R1A is
Figure imgf000038_0004
or ; RA is halo, -OH, -CN, -NH2, -NO2, -C1-6alkyl, alkenyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; and p is 0, 1, 2, or 3. [0124] In some embodiments of formula II R1A is
Figure imgf000038_0005
or . [0125] In some embodiments of formula II, R is
Figure imgf000039_0001
wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2. [0126] In some embodiments of formula II, R1A is
Figure imgf000039_0002
. [0127] In some embodiments of formula II, R1A is R2 is H. [0128] In some embodiments of formula II, R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; and R5 is H. [0129] In some embodiments of formula II, R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C1-6alkyl; and R4 is H. [0130] In some embodiments of formula II, R6 is
Figure imgf000039_0003
O ; and each R9 is independently H, C1-6alkyl, or cycloalkyl [0131] In some embodiments of formula II, R6 is
Figure imgf000039_0004
or . [0132] In some embodiments of formula II, R6 is
Figure imgf000039_0005
. [0133] In some embodiments of formula II is a compound of formula II-A or II-B:
Figure imgf000039_0006
(II-A) or (II-B) [0134] In some embodiments of formula II is a compound of formula II-A or II-B, wherein the compound is of the formula:
Figure imgf000040_0001
, or , or a pharmaceutically acceptable salt thereof. [0135] In some embodiments, provided herein in is a pharmaceutical composition for treating a coronavirus infection in a human in need thereof, comprising a compound of formula (I) and formula (II), or a pharmaceutically acceptable salt thereof. [0136] In some embodiments, provided herein in is a method of treating a viral infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formlula (I) or formula (II), or a pharmaceutically acceptable salt thereof. [0137] In some embodiments, wherein the viral infection is caused by a coronavirus. [0138] In some embodiments, wherein the viral infection is a coronavirus infection caused by SARS-CoV-2, SARS-CoV, MERS-CoV, 229E, NL63, OC43, or HKUl. [0139] In some embodiments, wherein the coronavirus infection is caused by SARS-CoV-2. [0140] In some embodiments, wherein the patient is suffering from COVID-19. [0141] In some embodiments, wherein the coronavirus infection is caused by SARS-CoV. [0142] In some embodiments, wherein the coronavirus infection is caused by MERS-CoV. [0143] In some embodiments, wherein the treatment method inhibits Mpro. [0144] In some embodiments, wherein the treatment method is administered orally. [0145] In some embodiments, wherein the treatment is administered once a day, twice a day, or three times a day. [0146] In some embodiments, wherein the therapeutically effective amount of the treatment is from 0.5 mg to 100 mg, 1 mg to 80 mg, or from 1 mg to 60 mg. [0147] In some embodiments, wherein in the treatment, the compound of formula (I) or (II) is formulated in a solid dosage form. [0148] In some embodiments, the present disclosure provides a compound selected from any of the compounds 1-138 described in the examples, or a pharmaceutically acceptable salt thereof. PHARMACEUTICALLY ACCEPTABLE SALTS [0149] The present disclosure encompasses the preparation and use of salts of compounds of the present disclosure. As used herein, the pharmaceutical "pharmaceutically acceptable salt" refers to salts or zwitterionic forms of compounds of the present disclosure. Salts of compounds of the present disclosure can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with a suitable acid. The pharmaceutically acceptable salts can be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Non-limiting examples of salts of compounds of the present disclosure include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2- hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphsphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, paratoluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzene sulfonate, and p-toluenesulfonate salts. In addition, available amino groups present in the compounds of the present disclosure can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. In light of the foregoing, any reference compounds of the present disclosure appearing herein is intended to include compounds of the present disclosure as well as pharmaceutically acceptable salts, hydrates, or solvates thereof. [0150] The present disclosure encompasses the preparation and use of solvates of compounds of the present disclosure. Solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents. The term "solvate" as used herein is a combination, physical association and/or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution-phase and isolatable solvates. Compounds of the present disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, and ethanol, and it is intended that the disclosure includes both solvated and unsolvated forms of compounds of the present disclosure. One type of solvate is a hydrate. A hydrate relates to a particular subgroup of solvates where the solvent molecule is water. Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M. Caira et al, J. Pharmaceut. Sci., 93(3):601- 611 (2004), which describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparation of solvates, hemisolvates, hydrates, and the like are described by E.C. van Tonder et al., AAPS Pharm. Sci. Tech., 5(1):Article 12 (2004), and A.L. Bingham et al., Chem. Commun.603-604 (2001). A typical, non-limiting, process of preparing a solvate would involve dissolving a compound of the present disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvate in a crystal of the solvate. MEDICAL TREATMENTS OR USES [0151] Compounds of the present disclosure inhibit protease Mpro and are thus useful in the treatment or prevention of a variety of diseases and conditions. In particular, compounds of the present disclosure are useful in methods of treating or preventing a disease or condition wherein inhibition of Mpro provides a benefit. These diseases and conditions include viral infections. [0152] In certain embodiments, the viral infection is caused by a coronavirus. [0153] In certain embodiments, the coronavirus infection is caused by a coronavirus including SARS-CoV-1, SARS-CoV-2, MERS-CoV, HCoV-229E, HCoV-HKU1, HCoV-NL63 and HCoV-OC43. [0154] In certain embodiments, the coronavirus infection is caused by a coronavirus including SARS-CoV and MERS-CoV. [0155] In certain embodiments, the coronavirus infection is caused by SARS-CoV-2. [0156] In certain embodiments, the patient is suffering from COVID-19. [0157] In certain embodiments, the patient is suffering from upper respiratory illness, severe interstitial pneumonia, and/or acute respiratory distress syndrome, aggravated by thrombosis in the pulmonary microcirculation. In certain embodiments, the patient is suffering from multi-organ failure. [0158] In certain embodiments, the patient is suffering from fever, cough, tiredness, loss of taste or smell, shortness of breath or difficulty breathing, muscle aches, chills, sore throat, runny nose, headache, chest pain, and/or pink eye. [0159] In certain embodiments, the coronavirus replication is inhibited. [0160] In certain embodiments, the coronavirus polymerase is inhibited. [0161] In certain embodiments, the coronaviral membrane fusion is inhibited. [0162] In certain embodiments, the inhibition is in vitro or in vivo. [0163] In some embodiments, the present disclosure relates to a method of treating an individual suffering from a disease or condition wherein inhibition of Mpro provides a benefit comprising administering a therapeutically effective amount of a compound of the present disclosure to an individual in need thereof. [0164] Compounds of the present disclosure are inhibitors of Mpro protein. Accordingly, diseases and conditions mediated by Mpro can be treated by employing these compounds. The present disclosure is thus directed generally to a method for treating a condition or disorder responsive to Mpro inhibition in a subject, e.g., a human subject, suffering from, or at risk of suffering from, the condition or disorder, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure. [0165] In some embodiments, the present disclosure is directed to a method of inhibiting Mpro in a subject in need thereof, said method comprising administering to the subject an effective amount of at least one compound of the present disclosure. [0166] In certain embodiments, the Mpro is SARS-CoV-2 Mpro. [0167] The methods of the present disclosure can be accomplished by administering a compound of the present disclosure as the neat compound or as a pharmaceutical composition. [0168] In some embodiments, a human subject is treated with a compound of the present disclosure, or a pharmaceutical composition comprising a compound of the present disclosure, wherein the compound is administered in an amount sufficient to inhibit Mpro in the subject. COMBINATION THERAPY [0169] In some embodiments, a compound of the present disclosure is administered in conjunction with a second therapeutic agent useful in the treatment of a disease or condition wherein inhibition of Mpro provides a benefit. The second therapeutic agent is different from the compound of the present disclosure. [0170] The second therapeutic agent can be an antiviral agent or an anti-inflamatory/host immune modulator. The antiviral agent may include anti-SARS-CoV-2 monoclonal antibodies such as bamlanivimab/etesevimab, casirivimab/imdevimab, and Sotrovimab; RNA-polymerase inhibitors such as molnupiravir and remdesivir; papin-like protease inhibitors; and methyl transferase inhibitors. The anti-inflamatory/host immune modulator may include steroidal such as dexamethasone; JAK inhibitors such as baricitinib and tofacitinib; and IL-6R blocking monoclonal antibodies such as tocilizumab and sarilumab. [0171] A compound of the present disclosure and the second therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect. In addition, the compound of the present disclosure and second therapeutic agent can be administered from a single composition or two separate compositions. [0172] The second therapeutic agent is administered in an amount to provide its desired therapeutic effect. The effective dosage range for each second therapeutic agent is known in the art, and the second therapeutic agent is administered to an individual in need thereof within such established ranges. [0173] A compound of the present disclosure and the second therapeutic agent can be administered together as a single-unit dose or separately as multi-unit doses, wherein the compound of the present disclosure is administered before the second therapeutic agent or vice versa. One or more doses of the compound of the present disclosure and/or one or more dose of the second therapeutic agent can be administered. The compound of the present disclosure therefore can be used in conjunction with one or more second therapeutic agents, for example, but not limited to, anticancer agents. ADMINISTRATIONS AND DOSAGE [0174] A compound of the present disclosure can be administered by any suitable route, for example by oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal through lumbar puncture, transurethral, nasal, percutaneous, i.e., transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and/or surgical implantation at a particular site) administration. Parenteral administration can be accomplished using a needle and syringe or using a high pressure technique. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally. [0175] Pharmaceutical compositions include those wherein a compound of the present disclosure is administered in an effective amount to achieve its intended purpose. The exact formulation, route of administration, and dosage is determined by an individual physician in view of the diagnosed condition or disease. Dosage amount and interval can be adjusted individually to provide levels of a compound of the present disclosure that is sufficient to maintain therapeutic effects. [0176] Toxicity and therapeutic efficacy of the compounds of the present disclosure can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) of a compound, which defines as the highest dose that causes no toxicity in animals. The dose ratio between the maximum tolerated dose and therapeutic effects (e.g. inhibiting of tumor growth) is the therapeutic index. The dosage can vary within this range depending upon the dosage form employed, and the route of administration utilized. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. [0177] A therapeutically effective amount of a compound of the present disclosure required for use in therapy varies with the nature of the condition being treated, the length of time that activity is desired, and the age and the condition of the subject, and is ultimately determined by the attendant physician. Dosage amounts and intervals can be adjusted individually to provide plasma levels of the compound of the present disclosure that are sufficient to maintain the desired therapeutic effects. The desired dose can be administered in a single dose, or as multiple doses administered at appropriate intervals, for example as one, two, three, four or more subdoses per day. Multiple doses sometimes are desired, or required. For example, a compound of the present disclosure can be administered at a frequency of: four doses delivered as one dose per day at four-day intervals (q4d x 4); four doses delivered as one dose per day at three-day intervals (q3d x 4); one dose delivered per day at five-day intervals (qd x 5); one dose per week for three weeks (qwk3); five daily doses, with two-day rest, and another five daily doses (5/2/5); or, any dose regimen determined to be appropriate for the circumstance. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, or three times a day. [0178] A compound of the present disclosure used in a method of the present disclosure can be administered in an amount of about 0.005 to about 500 milligrams per dose, about 0.05 to about 250 milligrams per dose, or about 0.5 to about 100 milligrams per dose. For example, a compound of the present disclosure can be administered, per dose, in an amount of about 0.005, about 0.05, about 0.5, about 5, about 10, about 20, about 30, about 40, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 milligrams, including all doses between 0.005 and 500 milligrams. In some embodiments, the therapeutically effective amount is from 0.5 mg to 100 mg, 1 mg to 80 mg, or from 1 mg to 60 mg. [0179] The dosage of a composition containing a compound of the present disclosure, or a composition containing the same, can be from about 1 μg/kg to about 200 mg/kg, about 1 μg/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg. The dosage of a composition can be at any dosage including, but not limited to, about 1 μg/kg. The dosage of a composition may be at any dosage including, but not limited to, about 1 μg/kg, about 10 μg/kg, about 25 μg/kg, about 50 μg/kg, about 75 μg/kg, about 100 μg/kg, about 125 μg/kg, about 150 μg/kg, about 175 μg/kg, about 200 μg/kg, about 225 μg/kg, about 250 μg/kg, about 275 μg/kg, about 300 μg/kg, about 325 μg/kg, about 350 μg/kg, about 375 μg/kg, about 400 μg/kg, about 425 μg/kg, about 450 μg/kg, about 475 μg/kg, about 500 μg/kg, about 525 μg/kg, about 550 μg/kg, about 575 μg/kg, about 600 μg/kg, about 625 μg/kg, about 650 μg/kg, about 675 μg/kg, about 700 μg/kg, about 725 μg/kg, about 750 μg/kg, about 775 μg/kg, about 800 μg/kg, about 825 μg/kg, about 850 μg/kg, about 875 μg/kg, about 900 μg/kg, about 925 μg/kg, about 950 μg/kg, about 975 μg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg, or more. [0180] The above dosages are exemplary of the average case, but there can be individual instances in which higher or lower dosages are merited, and such are within the scope of this disclosure. In practice, the physician determines the actual dosing regimen that is most suitable for an individual subject, which can vary with the age, weight, and response of the particular subject. PHARMACEUTICAL COMPOSITIONS [0181] In some embodiments, compounds of the present disclosure typically are administered in admixture with a pharmaceutical carrier to give a pharmaceutical composition selected with regard to the intended route of administration and standard pharmaceutical practice. [0182] Pharmaceutical compositions for use in accordance with the present disclosure are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of compound of the present disclosure. [0183] These pharmaceutical compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen. When a therapeutically effective amount of the compound of the present disclosure is administered orally, the composition typically is in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition additionally can contain a solid carrier, such as a gelatin or an adjuvant. The tablet, capsule, and powder contain about 0.01% to about 95%, and preferably from about 1% to about 50%, of a compound of the present disclosure. When administered in liquid form, a liquid carrier, such as water, petroleum, or oils of animal or plant origin, can be added. The liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solutions, or glycols. When administered in liquid form, the composition contains about 0.1% to about 90%, and preferably about 1% to about 50%, by weight, of a compound of the present disclosure. [0184] When a therapeutically effective amount of a compound of the present disclosure is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains, an isotonic vehicle. [0185] Compounds of the present disclosure can be readily combined with pharmaceutically acceptable carriers well-known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed.1995. Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. [0186] Pharmaceutical preparations for oral use can be obtained by adding the compound of the present disclosure to a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrating agents can be added. [0187] Compound of the present disclosure can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and/or dispersing agents. [0188] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Additionally, suspensions of a compound of the present disclosure can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension. Optionally, the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions. Alternatively, a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. [0189] Compounds of the present disclosure also can be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases. In addition to the formulations described previously, the compound of the present disclosure also can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compound of the present disclosure can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins. [0190] In particular, the compounds of the present disclosure can be administered orally, buccally, or sublingually in the form of tablets containing excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents. Compound of the present disclosure also can be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily. [0191] For parenteral administration, the compound of the present disclosure are typically used in the form of a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood. MEDICAL KITS [0192] In some embodiments, the present disclosure provides kits which comprise a compound of the present disclosure (or a composition comprising a compound of the present disclosure) packaged in a manner that facilitates their use to practice methods of the present disclosure. In one embodiment, the kit includes a compound of the present disclosure (or a composition comprising a compound of the present disclosure) packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method of the present disclosure. [0193] In some embodiments, the kit further can include a device suitable for administering the composition according to the intended route of administration. GENERAL SYNTHETIC METHODS [0194] In some embodiments, the compounds of the present disclosure and intermediates can be prepared according to Scheme 1 below. In the general scheme, variables such as R1, R2, R3, R4, R5, R6, R7, R8 and n are the same as defined herein. R10 is alkyl such as C1-6alkyl. The expression “P” refers to H or an amino protecting group such as Boc. In some embodiments, R1 is selected from any of the groups in Table 1, Table 2, or Table 3. Scheme 1
Figure imgf000050_0001
[0195] Steps 1a & 1b: Steps 1a and 1b can be carried out in the presence of a suitable base and solvent. The base may be an inorganic base or an organic base. Non-limiting examples of the inorganic base may include hydroxides such as sodium hydroxide, lithium hydroxide, or potassium hydroxide; bicarbonates; carbonates; phosphates; and acetates. The organic base may include but is not limited to amines, e.g., tertiary amines; pyridine; and piperidine. The suitable solvent includes but is not limited to protic and aprotic solvents such as water, methanol, ethanol, DMF, DCM, EA, THF, DMSO, ether, ketone, 1,4-dioxane, and the like. The suitable solvent may also be a combination of two or three solvents. The hydrolysis product may be acidified to afford the free acid. [0196] Steps 2a & 2b: Steps 2a & 2b can be performed in the presence of a suitable base, a coupling reagent, and a solvent. Non-limiting examples of the inorganic base may include bicarbonates, carbonates, phosphates, and acetates. The organic base may include but is not limited to amines, e.g., tertiary amines such as DIEA. The coupling reagent can be a suitable peptide coupling reagent including, without limitation, T3P, HOAt, HOBt, HUTA, DCC, EDC, DIC, BOP, PyBOP, HATU, HBTU, TOTU, COMU, and TBTU. The suitable solvent includes but is not limited to DCM, DMF, THF, DMSO, acetonitrile, ethers, ethyl acetate, 1,4-dioxane, and the like. [0197] Steps 3a & 3b: Steps 3a & 3b can be performed in the presence of a suitable acid and a solvent. The acid may be an inorganic acid or an organic acid. Non-limiting examples of the inorganic base may include hydrochloric acid, phosphoric acid, and sulfuric acid. The organic acid may include but is not limited to TFA and p-toluenesulfonic acid. The suitable solvent includes but is not limited to protic and aprotic solvents such as water, methanol, ethanol, DMF, DCM, EA, THF, DMSO, ether, ketone, 1,4-dioxane, and the like. The suitable solvent may also be a combination of two or three solvents. [0198] Steps 4a & 4b: Steps 4a & 4b can be performed in the presence of a suitable base, a coupling reagent, and a solvent. Non-limiting examples of the inorganic base may include bicarbonates, carbonates, phosphates, and acetates. The organic base may include but is not limited to amines, e.g., tertiary amines such as DIEA. The coupling reagent can be a suitable peptide coupling reagent including, without limitation, T3P, HOAt, HOBt, HUTA, DCC, EDC, DIC, BOP, PyBOP, HATU, HBTU, TOTU, COMU, and TBTU. The suitable solvent includes but is not limited to DCM, DMF, THF, DMSO, acetonitrile, ethers, ethyl acetate, 1,4-dioxane, and the like. [0199] In some embodiments, R6 is –COOR9, and the process further comprises the following steps:
Figure imgf000052_0001
[0200] Step 5: Step 5 can be performed in the presence of a reducing reagent and a suitable solvent. A suitable solvent includes protic solvents or aprotic solvents. Protic solvents include but is not limited to water and alcohols such as methanol, ethanol, propanol, and the like. Aprotic solvents include but is not limited to solvents such as DCM, THF, DMF, acetonitrile, and the like. The suitable solvent may also be a combination of two or three solvents. The reducing reagent includes but is not limited to a borohydride reagent or a metal hydride reagent. Non-limiting examples are lithium borohydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and lithium aluminium hydride. [0201] Step 6: Step 6 can be performed in the presence of an oxidizing reagent and a suitable solvent. A suitable solvent includes protic solvents or aprotic solvents. Protic solvents include but is not limited to water and alcohols such as methanol, ethanol, propanol, and the like. Aprotic solvents include but is not limited to solvents such as DCM, THF, DMF, acetonitrile, and the like. The suitable solvent may also be a combination of two or three solvents. The oxidizing reagent includes but is not limited to dichromate, Collins reagent, Dess–Martin periodinane, PCC, PDC, and DMSO/oxalyl chloride. EXAMPLES [0202] The following abbreviations may be used throughout the specification, including in the description of the synthesis of each of the example compounds.
Figure imgf000052_0002
DIC N,N -Diisopropylcarbodiimide
Figure imgf000053_0002
3 ropyp osp onc an ydrde [0203] Example 1: (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-(1-phenylcyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 1)
Figure imgf000053_0001
[0204] Step 1: (1R,2S,5S)-3-tert-butyl 2-methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2,3-dicarboxylate
Figure imgf000054_0001
[0205] To a solution of (1R,2S,5S)-methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate hydrochloride (2.70 g, 13.13 mmol, HCl) in DCM (10 mL) was added (Boc)2O (4.30 g, 19.69 mmol) and TEA (3.98 g, 39.38 mmol) dropwise at 25°C. The mixture was stirred at 25°C for 10 hours. The reaction mixture was poured into water (50 mL). The aqueous phase was extracted with DCM (20 mL x3). The combined organic phase was washed with brine (20 mL x2), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The title compound was obtained as yellow oil (3.3 g, 87.74% yield) which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 4.23 - 4.05 (m, 1H), 3.78 - 3.75 (m, 3H), 3.70 - 3.60 (m, 1H), 3.49 - 3.35 (m, 1H), 1.54 - 1.45 (m, 2H), 1.49 - 1.35 (m, 9H), 0.99 - 0.96 (m, 3H). [0206] Step 2: (1R,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid
Figure imgf000054_0002
[0207] To a solution of (1R,2S,5S)-3-tert-butyl 2-methyl 6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.50 g, 5.57 mmol) in H2O (4 mL) and THF (12 mL) was added LiOH.H2O (467 mg, 11.14 mmol) in one portion at 25°C. The mixture was stirred at 25°C for 10 hours. The mixture was poured into water (15 mL) and then acidified with 2M HCl (5 mL) to pH ~ 6. The aqueous phase was extracted with DCM (20 mL x4). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The title compound was obtained as yellow oil (1.2 g, 70.05% yield) which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 4.22 - 4.09 (m, 1H), 3.70 - 3.54 (m, 1H), 3.49 - 3.40 (m, 1H), 1.75 (d, J = 7.6 Hz, 1H), 1.55 - 1.35 (m, 10H), 1.10 - 1.05 (m, 3H), 1.02 - 0.93 (m, 3H). [0208] Step 3: (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000055_0001
[0209] To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin- 3-yl)propanoate (1.35 g, 4.72 mmol) in dioxane (10 mL) was added HCl/dioxane (4 M, 14 mL) in one portion at 25°C. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure. The title compound was obtained as a white solid (1.05 g, crude, HCl) which was used to the next step without further purification. [0210] Step 4: (1R,2S,5S)-tert-butyl 2-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure imgf000055_0002
[0211] To a solution of (1R,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (1.20 g, 4.70 mmol) and DIEA (2.43 g, 18.80 mmol) in DCM (15 mL) was added T3P (4.49 g, 7.05 mmol, 50% purity in EtOAc) dropwise at 0°C. After addition, the reaction mixture was stirred at the same temperature for 30 mins. Then (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate (1.05 g, 4.72 mmol, HCl) in DCM (10 mL) was added in one portion at 0°C. The mixture was stirred at 25°C for 10 hours. The mixture was poured in to 5% H3PO4 (20 mL). The aqueous phase was extracted with DCM (20 mL x3). The combined organic phase was washed with sat.aq. NaHCO3 (20 mL) and brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The title compound was obtained as a white solid (1.00 g, 20.10% yield) which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 7.75 - 7.20 (m, 1H), 6.32 - 5.87 (m, 1H), 4.71 - 4.44 (m, 1H), 4.15 - 4.03 (m, 1H), 3.74 (s, 3H), 3.67 - 3.41 (m, 2H), 3.40 - 3.28 (m, 2H), 2.51 - 2.34 (m, 2H), 2.26 - 2.12 (m, 1H), 1.95 - 1.77 (m, 4H), 1.47 - 1.39 (m, 9H), 1.07 - 0.86 (m, 6H). [0212] Step 5: (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000056_0001
[0213] To a solution of (1R,2S,5S)-tert-butyl 2-(((S)-1-methoxy-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3- carboxylate (300 mg, 708.38 μmol) in dioxane (3 mL) was added HCl/dioxane (4 M, 4 mL) in one portion at 25°C. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduce pressure. The title compound was obtained as a white solid (250 mg, crude, HCl) which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ ppm 10.47 (br s, 1H), 9.30 (d, J = 7.2 Hz, 1H), 8.84 (brs, 1H), 7.72 (s, 1H), 4.42 - 4.29 (m, 1H), 4.05 (s, 1H), 3.66 (s, 3H), 3.63 - 3.58 (m, 1H), 3.23 - 3.00 (m, 3H), 2.44 - 2.29 (m, 1H), 2.22 - 2.01 (m, 2H), 1.77 - 1.59 (m, 4H), 1.13 - 1.02 (m, 6H). [0214] Step 6: (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(1-phenylcyclopropanecarbonyl)- 3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000056_0002
[0215] To a solution of 1-phenylcyclopropanecarboxylic acid (114 mg, 708.63 μmol) and DIEA (366 mg, 2.83 mmol) in DCM (5 mL) was added T3P (676 mg, 1.06 mmol, 50% purity in EtOAc) dropwise at 0°C. After addition, the mixture was stirred at the same temperature for 30 min, and then (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (255 mg, 708.63 μmol, HCl) was added at 25°C. The resulting mixture was stirred at 25°C for 11.5 hrs. The mixture was diluted with sat.aq. NH4Cl (8 mL), extracted with DCM (10 mL x3). The organic layer was dried over Na2SO4, filtered and concentrated to crude product. The residue was purified by prep-HPLC (column: Welch Ultimate XB-CN 250×50×10 μm; mobile phase: [Heptane- EtOH (0.1%NH3H2O)]; B%: 10%-%, 8 min). The title compound (135 mg, 37.89% yield) was obtained as a white solid. ESI-MS [M+H]+ calc’d for C26H33N3O5, 468.24; found, 468.3. [0216] Step 7: (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6- dimethyl-3-(1-phenylcyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000057_0001
[0217] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(1- phenylcyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2- oxopyrrolidin-3-yl)propanoate (130 mg, 278.04 μmol) in THF (4 mL) was added LiBH4 (18 mg, 834.12 μmol) at 0oC. The mixture was stirred at 0oC for 1 hr. The mixture was quenched with H2O (10 mL), and extracted with DCM (5 mL x3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (77 mg, 37.80% yield) was obtained as a white solid. ESI-MS [M+H]+ calc’d for C25H33N3O4, 440.25; found, 440.3. [0218] Step 8: (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-3-(1-phenylcyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0219] A mixture of (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)-6,6-dimethyl-3-(1-phenylcyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (77 mg, 175.18 μmol) and DMP (222 mg, 525.54 μmol) in DCM (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25°C for 0.5 hr under N2 atmosphere. The mixture was filtered and the filtrate was concentrated to give crude product. The crude product was purified by prep-HPLC (column: Phenomenex C18 75×30mm×3μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 22%-45%, 10 min).
Figure imgf000057_0002
Compound 1 was obtained as a white solid (5.7 mg, 7.14% yield, 96% purity).1H NMR (400 MHz, CD3OD) δ ppm 7.25 - 7.08 (m, 5H), 4.48 (s, 1H), 4.40 - 4.18 (m, 1H), 3.94 - 3.81 (m, 1H), 3.54 - 3.43 (m, 1H), 3.29 - 3.22 (m, 2H), 2.61 - 2.18 (m, 2H), 2.00 - 1.86 (m, 1H), 1.73 - 1.41 (m, 2H), 1.38 - 1.11 (m, 5H), 1.06 - 0.97 (m, 1H), 0.92 - 0.78 (m, 3H), 0.67 - 0.33 (m, 3H). ESI-MS [M+H]+ calc’d for C25H31N3O4, 438.23; found, 438.4. [0220] Example 2: (S)-5-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (Compound 2)
Figure imgf000058_0001
[0221] Step 1: (S)-tert-butyl 6-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)carbamoyl)-5-azaspiro[2.4]heptane-5-carboxylate
Figure imgf000058_0002
[0222] To a solution of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (500 mg, 2.07 mmol) and DIEA (1.07 g, 8.29 mmol) in DCM (5 mL) was added dropwise T3P (1.98 g, 3.11 mmol, 1.85 mL, 50% purity in EtOAc) at 0°C. After addition, the mixture was stirred at the same temperature for 30min, and then (S)-methyl 2-amino-3-((S)- 2-oxopyrrolidin-3-yl)propanoate hydrochloride (461 mg, 2.07 mmol, HCl) was added at 25°C. The resulting mixture was stirred at 25°C for 10 hr. The reaction mixture was diluted with EtOAc (30 mL) and 5% H3PO4 (30 mL). The layers were separated. The aqueous phase was extracted with EtOAc (50 mL). The combined organic layers were washed with 5% H3PO4 (30 mL x3), sat.aq.NaHCO3 (30 mL x 4), water (30 mL), and brine (30 mL), and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The title compound (680 mg, 1
Figure imgf000058_0003
57.83% yield) was obtained as colorless oil. H NMR (400 MHz, DMSO-d6) δ ppm 8.52 - 8.29 (m, 1H), 7.72 - 7.58 (m, 1H), 4.37 - 4.26 (m, 1H), 4.25 - 4.19 (m, 1H), 3.61 (s, 3H), 3.30 - 3.19 (m, 2H), 3.17 - 3.04 (m, 2H), 2.41 - 2.18 (m, 2H), 2.16 - 2.00 (m, 2H), 1.74 - 1.51 (m, 3H), 1.42 - 1.29 (m, 9H), 0.59 - 0.36 (m, 4H). [0223] Step 2: (S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-((S)-5-azaspiro[2.4]heptane-6- carboxamido)propanoate
Figure imgf000059_0001
[0224] A mixture of (S)-tert-butyl 6-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)carbamoyl)-5-azaspiro[2.4]heptane-5-carboxylate (650 mg, 1.59 mmol) in HCl/dioxane (7 mL, 4M) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated to dryness. The title compound (548 mg, 99.83% yield, HCl) was obtained as a white solid which was used in the next step without further purification. [0225] Step 3: (S)-methyl 2-((S)-5-(7-chloro-1H-indole-2-carbonyl)-5- azaspiro[2.4]heptane-6-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000059_0002
[0226] To a solution of compound (S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-((S)-5- azaspiro[2.4]heptane-6-carboxamido)propanoate (165 mg, 477.13 μmol, 1 eq, HCl), 7- chloro-1H-indole-2-carboxylic acid (93 mg, 477.13 μmol) and DIEA (185 mg, 1.43 mmol, 249.31 μL) in DCM (3 mL) was added HATU (363 mg, 954.25 μmol) slowly at 0°C. The mixture was stirred at 25°C for 10 hr. Sat.aq.NH4Cl (20 mL) was added to the residue. The resulting mixture was extracted with DCM (30 mL x3). The combined organic phase was washed with water (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Xtimate C18 150×40mm×10μm;mobile phase: [water(10mM NH4HCO3)-ACN];B%: 25%-55%,10min). The title compound (105 mg, 43.74% yield) was obtained as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 9.84 - 9.37 (m, 1H), 9.17 - 8.07 (m, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.12 - 6.85 (m, 2H), 6.40 - 5.69 (m, 1H), 5.06 - 4.89 (m, 1H), 4.61 - 4.31 (m, 1H), 4.08 - 3.74 (m, 2H), 3.74 - 3.44 (m, 3H), 3.44 - 3.26 (m, 2H), 2.61 - 2.30 (m, 2H), 2.27 - 2.04 (m, 2H), 1.99 - 1.79 (m, 2H), 1.77 - 1.67 (m, 1H), 0.81 - 0.42 (m, 4H). [0227] Step 4: (S)-5-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide
Figure imgf000060_0001
[0228] To a solution of (S)-methyl 2-((S)-5-(7-chloro-1H-indole-2-carbonyl)-5- azaspiro[2.4]heptane-6-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (105 mg, 215.63 μmol) in THF (2 mL) was added LiBH4 (19 mg, 862.52 μmol) at 0°C. The mixture was stirred at 25 °C for 1 hr. The reaction was quenched with water (10 mL) drop-wise. The resulting mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The title compound (85 mg, crude) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.99 - 9.53 (m, 1H), 8.84 - 8.11 (m, 1H), 7.60 - 7.41 (m, 1H), 7.30 - 7.26 (m, 1H), 7.09 - 6.99 (m, 1H), 6.98 - 6.79 (m, 1H), 6.03 - 5.61 (m, 1H), 5.04 - 4.79 (m, 2H), 4.08 - 3.80 (m, 2H), 3.67 - 3.45 (m, 2H), 3.40 - 3.16 (m, 2H), 2.64 - 2.46 (m, 1H), 2.46 - 2.08 (m, 3H), 2.07 - 1.95 (m, 1H), 1.82 - 1.56 (m, 3H), 0.77 - 0.47 (m, 4H). [0229] Step 5: (S)-5-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide [0230] To a solution of (S)-5-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (70 mg, 152.53 μmol) in DCM (10 mL) was added DMP (129 mg, 305.05 μmol). The mixture was stirred at 25 °C for 10 min. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3μm;mobile phase: [water(10mM NH4HCO3)-ACN];B%: 19%-54%,10min). Compound 2 (7 mg, 9.79% yield, 97.45% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.65 - 7.44 (m, 1H), 7.32 - 7.21 (m, 1H), 7.13 - 6.89 (m, 2H), 5.22 - 4.87 (m, 1H), 4.60 - 4.33 (m, 1H), 4.11 - 3.65 (m, 3H), 3.08 - 2.60 (m, 1H), 2.57 - 2.15 (m, 2H), 2.15 - 1.72 (m, 3H), 1.70 - 1.53 (m, 1H), 1.52 - 1.25 (m, 1H), 0.84 - 0.54 (m, 4H). ESI-MS [M+H]+ calc’d for C23H25ClN4O4, 457.16; found, 457.3. [0231] Example 3: (S)-5-(4-fluoro-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (Compound 3)
Figure imgf000061_0001
[0232] Step 1: (S)-methyl 2-((S)-5-(4-fluoro-1H-indole-2-carbonyl)-5- azaspiro[2.4]heptane-6-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000061_0002
[0233] To a solution of (S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-((S)-5- azaspiro[2.4]heptane-6-carboxamido)propanoate (169 mg, 488.69 μmol, HCl) in DCM (2 mL) was added DIEA (189 mg, 1.47 mmol) and 4-fluoro-1H-indole-2-carboxylic acid (88 mg, 488.69 μmol) dropwise at 0°C. The mixture was stirred at 0°C for 20 mins. Then HATU (372 mg, 977.38 μmol) in DCM (2 mL) was added in one portion at 0°C. The mixture was stirred at 25°C 10 hr. H2O (10 mL) was added and the resulting mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with sat.aq.NaHCO3 (10 mL x2), brine (10 mL) and water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 µm; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 17%-57%, 11 min). The title compound (90 mg, 38.71% yield) was obtained as a white solid.1H NMR (400MHz, CDCl3) δ ppm 10.02 - 9.77 (m, 1H), 9.24 - 7.90 (m, 1H), 7.24 - 7.07 (m, 2H), 7.00 - 6.87 (m, 1H), 6.82 - 6.68 (m, 1H), 6.29 - 5.82 (m, 1H), 5.02 - 4.88 (m, 1H), 4.68 - 4.35 (m, 1H), 4.15 - 3.79 (m, 2H), 3.71 (s, 3H), 3.46 - 3.25 (m, 2H), 2.53 - 2.35 (m, 2H), 2.24 - 2.13 (m, 2H), 2.03 - 1.77 (m, 3H), 0.76 - 0.50 (m, 4H). [0234] Step 2: (S)-5-(4-fluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide
Figure imgf000062_0001
[0235] To a solution of (S)-methyl 2-((S)-5-(4-fluoro-1H-indole-2-carbonyl)-5- azaspiro[2.4]heptane-6-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (90 mg, 191.29 μmol) in THF (6 mL) was added LiBH4 (12.5 mg, 573.87 μmol) in one portion at 0°C. The mixture was stirred at 0°C for 1 hr. H2O (10 mL) was added to the reaction mixture. The resulting mixture was extracted with DCM (15 mL x3). The combined organic phase was washed with brine (25 mL), water (25 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (90 mg, crude) was obtained as a white solid.1H NMR (400MHz, CDCl3) δ ppm = 10.35 - 9.85 (m, 1H), 8.51 - 7.88 (m, 1H), 7.24 - 7.12 (m, 2H), 6.95 - 6.84 (m, 1H), 6.75 (t, J = 8.4 Hz, 1H), 6.10 - 5.85 (m, 1H), 5.03 - 4.78 (m, 1H), 4.07 - 3.92 (m, 2H), 3.91 - 3.82 (m, 1H), 3.72 - 3.43 (m, 2H), 3.31 - 3.20 (m, 2H), 2.60 - 2.44 (m, 1H), 2.42 - 2.27 (m, 1H), 2.25 - 2.17 (m, 1H), 2.13 - 2.00 (m, 2H), 1.81 - 1.69 (m, 1H), 1.57 (m, 1H), 1.35 - 1.18 (m, 1H), 0.76 - 0.55 (m, 4H). [0236] Step 3: (S)-5-(4-fluoro-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin- 3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide [0237] To a solution of (S)-5-(4-fluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (70 mg, 158.20 μmol) in DCM (3 mL) was added DMP (134 mg, 316.40 μmol) at 25°C, and the reaction mixture was stirred at 25°C for 0.5 hr. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 μm; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 13%-53%, 11 min). Compound 3 (15.6 mg, 21.84% yield, 97.569% purity) was obtained as a white solid.1H NMR (400MHz, CD3OD) δ ppm = 7.29 - 7.22 (m, 1H), 7.22 - 7.12 (m, 1H), 7.08 - 6.85 (m, 1H), 6.78 - 6.67 (m, 1H), 4.63 - 4.35 (m, 1H), 4.10 - 3.84 (m, 2H), 3.81 - 3.45 (m, 1H), 3.09 - 2.49 (m, 2H), 2.46 - 1.92 (m, 4H), 1.89 - 1.17 (m, 3H), 0.82 - 0.56 (m, 4H). ESI-MS [M+H]+ calc’d. for C23H25FN4O4, 441.19, found 441.4. [0238] Example 4: (1R,2S,5S)-3-(6,7-difluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 4)
Figure imgf000063_0001
[0239] Step 1: ethyl 6,7-difluoro-1H-indole-2-carboxylate
Figure imgf000063_0002
[0240] To a solution of (2,3-difluorophenyl)hydrazine (500 mg, 2.77 mmol, HCl) and ethyl 2-oxopropanoate (321 mg, 2.77 mmol, 0.31 mL) in toluene (10 mL) was added TsOH.H2O (50 mg, 0.27 mmol) at 15°C. The mixture was stirred at 120°C for 2 hr. TsOH.H2O (1.58 g, 8.31 mmol) was added. The mixture was stirred at 120°C for 10 hr. The reaction mixture was concentrated, sat.aq NaHCO3 (30 mL) was added to the residue. The resulting mixture was extracted with EtOAc (30 mLx3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash silica gel chromatography (eluent of 7 % EtOAc/PE). The title compound (170 mg, 27.26% yield) was obtained as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 9.04 (brs 1H), 7.41 - 7.33 (m, 1H), 7.24-7.20 (m, 1H), 7.06 - 7.92 (m, 1H), 4.43 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H). [0241] Step 2: 6,7-difluoro-1H-indole-2-carboxylic acid
Figure imgf000063_0003
[0242] To a mixture of ethyl 6,7-difluoro-1H-indole-2-carboxylate (170 mg, 0.75 mmol,) in H2O (1 mL) and MeOH (1 mL) was added LiOH.H2O (63 mg, 1.51 mmol). The mixture was stirred at 50 °C for 3 hr. The reaction mixture was poured into water (20 mL) and then extracted with PE (50 mL x2). The aqueous phase was then adjusted to pH~5 by aqueous HCl (1M). The resulting mixture was extracted with EtOAc (50 mL x2). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (114 mg, crude) was obtained as a yellow solid.1H NMR (400 MHz, CD3OD) δ ppm 7.45 - 7.37 (m, 1H), 7.21 - 7.16 (m, 1H), 7.03 - 6.92 (m, 1H). [0243] Step 3: (S)-methyl-2-((1R,2S,5S)-3-(6,7-difluoro-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000064_0001
[0244] To a mixture of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (182 mg, 0.51 mmol,) and 6,7- difluoro-1H-indole-2-carboxylic acid (100 mg, 0.51 mmol) in DCM (3 mL) was added DIEA (197 mg, 1.52 mmol, 0.26 mL). The mixture was stirred at 0 °C for 20 mins. HATU (386 mg, 1.01 mmol) was added to the above mixture. The mixture was stirred at 25 °C for 3 hr. The reaction was quenched with aqueous NaHCO3 (10 mL) drop-wise. The resulting mixture was extracted with DCM (30 mL x2). The combined organic phase was washed with water (20 mL x2), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash silica gel chromatography (eluent of 0-100% EtOAc/PE). The title compound was obtained as a white solid (207 mg, 48.07% yield).1H NMR (400 MHz, CDCl3) δ ppm 9.91 - 9.50 (m, 1H), 8.54 - 7.53 (m, 1H), 7.40 - 7.30 (m, 1H), 7.02 - 6.96 (m, 1H), 6.96 - 6.85 (m, 1H), 4.72 - 4.56 (m, 1H), 4.49 - 4.17 (m, 1H), 4.01 - 3.90 (m, 1H), 3.81 - 3.56 (m, 4H), 3.54 - 3.34 (m, 2H), 2.78 - 2.63 (m, 1H), 2.52 - 2.34 (m, 1H), 2.22 - 2.12 (m, 1H), 2.03 - 1.80 (m, 2H), 1.70 - 1.52 (m, 1H), 1.46-1.42 (m, 1H), 1.15 - 0.83 (m, 6H). [0245] Step 4: (1R,2S,5S)-3-(6,7-difluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)- 2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000064_0002
[0246] To a mixture of (S)-methyl 2-((1R,2S,5S)-3-(6,7-difluoro-1H-indole-2-carbonyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (200 mg, 0.40 mmol) in THF (3 mL) was added LiBH4 (20 mg, 0.92 mmol) at 0°C. The mixture was stirred at 25 °C for 1hr. The reaction was quenched with water (10 mL) drop-wise. The resulting mixture was extracted with DCM (20 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep- HPLC (column: Phenomenex Gemini-NX C1875×30mm×3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 16% -56%, 11 min). The title compound (37 mg, 18.79% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 10.20 - 9.76 (m, 1H), 8.17 (d, J =6.4 Hz, 1H), 7.38 - 7.31 (m, 1H), 7.04 - 6.83 (m, 2H), 5.72 (brs, 1H), 4.70 - 4.63 (m, 1H), 4.30 - 4.22 (m, 1H), 4.08 - 3.95 (m, 1H), 3.88 - 3.82 (m, 1H), 3.81 - 3.76 (m, 1H), 3.64 - 3.56 (m, 1H),3.40 - 3.26 (m, 2H), 2.68 - 2.29 (m, 2H), 2.11 - 1.91 (m, 2H), 1.90 - 1.86 (m, 1H), 1.72 - 1.67 (m, 1H), 1.67 - 1.61 (m, 2H), 1.11 - 0.88 (m, 6H). [0247] Step 5: (1R,2S,5S)-3-(6,7-difluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0248] To a solution of (1R,2S,5S)-3-(6,7-difluoro-1H-indole-2-carbonyl)-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (30 mg, 63.22 μmol) in DCM (5 mL) was added DMP (81 mg, 189.67 μmol) at 25°C. The reaction mixture was stirred at 25°C for 0.5 hr. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm× 3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 22%-52%, 10 min). Compound 4 (10 mg, 33.16% yield, 99.065% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.47 - 7.23 (m, 1H), 7.15 - 6.85 (m, 2H), 4.65 - 4.62 (m, 1H), 4.53 - 3.88 (m, 3H), 3.83 - 3.68 (m, 1H), 3.26 - 2.97 (m, 1H), 2.68 - 2.41 (m, 1H), 2.40 - 1.77 (m, 2H), 1.74 - 1.67 (m, 1H), 1.62 - 1.30 (m, 3H), 1.16 - 0.92 (m, 6H). ESI-MS [M+H]+ calc’d for C24H26F2N4O4, 473.19, found 473.4. [0249] Example 5: (1R,2S,5S)-3-(7-chloro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 5)
Figure imgf000065_0001
[0250] Step 1: (S)-methyl 2-((1R,2S,5S)-3-(7-chloro-1H-indole-2-carbonyl)-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000066_0001
[0251] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (181 mg, 927.68 μmol) and DIEA (360 mg, 2.78 mmol) in DCM (5 mL) was added 7-chloro-1H-indole-2-carboxylic acid (300 mg, 927.68 μmol, HCl). After addition, HATU (705 mg, 1.86 mmol) was added at 0°C. The mixture was stirred at 25 °C for 12 hr. The reaction mixture was poured into sat.aq NH4Cl (20 mL). The resulting mixture was extracted with EtOAc (20 mL x2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: Xtimate C18 150×40 mm×10 μm; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 25%-55%, 10 min). The title compound (216 mg, 45.52% yield) was obtained as a white solid.
Figure imgf000066_0002
H NMR (400 MHz, CDCl3) δ ppm 9.65-9.40 (m, 1H), 8.12-8.04 (m, 1H), 7.62-7.49 (m, 1H), 7.30- 7.27 (m, 1H), 7.10-6.96 (m, 2H), 5.80-5.61 (m, 1H), 4.76-4.65 (m, 1H), 4.59-4.49 (m, 1H), 4.27-4.16 (m, 1H), 4.03-3.89 (m, 1H), 3.78-3.66 (m, 3H), 3.39-3.28 (m, 2H), 2.66-2.51 (m, 1H), 2.49-2.39 (m, 1H), 2.35 - 2.25 (m, 1H), 2.24-2.11 (m, 1H), 2.01-1.73 (m, 3H), 1.11-1.05 (m, 3H), 0.95 - 0.91 (m, 3H). [0252] Step 2: (1R,2S,5S)-3-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000066_0003
[0253] To a solution of (S)-methyl 2-((1R,2S,5S)-3-(7-chloro-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (210 mg, 419.18 μmol) in THF (8 mL) was added LiBH4 (27 mg, 1.26 mmol) at 0°C. Then the mixture was stirred at 25°C for 1 hr. Water (20 mL) was added to the mixture. The resulting mixture was extracted with ethyl acetate (20 mL x2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (170 mg, crude) was obtained as a white solid. H NMR (400 MHz, CDCl3) δ ppm 10.00 (brs, 1H), 8.30 - 8.14 (m, 1H), 7.60 - 7.49 (m, 1H), 7.25 - 7.23 (m, 1H), 7.09 - 6.96 (m, 3H), 6.27 - 6.02 (m, 1H), 4.67 (s, 1H), 4.34 - 4.25 (m, 1H), 4.07 - 3.90 (m, 2H), 3.77 - 3.72 (m, 2H), 3.33 - 3.24 (m, 2H), 2.60 - 2.31 (m, 2H), 2.16 - 2.03 (m, 2H), 1.88 - 1.82 (m, 2H), 1.81 - 1.70 (m, 1H), 1.04 (s, 3H), 0.89 (s, 3H). [0254] Step 3: (1R,2S,5S)-3-(7-chloro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1-oxo- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0255] To a solution of (1R,2S,5S)-3-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (80 mg, 169.15 μmol) in DCM (3 mL) was added DMP (215 mg, 507.44 μmol) at 25oC. The mixture was stirred at 25oC for 1 hr. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 15%-55%, 11 min). Compound 5 (17 mg, 21.13% yield, 99% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.67 - 7.45 (m, 1H), 7.32 - 7.23 (m, 1H), 7.16 - 6.94 (m, 2H), 6.87 - 6.87 (m, 1H), 5.02 - 4.60 (m, 1H), 4.54 - 4.24 (m, 1H), 4.09 - 3.94 (m, 1H), 3.93 - 3.72 (m, 1H), 3.30 - 2.88 (m, 2H), 2.67 - 1.99 (m, 2H), 1.89 - 1.27 (m, 5H), 1.19 - 0.94 (m, 6H) ESI-MS [M+H]+ calc’d for C24H27ClN4O4, 471.17; found, 471.4. [0256] Example 6: (1R,2S,5S)-3-(7-fluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 6)
Figure imgf000067_0001
[0257] Step 1: (S)-methyl 2-((1R,2S,5S)-3-(7-fluoro-1H-indole-2-carbonyl)-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000068_0001
[0258] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (250 mg, 694.74 μmol, HCl), 7- fluoro-1H-indole-2-carboxylic acid (124 mg, 692.17 μmol) and DIEA (269.37 mg, 2.08 mmol) in DCM (5 mL) was added HATU (528.32 mg, 1.39 mmol) in one portion at 0°C. The mixture was stirred at 25°C for 10 hours. The reaction mixture was poured into sat.aq.NH4Cl (20 mL). The mixture was extracted with DCM (20 mL x2). The combined organic phase was washed with brine (10 mL x3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Xtimate C18150×40 mm×10 μm; mobile phase: [water(0.05%HCl)-ACN]; B%: 25%-55%, 10 min). The title compound was obtained as a white solid (160 mg, 47.44% yield).1H NMR (400 MHz, CD3OD) δ ppm 7.49 - 7.33 (m, 1H), 7.15 - 6.90 (m, 3H), 5.00 (s, 1H), 4.57 (dd, J = 4.0, 11.6 Hz, 1H), 4.39 - 4.21 (m, 1H), 4.06 - 3.89 (m, 1H), 3.80 - 3.64 (m, 3H), 3.35 - 3.32 (m, 1H), 3.06 - 2.64 (m, 1H), 2.61 - 2.29 (m, 1H), 2.25 - 1.94 (m, 1H), 1.92 - 1.75 (m, 2H), 1.74 - 1.36 (m, 3H), 1.16 - 0.94 (m, 6H). [0259] Step 2: (1R,2S,5S)-3-(7-fluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000068_0002
[0260] To a solution of (S)-methyl 2-((1R,2S,5S)-3-(7-fluoro-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (160 mg, 330.22 μmol) in THF (3 mL) was added LiBH4 (21.6 mg, 990.67 μmol) in one portion at 0°C. The mixture was stirred at 25 °C for 2 hr. The residue was poured into water (10 mL). The aqueous phase was extracted with DCM (5 mL x3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 10%-50%, 11 min). The title compound was obtained as a white solid (60 mg, 37.41% yield). 1H NMR (400 MHz, CD3OD) δ ppm 7.49 - 7.32 (m, 1H), 7.14 - 6.91 (m, 3H), 4.95 - 4.90 (m, 1H), 4.35 - 4.27 (m, 1H), 4.08 - 3.99 (m, 1H), 3.95 (d, J = 10.8 Hz, 1H), 3.83 - 3.72 (m, 1H), 3.56 (d, J = 5.6 Hz, 1H), 3.49 - 3.41 (m, 1H), 3.30 - 3.25 (m, 1H), 3.00 - 2.59 (m, 1H), 2.46 - 2.31 (m, 1H), 2.03 - 1.93 (m, 1H), 1.86 - 1.66 (m, 3H), 1.60 - 1.44 (m, 2H), 1.15 - 0.97 (m, 6H). [0261] Step 3: (1R,2S,5S)-3-(7-fluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1-oxo- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0262] To a solution of (1R,2S,5S)-3-(7-fluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (55 mg, 120.48 μmol) in DCM (3 mL) was added DMP (153.0 mg, 361.44 μmol) in one portion at 25°C. The mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered. The cake was washed with DCM (2 mL). The combined organic phase was washed with sat.aq.NaHCO3 (1 mL x2) and sat.aq.Na2SO3 (1 mL x2), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 μm; mobile phase: [water (0.05%NH3H2O+10 mM NH4HCO3)-ACN]; B%: 14%-54%, 11 min). Compound 6 was obtained as a white solid (4.2 mg, 7.62% yield, 99.38% purity).1H NMR (400 MHz, CD3OD) δ ppm 7.50 - 7.31 (m, 1H), 7.15 - 6.88 (m, 3H), 5.00 - 4.91 (m, 1H), 4.54 - 4.37 (m, 1H), 4.34 - 3.89 (m, 2H), 3.81 - 3.66 (m, 1H), 3.29 - 3.19 (m, 1H), 2.98 - 2.56 (m, 1H), 2.41 - 2.28 (m, 1H), 2.10 - 1.80 (m, 1H), 1.74 - 1.52 (m, 3H), 1.45 - 1.32 (m, 1H), 1.17 - 0.95 (m, 6H). ESI- MS [M+H]+ calc’d for C24H27FN4O4, 455.20; found, 455.4. [0263] Example 7: (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-((R)-2-(m-tolyl)propanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 7)
Figure imgf000070_0001
[0264] Step 1: (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-((R)-2-(m-tolyl)propanoyl)-3- azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000070_0002
[0265] To a mixture of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (255 mg, 788.53 μmol) and (R)-2- (m-tolyl)propanoic acid (129 mg, 788.53 μmol) in DCM (5 mL) was added DIEA (305 mg, 2.37 mmol) and HATU (599 mg, 1.58 mmol) at 0°C. The mixture was stirred at 25°C for 12 hr. The mixture was diluted with sat.aq. NH4Cl (8 mL), extracted with DCM (10 mL x3). The combined organic layer was dried over Na2SO4, filtered and concentrated to crude product. The crude product was purified by prep-HPLC (column: Welch Ultimate XB-CN 250×50×10 μm; mobile phase: [Heptane-EtOH (0.1%NH3H2O)]; B%: 10%-30%, 8 min). The title compound (80 mg, 17.50% yield) was obtained as a white solid. ESI-MS [M+H]+ calc’d for C26H35N3O5, 470.26; found, 470.3. [0266] Step 2: (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6- dimethyl-3-((R)-2-(m-tolyl)propanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000071_0001
[0267] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-((R)-2-(m- tolyl)propanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (80 mg, 170.37 μmol) in THF (5 mL) was added LiBH4 (11 mg, 511.10 μmol) at 0℃. The mixture was stirred at 0℃ for 1 hr. The mixture was quenched with H2O (10 mL), and extracted with DCM (5 mL x3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to dryness. The crude product was used to next step directly. The title compound (80 mg, 63.81% yield) was obtained as a white solid. ESI- MS [M+H]+ calc’d for C25H35N3O4, 442.26; found, 442.3. [0268] Step 3: (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-3-((R)-2-(m-tolyl)propanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0269] A mixture of (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)-6,6-dimethyl-3-((R)-2-(m-tolyl)propanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (80 mg, 181.18 μmol) and DMP (230 mg, 543.53 μmol) in DCM (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25°C for 0.5 hr under N2 atmosphere. The mixture was filtered and the filtrate was concentrated to give crude product. The residue was purified by prep-HPLC (column: Phenomenex C1875×30 mm×3 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 22%-50%, 8 min). Compound 7 (10.7 mg, 12.76% yield, 95% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.26 - 7.15 (m, 1H), 7.12 - 6.97 (m, 3H), 4.54 - 4.23 (m, 2H), 4.09 - 3.84 (m, 2H), 3.77 (q, J = 6.6 Hz, 1H), 2.75 - 2.61 (m, 1H), 2.46 - 2.35 (m, 1H), 2.31 (s, 3H), 2.12 - 2.00 (m, 1H), 1.85 - 1.37 (m, 5H), 1.33 (dd, J = 1.3, 6.9 Hz, 3H), 0.96 (s, 3H), 0.46 (s, 3H). ESI-MS [M+H]+ calc’d for C25H33N3O4, 440.25; found, 440.3. [0270] Example 8: (1R,2S,5S)-3-(1-(3-chlorophenyl)cyclopropanecarbonyl)-6,6-dimethyl- N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 8)
Figure imgf000072_0001
[0271] Step 1: (S)-methyl 2-((1R,2S,5S)-3-(1-(3-chlorophenyl)cyclopropanecarbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000072_0002
[0272] To a solution of 1-(3-chlorophenyl)cyclopropanecarboxylic acid (139 mg, 708.13 μmol) in DCM (3 mL) was added (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (229 mg, 708.13 μmol), DIEA (389 mg, 3.02 mmol, 525 μL) and HATU (269 mg, 708.13 μmol). The mixture was stirred at 20 °C for 5 hr. The reaction mixture was poured into water (20 mL). The resulting mixture was extracted with DCM (15 mL x3). The combined organic phase was washed with sat.aq.NaHCO3 (15 mL x2) and brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: C18-6 100×30mm×5μm;mobile phase: [water(FA)-ACN];B%: 42%-72%,8min). The title
Figure imgf000072_0003
compound (71 mg, 19.97% yield) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 7.43 - 7.34 (m, 1H), 7.24 - 7.21 (m, 1H), 7.19 - 7.02 (m, 3H), 5.98 - 5.76 (m, 1H), 4.71 - 4.55 (m, 1H), 4.34 (s, 1H), 3.76 (s, 3H), 3.46 - 3.30 (m, 4H), 2.62 - 2.39 (m, 2H), 2.21 - 2.13 (m, 1H), 1.61 – 1.52 (m, 1H), 1.49 - 1.44 (m, 1H), 1.38 - 1.31 (m, 1H), 1.25 - 1.18 (m, 2H), 1.11 - 1.04 (m, 1H), 0.99 (s, 3H), 0.78 (s, 3H). [0273] Step 2: (1R,2S,5S)-3-(1-(3-chlorophenyl) cyclopropanecarbonyl)-N-((S)-1-hydroxy- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide
Figure imgf000073_0001
[0274] To a solution of (S)-methyl 2-((1R,2S,5S)-3-(1-(3- chlorophenyl)cyclopropanecarbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (60 mg, 119.52 μmol) in THF (4 mL) was added LiBH4 (7 mg, 321.40 μmol) dropwise at 0°C. The mixture was stirred at 0°C for 1 hr. H2O (10 mL) was added to the reaction mixture. The resulting mixture was extracted with DCM (5 mL x3). The combined organic phase was washed with brine (5 mL) and water (5 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (60 mg, 83.47% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 7.68 - 7.35 (m, 1H), 7.26 - 7.10 (m, 4H), 5.91 (brs, 1H), 4.40 - 4.28 (m, 1H), 4.10 - 4.00 (m, 1H), 3.83 - 3.67 (m, 2H), 3.62 - 3.50 (m, 2H), 3.40 - 3.28 (m, 2H), 2.62 - 2.40 (m, 2H), 2.06 (m, 1H), 1.93 - 1.82 (m, 2H), 1.71 - 1.53 (m, 2H), 1.38 - 1.31 (m, 1H), 1.30 - 1.25 (m, 1H), 1.22 - 1.09 (m, 2H), 1.05 - 0.67 (m, 6H). [0275] Step 3: (1R,2S,5S)-3-(1-(3-chlorophenyl)cyclopropanecarbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide [0276] To a solution of (1R,2S,5S)-3-(1-(3-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (55 mg, 116.04 μmol) in DCM (6 mL) was added DMP (148 mg, 348.11 μmol) at 25°C. The reaction mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered. The filtrate was concentrated. The residue was purified by prep-HPLC (column: Phenomenex C1875×30 mm×3 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%- 55%, 10 min). Compound 8 was obtained as a white solid (3.2 mg, 5.54% yield, 94.796% purity).1H NMR (400 MHz, CD3OD) δ ppm 7.37 - 7.13 (m, 4H), 4.52 - 4.29 (m, 2H), 4.14 - 3.92 (m, 1H), 3.67 - 3.33 (m, 3H), 2.72 - 2.57 (m, 1H), 2.48 - 2.32 (m, 1H), 2.11 - 1.94 (m, 1H), 1.83 - 1.69 (m, 1H), 1.65 - 1.53 (m, 1H), 1.50 - 1.36 (m, 3H), 1.32 - 1.21 (m, 2H), 1.20 - 1.13 (m, 1H), 1.04 - 0.73 (m, 6H). ESI-MS [M+H]+ calc’d for C25H30ClN3O4, 472.19; found, 472.4. [0277] Example 9: (S)-1-(7-chloro-1H-indole-2-carbonyl)-4,4-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 9)
Figure imgf000074_0001
[0278] Step 4: (S)-tert-butyl 2-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)carbamoyl)-4,4-dimethylpyrrolidine-1-carboxylate
Figure imgf000074_0002
[0279] To a solution of (S)-1-(tert-butoxycarbonyl)-4,4-dimethylpyrrolidine-2-carboxylic acid (500 mg, 2.06 mmol) and DIEA (1.06 g, 8.22 mmol) in DCM (10 mL) was added dropwise T3P (1.96 g, 3.08 mmol, 50% purity in EtOAc) at 0°C. After addition, the mixture was stirred at the same temperature for 30 min, and then (S)-methyl 2-amino-3-((S)-2- oxopyrrolidin-3-yl)propanoate hydrochloride (458 mg, 2.06 mmol, HCl) was added at 25°C. The resulting mixture was stirred at 25°C for 10 hr. The reaction mixture was diluted with DCM (30 mL) and 5% H3PO4 (30 mL). The layers were separated and the aqueous phase was extracted with DCM (50 mL). The combined organic layer was washed with 5% H3PO4 (30 mL), sat.aq.NaHCO3 (30 mL x2) and water (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The title compound (760 mg, crude) was obtained as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 7.73 - 7.29 (m, 1H), 6.23 - 5.45 (m, 1H), 4.70 - 4.41 (m, 1H), 4.26 (t, J = 8.0 Hz, 1H), 3.80 - 3.63 (m, 3H), 3.53 - 3.22 (m, 3H), 3.18 - 3.02 (m, 1H), 2.59 - 2.27 (m, 2H), 2.25 - 2.12 (m, 1H), 2.01 - 1.65 (m, 4H), 1.44 (s, 9H), 1.17 - 0.91 (m, 6H). [0280] Step 5: (S)-methyl 2-((S)-4,4-dimethylpyrrolidine-2-carboxamido)-3-((S)-2- oxopyrrolidin-3-yl)propanoate
Figure imgf000075_0001
[0281] To a mixture of (S)-tert-butyl 2-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)carbamoyl)-4,4-dimethylpyrrolidine-1-carboxylate (200 mg, 486.04 μmol) in dioxane (2 mL) was added HCl/dioxane (4 M, 2 mL). The mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated to dryness directly. The title compound (168 mg, crude, HCl) was obtained as a white solid, which was used to next step without further purification. [0282] Step 6: (S)-methyl 2-((S)-1-(7-chloro-1H-indole-2-carbonyl)-4,4- dimethylpyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000075_0002
[0283] To a solution of (S)-methyl 2-((S)-4,4-dimethylpyrrolidine-2-carboxamido)-3-((S)- 2-oxopyrrolidin-3-yl)propanoate (165 mg, 474.36 μmol HCl), 7-chloro-1H-indole-2- carboxylic acid (93 mg, 474.36 μmol) and DIEA (184 mg, 1.42 mmol) in DCM (3 mL) was added HATU (361 mg, 948.72 μmol) slowly at 0°C. The mixture was stirred at 25°C for 10 hr. Sat.aq.NH4Cl (20 mL) was added. The resulting mixture was extracted with DCM (30 mL x3). The combined organic phase was washed with water (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: Xtimate C18150×40mm×10μm;mobile phase: [water(10mM NH4HCO3)- ACN];B%: 25%-55%,10min). The title compound (80 mg, 33.74% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.65 - 9.39 (m, 1H), 8.69 - 8.00 (m, 1H), 7.62 - 7.42 (m, 1H), 7.31 - 7.26 (m, 1H), 7.06 (t, J = 8.0 Hz, 1H), 6.97 - 6.89 (m, 1H), 6.14 - 5.67 (m, 1H), 4.98 - 4.69 (m, 1H), 4.61 - 4.14 (m, 1H), 3.82 - 3.75 (m, 1H), 3.73 - 3.65 (m, 4H), 3.55 - 3.27 (m, 2H), 2.67 - 2.54 (m, 1H), 2.49 - 2.37 (m, 1H), 2.23 - 1.99 (m, 3H), 1.98 - 1.71 (m, 2H), 1.30 - 0.96 (m, 6H). [0284] Step 7: (S)-1-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-4,4-dimethylpyrrolidine-2-carboxamide
Figure imgf000076_0001
[0285] To a solution of (S)-methyl 2-((S)-1-(7-chloro-1H-indole-2-carbonyl)-4,4- dimethylpyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (75 mg, 153.39 μmol) in THF (2 mL) was added LiBH4 (13 mg, 613.54 μmol) at 0°C. The mixture was stirred at 25 °C for 1 hr. The reaction was quenched with water (10 mL) drop-wise. The resulting mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (70 mg, crude) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.96 - 9.58 (m, 1H), 9.02 - 8.10 (m, 1H), 7.63 - 7.39 (m, 1H), 7.32 - 7.26 (m, 1H), 7.18 - 6.92 (m, 2H), 6.44 - 5.72 (m, 1H), 4.92 - 4.65 (m, 1H), 3.83 - 3.71 (m, 3H), 3.70 - 3.63 (m, 1H), 3.58 - 3.47 (m, 1H), 3.39 - 3.16 (m, 2H), 2.74 - 2.52 (m, 1H), 2.49 - 2.32 (m, 1H), 2.15 - 1.88 (m, 3H), 1.87 - 1.72 (m, 2H), 1.67 - 1.58 (m, 1H), 1.30 - 0.94 (m, 6H). [0286] Step 8: (S)-1-(7-chloro-1H-indole-2-carbonyl)-4,4-dimethyl-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide [0287] To a solution of (S)-1-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-4,4-dimethylpyrrolidine-2-carboxamide (50 mg, 108.47 μmol,) in DCM (2 mL) was added DMP (92 mg, 216.94 μmol). The mixture was stirred at 25 °C for 10 min. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3μm;mobile phase: [water(10mM NH4HCO3)-ACN];B%: 17%-57%,11min). Compound 9 (5 mg, 9.94% yield, 99.01% purity) was obtained as a whilte solid.1H NMR (400 MHz, CD3OD) δ ppm 7.68 - 7.44 (m, 1H), 7.34 - 7.21 (m, 1H), 7.15 - 6.86 (m, 2H), 4.76 - 4.66 (m, 1H), 4.61 - 4.26 (m, 1H), 4.07 - 3.91 (m, 1H), 3.81 - 3.68 (m, 1H), 3.67 - 3.42 (m, 1H), 2.97 - 2.61 (m, 1H), 2.49 - 1.96 (m, 3H), 1.95 - 1.69 (m, 2H), 1.68 - 1.52 (m, 1H), 1.50 - 1.31 (m, 1H), 1.31 - 1.00 (m, 6H). ESI-MS [M+H]+ calc’d for C23H27ClN4O4, 459.17; found, 459.3. [0288] Example 10: (S)-6-(1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-6-azaspiro[3.4]octane-7-carboxamide (Compound 10)
Figure imgf000077_0001
[0289] Step 1: (S)-tert-butyl-7-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)carbamoyl)-6-azaspiro[3.4]octane-6-carboxylate
Figure imgf000077_0002
[0290] To a solution of (S)-6-(tert-butoxycarbonyl)-6-azaspiro[3.4]octane-7-carboxylic acid (450 mg, 1.76 mmol) in DCM (7 mL) and DIEA (682 mg, 5.28 mmol) was added dropwise T3P (1.68 g, 2.64 mmol, 50% purity in EtOAc) at 0°C. After addition, the mixture was stirred at the same temperature for 30 min, and then (S)-methyl 2-amino-3-((S)-2- oxopyrrolidin-3-yl)propanoate (391 mg, 1.76 mmol, HCl) in DCM (5 mL) was added at 25°C. The resulting mixture was stirred at 25°C for 11.5 hrs. The reaction mixture was diluted with DCM (30 mL). The combined organic layers were washed with 5% H3PO4 (10 mL), sat.aq. NaHCO3 (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (740 mg, 46.66% yield) was obtained as a yellow solid which was used in the next step without further purification. ESI-MS [M+H]+ calc’d for C21H33N3O6, 424.24, found 424.2. [0291] Step 2: (S)-methyl-3-((S)-2-oxopyrrolidin-3-yl)-2-((S)-6-azaspiro[3.4]octane-7- carboxamido)propanoate
Figure imgf000078_0001
[0292] A mixture of (S)-tert-butyl 7-(((S)-1-methoxy-1-oxo-3-(2-oxoimidazolidin-1- yl)propan-2-yl)carbamoyl)-6-azaspiro[3.4]octane-6-carboxylate (700 mg, 1.65 mmol) in HCl/dioxane (4M, 10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 1 hr under N2 atmosphere. The mixture was concentrated to give crude product. The title compound (590 mg, crude, HCl) was obtained as a white solid, which was used to next step directly without further purification. [0293] Step 3: (S)-methyl-2-((S)-6-(1H-indole-2-carbonyl)-6-azaspiro[3.4]octane-7- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000078_0002
[0294] To a mixture of (S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-((S)-6- azaspiro[3.4]octane-7-carboxamido)propanoate (590 mg, 1.64 mmol, HCl) and 1H-indole-2- carboxylic acid (264 mg, 1.64 mmol) in DCM (10 mL) were added DIEA (635 mg, 4.92 mmol) and HATU (1.25 g, 3.28 mmol) at 0°C. The mixture was stirred at 25°C for 2 hr. The mixture was diluted with sat.aq. NH4Cl (20 mL), and extracted with DCM (20 mL x3). The combined organic layers were dried over Na2SO4, filtered and concentrated to crude product. The residue was purified by column chromatography (SiO2, DCM/MeOH = 5% to 10%). The
Figure imgf000078_0003
title compound (336 mg, 40.41% yield) was obtained as a yellow solid.1H NMR (400 MHz, CD3OD) δ ppm 7.71 - 7.43 (m, 2H), 7.29 - 7.20 (m, 1H), 7.14 - 6.80 (m, 2H), 4.70 - 4.52 (m, 2H), 4.12 - 3.98 (m, 1H), 3.78 - 3.69 (m, 3H), 3.00 - 2.71 (m, 1H), 2.65 - 2.33 (m, 3H), 2.26 - 1.92 (m, 10H), 1.91 - 1.75 (m, 2H). [0295] Step 4: (S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6-(1H- indole-2-carbonyl)-6-azaspiro[3.4]octane-7-carboxamide
Figure imgf000079_0001
[0296] A mixture of (S)-methyl 2-((S)-6-(1H-indole-2-carbonyl)-6-azaspiro[3.4]octane-7- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (120 mg, 257.22 μmol) and LiBH4 (16 mg, 771.66 μmol) in THF (3 mL) was degassed and purged with N2 for 3 times at 0℃, and then the mixture was stirred at 0℃ for 1 hr under N2 atmosphere. The reaction was quenched by water (20 mL). The reaction mixture was extracted with DCM (20 mL x3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated to dryness. The title compound (67 mg, 59.40% yield) was obtained as a yellow solid.1H NMR (400 MHz, CD3OD) δ ppm 7.77 - 6.68 (m, 5H), 4.19 - 3.96 (m, 1H), 3.95 - 3.85 (m, 1H), 3.83 - 3.51 (m, 2H), 3.49 - 3.25 (m, 3H), 2.91 - 2.56 (m, 1H), 2.52 - 2.15 (m, 2H), 2.13 - 1.74 (m, 8H), 1.72 - 1.34 (m, 4H). [0297] Step 5: (S)-6-(1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-6-azaspiro[3.4]octane-7-carboxamide [0298] To a solution of (S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6- (1H-indole-2-carbonyl)-6-azaspiro[3.4]octane-7-carboxamide (60 mg, 136.82 μmol) in DCM (2 mL) was added DMP (174 mg, 410.47 μmol) at 25 °C. The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was filtered. And the filtrate was concentrated directly to give crude product. The residue was purified by prep-HPLC (column: Phenomenex Gemini- NX C1875×30mm×3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 15%-45%, 10 min). Compound 10 (5 mg, 8.07% yield, 96.43% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.59 - 7.37 (m, 1H), 7.35 - 7.28 (m, 1H), 7.16 - 7.06 (m, 1H), 7.01 - 6.69 (m, 2H), 4.57 - 4.21 (m, 2H), 4.01 - 3.80 (m, 2H), 3.72 - 3.55 (m, 1H), 2.81 - 2.22 (m, 3H), 2.11 - 1.82 (m, 8H), 1.62 - 1.45 (m, 1H), 1.35 - 1.30 (m, 1H), 1.25 - 1.16 (m, 1H). ESI-MS [M+H]+ calc’d for C24H28N4O4, 437.21, found 437.4. [0299] Example 11: (1R,2S,5S)-3-(1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopiperidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 11)
Figure imgf000080_0001
[0300] Step 1: (1R,2S,5S)-tert-butyl 2-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure imgf000080_0002
[0301] To a solution of (1R,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (300 mg, 1.18 mmol) and DIEA (607 mg, 4.70 mmol) in DCM (5 mL) was added dropwise T3P (1.12 g, 1.76 mmol, 50% purity in EtOAc) at 0°C. After addition, the mixture was stirred at the same temperature for 30 min, and then (S)-methyl 2-amino-3-((S)-2-oxopiperidin-3-yl)propanoate (278 mg, 1.18 mmol, HCl) in DCM(5 mL) was added at 25°C. The resulting mixture was stirred at 25°C for 10 hrs. The reaction mixture was diluted with H2O (10 mL). The reaction mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with 5% H3PO4 (10 mL x2), sat.aq.NaHCO3 (10 mL x2) and brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (416 mg) was obtained as a white solid. ESI-MS [M+H]+ calc’d for C22H35N3O6, 438.26, found 438.3. [0302] Step 2: (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate hydrochloride
Figure imgf000080_0003
[0303] A mixture of (1R,2S,5S)-tert-butyl 2-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopiperidin- 3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (416 mg, 950.80 μmol) in HCl/dioxane (4 M, 10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 ℃ for 1 hr under N2 atmosphere. The mixture was concentrated to give crude product. The title compound (355 mg, crude, HCl) was obtained as a white solid, which was used to next step directly. [0304] Step 3: (S)-methyl 2-((1R,2S,5S)-3-(1H-indole-2-carbonyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate
Figure imgf000081_0001
[0305] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate hydrochloride (355 mg, 949.52 μmol, HCl) in DCM (5 mL) was added 1H-indole-2-carboxylic acid (153 mg, 949.52 μmol) and DIEA (490 mg, 3.80 mmol). And then HATU (469 mg, 1.23 mmol) was added slowly at 0°C. The resulting mixture was stirred at 25 °C for 10 h. Water (15 mL) was added to the reaction mixture. The mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with sat.aq.NH4Cl (10 mL x2), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30mm×3 μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 23%-63%, 11min). The title compound (233 mg) was obtained as a white solid. ESI-MS [M+H]+ calc’d for C26H32N4O5, 481.24, found 481.3. [0306] Step 4: (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-3- (1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000081_0002
[0307] To a mixture of (S)-methyl 2-((1R,2S,5S)-3-(1H-indole-2-carbonyl)-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate (233 mg, 484.86 μmol) in THF (5 mL) was added LiBH4 (31 mg, 1.45 mmol) in one portion at 0 C under N2. The mixture was stirred at 25 °C for 1 h. Water (10 mL) was added to the mixture. The aqueous layer was extracted with DCM (10 mL x2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini- NX C1875×30mm×3μm; mobile phase: [water (0.05%NH3H2O+10mM NH4HCO3)-ACN]; B%: 16%-56%, 11min). The title compound (118 mg, 261.91 μmol) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.56 (s, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.75 - 7.60 (m, 1H), 7.47 - 7.27 (m, 2H), 7.19 - 7.05 (m, 1H), 6.99 - 6.84 (m, 1H), 5.91 (s, 1H), 4.72 - 4.64 (m, 1H), 4.27 (dd, J = 2.8, 9.6 Hz, 1H), 4.07 - 3.91 (m, 2H), 3.75 (dd, J = 3.6, 11.6 Hz, 1H), 3.59 - 3.42 (m, 1H), 3.31 - 3.19 (m, 2H), 2.48 - 2.33 (m, 1H), 2.24 - 1.95 (m, 3H), 1.83 - 1.74 (m, 3H), 1.71-1.67 (m, 1H), 1.58 - 1.41 (m, 2H), 1.12 - 1.04 (m, 3H), 0.95 - 0.87 (m, 3H). [0308] Step 5: (1R,2S,5S)-3-(1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2- oxopiperidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0309] To a solution of (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopiperidin-3-yl)propan-2- yl)-3-(1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (60 mg, 132.58 μmol.) in DCM (6 mL) was added DMP (112 mg, 265.17 μmol, 82.09 uL.) at 25 ℃. The mixture was stirred at 25 ℃ for 1 hr. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30mm×3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 20%-50%, 10 min). Compound 11 was obtained as a brown solid (9.5 mg, 15.26% yield, 95.972% purity).1H NMR (400 MHz, CD3OD) δ ppm 7.70 - 7.51 (m, 1H), 7.48 - 7.37 (m, 1H), 7.22 (q, J = 7.2 Hz, 1H), 7.11 - 6.89 (m, 2H), 5.04 - 4.87 (m, 1H), 4.63 - 4.31 (m, 2H), 4.04 - 3.96 (m, 1H), 3.88 - 3.75 (m, 1H), 3.05 - 2.73 (m, 1H), 2.42 - 2.00 (m, 2H), 1.83 - 1.66 (m, 3H), 1.63 - 1.47 (m, 2H), 1.35 - 1.23 (m, 1H), 1.15 - 0.96 (m, 7H). ESI-MS [M+H]+ calc’d for C25H30N4O4, 451.23, found 451.4. [0310] Example 12: (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido) butanoyl)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3- azabicyclo[3.1.0]hexane-2-carboxamide (Compound 12)
Figure imgf000083_0001
[0311] Compound 12 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 4.53 - 4.41 (m, 1H), 4.38 - 4.26 (m, 1H), 4.08 - 3.72 (m, 3H), 3.29 - 3.12 (m, 2H), 2.73 - 2.49 (m, 1H), 2.43 - 2.24 (m, 1H), 2.11 - 1.90 (m, 1H), 1.83 - 1.67 (m, 1H), 1.65 - 1.37 (m, 3H), 1.16 - 0.85 (m, 15H). ESI-MS [M+H]+ calc’d for C23H33F3N4O5, 503.53; found, 503.5. [0312] Example 13: (1R,2S,5S)-3-(4,7-difluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 13)
Figure imgf000083_0002
[0313] Step 1: ethyl 4,7-difluoro-1H-indole-2-carboxylate
Figure imgf000083_0003
[0314] To a solution of (2,5-difluorophenyl)hydrazine (1.0 g, 5.54 mmol, HCl) in toluene (20 mL) was added 4-methylbenzenesulfonic acid (3.4 g, 19.74 mmol) and ethyl 2- oxopropanoate (643 mg, 5.54 mmol, 612.38 μL) at 25°C. The mixture was stirred at 120°C for 12 hr. Water (30 mL) was added and the reaction mixture was adjusted to pH~7 by sat.aq.NaHCO3. The resulting mixture was extracted with EtOAc (50 mL x3). The combined organic phase was washed with water (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash silica gel chromatography (Eluent of 0~5% EtOAc in PE). The title compound (144 mg, 11.55% yield) was obtained as a yellow solid. H NMR (400 MHz, CDCl3) δ ppm 9.12 (s, 1H), 7.30 (t, J = 2.4 Hz, 1H), 6.99 - 6.85 (m, 1H), 6.70 (dt, J = 3.2, 8.8 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H). [0315] Step 2: 4, 7-difluoro-1H-indole-2-carboxylic acid
Figure imgf000084_0001
[0316] To a solution of ethyl 4,7-difluoro-1H-indole-2-carboxylate (120 mg, 532.88 μmol) in MeOH (1 mL) and H2O (1 mL) was added LiOH.H2O (45 mg, 1.07 mmol). And then the mixture was stirred at 50 °C for 1 hr. Water (10 mL) was added and the reaction mixture was adjusted to pH~5 by aq. HCl (1 N). The resulting mixture was extracted with DCM (10 mL x3). The combined organic layers were washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (75 mg, crude) was obtained as a yellow solid.1H NMR (400 MHz, CD3OD) δ ppm 7.18 (d, J = 3.2 Hz, 1H), 6.98 - 6.85 (m, 1H), 6.68 (td, J = 3.2, 9.6 Hz, 1H). [0317] Step 3: (S)-methyl 2-((1R,2S,5S)-3-(4,7-difluoro-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000084_0002
[0318] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (91 mg, 253.63 μmol, HCl), 4,7- difluoro-1H-indole-2-carboxylic acid (50 mg, 253.63 μmol,) and DIEA (98 mg, 760.89 μmol) in DCM (3 mL) was added slowly HATU (193 mg, 507.26 μmol) at 0°C. The resulting mixture was stirred at 25°C for 10 hr. The reaction mixture was concentrated. Sat.aq.NH4Cl (10 mL) was added to the residue. The resulting mixture was extracted with DCM (20 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash silica gel chromatography (Eluent of 0~94% EtOAc in PE). The title compound (150 mg, 92.60% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 10.46 - 9.79 (m, 1H), 9.00 - 7.93 (m, 1H), 7.03 - 6.91 (m, 1H), 6.90 - 6.79 (m, 1H), 6.70 - 6.56 (m, 1H), 6.31 - 6.11 (m, 1H), 4.77 - 4.64 (m, 1H), 4.34 - 4.22 (m, 1H), 4.04 - 3.86 (m, 1H), 3.72 (s, 3H), 3.62 - 3.46 (m, 1H), 3.42 - 3.27 (m, 2H), 2.69 - 2.52 (m, 1H), 2.48 - 2.29 (m, 2H), 2.00 - 1.89 (m, 1H), 1.87 - 1.75 (m, 1H), 1.72 - 1.55 (m, 2H), 1.13 - 0.89 (m, 6H). [0319] Step 4: (1R,2S,5S)-3-(4,7-difluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)- 2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000085_0001
[0320] To a solution of (S)-methyl 2-((1R,2S,5S)-3-(4,7-difluoro-1H-indole-2-carbonyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (150 mg, 298.50 μmol) in THF (3 mL) was added LiBH4 (50 mg, 2.30 mmol) at 0°C. The mixture was stirred at 25°C for 1 h. The reaction was quenched with water (10 mL) drop-wise. The resulting mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30mm×3μm; mobile phase: [water (0.05%NH3H2O+10mM NH4HCO3)- ACN]; B%: 15%-48%, 10 min). The title compound (20 mg, 13.92% yield) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.13 (d, J = 2.8 Hz, 1H), 6.96 - 6.86 (m, 1H), 6.76 - 6.61 (m, 1H), 4.32 (dd, J = 5.6, 10.4 Hz, 1H), 4.09 - 3.98 (m, 1H), 3.94 (d, J = 10.8 Hz, 1H), 3.86 - 3.74 (m, 1H), 3.56 (d, J = 5.6 Hz, 1H), 3.50 - 3.42 (m, 1H), 3.29 - 3.25 (m, 1H), 2.75 - 2.53 (m, 1H), 2.44 - 2.29 (m, 1H), 2.05 - 1.68 (m, 3H), 1.67 - 1.27 (m, 3H), 1.18 - 0.92 (m, 6H). [0321] Step 5: (1R,2S,5S)-3-(4,7-difluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0322] To a solution of (1R,2S,5S)-3-(4,7-difluoro-1H-indole-2-carbonyl)-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (20 mg, 42.15 μmol) in DCM (4 mL) was added DMP (36 mg, 84.30 μmol, 26.10 μL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30mm×3μm; mobile phase: [water (10mM NH4HCO3)- ACN]; B%: 12%-42%, 10 min). Compound 13 (5.4 mg, 26.07% yield, 96.16% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.17 - 6.85 (m, 2H), 6.75 - 6.59 (m, 1H), 4.54 - 4.38 (m, 1H), 4.35 - 3.96 (m, 2H), 3.96 - 3.89 (m, 1H), 3.85 - 3.69 (m, 1H), 2.69 - 2.27 (m, 2H), 2.09 - 1.68 (m, 3H), 1.65 - 1.29 (m, 3H), 1.21 - 0.92 (m, 6H). ESI- MS [M+H]+ calc’d for C24H26F2N4O4, 473.19, found 473.4. [0323] Example 14: (1R,2S,5S)-3-(4-ethyl-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 14)
Figure imgf000086_0001
[0324] Step 1: methyl 4-vinyl-1H-indole-2-carboxylate
Figure imgf000086_0002
[0325] To a solution of methyl 4-bromo-1H-indole-2-carboxylate (2 g, 7.87 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.4 g, 15.74 mmol, 2.67 mL) in dioxane (16 mL) and H2O (4 mL) was added Cs2CO3 (7.7 g, 23.61 mmol) and Pd(dppf)Cl2 (576 mg, 787.15 μmol) at 25°C. Then the mixture was stirred at 100°C for 10 hours under N2 atmosphere. The reaction mixture was filtered. Sat.aq. NH4Cl (10 mL) was added to the filtrate. The aqueous phase was extracted with DCM (10 mL x2). The combined organic phase was washed with brine (10 mL x2), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash silica gel chromatography (Eluent of 0~20% EtOAc/PE). The title compound (1 g, 56.82% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.90 (s, 1H), 7.48 - 7.40 (m, 1H), 7.35 - 7.28 (m, 2H), 7.19 - 7.05 (m, 1H), 5.94 (d, J = 17.6 Hz, 1H), 5.44 (dd, J = 1.2, 11.2 Hz, 1H), 3.96 (s, 3H). [0326] Step 2: methyl 4-ethyl-1H-indole-2-carboxylate
Figure imgf000086_0003
[0327] To a solution of methyl 4-vinyl-1H-indole-2-carboxylate (600 mg, 2.98 mmol) in THF (15 mL) was added wet Pd/C (635 mg, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The reaction mixture was stirred under H2 (15 psi) at 25°C for 2 hrs. The reaction mixture was filtered through the celites. The filtrate was concentrated to dryness. The title compound (500 mg, 74.26% yield) was obtained as a white solid which was used to the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 8.93 (br, 1H), 7.31-7.27 (m, 2H), 7.25 - 7.13 (m, 1H), 7.02 - 6.94 (m, 1H), 3.95 (s, 3H), 2.94 (q, J = 7.6 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H) [0328] Step 3: 4-ethyl-1H-indole-2-carboxylic acid
Figure imgf000087_0001
[0329] To a solution of methyl 4-ethyl-1H-indole-2-carboxylate (500 mg, 2.46 mmol) in THF (5 mL) and H2O (5 mL) was added LiOH.H2O (206 mg, 4.92 mmol) at 25℃. The mixture was stirred at 25°C for 10 hrs. The reaction was diluted with water (10 mL). The resulting mixture was extracted with DCM (5 mL x3). The aqueous phase was acidified to pH~4 with aq. HCl (2M). The resulting suspension was filtered. The filter cake was then dried under vacuum. The title compound (300 mg, 58.00% yield) was obtained as a pink solid which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 8.88 (brs, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.05 - 6.93 (m, 1H), 2.97 (q, J = 7.6 Hz, 2H), 1.37 (t, J = 7.6 Hz, 3H). [0330] Step 4: (S)-methyl 2-((1R,2S,5S)-3-(4-ethyl-1H-indole-2-carbonyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000087_0002
[0331] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (150 mg, 416.84 μmol, HCl) and 4- ethyl-1H-indole-2-carboxylic acid (79 mg, 416.84 μmol) in DCM (5 mL) was added DIEA (162 mg, 1.25 mmol) at 0°C. The mixture was stirred for 5 min. And HATU (317 mg, 833.69 μmol) was added into the above mixture at 0°C. The mixture was stirred at 25°C for 10 hrs. 5% phosphoric acid solution (10 mL) was added to the reaction mixture. The mixture was extracted with DCM (10 mL x3). Then the combined organic phase was washed with sat.aq NaHCO3 (20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (Column: Phenomenex Gemini-NX C18 75×30mm×3μm; mobile phase: [water (0.05%NH3H2O+10mM NH4HCO3)-ACN]; B%: 26%-66%, 11min). The title compound (70 mg, 30.56% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.54 - 9.32 (m, 1H), 8.45 - 7.59 (m, 1H), 7.18 - 7.07 (m, 2H), 6.98 - 6.76 (m, 2H), 5.96 - 5.59 (m, 1H), 4.73 - 4.61 (m, 1H), 4.57 - 4.29 (m, 1H), 4.21 - 4.03 (m, 1H), 4.01 - 3.83 (m, 1H), 3.68 - 3.38 (m, 3H), 3.27 - 3.07 (m, 2H), 2.94 - 2.75 (m, 2H), 2.51 - 2.39 (m, 1H), 2.35 - 2.20 (m, 1H), 2.20 - 2.08 (m, 1H), 1.90 - 1.71 (m, 2H), 1.69 - 1.61 (m, 3H), 1.32 - 1.24 (m, 3H), 1.05 - 0.96 (m, 3H), 0.91 - 0.78 (m, 3H). [0332] Step 5: (1R,2S,5S)-3-(4-ethyl-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000088_0001
[0333] To a solution of (S)-methyl 2-((1R,2S,5S)-3-(4-ethyl-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (70 mg, 141.53 μmol) in THF (2 mL) was added LiBH4 (30 mg, 1.38 mmol) at 0°C. Then the mixture was stirred at 25°C for 2 hrs under N2 atmosphere. The reaction was quenched with water (10 mL) drop-wise. The resulting mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The reaction mixture was concentrated directly. The title compound (55 mg, 74.96% yield, 90% purity) was obtained as a white solid which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 9.73 (s, 1H), 8.19 - 7.72 (m, 1H), 7.39 - 7.29 (m, 1H), 7.23 - 7.17 (m, 1H), 7.01 - 6.84 (m, 2H), 4.69 - 4.56 (m, 1H), 4.21 - 4.09 (m, 1H), 4.11 - 3.79 (m, 3H), 3.78 -3.71 (m, 2H), 3.57 - 3.47 (m, 1H), 3.33 - 3.18 (m, 2H), 2.97 - 2.82 (m, 2H), 2.41 (s, 2H), 2.15 - 2.00 (m, 1H), 1.71 - 1.58 (m, 2H), 1.35 - 1.28 (m, 3H), 1.08 (s, 3H), 0.94 - 0.88 (m, 3H). [0334] Step 6: (1R,2S,5S)-3-(4-ethyl-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0335] To a solution of (1R,2S,5S)-3-(4-ethyl-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (50 mg, 107.16 μmol) in DCM (2 mL) was added NaHCO3 (18.0 mg, 214.33 μmol) and DMP (136 mg, 321.49 μmol) in one portion at 25°C. The mixture was stirred at 25°C for 1 hr. The mixture was diluted with MeOH (3 mL) and then filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30mm×3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 18%-58%, 11 min). Compound 14 (16.2 mg, 32.25% yield, 99.105% purity) was obtained as a whilte solid.1H NMR (400 MHz, CD3OD) δ ppm 7.26 (t, J = 8.0 Hz, 1H), 7.19 - 7.11 (m, 1H), 7.11 - 6.83 (m, 2H), 5.03 - 4.89 (m, 1H), 4.81 - 4.63 (m, 1H), 4.53 - 4.29 (m, 1H), 4.05 - 3.93 (m, 1H), 3.79 - 3.65 (m, 1H), 3.29 - 3.22 (m, 1H), 2.99 - 2.79 (m, 2H), 2.68 - 2.28 (m, 1H), 2.13 - 1.98 (m, 1H), 1.91 - 1.69 (m, 2H), 1.68 - 1.50 (m, 2H), 1.40 - 1.20 (m, 4H), 1.18 - 0.95 (m, 6H). ESI-MS [M+H]+ calc’d for C26H32N4O4, 465.24; found, 465.4. [0336] Example 15: (1R,2S,5S)-3-(4-fluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 15)
Figure imgf000089_0001
[0337] Step 1: (S)-methyl 2-((1R,2S,5S)-3-(4-fluoro-1H-indole-2-carbonyl)-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000089_0002
[0338] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (254 mg, 705.85 μmol, HCl) and 4- fluoro-1H-indole-2-carboxylic acid (126 mg, 705.85 μmol) in DCM (5 mL) was added DIPEA (365 mg, 2.82 mmol) dropwise and HATU (403 mg, 1.06 mmol) slowly at 0°C. Then the mixture was stirred at 25°C for 3 hours. Saturated aq. NaHCO3 (10 mL) was added and the mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with brine (10 mL x2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 µm; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 23%-63%, 11 min). The title compound (190 mg, 53.25% yield) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.28 - 7.22 (m, 1H), 7.21 - 7.14 (m, 1H), 7.12 - 6.89 (m, 1H), 6.74 -6.69 (m, 1H), 4.85 -4.78 (m, 1H), 4.63 - 4.52 (m, 1H), 4.41 - 4.25 (m, 1H), 4.04 - 3.94 (m, 1H), 3.84 - 3.67 (m, 3H), 3.35 - 3.31 (m, 2H), 3.07 - 2.30 (m, 2H), 2.23 (s, 1H), 1.90 - 1.67 (m, 2H), 1.64 - 1.43 (m, 2H), 1.20 - 0.92 (m, 6H). [0339] Step 2: (1R,2S,5S)-3-(4-fluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000090_0001
[0340] To a solution of (S)-methyl 2-((1R,2S,5S)-3-(4-fluoro-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (160 mg, 330.22 μmol) in THF (5 mL) was added LiBH4 (22 mg, 990.67 μmol) slowly at 0°C. Then the mixture was stirred at 25°C for 1 hour. Saturated aq. NH4Cl (10 mL) was added to the reaction mixture. Then the mixture was extracted with DCM (5 mL x3). The combined organic phase was washed with brine (5 mL x2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The title compound (170 mg, crude) was obtained as a white solid. ESI-MS [M+H]+ calc’d for C24H29FN4O4, 457.22; found, 457.2. [0341] Step 3: (1R,2S,5S)-3-(4-fluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1-oxo- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0342] To a solution of (1R,2S,5S)-3-(4-fluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (96 mg, 210.29 μmol) in DCM (4 mL) was added DMP (268 mg, 630.88 μmol) slowly. Then the mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered. Saturated NaHCO3 (5 mL) was added to the filtrate and the mixture was extracted with DCM (5 mL x3). The combined organic phase was washed with brine (4 mL x2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep- HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 µm; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 17%-57%, 11 min). Compound 15 (26.1 mg, 27.01% yield, 98.913% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.29 - 7.22 (m, 1H), 7.22 - 7.13 (m, 1H), 7.12 - 6.91 (m, 1H), 6.73 (m, 1H), 4.63 - 4.40 (m, 1H), 4.36 - 3.70 (m, 3H), 3.29 - 3.24 (m, 1H), 2.97 - 2.58 (m, 1H), 2.45 - 2.28 (m, 1H), 2.09 - 1.33 (m, 6H), 1.16 - 0.95 (m, 6H). ESI-MS [M+H]+ calc’d for C24H27FN4O4, 455.20; found, 455.1. [0343] Example 16: (1R,2S,5S)-3-(2-(4,4-difluorocyclohexyl)acetyl)-6,6-dimethyl-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 16)
Figure imgf000091_0001
[0344] Step 1: (S)-methyl 2-((1R,2S,5S)-3-(2-(4,4-difluorocyclohexyl)acetyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000091_0002
[0345] To a solution of 2-(4,4-difluorocyclohexyl)acetic acid (100 mg, 561.24 μmol) in DCM (2 mL) was added DIEA (290 mg, 2.24 mmol) and T3P (535 mg, 841.86 µmol, 50% purity in EtOAc) dropwise at 0°C. The mixture was stirred at 0°C for 20 mins. Then (S)- methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2- oxopyrrolidin-3-yl)propanoate (213 mg, 591.92 μmol, HCl) in DCM (2 mL) was added in one portion at 0°C. The mixture was stirred at 25°C for 10 hr. The reaction mixture was poured into water (20 mL). The resulting mixture was extracted with DCM (15 mL x3). The combined organic phase was washed with sat.aq.NaHCO3 (15 mL x2) and brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: Xtimate C18150×40 mm×10 μm; mobile phase: [water (0.05%HCl)-ACN]; B%: 25%-55%, 10 min). The title compound (86 mg, 18.97% yield) was obtained as a white solid. H NMR (400 MHz, CDCl3) δ ppm 8.68 - 7.56 (m, 1H), 6.81 - 6.69 (m, 1H), 6.45 - 6.23 (m, 1H), 4.69 - 4.51 (m, 1H), 4.46 - 4.13 (m, 1H), 4.00 - 3.83 (m, 1H), 3.81 - 3.69 (m, 3H), 3.56 - 3.30 (m, 3H), 2.45 - 2.41 (m, 1H), 2.32 - 1.63 (m, 13H), 1.61 - 1.46 (m, 2H), 1.35 - 1.22 (m, 2H), 1.12 - 0.87 (m, 6H). [0346] Step 2: (1R,2S,5S)-3-(2-(4,4-difluorocyclohexyl)acetyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000092_0001
[0347] To a solution of (S)-methyl 2-((1R,2S,5S)-3-(2-(4,4-difluorocyclohexyl)acetyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (85 mg, 175.78 μmol) in THF (6 mL) was added LiBH4 (12 mg, 527.35 μmol) at 0°C. The mixture was stirred at 0°C for 1 hr. H2O (15 mL) was added to the reaction mixture. The resulting mixture was extracted with DCM (15 mLx3). The combined organic phase was washed with water (15 mL) and brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (75 mg, 36.07% yield) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 8.19 - 7.45 (m, 1H), 6.06 - 5.67 (m, 1H), 4.46 - 3.19 (m, 8H), 2.53 - 2.39 (m, 1H), 2.31 - 2.12 (m, 2H), 2.08 - 1.98 (m, 3H), 1.89 - 1.64 (m, 8H), 1.54 - 1.48 (m, 1H), 1.33 - 1.25 (m, 3H), 1.12 - 0.79 (m, 6H). [0348] Step 3: (1R,2S,5S)-3-(2-(4,4-difluorocyclohexyl)acetyl)-6,6-dimethyl-N-((S)-1-oxo- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0349] To a solution of (1R,2S,5S)-3-(2-(4,4-difluorocyclohexyl)acetyl)-N-((S)-1-hydroxy- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (65 mg, 142.69 μmol) in DCM (3 mL) was added DMP (182 mg, 428.07 μmol) at 25°C. The reaction mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 μm; mobile phase: [water (10 mM NH4HCO3)- ACN]; B%: 20%-50%, 10 min) and prep-HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 µm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 28%-58%, 10 min). Compound 16 (2.5 mg, 3.70% yield, 95.679% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 4.53 - 4.26 (m, 2H), 4.00 - 3.69 (m, 2H), 3.69 - 3.54 (m, 1H), 3.29 - 3.22 (m, 1H), 2.65 - 2.52 (m, 1H), 2.35 - 2.12 (m, 3H), 2.04 - 1.94 (m, 3H), 1.89 - 1.69 (m, 5H), 1.63 - 1.42 (m, 3H), 1.37 - 1.12 (m, 3H), 1.11 - 0.93 (m, 6H). ESI-MS [M+H]+ calc’d for C23H33F2N3O4, 454.24; found, 454.3. [0350] Example 17: (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-(1-phenylcyclopentanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 17)
Figure imgf000093_0001
[0351] Step 1: (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(1-phenylcyclopentanecarbonyl)- 3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000093_0002
[0352] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (220 mg, 611.37 μmol, HCl), 1- phenylcyclopentanecarboxylic acid (116 mg, 611.37 μmol) and DIEA (237 mg, 1.83 mmol) in DCM (4 mL) was added slowly HATU (465 mg, 1.22 mmol) at 0°C. The resulting mixture was stirred at 25°C for 5 hr. Sat.aq.NH4Cl (20 mL) was added to the reaction mixture. The resulting mixture was extracted with DCM (40 mL x3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex C1875×30 mm×3 μm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 31%-61%, 10 min). The title compound (45 mg, 12.97% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 7.31 - 7.22 (m, 6H), 5.67 (brs, 1H), 4.70 - 4.60 (m, 1H), 4.34 (s, 1H), 3.75 (s, 3H), 3.38 - 3.36 (m, 1H), 3.27 - 3.20 (m, 1H), 2.95 (d, J = 10.8 Hz, 1H), 2.64 - 2.09 (m, 7H), 1.97 - 1.87 (m, 3H), 1.66 - 1.53 (m, 3H), 1.41 - 1.19 (m, 3H), 0.90 (s, 3H), 0.60 (s, 3H). [0353] Step 2: (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6- dimethyl-3-(1-phenylcyclopentanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000094_0001
[0354] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(1- phenylcyclopentanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2- oxopyrrolidin-3-yl)propanoate (40 mg, 80.71 μmol) in THF (3 mL) was added LiBH4 (5 mg, 242.13 μmol) at 0°C. The mixture was stirred at 25°C for 1h. The reaction was quenched with water (10 mL) drop-wise. The resulting mixture was extracted with DCM (10 mLx3). The combined organic phase was washed with water (5 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (40 mg, crude) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 7.36 - 7.27 (m, 2H), 7.25 - 7.13 (m, 4H), 6.22 - 5.87 (m, 1H), 4.43 - 4.23 (m, 1H), 4.10 - 4.01 (m, 1H), 3.87 - 3.73 (m, 1H), 3.65 - 3.52 (m, 1H), 3.45 - 3.21 (m, 3H), 2.95 (d, J = 10.8 Hz, 1H), 2.57 - 2.23 (m, 4H), 2.22 - 1.99 (m, 2H), 1.98 - 1.83 (m, 2H), 1.79 - 1.56 (m, 5H), 1.37 - 1.29 (m, 1H), 1.27 - 1.22 (m, 1H), 0.90 (s, 3H), 0.57 (s, 3H). [0355] Step 3: (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-3-(1-phenylcyclopentanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0356] To a solution of (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-6,6-dimethyl-3-(1-phenylcyclopentanecarbonyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (40 mg, 85.54 μmol) in DCM (8 mL) was added DMP (109 mg, 256.63 μmol). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex C18 250×50 mm×10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%-55%, 10 min). Compound 17 (2.1 mg, 4.30 μmol, 5.03% yield, 95.427% purity) was obtained as a white solid. H NMR (400 MHz, CD3OD) δ ppm 7.36 - 7.29 (m, 2H), 7.28 - 7.20 (m, 3H), 4.52 - 4.28 (m, 1H), 4.08 - 3.87 (m, 1H), 3.44 - 3.37 (m, 1H), 3.35 - 3.25 (m, 2H), 2.92 (d, J = 10.4 Hz, 1H), 2.73 - 2.60 (m, 1H), 2.46 - 2.33 (m, 2H), 2.32 - 1.99 (m, 3H), 1.89 - 1.71 (m, 4H), 1.69 - 1.49 (m, 3H), 1.37 - 1.24 (m, 2H), 0.91 (s, 3H), 0.58 (s, 3H). ESI-MS [M+H]+ calc’d for C27H35N3O4, 466.26; found, 466.2. [0357] Example 18: (1R,2S,5S)-3-(6,7-dimethyl-1H-indole-2-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 18)
Figure imgf000095_0001
[0358] Step 1: (S)-methyl 2-((1R,2S,5S)-3-(6,7-dimethyl-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000095_0002
[0359] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (165 mg, 458.53 μmol HCl), 6,7- dimethyl-1H-indole-2-carboxylic acid (87 mg, 458.53 μmol) and DIEA (178 mg, 1.38 mmol) in DCM (3 mL) was added HATU (349 mg, 917.06 μmol) slowly at 0°C. The mixture was stirred at 25°C for 3 hr. Sat.aq.NH4Cl (20 mL) was added and the resulting mixture was extracted with DCM (30 mL x3). The combined organic phase was washed with water (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: Xtimate C18150×40mm×10μm;mobile phase: [water(10mM NH4HCO3)-ACN];B%: 30%-60%,10min). The title compound (100 mg, 40.35% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.29 - 9.11 (m, 1H), 8.62 - 7.86 (m, 1H), 7.44 - 7.28 (m, 1H), 6.99 - 6.91 (m, 1H), 6.91 - 6.77 (m, 1H), 6.28 - 5.87 (m, 1H), 4.78 - 4.66 (m, 1H), 4.63 - 4.36 (m, 1H), 4.24 - 4.07 (m, 1H), 4.02 - 3.89 (m, 1H), 3.77 - 3.47 (m, 3H), 3.34 - 3.17 (m, 2H), 2.56 - 2.45 (m, 1H), 2.40 - 2.28 (m, 6H), 2.25 - 2.08 (m, 1H), 2.02 - 1.92 (m, 1H), 1.89 - 1.72 (m, 2H), 1.70 - 1.36 (m, 2H), 1.16 - 0.78 (m, 6H). [0360] Step 2: (1R,2S,5S)-3-(6,7-dimethyl-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide
Figure imgf000096_0001
[0361] To a solution of (S)-methyl 2-((1R,2S,5S)-3-(6,7-dimethyl-1H-indole-2-carbonyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (94 mg, 190.06 μmol) in THF (2 mL) was added LiBH4 (9 mg, 433.24 μmol) at 0°C. The mixture was stirred at 25 °C for 1 hr. The reaction was quenched with water (10 mL) drop-wise. The resulting mixture was extracted with DCM (10 mLx3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (90 mg, crude) was obtained as a white solid, which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 9.46 - 9.21 (m, 1H), 8.10 - 7.81 (m, 1H), 7.44 - 7.32 (m, 1H), 7.00 - 6.76 (m, 2H), 6.01 - 5.74 (m, 1H), 4.73 - 4.57 (m, 1H), 4.30 - 4.22 (m, 1H), 4.08 - 3.90 (m, 2H), 3.78 - 3.74 (m, 1H), 3.62 - 3.46 (m, 1H), 3.31 - 3.16 (m, 2H), 2.57 - 2.46 (m, 1H), 2.42 - 2.33 (m, 6H), 2.13 - 1.91 (m, 2H), 1.89 - 1.74 (m, 2H), 1.73 - 1.51 (m, 3H), 1.14 - 0.76 (m, 6H) [0362] Step 3: (1R,2S,5S)-3-(6,7-dimethyl-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0363] To a solution of (1R,2S,5S)-3-(6,7-dimethyl-1H-indole-2-carbonyl)-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (80 mg, 171.46 μmol) in DCM (3 mL) was added DMP (218 mg, 514.39 μmol). The mixture was stirred at 25 °C for 10 min. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30mm×3μm;mobile phase: [water(10mM NH4HCO3)- ACN];B%: 21%-61%,11min). Compound 18 (30 mg, 60.94 μmol, 35.54% yield, 96.36% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.42 - 7.21 (m, 1H), 7.05 - 6.89 (m, 1H), 6.89 - 6.83 (m, 1H), 5.01 - 4.88 (m, 1H), 4.70 - 4.48 (m, 1H), 4.43 - 4.23 (m, 1H), 4.07 - 3.97 (m, 1H), 3.82 - 3.70 (m, 1H), 3.29 - 3.20 (m, 1H), 2.92 - 2.51 (m, 1H), 2.42 (s, 3H), 2.37 (d, J = 6.0 Hz, 3H), 2.26 - 1.97 (m, 1H), 1.93 - 1.77 (m, 1H), 1.76 - 1.60 (m, 2H), 1.59 - 1.51 (m, 1H), 1.37 - 1.27 (m, 1H), 1.18 - 0.92 (m, 6H). ESI-MS [M+H]+ calc’d for C26H32N4O4, 465.24; found, 465.4. [0364] Example 19: (1R,2S,5S)-3-(6-fluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 19)
Figure imgf000097_0001
[0365] Step 1: (S)-methyl 2-((1R,2S,5S)-3-(6-fluoro-1H-indole-2-carbonyl)-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000097_0002
[0366] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (254 mg, 705.85 μmol, HCl) and 6- fluoro-1H-indole-2-carboxylic acid (126 mg, 705.85 μmol) in DCM (5 mL) was added DIPEA (365 mg, 2.82 mmol) dropwise and HATU (402 mg, 1.06 mmol) slowly at 0°C. Then the mixture was stirred at 25°C for 3 hours. Saturated aq. NaHCO3 (10 mL) was added to the reaction mixture and the mixture was extracted with DCM (6 mL x3). The combined organic phase was washed with brine (10 mL x2), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 µm; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 23%-63%, 11 min). The title compound (190 mg, 54.09% yield) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.68 - 7.49 (m, 1H), 7.16 - 6.81 (m, 3H), 4.87 - 4.81 (m, 1H), 4.64 - 4.53 (m, 1H), 4.41 - 4.23 (m, 1H), 4.05 - 3.94 (m, 1H), 3.75 - 3.67 (m, 3H), 3.33 - 3.32 (m, 2H), 3.06 - 2.64 (m, 1H), 2.55 - 2.30 (m, 1H), 2.25 - 1.97 (m, 1H), 1.95 - 1.72 (m, 2H), 1.69 - 1.41 (m, 2H), 1.17 - 0.97 (m, 6H). [0367] Step 2: (1R,2S,5S)-3-(6-fluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000098_0001
[0368] To a solution of (S)-methyl 2-((1R,2S,5S)-3-(6-fluoro-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (160 mg, 330.22 μmol) in THF (5 mL) was added LiBH4 (22 mg, 990.67 μmol) slowly at 0°C. Then the mixture was stirred at 25°C for 1 hour. Saturated aq.NH4Cl (10 mL) was added to the reaction mixture. Then the mixture was extracted with DCM (5 mL x3). The combined organic phase was washed with brine (5 mL x2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The title compound (190 mg, crude) was obtained as a white solid. ESI-MS [M+H]+ calc’d for C24H29FN4O4, 457.22; found, 457.2. [0369] Step 3: (1R,2S,5S)-3-(6-fluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1-oxo- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0370] To a solution of (1R,2S,5S)-3-(6-fluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (96 mg, 210.29 μmol) in DCM (4 mL) was added DMP (268 mg, 630.88 μmol) slowly. Then the mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered. Saturated aq.NaHCO3 (10 mL) was added to the filtrate and the mixture was extracted with DCM (5 mL x3). The combined organic phase was washed with brine (4 mL x2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep- HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 µm; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 17%-57%, 11 min). Compound 19 (30 mg, 64.66 μmol, 30.75%
Figure imgf000098_0002
yield) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.69 - 7.46 (m, 1H), 7.16 - 6.78 (m, 3H), 4.65 - 4.38 (m, 1H), 4.33 - 3.70 (m, 3H), 3.28 - 3.23 (m, 1H), 2.99 - 2.57 (m, 1H), 2.41 - 2.27 (m, 1H), 2.10 - 1.32 (m, 6H), 1.16 - 0.95 (m, 6H). ESI-MS [M+H]+ calc’d for C24H27FN4O4, 455.20; found, 455.1. [0371] Example 20: (1R,2S,5S)-3-(4,6-difluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 20)
Figure imgf000099_0001
[0372] Step 1: (S)-methyl 2-((1R,2S,5S)-3-(4,6-difluoro-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000099_0002
[0373] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate hydrochloride (168 mg, 466.86 μmol, HCl) in DCM (5 mL) was added DIEA (181.0 mg, 1.40 mmol) and 4,6-difluoro-1H- indole-2-carboxylic acid (74 mg, 373.49 µmol) slowly at 25 °C. Then HATU (355 mg, 933.72 μmol) was added to the mixture at 0°C. The resulting mixture was stirred at 25°C for 10 h. Water (12 mL) was added and the reaction was extracted with DCM (30 mL x2). The combined organic phase was washed with sat.aq.NH4Cl (20 mL x2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30mm×3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 24%-64%, 11min). The title compound (73.1 mg, 30.24% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.98 - 9.60 (m, 1H), 9.14 - 7.80 (m, 1H), 7.02 - 6.75 (m, 2H), 6.68 - 6.49 (m, 1H), 6.02 - 5.53 (m, 1H), 4.70 - 4.64 (m, 1H), 4.62 - 4.38 (m, 1H), 4.28 - 4.19 (m, 1H), 4.15 - 3.90 (m, 1H), 3.80 - 3.64 (m, 3H), 3.45 - 3.22 (m, 2H), 2.58 - 2.34 (m, 2H), 2.25 - 2.09 (m, 1H), 2.00 - 1.77 (m, 2H), 1.74 - 1.64 (m, 2H), 1.14 -1.05 (m, 3H), 0.98 - 0.89 (m, 3H). [0374] Step 2: (1R,2S,5S)-3-(4,6-difluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide
Figure imgf000100_0001
[0375] To a solution of (S)-methyl 2-((1R,2S,5S)-3-(4,6-difluoro-1H-indole-2-carbonyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (73 mg, 145.27 μmol) in THF (3 mL) at 0°C was added LiBH4 (10 mg, 435.81 μmol) in one portion. The mixture was stirred at 25°C for 1 hour. The residue was poured into water (10 mL). The aqueous phase was extracted with DCM (10 mL x3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The title compound (93.3 mg, crude) was obtained as a white solid, which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 10.28 (brs, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.03 - 6.82 (m, 2H), 6.65 - 6.53 (m, 1H), 5.86 (brs, 1H), 4.84 - 4.56 (m, 1H), 4.33 - 4.24 (m, 1H), 4.10 - 4.01 (m, 1H), 3.97 -3.90 (m, 1H), 3.79 - 3.72 (m, 1H), 3.63 - 3.52 (m, 1H), 3.33 - 3.19 (m, 2H), 2.58 - 2.46 (m, 1H), 2.42 - 2.30 (m, 1H), 2.20 - 2.08 (m, 1H), 1.84 - 1.65 (m, 3H), 1.62 - 1.53 (m, 2H), 1.06 (s, 3H), 0.98 - 0.85 (m, 3H). [0376] Step 3: (1R,2S,5S)-3-(4,6-difluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0377] A mixture of (1R,2S,5S)-3-(4,6-difluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (70 mg, 147.52 μmol) in DCM (3 mL) was added DMP (188 mg, 442.57 µmol) and then the mixture was stirred at 25 °C for 1h under N2 atmosphere. The mixture was diluted with MeOH (3 mL) and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30mm×3μm;mobile phase: [water(10mM NH4HCO3)-ACN];B%: 10%-60%,15min) to give Compound 20 (6.5 mg, 12.94 µmol, 8.77% yield, 94.061% purity) as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.14 - 6.86 (m, 2H), 6.73 - 6.56 (m, 1H), 4.62 - 4.26 (m, 2H), 4.09 - 3.70 (m, 3H), 3.07 - 2.26 (m, 3H), 2.07 - 1.71 (m, 3H), 1.61 - 1.31 (m, 3H), 1.14 - 0.97 (m, 6H). ESI- MS [M+H]+ calc’d for C24H26F2N4O4, 473.19; found, 473.4. [0378] Example 21: (1R,2S,5S)-3-(6-chloro-7-fluoro-1H-indole-2-carbonyl)-6,6-dimethyl- N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 21)
Figure imgf000101_0001
[0379] Step 1: ethyl 6-chloro-7-fluoro-1H-indole-2-carboxylate
Figure imgf000101_0002
[0380] To a solution of (3-chloro-2-fluorophenyl) hydrazine (500 mg, 2.54 mmol, HCl) in toluene (10 mL) was added 4-methylbenzenesulfonic acid (1.31 g, 7.61 mmol) and ethyl 2- oxopropanoate (295 mg, 2.54 mmol) at 25°C. The mixture was stirred at 120°C for 12 hr. Water (30 mL) was added to the mixture and the reaction mixture was adjusted to pH~7 by sat.aq.NaHCO3.. The resulting mixture was extracted with EtOAc (10 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (Eluent of 0~5% EtOAc in PE). The title compound (192 mg, 31.31% yield) was obtained as a yellowed solid.1H NMR (400 MHz, CDCl3) δ ppm 9.09 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.22 (t, J = 2.8 Hz, 1H), 7.12 (dd, J = 2.8, 8.4 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H) [0381] Step 2: 6-chloro-7-fluoro-1H-indole-2-carboxylic acid
Figure imgf000101_0003
[0382] To a solution of ethyl 6-chloro-7-fluoro-1H-indole-2-carboxylate (190 mg, 786.28 μmol) in THF (2 mL) and H2O (2 mL) was added LiOH.H2O (66 mg, 1.57 mmol). And then the mixture was stirred at 50 °C for 1 hr. Water (30 mL) was added to the mixture and the reaction mixture was adjusted to pH~5 by aq. HCl (1 N). The resulting mixture was extracted with DCM (20 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The title compound (130 mg, crude) was obtained as a yellow solid. H NMR (400 MHz, CD3OD) δ ppm 7.41 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 3.2 Hz, 1H), 7.07 (dd, J = 6.4, 8.4 Hz, 1H). [0383] Step 3: (S)-methyl 2-((1R,2S,5S)-3-(6-chloro-7-fluoro-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000102_0001
[0384] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (168 mg, 468.18 μmol, HCl), 6- chloro-7-fluoro-1H-indole-2-carboxylic acid (100 mg, 468.18 μmol,) and DIEA (182 mg, 1.40 mmol) in DCM (3 mL) was added slowly HATU (356 mg, 936.36 μmol) at 0°C. The resulting mixture was stirred at 25°C for 10 hr. Sat.aq.NH4Cl (10 mL) was added. The resulting mixture was extracted with DCM (20 mLx3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3μm; mobile phase: [water (0.05%NH3H2O+10mM NH4HCO3)-ACN]; B%: 25%-65%, 11 min). The title compound (53 mg, 20.98% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.95 - 9.53 (m, 1H), 8.81 - 8.06 (m, 1H), 7.40 - 7.28 (m, 1H), 7.17 - 6.99 (m, 1H), 6.98 - 6.37 (m, 1H), 5.92 - 5.61 (m, 1H), 4.86 - 4.64 (m, 1H), 4.57 - 4.35 (m, 1H), 4.26 - 4.08 (m, 1H), 4.01 - 3.84 (m, 1H), 3.79 - 3.52 (m, 3H), 3.42 - 3.25 (m, 2H), 2.63 - 2.30 (m, 2H), 2.24 - 2.04 (m, 1H), 2.02 - 1.81 (m, 2H), 1.78 - 1.68 (m, 1H), 1.46 - 1.21 (m, 1H), 1.14 - 0.82 (m, 6H). [0385] Step 4: (1R,2S,5S)-3-(6-chloro-7-fluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide
Figure imgf000103_0001
[0386] To a solution of (S)-methyl 2-((1R,2S,5S)-3-(6-chloro-7-fluoro-1H-indole-2- carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (50 mg, 96.35 μmol) in THF (3 mL) was added LiBH4 (30 mg, 1.38 mmol) at 0°C. The mixture was stirred at 25°C for 1h. The reaction was quenched with water (10 mL) drop-wise. The resulting mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The title compound (33 mg, crude) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 10.55 - 9.96 (m, 1H), 8.44 - 8.13 (m, 1H), 7.42 - 7.29 (m, 1H), 7.16 - 7.01 (m, 1H), 6.99 - 6.84 (m, 1H), 6.46 - 5.86 (m, 1H), 4.88 - 4.64 (m, 1H), 4.40 - 4.21 (m, 1H), 4.10 - 3.96 (m, 1H), 3.91 - 3.73 (m, 2H), 3.71 - 3.56 (m, 1H), 3.51 - 3.48 (m 1H), 3.42 - 3.20 (m, 2H), 2.68 - 2.46 (m, 1H), 2.45 - 2.29 (m, 1H), 2.20 - 1.96 (m, 1H), 1.66 - 1.55 (m, 2H), 1.45 - 1.39 (m, 1H), 1.30 - 1.21 (m, 1H), 1.12 - 0.82 (m, 6H). [0387] Step 5: (1R,2S,5S)-3-(6-chloro-7-fluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide [0388] To a solution of (1R,2S,5S)-3-(6-chloro-7-fluoro-1H-indole-2-carbonyl)-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (30 mg, 61.11 μmol) in DCM (6 mL) was added DMP (52 mg, 122.21 μmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30mm×3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 28%-58%, 10 min). Compound 21 (1 mg, 3.27% yield, 97.76% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.49 - 7.28 (m, 1H), 7.16 - 6.88 (m, 2H), 5.01 - 4.91 (m, 1H), 4.52 - 4.28 (m, 1H), 4.02 - 3.70 (m, 2H), 3.29 - 2.97 (m, 2H), 2.70 - 2.43 (m, 1H), 2.40 - 1.98 (m, 1H), 1.86 - 1.29 (m, 5H), 1.18 - 0.92 (m, 6H). ESI-MS [M+H]+ calc’d for C24H26ClFN4O4, 489.16, found 489.3. [0389] Example 22 Synthesis of Compound 22 [0390] Step 1: methyl 2-(3-oxocyclohexyl)acetate
Figure imgf000104_0001
[0391] A mixture of methyl 2-(3-hydroxycyclohexyl)acetate (500 mg, 2.90 mmol), PCC (1.88 g, 8.71 mmol) and silica gel (1.88 g) in DCM (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 2 hr under N2 atmosphere. The mixture was filtered and the filtrate was concentrated to give crude product. The residue was purified by flash silica gel chromatography (Eluent of 25% Ethyl acetate/Petroleum ether). The title compound (450 mg, 91.07% yield) was obtained as a colorless oil.1H NMR (400 MHz, CDCl3) δ ppm 3.70 (s, 3H), 2.51 - 2.34 (m, 4H), 2.32 - 2.22 (m, 2H), 2.16 - 2.02 (m, 2H), 2.00 - 1.92 (m, 1H), 1.78 - 1.64 (m, 1H), 1.52 - 1.36 (m, 1H). [0392] Step 2: methyl 2-(3,3-difluorocyclohexyl)acetate
Figure imgf000104_0002
[0393] To a mixture of methyl 2-(3-oxocyclohexyl)acetate (450 mg, 2.64 mmol) in DCM (15 mL) was added DAST (2.98 g, 18.51 mmol, 2.45 mL) dropwise at 0°C. The mixture was stirred at 25°C for 12 hr. The mixture was quenched with saturated aqueous NaHCO3 (60 mL) at 0°C, and extracted with DCM (30 mL x3). The organic layer was dried over Na2SO4 and concentrated to give crude product. The residue was purified by flash silica gel chromatography (Eluent of 5% Ethyl acetate/Petroleum ether). The title compound (450 mg, 88.56% yield) was obtained as a colorless oil.1H NMR (400 MHz, CDCl3) δ ppm 3.61 (s, 3H), 3.01 - 2.61 (m, 1H), 2.28 - 2.19 (m, 2H), 2.17 - 1.91 (m, 3H), 1.77 - 1.63 (m, 2H), 1.48 - 1.27 (m, 1H), 1.18 - 0.92 (m, 2H). [0394] Step 3: 2-(3,3-difluorocyclohexyl)acetic acid
Figure imgf000104_0003
[0395] A mixture of methyl 2-(3,3-difluorocyclohexyl)acetate (250 mg, 1.30 mmol) and LiOH.H2O (163 mg, 3.90 mmol) in H2O (2 mL) and THF (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 C for 4 hr under N2 atmosphere. The reaction mixture was concentrated. Water (10 mL) was added and the reaction mixture was then adjusted to pH~4 by aqueous HCl (2 N). The resulting mixture was extracted with DCM (30 mL x10). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (140 mg, crude) was obtained as yellow oil, which was used to next step directly.
Figure imgf000105_0001
NMR (400 MHz, CDCl3) δ ppm 2.42 - 2.28 (m, 2H), 2.25 - 2.13 (m, 2H), 1.89 - 1.76 (m, 2H), 1.72 - 1.36 (m, 3H), 1.36 - 0.81 (m, 2H). [0396] Step 4: (2S)-methyl 2-((1R,2S,5S)-3-(2-(3,3-difluorocyclohexyl)acetyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000105_0002
[0397] To a mixture of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (255 mg, 708.63 μmol, HCl) and 2- (3,3-difluorocyclohexyl)acetic acid (126 mg, 708.63 μmol) in DCM (5 mL) was added DIEA (366 mg, 2.83 mmol) and HATU (538 mg, 1.42 mmol) at 0°C. The mixture was stirred at 25°C for 12 hr. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL), and extracted with EtOAc (10 mL x2). The organic phase was washed with brine (10 mL x3), dried over Na2SO4, filtered and concentrated to give crude product. The crude product was purified by prep-HPLC (column: Welch Ultimate XB-CN 250×50×10 µm; mobile phase: [Heptane-EtOH (0.1%NH3H2O)]; B%: 10%-37%, 10 min). The title compound (120 mg, 27.67% yield) was obtained as a white solid. ESI-MS [M+H]+ calc’d for C24H35F2N3O5, 484.25; found, 484.3. [0398] Step 5: (1R,2S,5S)-3-(2-(3,3-difluorocyclohexyl)acetyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000106_0001
[0399] To a solution of (2S)-methyl 2-((1R,2S,5S)-3-(2-(3,3-difluorocyclohexyl)acetyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (120 mg, 248.17 μmol) in THF (2 mL) was added LiBH4 (90 mg, 4.13 mmol) at 0°C. The mixture was stirred at 0°C for 1 hr. The mixture was quenched with H2O (10 mL), extracted with DCM (10 mL x3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (90 mg, 47.77% yield) was obtained which was used in the next step without further purification. ESI-MS [M+H]+ calc’d for C25H33N3O4, 456.26; found, 456.4. [0400] Step 6: (1R,2S,5S)-3-(2-(3,3-difluorocyclohexyl)acetyl)-6,6-dimethyl-N-((S)-1-oxo- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 22)
Figure imgf000106_0002
[0401] A mixture of (1R,2S,5S)-3-(2-(3,3-difluorocyclohexyl)acetyl)-N-((S)-1-hydroxy-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (90 mg, 197.57 μmol) and DMP (251 mg, 592.71 μmol) in DCM (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25°C for 0.5 hr under N2 atmosphere. The mixture was filtered and the filtrate was concentrated to give crude product. The residue was purified by prep-HPLC (column: Phenomenex C1875×30 mm×3 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50% 10 min). Compound 22 (9.1
Figure imgf000106_0003
mg, 9.45% yield, 93% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 4.58 - 4.46 (m, 1H), 4.38 - 4.28 (m, 1H), 4.08 - 3.84 (m, 2H), 3.77 - 3.55 (m, 1H), 3.30 - 3.25 (m, 1H), 2.79 - 2.51 (m, 1H), 2.44 - 1.87 (m, 8H), 1.83 - 1.24 (m, 9H), 1.09 (s, 3H), 1.02 - 0.95 (m, 3H). ESI-MS [M+H] calc d for C23H33F2N3O4, 454.24; found, 454.4. [0402] Example 23: (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-(2-phenylacetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 23)
Figure imgf000107_0001
[0403] Step 1: (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(2-(4-methylcyclohexyl)acetyl)-3- azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000107_0002
[0404] To a mixture of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (255 mg, 708.63 μmol, HCl) and 2- phenylacetic acid (100 mg, 734.50 μmol) in DCM (5 mL) was added DIEA (366 mg, 2.83 mmol) and HATU (538 mg, 1.42 mmol) at 0°C. The mixture was stirred at 25°C for 12 hr. The reaction mixture was diluted with DCM (20 mL). The combined organic phase was washed with 5% H3PO4 (10 mL) and sat.aq. NaHCO3 (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by prep-HPLC (column: Xtimate C18100×30 mm×10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 10%-50%,
Figure imgf000107_0003
40 min). The title compound (70 mg, 20.81% yield) was obtained as a yellow solid.1H NMR (400 MHz, CD3OD) δ ppm 7.37 - 7.18 (m, 5H), 4.59 - 4.53 (m, 1H), 4.35 - 4.32 (m, 1H), 3.94 - 3.88 (m, 1H), 3.79 - 3.74 (m, 3H), 3.71 - 3.57 (m, 3H), 3.30 - 3.22 (m, 2H), 2.70 - 2.57 (m, 1H), 2.39 - 2.28 (m, 1H), 2.22 - 2.13 (m, 1H), 1.88 - 1.74 (m, 2H), 1.60 - 1.43 (m, 2H), 1.09 - 1.04 (m, 3H), 0.88 - 0.75 (m, 3H). [0405] Step 2: (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6- dimethyl-3-(2-phenylacetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000108_0001
[0406] To a mixture of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(2-phenylacetyl)-3- azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (70 mg, 158.54 μmol) in THF (5 mL) was added LiBH4 (10 mg, 475.63 μmol) at 0°C under N2. The mixture was stirred at 0°C for 1hr. The mixture was quenched with H2O (10 mL), and extracted with DCM (5 mL x3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep-HPLC (column: Welch Ultimate XB-NH2250 mm×100 mm×10μm; mobile phase: [Heptane-EtOH (0.1%NH3H2O)]; B%: 5%-40%, 15 min). The title compound (10 mg, 13.73% yield, 90% purity) was obtained as a white solid. ESI-MS [M+H]+ calc’d for C23H31N3O4, 414.23; found, 414.4. [0407] Step 3: (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-3-(2-phenylacetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0408] A mixture of (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)-6,6-dimethyl-3-(2-phenylacetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (10 mg, 24.18 μmol), DMP (30 mg, 72.55 μmol) in DCM (2 mL) was degassed and purged with N2 for 3 times. And the mixture was stirred at 25 °C for 0.5 hr under N2 atmosphere. The mixture was filtered and the filtrate was concentrated to give crude product. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 15%-45%, 10 min). Compound 23 (1.7 mg, 4.01 μmol, 16.57% yield, 97% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.33 - 7.17 (m, 5H), 4.54 - 4.25 (m, 2H), 4.04 - 3.85 (m, 2H), 3.80 - 3.45 (m, 4H), 2.63 - 2.51 (m, 1H), 2.37 - 2.25 (m, 1H), 2.08 - 1.96 (m, 1H), 1.79 - 1.40 (m, 4H), 1.06 - 1.00 (m, 3H), 0.82 - 0.75 (m, 3H). ESI-MS [M+H]+ calc’d for C24H37N3O4, 412.22; found, 412.4. [0409] Example 24: (1R,2S,5S)-3-(5-fluoro-1H-indole-2-carbonyl)-N-[(1S)-1-formyl-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 24)
Figure imgf000109_0001
[0410] Compound 24 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.44 - 7.37 (m, 1H), 7.35 - 7.15 (m, 1H), 7.08 - 6.84 (m, 2H), 5.00 - 4.89 (m, 1H), 4.65 - 4.56 (m, 1H), 4.54 - 4.25 (m, 1H), 4.02 - 3.71 (m, 2H), 2.98 - 2.59 (m, 1H), 2.44 - 2.29 (m, 1H), 2.10 - 1.83 (m, 1H), 1.81 - 1.68 (m, 2H), 1.66 - 1.55 (m, 1H), 1.53 - 1.25 (m, 2H), 1.20 - 0.88 (m, 6H). ESI-MS [M+H]+ calc’d for C24H27FN4O4, 455.20; found, 455.4. [0411] Example 25: (1R,2S,5S)-3-(7-chloro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 25)
Figure imgf000109_0002
[0412] Step 1: (S)-methyl 2-((1R,2S,5S)-3-(7-chloro-1H-indole-2-carbonyl)-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate
Figure imgf000109_0003
[0413] To a solution of 7-chloro-1H-indole-2-carboxylic acid (148 mg, 754.27 μmol) in DCM (5 mL) was added T3P (719 mg, 1.13 mmol, 50% purity in EtOAc) and DIEA (389 mg, 3.02 mmol) dropwise at 0°C. The mixture was stirred at 0°C for 20 mins. Then (S)-methyl 2- ((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopiperidin- 3-yl)propanoate (282 mg, 754.27 μmol, HCl) in DCM (2 mL) was added in one portion at 0°C. The mixture was stirred at 25°C for 10 hr. The reaction mixture was poured into water (20 mL). The resulting mixture was extracted with DCM (15 mL x3). The combined organic phase was washed with sat.aq.NaHCO3 (15 mL x2) and brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm× 3 μm; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 28%-58%, 10 min). The title compound (45 mg, 9.05% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 11.37 - 7.82 (m, 1H), 7.65 - 7.50 (m, 1H), 7.33 - 7.27 (m, 2H), 7.17 - 6.93 (m, 2H), 6.36 - 5.91 (m, 1H), 4.94 - 4.47 (m, 2H), 4.42 - 4.17 (m, 1H), 4.14 - 3.87 (m, 1H), 3.80 - 3.47 (m, 3H), 3.38 - 3.06 (m, 2H), 2.52 - 2.14 (m, 2H), 2.10 - 1.39 (m, 7H), 1.16 - 0.88 (m, 6H) [0414] Step 2: (1R,2S,5S)-3-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopiperidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000110_0001
[0415] To a solution of (S)-methyl 2-((1R,2S,5S)-3-(7-chloro-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate (45 mg, 87.38 μmol) in THF (6 mL) was added LiBH4 (7 mg, 321.40 μmol) dropwise at 0°C. The mixture was stirred at 0°C for 1 hr. H2O (10 mL) was added to the reaction mixture. The resulting mixture was extracted with DCM (5 mL x3). The combined organic phase was washed with brine (5 mL), water (5 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (50 mg, 77.57% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.16 - 8.17 (m, 1H), 7.63 - 7.43 (m, 1H), 7.34 - 7.28 (m, 1H), 7.13 - 6.89 (m, 2H), 6.02 (s, 1H), 4.72 - 4.53 (m, 1H), 4.28 - 3.92 (m, 2H), 3.84 - 3.68 (m, 3H), 3.61 - 3.45 (m, 1H), 3.38 - 2.83 (m, 2H), 2.44 - 2.25 (m, 1H), 2.15 - 2.01 (m, 1H), 1.80 - 1.71 (m, 3H), 1.65 - 1.52 (m, 3H), 1.26 (m, 1H), 1.15 - 0.83 (m, 6H). [0416] Step 3: (1R,2S,5S)-3-(7-chloro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1-oxo- 3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0417] To a solution of (1R,2S,5S)-3-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy- 3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (45 mg, 92.40 μmol) in DCM (3 mL) was added DMP (118 mg, 277.21 μmol) at 25°C. The reaction mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex C18250×50 mm×10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%- 55%, 10 min). Compound 25 (3.5 mg, 7.31% yield, 93.58% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.67 - 7.47 (m, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.17 - 6.93 (m, 2H), 5.03 - 4.89 (m, 1H), 4.81 - 4.64 (m, 1H), 4.54 - 4.27 (m, 1H), 4.11 - 3.92 (m, 1H), 3.90 - 3.74 (m, 1H), 3.26 - 3.21 (m, 1H), 3.04 - 2.79 (m, 1H), 2.53 - 2.15 (m, 1H), 2.13 - 1.91 (m, 1H), 1.87 - 1.58 (m, 3H), 1.57 - 1.22 (m, 3H), 1.19 - 0.92 (m, 6H). ESI-MS [M+H]+ calc’d for C25H29ClN4O4, 485.19; found, 485.3. [0418] Example 26: (1S,3aR,6aS)-2-(1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound 26)
Figure imgf000111_0001
[0419] Step 1: (1S,3aR,6aS)-tert-butyl 1-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
Figure imgf000111_0002
[0420] To a solution of (1S,3aR,6aS)-2-(tert- butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (400 mg, 1.57 mmol) in DCM (5 mL) and DIPEA (607 mg, 4.70 mmol) was added dropwise T3P (1.50 g, 2.35 mmol, 50% purity in EtOAc) at 0°C. After addition, the mixture was stirred at the same temperature for 30 min, and then (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate (380 mg, 1.71 mmol, HCl) in DCM(5 mL) was added at 25°C. The resulting mixture was stirred at 25 C for 11.5 hrs. The reaction mixture was diluted with DCM (20 mL). The combined organic phase was washed with 5% H3PO4 (10 mL) and sat.aq. NaHCO3 (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (573 mg, 57.00% yield) was obtained as a yellow oil.1H NMR (400 MHz, CD3OD) δ ppm 4.60 - 4.45 (m, 1H), 4.12 - 3.99 (m, 1H), 3.80 - 3.71 (m, 4H), 3.68 - 3.64 (m, 1H), 3.30 - 3.21 (m, 2H), 2.78 - 2.60 (m, 2H), 2.54 - 2.32 (m, 1H), 2.25 - 1.95 (m, 2H), 1.94 - 1.58 (m, 7H), 1.53 - 1.41 (m, 10H) [0421] Step 2: (S)-methyl 2-((1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxamido)- 3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000112_0001
[0422] A mixture of (1S,3aR,6aS)-tert-butyl 1-(((S)-1-methoxy-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)- carboxylate (200 mg, 472.25 μmol) in HCl/dioxane (4M, 3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 1hr under N2 atmosphere. The mixture was concentrated to give crude product. The title compound (130 mg, crude) was obtained as a white solid. [0423] Step 3: (S)-methyl 2-((1S,3aR,6aS)-2-(1H-indole-2- carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate
Figure imgf000112_0002
[0424] To a mixture of (S)-methyl 2-((1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (130 mg, 402.00 μmol) and 1H-indole- 2-carboxylic acid (65 mg, 402.00 μmol) in DCM (2 mL) was added HATU (305 mg, 803.99 μmol) and DIEA (155 mg, 1.21 mmol, 210 μL) at 0°C. The mixture was stirred at 25°C for 2 hr. The mixture was diluted with sat.aq. NH4Cl (10 mL), and extracted with DCM (20 mL x3). The combined organic layer was dried over Na2SO4, filtered and concentrated to give crude product. The crude product was purified by prep-HPLC (column: Phenomenex Gemini- NX C1875×30 mm×3 μm; mobile phase: [water (0.05% NH3H2O+10 mM NH4HCO3)- ACN]; B%: 21%-51%, 11 min). The title compound (76 mg, 39.31% yield) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.73 - 7.53 (m, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.29 - 7.20 (m, 1H), 7.13 - 6.82 (m, 2H), 4.64 - 4.01 (m, 3H), 3.91 - 3.48 (m, 4H), 3.06 - 2.70 (m, 3H), 2.56 - 1.43 (m, 12H). [0425] Step 4: (1S,3aR,6aS)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2- (1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
Figure imgf000113_0001
[0426] To a solution of (S)-methyl 2-((1S,3aR,6aS)-2-(1H-indole-2- carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (70 mg, 150.04 μmol) in THF (5 mL) was added LiBH4 (71 mg, 3.26 mmol) at 0°C. The mixture was stirred at 0 °C for 1 hr. The mixture was quenched with H2O (5 mL), and extracted with DCM (5 mL x3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (25 mg, 19.00% yield) was obtained as a white solid. ESI-MS [M+H]+ calc’d for C24H30N4O4, 439.23; found, 439.2. [0427] Step 5: (1S,3aR,6aS)-2-(1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide [0428] To a mixture of (1S,3aR,6aS)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-2-(1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (25 mg, 57.01 μmol) in DCM (2 mL) was added DMP (72 mg, 171.03 μmol). The mixture was stirred at 25 °C for 0.5 hr. The mixture was filtered and the filtrate was concentrated to give crude product. The crude product was purified by prep- HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 17%-47%, 10 min). Compound 26 (2 mg, 4.44 μmol, 7.80% yield, 97% purity) was obtained as a yellow solid.1H NMR (400 MHz, CD3OD) δ ppm 7.72 - 7.52 (m, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.12 - 6.85 (m, 2H), 4.60 - 4.26 (m, 2H), 4.14 - 3.62 (m, 3H), 3.03 - 2.26 (m, 5H), 2.09 - 2.02 (m, 1H), 1.98 - 1.85 (m, 3H), 1.80 - 1.70 (m, 2H), 1.66 - 1.54 (m, 2H), 1.41 - 1.30 (m, 1H). ESI-MS [M+H]+ calc’d for C24H28N4O4, 437.21; found, 437.2. [0429] Example 27: (1R,2S,5S)-3-(5H-[1,3]dioxolo[4,5-f]indole-6-carbonyl)-6,6-dimethyl- N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 27)
Figure imgf000114_0001
[0430] Step 1: (S)-methyl 2-((1R,2S,5S)-3-(5H-[1,3]dioxolo[4,5-f]indole-6-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000114_0002
[0431] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (150 mg, 463.84 μmol, HCl) and DIEA (180 mg, 1.39 mmol) in DCM (10 mL) was added 5H-[1,3]dioxolo[4,5-f]indole-6- carboxylic acid (95 mg, 463.84 μmol). After addition, HATU (353 mg, 927.68 μmol) was added at 0°C. The mixture was stirred at 25 °C for 12 hr. The reaction mixture was poured into sat.aq NH4Cl (20 mL). The resulting mixture was extracted with EtOAc (20 mL x2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (224 mg, crude) was obtained as a brown solid. ESI-MS [M+H]+ calc’d for C26H30N4O7, 511.21; found, 511.2. [0432] Step 2: (1R,2S,5S)-3-(5H-[1,3]dioxolo[4,5-f]indole-6-carbonyl)-N-((S)-1-hydroxy- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide
Figure imgf000115_0001
[0433] To a solution of (S)-methyl 2-((1R,2S,5S)-3-(5H-[1,3]dioxolo[4,5-f]indole-6- carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (200 mg, 391.74 μmol) in THF (3 mL) was added LiBH4 (10 mg, 459.14 μmol) at 0°C. Then the mixture was stirred at 0°C for 1 hr. The reaction was quenched with water (10 mL) drop-wise. The resulting mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30mm×3μm;mobile phase: [water(0.05%NH3H2O+10mM NH4HCO3)-ACN];B%: 14%-54%,11min). The title compound (70 mg, 35.67% yield, 96.31% purity) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.75 - 9.63 (m, 1H), 8.10 - 7.71 (m, 1H), 7.00 - 6.90 (m, 1H), 6.87 - 6.71 (m, 2H), 6.00 - 5.92 (m, 2H), 5.92 - 5.82 (m, 1H), 4.70 - 4.56 (m, 1H), 4.26 - 4.17 (m, 1H), 4.07 - 3.98 (m, 1H), 3.90 (d, J = 10.0 Hz, 1H), 3.81 - 3.72 (m, 1H), 3.58 - 3.44 (m, 1H), 3.30 - 3.16 (m, 2H), 2.60 - 2.47 (m, 1H), 2.38 - 2.28 (m, 1H), 2.13 - 2.06 (m, 1H), 1.78 - 1.68 (m, 1H), 1.68 - 1.62 (m, 1H), 1.62 - 1.56 (m, 1H), 1.55 - 1.39 (m, 1H), 1.15 - 0.75 (m, 6H). [0434] Step 3: (1R,2S,5S)-3-(5H-[1,3]dioxolo[4,5-f]indole-6-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide [0435] To a solution of (1R,2S,5S)-3-(5H-[1,3]dioxolo[4,5-f]indole-6-carbonyl)-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (40 mg, 82.90 μmol) in DCM (10 mL) was added DMP (105 mg, 248.69 μmol, 77 μL) at 25 ℃. The mixture was stirred at 25 ℃ for 1 hr. The reaction mixture was filtered and the filtrate was concentrated to dryness directly. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30mm×3μm;mobile phase: [water(10mM NH4HCO3)-ACN];B%:10%-60%,15min). Compound 27 (3.8 mg, 6.91 μmol, 8.33% yield, 87.36% purity) was obtained as a light yellow solid.1H NMR (400 MHz, CD3OD) δ ppm 7.06 - 6.93 (m, 1H), 6.91 - 6.83 (m, 1H), 6.83 - 6.44 (m, 1H), 6.06 - 5.81 (m, 2H), 4.99 - 4.92 (m, 1H), 4.69 - 4.56 (m, 1H), 4.52 - 4.30 (m, 1H), 4.29 - 3.89 (m, 2H), 3.87 - 3.66 (m, 1H), 2.70 - 2.44 (m, 1H), 2.41 - 2.26 (m, 1H), 2.10 - 1.89 (m, 1H), 1.75 - 1.65 (m, 1H), 1.63 - 1.47 (m, 2H), 1.43 - 1.28 (m, 1H), 1.17 - 0.93 (m, 6H). ESI-MS [M+H]+ calc’d for C25H28N4O6, 481.20; found, 481.4. [0436] Example 28: (1R,2S,5S)-3-(7-chloro-4-methoxy-1H-indole-2-carbonyl)-6,6- dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane- 2-carboxamide (Compound 28)
Figure imgf000116_0001
[0437] Step 1: (2-chloro-5-methoxyphenyl)hydrazine
Figure imgf000116_0002
[0438] To a solution of 2-chloro-5-methoxyaniline (2 g, 12.69 mmol) in HCl (12 M, 10.00 mL) was added dropwise a solution of NaNO2 (1.31 g, 19.04 mmol) in H2O (10 mL) in at 0 °C. After addition, the mixture was stirred at 0°C for 30 min, and then SnCl2 (4.81 g, 25.38 mmol) was added slowly at 0°C. The resulting mixture was stirred at 0°C for 2 hr. The reaction mixture was filtered. The filtrate was adjusted to pH~10 with aq. NaOH (6 M). The resulting mixture was extracted with DCM (100 mLx3). The combined organic phase was washed with water (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash silica gel chromatography (Eluent of 0~16% EtOAc in PE). The title compound (860 mg, 34.66% yield) was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.14 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 2.8 Hz, 1H), 6.31 (dd, J = 2.8, 8.8 Hz, 1H), 3.82 (s, 3H). [0439] Step 2: ethyl 7-chloro-4-methoxy-1H-indole-2-carboxylate
Figure imgf000117_0001
[0440] To a solution of (2-chloro-5-methoxyphenyl)hydrazine (860 mg, 4.98 mmol) in toluene (10 mL) was added TsOH (2.57 g, 14.95 mmol) and ethyl 2-oxopropanoate (579 mg, 4.98 mmol) at 25°C. The mixture was stirred at 120°C for 12 hr. Water (20 mL) was added and the reaction mixture was adjusted to pH~7 by sat.aq. NaHCO3. The resulting mixture was extracted with EtOAc (50 mL x3). The combined organic phase was washed with water (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash silica gel chromatography (Eluent of 0~5% EtOAc in PE). The title compound (80 mg, 6.33% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.97 (s, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.44 (d, J = 8.0 Hz, 1H), 4.41 (q, J = 7.2 Hz, 2H), 3.94 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H). [0441] Step 3: 7-chloro-4-methoxy-1H-indole-2-carboxylic acid
Figure imgf000117_0002
[0442] To a solution of ethyl 7-chloro-4-methoxy-1H-indole-2-carboxylate (80 mg, 315.36 μmol) in THF (1 mL) and H2O (1 mL) was added LiOH.H2O (26 mg, 630.71 μmol). And then the mixture was stirred at 25 °C for 10 hr. Water (10 mL) was added and the reaction mixture was adjusted to pH~5 by aq. HCl (1 N). The resulting mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (70 mg, crude) was obtained as a yellow solid.1H NMR (400 MHz, CD3OD) δ ppm 7.24 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.52 (d, J = 8.4 Hz, 1H), 3.93 (s, 3H). [0443] Step 4: (S)-methyl 2-((1R,2S,5S)-3-(7-chloro-4-methoxy-1H-indole-2-carbonyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate
Figure imgf000118_0001
[0444] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (112 mg, 310.25 μmol, HCl), 7- chloro-4-methoxy-1H-indole-2-carboxylic acid (70 mg, 310.25 μmol,) and DIEA (120 mg, 930.74 μmol) in DCM (3 mL) was added slowly HATU (236 mg, 620.49 μmol) at 0°C. The resulting mixture was stirred at 25°C for 3 hr. The reaction mixture was concentrated. Sat.aq.NH4Cl (10 mL) was added to the residue. The resulting mixture was extracted with DCM (20 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep- HPLC (column: Phenomenex C1875×30mm×3μm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 26%-50%, 9 min). The title compound (50 mg, 27.90% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.62 - 9.35 (m, 1H), 8.29 - 7.91 (m, 1H), 7.21 - 7.12 (m, 1H), 7.11 - 6.92 (m, 1H), 6.47 - 6.35 (m, 1H), 5.85 - 5.67 (m, 1H), 4.82 - 4.63 (m, 1H), 4.60 - 4.37 (m, 1H), 4.31 - 4.09 (m, 1H), 4.08 - 3.84 (m, 4H), 3.80 - 3.50 (m, 3H), 3.41 - 3.04 (m, 2H), 2.66 - 2.50 (m, 1H), 2.49 - 2.12 (m, 2H), 2.11 - 1.81 (m, 4H), 1.15 - 0.83 (m, 6H). [0445] Step 5: (1R,2S,5S)-3-(7-chloro-4-methoxy-1H-indole-2-carbonyl)-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide
Figure imgf000118_0002
[0446] To a solution of (S)-methyl 2-((1R,2S,5S)-3-(7-chloro-4-methoxy-1H-indole-2- carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (50 mg, 94.16 μmol) in THF (3 mL) was added LiBH4 (50 mg, 2.30 mmol) at 0°C. The mixture was stirred at 25°C for 1 h. The reaction was quenched with water (10 mL) drop-wise. The resulting mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with water (5 mL), dried over anhydrous Na2SO4, filtered and concentrated. The title compound (30 mg, 41.81% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.83 - 9.29 (m, 1H), 8.24 - 7.78 (m, 1H), 7.23 - 7.12 (m, 1H), 7.12 - 6.93 (m, 1H), 6.54 - 6.34 (m, 1H), 5.90 - 5.62 (m, 1H), 4.85 - 4.57 (m, 1H), 4.55 - 4.23 (m, 1H), 4.22 - 3.81 (m, 6H), 3.80 - 3.68 (m, 1H), 3.64 - 3.47 (m, 1H), 3.37 - 3.30 (m, 1H), 2.65 - 2.16 (m, 2H), 2.09 - 1.94 (m, 2H), 1.72 - 1.53 (m, 3H), 1.12 - 0.82 (m, 6H). [0447] Step 6: (1R,2S,5S)-3-(7-chloro-4-methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide [0448] To a solution of (1R,2S,5S)-3-(7-chloro-4-methoxy-1H-indole-2-carbonyl)-N-((S)- 1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (30 mg, 59.64 μmol) in DCM (6 mL) was added DMP (76 mg, 178.93 μmol). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by prep- HPLC (column: Phenomenex C1875×30mm×3μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 22%-52%, 10min). Compound 28 (5.4 mg, 17.69% yield, 97.902% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.26 - 6.93 (m, 2H), 6.59 - 6.41 (m, 1H), 5.04 - 4.94 (m, 1H), 4.53 - 4.25 (m, 1H), 4.06 - 3.97 (m, 1H), 3.95 - 3.85 (m, 3H), 3.83 - 3.69 (m, 1H), 3.27 - 2.86 (m, 1H), 2.70 - 2.30 (m, 1H), 2.28 - 1.88 (m, 2H), 1.81 - 1.48 (m, 3H), 1.43 - 1.32 (m, 1H), 1.21 - 0.90 (m, 6H). ESI-MS [M+H]+ calc’d for C25H29ClN4O5, 501.18, found 501.3. [0449] Example 29: (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-(7-(trifluoromethyl)-1H-indole-2-carbonyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 29)
Figure imgf000119_0001
[0450] Step 1: (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(7-(trifluoromethyl)-1H-indole-2- carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000120_0001
[0451] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (255 mg, 708.63 μmol, HCl) in DCM (4 mL) was added DIEA (274 mg, 2.13 mmol) and 7-(trifluoromethyl)-1H-indole-2- carboxylic acid (163 mg, 708.63 μmol) dropwise at 0°C. Then HATU (539 mg, 1.42 mmol) was added in one portion at 0°C. The mixture was stirred at 25°C for 10 hr. The reaction mixture was poured into water (20 mL). The resulting mixture was extracted with DCM (15 mL x3). The combined organic phase was washed with sat.aq.NaHCO3 (15 mL x2) and brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 30%-60%, 10 min). The title compound (95
Figure imgf000120_0002
mg, 23.80% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.88 - 9.53 (m, 1H), 8.70 - 8.21 (m, 1H), 7.90 - 7.52 (m, 2H), 7.25 - 6.98 (m, 2H), 5.94 - 5.58 (m, 1H), 4.75 - 4.33 (m, 2H), 4.25 - 3.85 (m, 2H), 3.78 - 3.48 (m, 3H), 3.44 - 3.22 (m, 2H), 2.66 - 2.31 (m, 2H), 2.03 - 1.92 (m, 1H), 1.69 - 1.49 (m, 4H), 1.14 - 0.88 (m, 6H). [0452] Step 2: (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6- dimethyl-3-(7-(trifluoromethyl)-1H-indole-2-carbonyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide
Figure imgf000120_0003
[0453] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(7-(trifluoromethyl)-1H- indole-2-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (95 mg, 177.73 μmol) in THF (6 mL) was added LiBH4 (12 mg, 533.18 μmol) dropwise at 0°C. The mixture was stirred at 0°C for 1 hr. H2O (15 mL) was added to the reaction mixture. The resulting mixture was extracted with DCM (15 mL x3). The combined organic phase was washed with brine (15 mL), water (15 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (104 mg, crude) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 10.27 - 9.51 (m, 1H), 8.48 - 8.20 (m, 1H), 7.91 - 7.52 (m, 2H), 7.24 - 7.00 (m, 2H), 5.73 (brs, 1H), 4.74 - 3.92 (m, 3H), 3.78 - 3.74 (m, 2H), 3.63 - 3.47 (m, 2H), 3.44 - 3.23 (m, 2H), 2.67 - 2.27 (m, 2H), 2.03 - 1.84 (m, 3H), 1.75 - 1.51 (m, 2H), 1.10 - 0.89 (m, 6H). [0454] Step 3: (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-3-(7-(trifluoromethyl)-1H-indole-2-carbonyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide [0455] To a solution of (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-6,6-dimethyl-3-(7-(trifluoromethyl)-1H-indole-2-carbonyl)-3-azabicyclo[3.1.0]hexane- 2-carboxamide (100 mg, 197.43 μmol) in DCM (6 mL) was added DMP (252 mg, 592.28 μmol) at 25°C. The reaction mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 26%-56%, 10 min). Compound 29 (29.9 mg, 29.44% yield, 98.07% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.99 - 7.80 (m, 1H), 7.61 - 7.53 (m, 1H), 7.29 - 7.01 (m, 2H), 5.01 - 4.89 (m, 1H), 4.54 - 3.97 (m, 3H), 3.93 - 3.36 (m, 2H), 2.96 - 2.57 (m, 1H), 2.41 - 1.68 (m, 4H), 1.66 - 1.52 (m, 2H), 1.30 (s, 1H), 1.16 - 0.97 (m, 6H). ESI-MS [M+H]+ calc’d for C25H27F3N4O4, 505.20; found, 505.4. [0456] Example 30: (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-(4H-thieno[3,2-b]pyrrole-5-carbonyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 30)
Figure imgf000121_0001
[0457] Step 1: (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(4H-thieno[3,2-b]pyrrole-5- carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000122_0001
[0458] To a mixture of 4H-thieno[3,2-b]pyrrole-5-carboxylic acid (75 mg, 444.63 μmol) and DIEA (229 mg, 1.78 mmol) in DCM (5 mL) was added T3P (424 mg, 666.95 μmol, 50% purity in EtOAc) at 0°C. After addition, the reaction mixture was stirred at the same temperature for 30 min. The above solution was added to a solution of (S)-methyl 2- ((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2- oxopyrrolidin-3-yl)propanoate (160 mg, 444.63 μmol, HCl) in DCM (2 mL) at 0°C. Then the resulting mixture was degassed and purged with N2 for 3 times, and the mixture was stirred at 25°C for 10 hours under N2 atmosphere. The reaction mixture was concentrated. To the residue was added water (10 mL). The resulting mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: Xtimate C18150×40mm×10μm; mobile phase: [water (0.225%FA)-ACN]; B%: 30%-60%, 10 min). The title compound (70 mg, 28.98% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.74 - 9.39 (m, 1H), 8.53 - 7.52 (m, 1H), 7.23 - 7.13 (m, 1H), 6.98 - 6.70 (m, 2H), 6.04 - 5.68 (m, 1H), 4.64 - 4.26 (m, 2H), 4.14 - 3.99 (m, 1H), 3.91 - 3.81 (m, 1H), 3.70 - 3.48 (m, 3H), 3.36 - 3.16 (m, 2H), 2.59 - 2.26 (m, 2H), 2.16 - 2.04 (m, 1H), 2.02 - 1.70 (m, 2H), 1.62 - 1.54 (m, 2H), 1.05 - 0.99 (m, 3H), 0.84 (s, 3H) [0459] Step 2: (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6- dimethyl-3-(4H-thieno[3,2-b]pyrrole-5-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000122_0002
[0460] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(4H-thieno[3,2-b]pyrrole- 5-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (70 mg, 148.13 μmol) in THF (5 mL) was added LiBH4 (10 mg, 444.39 μmol) at 0°C. Then the mixture was stirred at 25°C for 2 hours under N2 atmosphere. The reaction was quenched with water (10 mL) drop-wise. The resulting mixture was extracted with DCM (10 mLx3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The crude product was used in the next step directly. The title compound (47 mg, 67.80% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.12 - 9.70 (m, 1H), 8.06 - 7.58 (m, 1H), 7.22 - 7.15 (m, 1H), 6.94 - 6.71 (m, 2H), 5.96 - 5.68 (m, 1H), 4.53 (s, 1H), 4.20 - 4.09 (m, 1H), 3.98 - 3.75 (m, 2H), 3.65 - 3.52 (m, 1H), 3.50 - 3.35 (m, 1H), 3.28 - 3.04 (m, 2H), 2.46 - 2.35 (m, 1H), 2.30 - 2.18 (m, 1H), 2.03 - 1.89 (m, 1H), 1.70 - 1.65 (m, 1H), 1.61 - 1.41 (m, 3H), 0.99 (s, 3H), 0.87 - 0.76 (m, 3H) [0461] Step 3: (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-3-(4H-thieno[3,2-b]pyrrole-5-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0462] To a solution of (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-6,6-dimethyl-3-(4H-thieno[3,2-b]pyrrole-5-carbonyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (40 mg, 89.98 μmol) in DCM (6 mL) was added DMP (77 mg, 179.96 μmol) at 25°C. The reaction mixture was stirred at 25°C for 0.5 hr. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 μm; mobile phase: [water (10 mM NH4HCO3)- ACN]; B%: 15%-45%, 8 min). Compound 30 (3.5 mg, 8.65% yield, 98.413% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.37 - 7.25 (m, 1H), 7.06 - 6.84 (m, 2H), 4.61 - 4.40 (m, 1H), 4.26 - 3.73 (m, 3H), 3.28 - 2.98 (m, 2H), 2.69 - 2.27 (m, 2H), 2.06 - 1.93 (m, 1H), 1.80 - 1.60 (m, 2H), 1.59 - 1.39 (m, 2H), 1.16 - 0.92 (m, 6H). ESI- MS [M+H]+ calc’d for C22H26N4O4S, 443.17, found 443.4. [0463] Example 31: (S)-5-(4-Methoxy-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (Compound 31)
Figure imgf000123_0001
[0464] Compound 31 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CDCl3) δ ppm 9.69 - 9.53 (m, 1H), 9.53 - 9.44 (m, 1H), 8.66 - 8.39 (m, 1H), 7.24 - 7.18 (m, 1H), 7.07 - 6.97 (m, 2H), 6.50 (m, 1H), 5.88 - 5.61 (m, 1H), 5.09 - 4.90 (m, 1H), 4.44 - 4.25 (m, 1H), 3.96 (s, 3H), 3.94 - 3.88 (m, 2H), 3.35 - 3.23 (m, 2H), 2.67 - 2.31 (m, 3H), 2.30 - 2.21 (m, 1H), 2.17 - 2.09 (m, 1H), 1.98 - 1.91 (m, 2H), 0.72 - 0.63 (m, 4H). ESI- MS [M+H] calc d for C24H28N4O5, 453.21; found, 453.2. [0465] Example 32: (1R,2S,5S)-3-(7-cyano-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 32)
Figure imgf000124_0001
[0466] Step 1: (S)-methyl 2-((1R,2S,5S)-3-(7-cyano-1H-indole-2-carbonyl)-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000124_0002
[0467] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (250 mg, 694.74 μmol, HCl), 7- cyano-1H-indole-2-carboxylic acid (129 mg, 694.74 μmol), and DIEA (269 mg, 2.08 mmol) in DCM (4 mL) was added HATU (528 mg, 1.39 mmol) slowly at 0°C. The mixture was stirred at 25°C for 3 hr. The reaction mixture was diluted with 5% H3PO4 (30 mL) and was extracted with DCM (30 mL x2). The combined organic layer was washed with 5% H3PO4 (20 mL x 3), sat.aq.NaHCO3 (20 mL x 4), water (20 mL), and brine (20 mL), and dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep- HPLC (column: Xtimate C18150×40 mm×10 μm; mobile phase: [water(10 mM NH4HCO3)- ACN]; B%: 15%-45%, 10 min). The title compound (150 mg, 43.04% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 11.84 (br s, 1H), 9.39 (br d, J = 3.6 Hz, 1H), 7.97 - 7.86 (m, 1H), 7.65 - 7.53 (m, 1H), 7.23 - 7.12 (m, 2H), 7.05 - 6.95 (m, 1H), 4.95 (s, 1H), 4.28 - 4.20 (m, 1H), 4.15 - 4.05 (m, 1H), 3.73 (s, 3H), 3.52 - 3.44 (m, 2H), 3.42 - 3.37 (m, 1H), 2.73 - 2.61 (m, 1H), 2.56 - 2.43 (m, 1H), 2.12 - 1.99 (m, 2H), 1.80 - 1.76 (m, 1H), 1.72 - 1.69 (m, 1H), 1.33 - 1.25 (m, 1H), 1.01 (s, 3H), 0.89 (s, 3H). [0468] Step 2: (1R,2S,5S)-3-(7-cyano-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000125_0001
[0469] To a solution of (S)-methyl 2-((1R,2S,5S)-3-(7-cyano-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (145 mg, 294.99 μmol) in THF (3 mL) was added LiBH4 (26 mg, 1.18 mmol) at 0°C. The mixture was stirred at 25 °C for 1 hr. The reaction was quenched with water (10 mL) drop- wise. The resulting mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (103 mg, crude) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d) δ ppm 8.02 (d, J = 7.2 Hz, 1H), 7.98 - 7.78 (m, 1H), 7.76 - 7.65 (m, 1H), 7.62 - 7.48 (m, 1H), 7.37 - 7.14 (m, 2H), 7.11 - 6.87 (m, 1H), 4.75 - 4.68 (m, 1H), 4.25 - 4.12 (m, 1H), 3.87 - 3.71 (m, 2H), 3.68 - 3.54 (m, 2H), 3.17 - 2.81 (m, 2H), 2.40 - 2.30 (m, 1H), 2.23 - 2.07 (m, 1H), 1.64 - 1.50 (m, 2H), 1.49 - 1.32 (m, 3H), 1.21 - 1.14 (m, 1H), 1.08 - 1.02 (m, 3H), 0.99 - 0.80 (m, 3H). [0470] Step 3: (1R,2S,5S)-3-(7-cyano-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0471] To a solution of (1R,2S,5S)-3-(7-cyano-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (50 mg, 107.87 μmol) in DCM (5 mL) was added DMP (137 mg, 323.61 μmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 μm; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 14%-54%,11 min). Compound 32 (15 mg, 29.08% yield, 96.51% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 8.07 - 7.83 (m, 1H), 7.73 - 7.58 (m, 1H), 7.26 - 6.99 (m, 2H), 4.67 - 4.60 (m, 1H), 4.42 - 4.26 (m, 1H), 4.09 - 3.97 (m, 1H), 3.94 - 3.67 (m, 2H), 3.28 - 2.92 (m, 1H), 2.71 - 2.28 (m, 2H), 2.12 - 1.99 (m, 1H), 1.82 - 1.52 (m, 4H), 1.22 - 0.92 (m, 6H). ESI-MS [M+H]+ calc’d for C25H27N5O4, 462.21; found, 462.1. [0472] Example 33: (1R,2S,5S)-6,6-Dimethyl-3-(7-methyl-1H-indole-2-carbonyl)-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 33)
Figure imgf000126_0001
[0473] Compound 33 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.54 - 7.32 (m, 1H), 7.09 - 6.87 (m, 3H), 5.02 - 4.96 (m, 0.5H), 4.68 - 4.62 (m, 0.5H), 4.53 - 4.27 (m, 1H), 4.08 - 3.42 (m, 3H), 3.29 - 3.23 (m, 1H), 2.90 - 2.55 (m, 1H), 2.51 (s, 3H), 2.40 - 2.29 (m, 1H), 2.24 - 1.97 (m, 1H), 1.89 - 1.67 (m, 2H), 1.62 - 1.50 (m, 1H), 1.41 - 1.26 (m, 1H), 1.17 - 0.93 (m, 6H). ESI-MS [M+H]+ calc’d for C25H30N4O4, 451.23; found, 451.4. [0474] Example 34: (1R,2S,5S)-3-(4-isopropyl-1H-indole-2-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 34)
Figure imgf000126_0002
[0475] Step 1: methyl 4-(prop-1-en-2-yl)-1H-indole-2-carboxylate
Figure imgf000126_0003
[0476] To a solution of methyl 4-bromo-1H-indole-2-carboxylate (490 mg, 1.93 mmol) and potassium trifluoro(prop-1-en-2-yl)borate (571 mg, 3.86 mmol) in dioxane (8 mL) and H2O (2 mL) was added Cs2CO3 (1.89 g, 5.79 mmol) and Pd(dppf)Cl2 (141 mg, 192.85 μmol). Then the mixture was stirred at 100°C for 10 hours under N2 atmosphere. The reaction mixture was filtered. Saturated aq.NH4Cl (20 mL) was added to the filtrate and the mixture was extracted with DCM (20 mL x2). The combined organic phase was washed with brine (20 mL x2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluent of 0-16% PE/EtOAc). The title compound (410 mg, 96.27% yield) was obtained as a white solid. ESI-MS [M+H]+ calc’d for C13H13NO2, 216.09; found, 216.1. [0477] Step 2: methyl 4-isopropyl-1H-indole-2-carboxylate
Figure imgf000127_0001
[0478] To a solution of methyl 4-(prop-1-en-2-yl)-1H-indole-2-carboxylate (400 mg, 1.86 mmol) in MeOH (10 mL) was added wet Pd/C (0.09 g, 10% purity) slowly at 25°C. Then the mixture was degassed and purged with H2 for 3 times. The mixture was stirred at 25°C for 10 hours under H2 atmosphere. The reaction mixture was filtered and the cake was wahed with MeOH (5 mL x2). The combined filtrate was concentrated in vacuo. The title compound (220 mg, 54.49% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.85 (s, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.29 - 7.26 (m, 2H), 7.03 - 7.01 (m, 1H), 3.40 - 3.32 (m, 1H), 1.38 (d, J = 7.2 Hz, 1H) [0479] Step 3: 4-isopropyl-1H-indole-2-carboxylic acid
Figure imgf000127_0002
[0480] To a solution of methyl 4-isopropyl-1H-indole-2-carboxylate (220 mg, 1.01 mmol) in THF (5 mL) and H2O (1 mL) was added LiOH.H2O (85 mg, 2.03 mL) in one portion. Then the mixture was stirred at 25°C for 10 hours. Water (10 mL) was added. Then the mixture was washed with DCM (5 mL x2). The aqueous phase was adjusted to pH = 3 with HCl (1N). The resulting mixture was extracted with DCM (6 mL x3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The title compound (220 mg, crude) was obtained as a light brown solid. ESI-MS [M+H]+ calc’d for C12H13NO2, 204.09; found, 204.1. [0481] Step 4: (S)-methyl 2-((1R,2S,5S)-3-(4-isopropyl-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000127_0003
[0482] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (169 mg, 469.64 μmol, HCl) and 4- isopropyl-1H-indole-2-carboxylic acid (95 mg, 469.64 μmol) in DCM (5 mL) was added DIPEA (243 mg, 1.88 mmol) dropwise and HATU (268 mg, 704.47 μmol) slowly at 0°C. Then the mixture was stirred at 25°C for 3 hours. Saturated aq. NaHCO3 (10 mL) was added and the mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with brine (10 mL x2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 29%-69%, 11 min). The title compound (140 mg, 53.15% yield) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.30 - 7.23 (m, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.15 - 7.07 (m, 1H), 6.96 - 6.90 (m, 1H), 4.62 - 4.54 (m, 1H), 4.37 - 4.29 (m, 1H), 4.08 - 3.97 (m, 1H), 3.77 - 3.60 (m, 3H), 3.48 - 3.36 (m, 1H), 3.30 - 3.27 (m, 3H), 2.97 - 2.62 (m, 1H), 2.48 - 2.30 (m, 1H), 2.25 - 1.95 (m, 1H), 1.91 - 1.61 (m, 3H), 1.60 - 1.26 (m, 7H), 1.18 - 0.97 (m, 6H). [0483] Step 5: (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3- (4-isopropyl-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000128_0001
[0484] To a solution of (S)-methyl 2-((1R,2S,5S)-3-(4-isopropyl-1H-indole-2-carbonyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (140 mg, 275.26 μmol) in THF (5 mL) was added LiBH4 (70 mg, 3.21 mmol) slowly at 0°C. Then the mixture was stirred at 0°C for 1 hour. Saturated aq. NH4Cl (10 mL) was added to the reaction mixture dropwise. Then the aqueous phase was extracted with DCM (10 mL x3). The combined organic phase was washed with brine (10 mL x2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The title compound (170 mg, crude) was obtained as a light yellow solid. ESI-MS [M+H]+ calc’d for C27H36N4O4, 481.27; found, 481.3. [0485] Step 6: (1R,2S,5S)-3-(4-isopropyl-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0486] To a solution of (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-3-(4-isopropyl-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (80 mg, 166.46 μmol) in DCM (4 mL) was added DMP (212 mg, 499.38 μmol) slowly. Then the mixture was stirred at 25 C for 30 minutes. The reaction mixture was filtered. Saturated aq. NaHCO3 (5 mL) was added to the filtrate and the mixture was extracted with DCM (4 mL x2). The combined organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 24%-64%, 11 min). Compound 34 (9 mg, 10.98% yield, 97.228% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.29 - 7.15 (m, 2H), 7.14 - 6.87 (m, 2H), 4.68 - 4.48 (m, 1H), 4.40 - 4.30 (m, 1H), 4.10 - 3.72 (m, 2H), 3.51 - 3.32 (m, 2H), 3.27 - 3.21 (m, 1H), 2.88 - 2.57 (m, 1H), 2.41 - 2.12 (m, 1H), 2.10 - 1.50 (m, 5H), 1.40 - 1.28 (m, 6H), 1.18 - 0.95 (m, 6H). ESI-MS [M+H]+ calc’d for C27H34N4O4, 479.26; found, 479.1. [0487] Example 35 (S)-N-((S)-4-Amino-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2- yl)-5-(1H-indole-2-carbonyl)-5-azaspiro[2.4]heptane-6-carboxamide (Compound 35)
Figure imgf000129_0001
[0488] Compound 35 was synthesized by the same procedure as Compound 50.1H NMR (400 MHz, CD3OD) δ ppm 7.69 - 7.50 (m, 1H), 7.48 - 7.40 (m, 1H), 7.27 - 7.17 (m, 1H), 7.10 - 6.82 (m, 2H), 5.35 - 4.89 (m, 1H), 4.69 - 4.46 (m, 1H), 4.41 - 4.07 (m, 1H), 4.06 - 3.82 (m, 1H), 3.79 - 3.62 (m, 1H), 2.98 - 2.60 (m, 1H), 2.58 - 2.34 (m, 1H), 2.32 - 2.13 (m, 1H), 2.11 - 1.89 (m, 2H), 1.88 - 1.49 (m, 2H), 1.46 - 1.15 (m, 1H), 0.81 - 0.57 (m, 4H). ESI-MS [M+H]+ calc’d for C24H27N5O5, 466.20; found, 466.4. [0489] Example 36: (1R,2S,5S)-3-(7-Fluoro-4-methoxy-1H-indole-2-carbonyl)-6,6- dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane- 2-carboxamide (Compound 36)
Figure imgf000130_0001
[0490] Compound 36 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.14 - 6.96 (m, 1H), 6.92 - 6.80 (m, 1H), 6.44 - 6.30 (m, 1H), 4.65 - 4.62 (m, 1H), 4.53 - 4.26 (m, 1H), 4.06 - 3.95 (m, 1H), 3.93 - 3.82 (m, 3H), 3.80 - 3.71 (m, 1H), 3.38 - 3.33 (m, 1H), 3.29 - 3.24 (m, 1H), 2.93 - 2.17 (m, 2H), 2.15 - 1.73 (m, 2H), 1.70 - 1.41 (m, 2H), 1.40 - 1.32 (m, 1H), 1.18 - 0.91 (m, 6H). ESI-MS [M+H]+ calc’d for C25H29FN4O5, 485.21; found, 485.4. [0491] Example 37: (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-((R)-2-phenylpropanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 37)
Figure imgf000130_0002
[0492] Step 1: (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-((R)-2-phenylpropanoyl)-3- azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000130_0003
[0493] To a solution of (R)-2-phenylpropanoic acid (70 mg, 469.64 μmol) and DIEA (242 mg, 1.88 mmol) in DCM (5 mL) was added dropwise T3P (448 mg, 704.47 μmol, 50% purity in EtOAc) drowise at 0°C. After addition, the mixture was stirred at the same temperature for 30 min, and then (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (169 mg, 469.64 μmol, HCl) was added at 25 C. The resulting mixture was stirred at 25 C for 11.5 hrs. The reaction mixture was diluted with DCM (30 mL). The combined organic phase was washed with 5% H3PO4 (15 mL x2), sat.aq. NaHCO3 (15 mL x2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30mm×3μm; mobile phase: [water (0.05%NH3H2O+10mM NH4HCO3)- ACN]; B%: 19%-59%, 11 min). The title compound (38 mg, 16.48% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 7.60 (d, J = 7.2 Hz, 1H), 7.27 - 7.22 (m, 5H), 5.50 (s, 1H), 4.65 - 4.58 (m, 1H), 4.30 (s, 1H), 3.87 - 3.80 (m, 1H), 3.77 (s, 3H), 3.70 - 3.60 (m, 1H), 3.40 - 3.33 (m, 3H), 2.67 - 2.44 (m, 2H), 2.27 - 2.16 (m, 1H), 2.02 - 1.84 (m, 2H), 1.45 - 1.39 (m, 5H), 0.94 (s, 3H), 0.41 (s, 3H). [0494] Step 2: (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6- dimethyl-3-((R)-2-phenylpropanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000131_0001
[0495] To a mixture of methyl (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-((R)-2- phenylpropanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (35 mg, 76.83 μmol) in THF (2 mL) was added LiBH4 (5 mg, 230.49 μmol) at 0°C under N2. The mixture was stirred at 0°C for 1 hr. The mixture was quenched with H2O (2 mL), extracted with DCM (5 mL x3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was used to next step directly. The title compound (36 mg, 83.29% yield) was obtained as a white solid. ESI-MS [M+H]+ calc’d for C24H33N3O4428.25, found 428.2. [0496] Step 3: (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-3-((R)-2-phenylpropanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0497] To a mixture of (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-6,6-dimethyl-3-((R)-2-phenylpropanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (30 mg, 70.17 μmol) in DCM (2 mL) was added DMP (89 mg, 210.51 μmol). The mixture was stirred at 25 °C for 0.5 hr. The mixture was filtered and the filtrate was concentrated to give crude product. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30mm×3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 24%-54%, 10 min). Compound 37 (8.6 mg, 28.51% yield) was obtained as a white solid. H NMR (400 MHz, CD3OD) δ ppm 7.35 - 7.22 (m, 5H), 4.63 - 4.48 (m, 1H), 4.27 - 4.22 (m, 1H), 4.08 - 3.98 (m, 1H), 3.95 - 3.87 (m, 1H), 3.81 (q, J = 6.8 Hz, 1H), 3.31 - 3.29 (m, 2H), 2.74 - 2.61 (m, 1H), 2.47 - 2.32 (m, 1H), 2.11 - 1.99 (m, 1H), 1.82 - 1.54 (m, 2H), 1.47 - 1.38 (m, 2H), 1.38 - 1.33 (m, 3H), 0.97 - 0.92 (m, 3H), 0.46 - 0.38 (m, 3H). ESI-MS [M+H]+ calc’d for C24H31N3O4426.23, found 426.2. [0498] Example 38: (2S,4S)-4-Cyclohexyl-1-(4-fluoro-1H-indole-2-carbonyl)-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 38)
Figure imgf000132_0001
[0499] Compound 38 was synthesized by the same procedure as Compound 2. 1H NMR (400 MHz, CD3OD) δ ppm 7.32 - 7.25 (m, 1H), 7.24 - 7.15 (m, 1H), 7.12 - 6.87 (m, 1H), 6.84 - 6.68 (m, 1H), 5.17 - 4.91 (m, 1H), 4.85 - 4.24 (m, 3H), 4.19 - 3.92 (m, 1H), 3.92 - 3.56 (m, 1H), 3.11 - 2.32 (m, 3H), 2.24 - 1.94 (m, 3H), 1.85 - 1.49 (m, 7H), 1.38 - 0.97 (m, 6H). ESI-MS [M+H]+ calc’d for C27H33FN4O4, 497.25; found, 497.4. [0500] Example 39: (1R,2S,5S)-3-(7-fluoro-4-isopropyl-1H-indole-2-carbonyl)-6,6- dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane- 2-carboxamide (Compound 39)
Figure imgf000132_0002
[0501] Step 1: 2-fluoro-5-(prop-1-en-2-yl)aniline
Figure imgf000133_0001
[0502] To a solution of 5-bromo-2-fluoroaniline (5.0 g, 26.3 mmol) and 4,4,5,5- tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (5.31 g, 78.9 mmol) in dioxane (60 mL) and H2O (12 mL) was added Cs2CO3 (25.7 g, 78.9 mmol) and Pd(dppf)Cl2 (963 mg, 1.32 mmol). The mixture was stirred at 100 °C for 12 hr under N2. H2O (20 mL) was added. The reaction mixture was filtered and the cake was washed with DCM (10 mL x2). The filtrate was extracted with DCM (20 mL x3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluent of 0~20% PE/EtOAc). The title compound (2.88 g, 72.40% yield) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 6.99 - 6.86 (m, 2H), 6.82 - 6.75 (m, 1H), 5.26 (s, 1H), 5.02 (s, 1H), 2.10 (s, 3H). [0503] Step 2: 2-fluoro-5-isopropylaniline
Figure imgf000133_0002
[0504] To a solution of 2-fluoro-5-(prop-1-en-2-yl)aniline (2.88 g, 19.1 mmol) in MeOH (50 mL) was added Pd/C (1.0 g, 10 % purity). The mixture was stirred at 20 °C under H2 (30 psi) for 10 hr. The reaction mixture was filtered and the filtrate was concentrated to give a crude product. The title compound (2.1 g, 71.96% yield) was obtained as red oil.1H NMR (400 MHz, CDCl3) δ ppm 6.85 - 6.76 (m, 1H), 6.64 (dd, J = 8.8, 2.0 Hz, 1H), 6.55 - 6.51 (m, 1H), 2.86 - 2.69 (m, 1H), 1.20 (d, J = 6.8 Hz, 6H). [0505] Step 3: (2-fluoro-5-isopropylphenyl)hydrazine
Figure imgf000133_0003
[0506] To a solution of 2-fluoro-5-isopropylaniline (1 g, 6.53 mmol) in HCl (12 M, 10 mL) was added a solution of NaNO2 (675 mg, 9.79 mmol) in H2O (10 mL) at 0°C. The mixture was stirred at 0 °C for 0.5 hr. SnCl2.2H2O (2.95 g, 13.1 mmol) was added and the mixture was stirred at 0 C for 2 h. The reaction mixture was adjusted to pH~11 by NaOH (6 M). The resulting mixture was extracted with EtOAc (10 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 0~10% EtOAc in PE). The title compound (671 mg, 61.11% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 7.04 - 6.97 (m, 1H), 6.90 - 6.82 (m, 1H), 6.52 - 6.39 (m, 2H), 3.98 (s, 2H), 2.34 - 2.26 (m, 1H), 1.16 (d, J = 6.8 Hz, 6H). [0507] Step 4: ethyl 7-fluoro-4-isopropyl-1H-indole-2-carboxylate
Figure imgf000134_0001
[0508] To a solution of (2-fluoro-5-isopropylphenyl)hydrazine (671 mg, 3.99 mmol) in toluene (5 mL) was added ethyl 2-oxopropanoate (926 mg, 7.89 mmol) and TsOH (2.06 g, 12.0 mmol) at 25 °C. The mixture was stirred at 120°C for 12 hr. Water (10 mL) was added and the reaction mixture was adjusted to pH~7 by sat.aq.NaHCO3. The resulting mixture was extracted with EtOAc (10 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (Eluent of 0~10% EtOAc in PE. The title compound (251 mg, 25.24% yield) was obtained as an off-white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.02 (br s, 1H), 7.26 (dd, J=2.4, 3.2 Hz, 1H), 6.93 - 6.85 (m, 1H), 6.84 - 6.78 (m, 1H), 4.36 (q, J = 7.2 Hz, 2H), 3.33 - 3.13 (m, 1H), 1.36 (t, J = 7.2 Hz, 3H) [0509] Step 5: 7-fluoro-4-isopropyl-1H-indole-2-carboxylic acid
Figure imgf000134_0002
[0510] To a solution of ethyl 7-fluoro-4-isopropyl-1H-indole-2-carboxylate (200 mg, 802.31 μmol) in THF (2 mL) and H2O (2 mL) was added LiOH.H2O (67 mg, 1.60 mmol). And the mixture was stirred at 25°C for 10 hr. Water (10 mL) was added and the reaction mixture was adjusted to pH~5 by aq. HCl (1 N). The resulting mixture was extracted with DCM (20 mL x3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vauco. The title compound (100 mg, crude) was obtained as a yellow solid. H NMR (400 MHz, CD3OD) δ ppm 7.29 (d, J = 3.2 Hz, 1H), 6.96 - 6.82 (m, 2H), 3.39 - 3.32 (m, 1H), 1.35 (d, J = 7.2 Hz, 6H). [0511] Step 6: (S)-methyl 2-((1R,2S,5S)-3-(7-fluoro-4-isopropyl-1H-indole-2-carbonyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate
Figure imgf000135_0001
[0512] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (163 mg, 452.02 μmol, HCl), 7- fluoro-4-isopropyl-1H-indole-2-carboxylic acid (100 mg, 452.02 μmol) and DIEA (175 mg, 1.36 mmol) in DCM (3 mL) was added slowly HATU (344 mg, 904.05 μmol) at 0°C. The resulting mixture was stirred at 25°C for 3 hr. Sat.aq.NH4Cl (10 mL) was added to the residue. The resulting mixture was extracted with DCM (20 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex C18 75×30 mm×3 μm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 34%-64%, 10 min). The title compound (45 mg, 12.87% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.79 (s, 1H), 8.62 - 7.90 (m, 1H), 7.08 - 6.97 (m, 1H), 6.97 - 6.76 (m, 2H), 6.19 - 5.80 (m, 1H), 4.78 - 4.64 (m, 1H), 4.60 - 4.37 (m, 1H), 4.36 - 4.12 (m, 1H), 4.07 - 3.90 (m, 1H), 3.77 - 3.40 (m, 3H), 3.38 - 3.07 (m, 3H), 2.67 - 2.29 (m, 2H), 2.26 - 2.12 (m, 1H), 1.94 - 1.72 (m, 4H), 1.40 - 1.26 (m, 6H), 1.15 - 0.86 (m, 6H). [0513] Step 7: (1R,2S,5S)-3-(7-fluoro-4-isopropyl-1H-indole-2-carbonyl)-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide
Figure imgf000136_0001
[0514] To a solution of (S)-methyl 2-((1R,2S,5S)-3-(7-fluoro-4-isopropyl-1H-indole-2- carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (45 mg, 85.45 μmol) in THF (3 mL) was added LiBH4 (6 mg, 256.36 μmol) at 0°C. The mixture was stirred at 25°C for 1 h. The reaction was quenched with water (10 mL) drop-wise. The resulting mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The title compound (50 mg, crude) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 10.17 - 9.43 (m, 1H), 9.03 - 7.87 (m, 1H), 7.10 - 6.75 (m, 3H), 6.56 - 5.67 (m, 1H), 5.04 - 4.60 (m, 1H), 4.57 - 4.22 (m, 1H), 4.18 - 3.77 (m, 3H), 3.65 - 3.49 (m, 1H), 3.44 - 3.21 (m, 3H), 2.61 - 2.48 (m, 1H), 2.45 - 2.31 (m, 1H), 2.13 - 1.97 (m, 1H), 1.85 - 1.75 (m, 2H), 1.49 - 1.25 (m, 8H), 1.12 - 0.85 (m, 6H). [0515] Step 8: (1R,2S,5S)-3-(7-fluoro-4-isopropyl-1H-indole-2-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide [0516] To a solution of (1R,2S,5S)-3-(7-fluoro-4-isopropyl-1H-indole-2-carbonyl)-N-((S)- 1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (50 mg, 100.28 μmol) in DCM (5 mL) was added DMP (128 mg, 300.85 μmol). The mixture was stirred at 25°C for 0.5 hr. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex C1875×30 mm×3 µm; mobile phase: [water (NH4HCO3)- ACN]; B%: 28%-58%, 10 min). Compound 39 (7.7 mg, 14.88% yield, 96.239% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.15 (d, J = 3.2 Hz, 1H), 6.96 - 6.79 (m, 2H), 4.42 - 4.29 (m, 1H), 4.09 - 3.94 (m, 1H), 3.94 - 3.66 (m, 1H), 3.50 - 3.34 (m, 1H), 3.29 - 3.12 (m, 3H), 2.96 - 2.56 (m, 1H), 2.43 - 2.26 (m, 1H), 2.13 - 1.91 (m, 1H), 1.86 - 1.67 (m, 2H), 1.66 - 1.50 (m, 2H), 1.49 - 1.23 (m, 6H), 1.22 - 0.86 (m, 6H). ESI-MS [M+H]+ calc’d for C27H33FN4O4, 497.25; found, 497.4. [0517] Example 40: (1R,2S,5S)-6,6-Dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-(2-(5,6,7,8-tetrahydronaphthalen-2-yl)acetyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound
Figure imgf000137_0001
[0518] Compound 40 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.06 - 6.75 (m, 3H), 4.53 - 4.42 (m, 1H), 4.35 - 4.22 (m, 1H), 4.04 - 3.72 (m, 2H), 3.59 - 3.50 (m, 2H), 3.27 - 3.10 (m, 2H), 2.81 - 2.66 (m, 4H), 2.65 - 2.50 (m, 1H), 2.37 - 2.22 (m, 1H), 2.08 - 1.91 (m, 1H), 1.80 - 1.76 (m, 3H), 1.74 - 1.22 (m, 5H), 1.11 - 0.65 (m, 6H). ESI-MS [M+H]+ calc’d for C27H35N3O4, 466.26; found, 466.4. [0519] Example 41: (1R,2S,5S)-3-(4-Cyclopropyl-1H-indole-2-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 41)
Figure imgf000137_0002
[0520] Compound 41 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.25 - 7.04 (m, 3H), 6.68 - 6.55 (m, 1H), 5.05 - 4.91 (m, 1H), 4.78 - 4.63 (m, 1H), 4.53 - 4.32 (m, 1H), 4.05 - 3.94 (m, 1H), 3.89 - 3.67 (m, 1H), 3.29 - 3.23 (m, 1H), 2.82 - 2.57 (m, 1H), 2.41 - 2.25 (m, 1H), 2.20 - 2.04 (m, 1H), 1.88 - 1.70 (m, 2H), 1.61 - 1.51 (m, 1H), 1.44 - 1.20 (m, 2H), 1.17 - 1.11 (m, 4H), 1.07 - 1.00 (m, 2H), 1.05 - 0.98 (m, 2H), 0.92 - 0.58 (m, 2H). ESI-MS [M+H]+ calc’d for C27H32N4O4, 477.24; found, 477.4. [0521] Example 42: (1R,2S,5S)-3-(6-Chloro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 42)
Figure imgf000138_0001
[0522] Compound 42 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.66 - 7.47 (m, 1H), 7.46 - 7.42 (m, 1H), 7.09 - 6.87 (m, 2H), 4.99 - 4.89 (m, 1H), 4.53 - 4.37 (m, 1H), 4.33 - 3.94 (m, 2H), 3.81 - 3.69 (m, 1H), 3.29 - 3.22 (m, 1H), 3.01 - 2.57 (m, 1H), 2.42 - 2.28 (m, 1H), 2.11 - 1.83 (m, 1H), 1.82 - 1.66 (m, 2H), 1.62 - 1.52 (m, 1H), 1.47 - 1.32 (m, 1H), 1.18 - 0.88 (m, 6H). ESI-MS [M+H]+ calc’d for C24H27ClN4O4, 471.17; found, 471.4. [0523] Example 43: (1R,2S,5S)-3-(4-Chloro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 43)
Figure imgf000138_0002
[0524] Compound 43 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.38 (dd, J = 4.4, 8.4 Hz, 1H), 7.22 - 7.14 (m, 1H), 7.12 - 6.89 (m, 2H), 5.02 - 4.89 (m, 1H), 4.55 - 4.39 (m, 1H), 4.36 - 3.92 (m, 2H), 3.83 - 3.68 (m, 1H), 3.29 - 3.22 (m, 1H), 2.92 - 2.20 (m, 2H), 2.11 - 1.93 (m, 1H), 1.86 - 1.51 (m, 3H), 1.44 - 1.26 (m, 1H), 1.17 - 0.95 (m, 6H). ESI-MS [M+H]+ calc’d for C24H27ClN4O4, 471.17; found, 471.3. [0525] Example 44: (1R,2S,5S)-3-(5,7-Dichloro-1H-indole-2-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 44)
Figure imgf000139_0001
[0526] Compound 44 was synthesized by the same procedure as Compound 83.1H NMR (400 MHz, CD3OD) δ ppm 7.66 - 7.48 (m, 1H), 7.32 - 7.26 (m, 1H), 7.11 - 6.88 (m, 1H), 4.96 - 4.88 (m, 1H), 4.54 - 4.37 (m, 1H), 4.31 - 4.01 (m, 1H), 3.90 - 3.71 (m, 1H), 3.28 - 2.98 (m, 1H), 2.67 - 2.49 (m, 1H), 2.38 - 1.98 (m, 1H), 1.86 - 1.23 (m, 6H), 1.18 - 0.95 (m, 6H). ESI-MS [M+H]+ calc’d for C24H26Cl2N4O4, 505.13; found, 505.3. [0527] Example 45: (1R,2S,5S)-3-(1-(3-Chlorophenyl) cyclopropanecarbonyl)-N-((S)-4- (cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (Compound 45)
Figure imgf000139_0002
[0528] Compound 45 was synthesized by the same procedure as Compound 119.1H NMR (400 MHz, CD3OD) δ ppm 7.40 - 7.09 (m, 4H), 4.62 - 4.11 (m, 2H), 3.67 - 3.54 (m, 1H), 3.41 - 3.32 (m, 2H), 3.29 - 3.15 (m, 1H), 2.80 - 2.55 (m, 2H), 2.53 - 2.30 (m, 1H), 2.14 - 1.57 (m, 3H), 1.48 - 1.40 (m, 2H), 1.39 - 1.08 (m, 4H), 1.05 - 0.92 (m, 3H), 0.85 - 0.46 (m, 7H). ESI-MS [M+H]+ calc’d for C29H35ClN4O5, 555.23; found, 555.4. [0529] Example 46: (S)-5-(7-cyano-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (Compound 46)
Figure imgf000139_0003
[0530] Step 1: (S)-methyl 2-((S)-5-(7-cyano-1H-indole-2-carbonyl)-5- azaspiro[2.4]heptane-6-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000140_0001
[0531] To a solution of (S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-((S)-5- azaspiro[2.4]heptane-6-carboxamido)propanoate (170 mg, 491.58 μmol, HCl) and DIEA (191 mg, 1.47 mmol) in DCM (10 mL) was added 7-cyano-1H-indole-2-carboxylic acid (92 mg, 491.58 μmol). After addition, HATU (374 mg, 983.17 μmol) was added at 0°C. The mixture was stirred at 25°C for 12 hr. The reaction mixture was poured into sat.aq NH4Cl (10 mL). The resulting mixture was extracted with EtOAc (10 mL x2). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (480 mg, crude) was obtained as a light yellow solid. ESI-MS [M+H]+ calc’d. for C25H27N5O5, 478.20, found 478.1. [0532] Step 2: (S)-5-(7-cyano-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide
Figure imgf000140_0002
[0533] To a solution of (S)-methyl 2-((S)-5-(7-cyano-1H-indole-2-carbonyl)-5- azaspiro[2.4]heptane-6-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (230 mg, 481.66 μmol) in THF (3 mL) was added LiBH4 (40 mg, 1.84 mmol) at 0°C. Then the mixture was stirred at 25°C for 10 hr. The reaction was quenched with water (10 mL) drop-wise. The resulting mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 10%-40%, 10min). The title compound (28 mg, 12.74% yield) was obtained as a white solid.1H NMR (400MHz CDCl3) δ ppm 12.07 (s, 1H), 9.27 (d, J = 3.6 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.61 - 7.53 (d, J = 6.8 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.13 (s, 1H), 7.04 - 6.98 (m, 1H), 5.13 (q, J = 4.4 Hz, 1H), 3.93 - 3.84 (m, 1H), 3.82 - 3.70 (m, 2H), 3.64 - 3.42 (m, 3H), 3.28 (d, J = 10.0 Hz, 1H), 2.62 - 2.44 (m, 2H), 2.33 - 2.24 (m, 1H), 2.10 - 1.87 (m, 3H), 1.78 - 1.72 (m, 1H), 0.75 - 0.38 (m, 4H). [0534] Step 3: (S)-5-(7-cyano-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin- 3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide [0535] To a solution of (S)-5-(7-cyano-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (24 mg, 53.39 μmol) in DCM (4 mL) was added DMP (68 mg, 160.18 μmol) at 25 ℃. The mixture was stirred at 25 ℃ for 1 hr. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30mm×3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 9%-39%, 10min). Compound 46 (1.8 mg, 7.33% yield, 97.33% purity) was obtained as a white solid. 1H NMR (400MHz, CD3OD) δ ppm 8.10 - 7.80 (m, 1H), 7.73 - 7.61 (m, 1H), 7.28 - 6.99 (m, 2H), 4.52 - 4.29 (m, 1H), 4.11 - 3.68 (m, 3H), 3.30 - 3.00 (m, 2H), 2.72 - 2.37 (m, 2H), 2.28 - 1.97 (m, 3H), 1.88 - 1.57 (m, 2H), 0.84 - 0.56 (m, 4H). ESI-MS [M+H]+ calc’d. for C24H25N5O4, 448.19, found 448.4. [0536] Example 47: (S)-5-(1H-Indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (Compound 47)
Figure imgf000141_0001
[0537] Compound 47 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.69 - 7.51 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.29 - 7.16 (m, 1H), 7.11 - 6.85 (m, 2H), 5.27 - 5.11 (m, 1H), 4.52 - 4.31 (m, 1H), 4.11 - 3.83 (m, 2H), 3.79 - 3.63 (m, 1H), 2.76 - 2.31 (m, 2H), 2.28 - 2.13 (m, 1H), 2.12 - 1.95 (m, 2H), 1.94 - 1.69 (m, 1H), 1.68 - 1.31 (m, 2H), 0.87 - 0.54 (m, 4H). ESI-MS [M+H]+ calc’d for C23H26N4O4, 423.20; found, 423.4. [0538] Example 48: (1R,2S,5S)-6,6-dimethyl-3-(2-methyl-2-phenylpropanoyl)-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 48)
Figure imgf000142_0001
[0539] Step 1: (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(2-methyl-2-phenylpropanoyl)-3- azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000142_0002
[0540] To a solution of 2-methyl-2-phenylpropanoic acid (127 mg, 778.94 μmol) in DCM (3 mL) was added (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (229 mg, 708.13 μmol, HCl), DIEA (389 mg, 3.02 mmol) and HATU (269 mg, 708.13 μmol). The mixture was stirred at 20°C for 5 hr. The reaction mixture was poured into water (20 mL). The resulting mixture was extracted with DCM (15 mL x3). The combined organic phase was washed with sat.aq.NaHCO3 (15 mL x2) and brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: C18-6100×30 mm×5 μm; mobile phase: [water(FA)-ACN]; B%: 42%-72%, 8min). The title compound (71 mg, 19.97% yield) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 7.33 - 7.30 (m, 2H), 7.24 - 7.21 (m, 2H), 7.19 - 7.12 (m, 1H), 5.78 (s, 1H), 4.70 - 4.61 (m, 1H), 4.38 (s, 1H), 3.76 (s, 3H), 3.46 - 3.30 (m, 2H), 3.10 - 3.01 (m, 1H), 2.81 (d, J = 10.8 Hz, 1H), 2.62 - 2.46 (m, 2H), 2.22 - 2.15 (m, 1H), 2.00 - 1.89 (m, 2H), 1.60 - 1.47 (m, 6H), 1.36 (d, J = 7.6 Hz, 1H), 1.25 - 1.19 (m, 1H), 0.91 (s, 3H), 0.72 (s, 3H). [0541] Step 2: (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6- dimethyl-3-(2-methyl-2-phenylpropanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000143_0001
[0542] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(2-methyl-2- phenylpropanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (60 mg, 127.78 μmol) in THF (3 mL) was added LiBH4 (13 mg, 638.88 μmol) at 0°C. The mixture was stirred at 0 °C for 1 hr. The mixture was quenched with H2O (2 mL), extracted with DCM (5 mL x3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was used to next step directly. The title compound (40 mg, 42.54% yield) was obtained as a white solid. ESI-MS [M+H]+ calc’d for C25H35N3O4, 442.26; found, 442.3. [0543] Step 3: (1R,2S,5S)-6,6-dimethyl-3-(2-methyl-2-phenylpropanoyl)-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0544] A mixture of (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)-6,6-dimethyl-3-(2-methyl-2-phenylpropanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (40 mg, 90.59 μmol), DMP (115 mg, 271.76 μmol) in DCM (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 0.5 hr under N2 atmosphere. The mixture was filtered and the filtrate was concentrated. The residue was purified by prep- HPLC (column: Phenomenex C1875×30 mm×3 µm; mobile phase: [water (NH4HCO3)- ACN]; B%: 24%-54%, 10 min). Compound 48 (1.2 mg, 2.83% yield, 94% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.42 - 7.22 (m, 5H), 4.52 - 4.38 (m, 1H), 4.12 - 3.92 (m, 1H), 3.39 - 3.36 (m, 1H), 3.23 - 3.14 (m, 1H), 2.85 - 2.79 (m, 1H), 2.77 - 2.62 (m, 1H), 2.50 - 2.36 (m, 1H), 2.15 - 2.00 (m, 1H), 1.87 - 1.74 (m, 1H), 1.71 - 1.59 (m, 1H), 1.54 (s, 3H), 1.48 (s, 3H), 1.41 - 1.24 (m, 3H), 0.96 (s, 3H), 0.75 (s, 3H). ESI- MS [M+H]+ calc’d for C25H33N3O4, 440.25; found, 440.3. [0545] Example 49: (1R,2S,5S)-3-(7-chloro-4-fluoro-1H-indole-2-carbonyl)-6,6-dimethyl- N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 49)
Figure imgf000144_0001
[0546] Step 1: ethyl 7-chloro-4-fluoro-1H-indole-2-carboxylate
Figure imgf000144_0002
[0547] To a solution of (2-chloro-5-fluorophenyl)hydrazine (2 g, 10.15 mmol, HCl) in toluene (15 mL) was added ethyl 2-oxopropanoate (1.18 g, 10.15 mmol, 1.12 mL) and TsOH (5.24 g, 30.45 mmol) at 25°C. The mixture was stirred at 120°C for 12 hr. Water (20 mL) was added and the reaction mixture was adjusted to pH~7 by sat.aq. NaHCO3. The resulting mixture was extracted with EtOAc (10 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 0~9% Ethylacetate/Petroleum ether). The title compound (200 mg, 2.72% yield) was obtained as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 9.07 (br s, 1H), 7.34 - 7.31 (m, 1H), 7.26 - 7.22 (m, 1H), 6.83 - 6.75 (m, 1H), 4.45 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H). [0548] Step 2: 7-chloro-4-fluoro-1H-indole-2-carboxylic acid
Figure imgf000144_0003
[0549] To a solution of ethyl 7-chloro-4-fluoro-1H-indole-2-carboxylate (300 mg, 1.24 mmol) in THF (5 mL) and H2O (5 mL) was added LiOH.H2O (105 mg, 2.48 mmol) in one portion. The mixture was stirred at 50°C for 1 hr. The reaction mixture was adjusted to pH~3 with aq. HCl (1 N). H2O (15 mL) was added to the reaction mixture. The resulting mixture was extracted with DCM (20 mL x3). The combined organic phase was washed with brine (20 mL), water (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The title compound (230 mg, 81.13% yield) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d) δ ppm 13.33 (br s, 1H), 12.38 (br s, 1H), 7.34 - 7.29 (m, 1H), 7.20 (d, J = 2.4 Hz, 1H), 6.95 - 6.87 (m, 1H). [0550] Step 3: (S)-methyl 2-((1R,2S,5S)-3-(7-chloro-4-fluoro-1H-indole-2-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000145_0001
[0551] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (255 mg, 708.63 μmol, HCl) in DCM (5 mL) was added DIEA (275 mg, 2.13 mmol) and 7-chloro-4-fluoro-1H-indole-2- carboxylic acid (152 mg, 708.63 μmol) at 0°C. Then HATU (539 mg, 1.42 mmol) was added in one portion at 0°C. The mixture was stirred at 25°C for 10 hr. The reaction mixture was poured into water (20 mL). The resulting mixture was extracted with DCM (15 mL x3). The combined organic phase was washed with sat.aq.NaHCO3 (15 mL x2) and brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: Xtimate C18150×40 mm×10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 30%-60%, 15 min). The title compound (108.5 mg, 28.63% yield) was obtained as a brown solid.1H NMR (400 MHz, CDCl3) δ ppm 9.75 - 8.96 (m, 1H), 8.17 - 7.53 (m, 1H), 7.23 - 7.13 (m, 1H), 7.08 - 6.91 (m, 1H), 6.80 - 6.52 (m, 1H), 5.84 - 5.53 (m, 1H), 4.97 - 4.29 (m, 2H), 4.27 - 3.82 (m, 2H), 3.78 - 3.48 (m, 3H), 3.42 - 3.29 (m, 2H), 2.63 - 2.10 (m, 3H), 2.03 - 1.82 (m, 2H), 1.71 - 1.65 (m, 1H), 1.52 - 1.25 (m, 1H), 1.12 - 0.91 (m, 6H). [0552] Step 4: (1R,2S,5S)-3-(7-chloro-4-fluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide
Figure imgf000145_0002
[0553] To a solution of (S)-methyl 2-((1R,2S,5S)-3-(7-chloro-4-fluoro-1H-indole-2- carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (107 mg, 206.18 μmol) in THF (8 mL) was added LiBH4 (13 mg, 618.54 μmol) dropwise at 0°C. The mixture was stirred at 0°C for 1 hr. H2O (15 mL) was added to the reaction mixture. The resulting mixture was extracted with DCM (15 mL x3). The combined organic phase was washed with brine (15 mL), water (15 mL), dried over anhydrous Na2SO4, filtered and concentrated. The title compound (110 mg, 88.39% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 10.05 - 9.44 (m, 1H), 8.67 - 7.73 (m, 1H), 7.26 - 7.14 (m, 1H), 7.10 - 6.97 (m, 1H), 6.90 - 6.49 (m, 1H), 5.77 - 5.46 (m, 1H), 4.95 - 4.48 (m, 1H), 4.40 - 4.23 (m, 1H), 4.07 - 3.94 (m, 1H), 3.86 - 3.81 (m, 1H), 3.78 - 3.75 (m, 1H), 3.60 - 3.52 (m, 1H), 3.41 - 3.22 (m, 2H), 2.63 - 2.27 (m, 2H), 2.15 - 1.97 (m, 1H), 1.74 - 1.64 (m, 2H), 1.44 (s, 1H), 1.33 - 1.20 (m, 1H), 1.11 - 0.91 (m, 6H). [0554] Step 5: (1R,2S,5S)-3-(7-chloro-4-fluoro-1H-indole-2-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide [0555] To a solution of (1R,2S,5S)-3-(7-chloro-4-fluoro-1H-indole-2-carbonyl)-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (55 mg, 112.03 μmol) in DCM (5 mL) was added DMP (143 mg, 336.08 μmol) at 25°C. The reaction mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered. The filtrate was concentrated. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 μm; mobile phase: [water (10 mM NH4HCO3)- ACN]; B%: 25%-55%, 10 min). Compound 49 (8.2 mg, 14.88% yield, 99.412% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.38 - 7.17 (m, 1H), 7.16 - 6.94 (m, 1H), 6.82 - 6.57 (m, 1H), 4.98 - 4.85 (m, 1H), 4.54 - 4.27 (m, 1H), 4.08 - 3.92 (m, 1H), 3.90 - 3.73 (m, 1H), 3.27 - 2.97 (m, 2H), 2.69 - 2.50 (m, 1H), 2.40 - 2.28 (m, 1H), 2.14 - 1.98 (m, 1H), 1.85 - 1.51 (m, 4H), 1.18 - 0.97 (m, 6H). ESI-MS [M+H]+ calc’d for C24H26ClFN4O4, 489.16; found, 489.4. [0556] Example 50: (1R, 2S, 5S)-N-((S)-4-amino-3, 4-dioxo-1-((S)-2-oxopyrrolidin-3- yl)butan-2-yl)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (Compound 50)
Figure imgf000147_0001
[0557] Step 1: (1R,2S,5S)-methyl 3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
Figure imgf000147_0002
[0558] To a solution of (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid (2 g, 8.68 mmol) in DCM (30 mL) and DIPEA (4.49 g, 34.74 mmol) was added T3P (8.29 g, 13.03 mmol, 7.75 mL, 50% purity in EtOAc) at 0°C. After addition, the mixture was stirred at this temperature for 30 min, and then (1R,2S,5S)-methyl 6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (2.14 g, 10.42 mmol) was added to the mixture. The resulting mixture was stirred at 25°C for 10 hr. The reaction mixture was diluted with EtOAc (150 mL) and 5% H3PO4 (150 mL) for 30 min. The aqueous phase was extracted with EtOAc (100 mL). The combined organic layer was washed with 5% H3PO4 (150 mL x 3), sat.aq.NaHCO3 (150 mL x4), water (150 mL), and brine (150 mL), and dried over anhydrous Na2SO4, filtered and concentrated. Crude product (3.29 g, crude) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 5.95 (s, 1H), 5.89 (d, J = 10.0 Hz, 1H), 4.21 - 4.11 (m, 2H), 4.02 (d, J = 10.4 Hz, 1H), 3.80 - 3.72 (m, 1H), 3.64 (s, 3H), 1.55 - 1.47 (m, 1H), 1.43 - 1.36 (m, 1H), 1.16 (s, 9H), 0.99 (s, 3H), 0.90 (s, 9H), 0.82 (s, 3H) [0559] Step 2: (1R,2S,5S)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid
Figure imgf000147_0003
[0560] To a solution of (1R,2S,5S)-methyl 3-((S)-2-(3-(tert-butyl)ureido)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1 g, 2.62 mmol) in THF (5 mL) and H2O (5 mL) was added LiOH.H2O (220 mg, 5.24 mmol). The mixture was stirred at 25 °C for 1 hr. The reaction was extracted with ethyl acetate (5 mL x 2). The water phase was then adjusted to pH = 4 by aq. HCl (1 N). The resulting mixture was extracted with DCM (10 mL x 3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The title compound (1.03 g, 97.31% yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 5.96 (s, 1H), 5.89 (d, J = 10.0 Hz, 1H), 4.17 - 4.08 (m, 3H), 3.99 (d, J = 10.0 Hz, 1H), 3.78 - 3.71 (m, 1H), 1.50 - 1.45 (m, 1H), 1.37 (d, J = 8.0 Hz, 1H), 1.16 (s, 9H), 1.00 (s, 3H), 0.91 (s, 9H), 0.81 (s, 3H) [0561] Step 3: tert-butyl ((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)carbamate
Figure imgf000148_0001
[0562] To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin- 3-yl)propanoate (5 g, 17.46 mmol) in THF (50 mL) was added LiBH4 (1.85 g, 84.93 mmol) at 0°C. Then the mixture was stirred at 25°C for 3 hrs. Water (200 mL) was added to the mixture. The aqueous layer was extracted with ethyl acetate (200 mL x 5). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product (4.5 g, 99.76% yield) as a white solid was used for next step directly without further purification.1H NMR (400 MHz, CDCl3) δ ppm 5.85 (s, 1H), 5.45 (s, 1H), 3.73 (s, 1H), 3.66 - 3.55 (m, 2H), 3.41 - 3.28 (m, 2H), 2.58 - 2.34 (m, 2H), 1.89 - 1.77 (m, 2H), 1.68 - 1.57 (m, 1H), 1.44 (s, 9H). [0563] Step 4: tert-butyl ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate
Figure imgf000148_0002
[0564] To a solution of tert-butyl ((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)carbamate (2.5 g, 9.68 mmol) in DCM (25 mL) was added SO3.Py (9.24 g, 58.07 mmol) and TEA (5.88 g, 58.07 mmol) and DMSO (7.56 g, 96.78 mmol). Then the mixture was stirred at 25 °C for 1 h. Water (100 mL) was added to the mixture. The aqueous layer was extracted with DCM (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (MeOH in DCM 0-5%) to give the title compound (2.4 g, 96.76% yield) as a black brown oil.1H NMR (400 MHz, CDCl3) δ ppm 9.55 (s, 1H), 8.61 (d, J = 4.0 Hz, 1H), 5.54 -5.41 (m, 1H), 4.20 - 4.13(m, 1H), 3.45 (s, 2H), 2.04 - 2.01 (m, 5H), 1.43 (s, 9H). [0565] Step 5: tert-butyl ((2S)-1-cyano-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)carbamate
Figure imgf000149_0001
[0566] tert-butyl ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (2.4 g, 9.36 mmol) was dissolved in MeOH (15 mL) and cooled to 0°C. The solution of NaHSO3 (1.46 g, 14.05 mmol) dissolved in H2O (22 mL) was added to the above mixture. Then the mixture was stirred at 25°C for 5 hrs. NaCN (550 mg, 11.22 mmol) was dissolved in H2O (5 mL) and added with EtOAc (50 mL) to the above mixture. The reaction was stirred at 25°C for 5 hrs. Water (100 mL) was added to the mixture. The aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (EtOAc in Petroleum ether = 0-5%) to give the title compound (1.3 g, 49.00% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ ppm 6.02 - 5.87 (m, 1H), 4.75 - 4.45 (m, 1H), 4.01 - 3.85 (m, 1H), 3.44 - 3.30 (m, 2H), 2.60 - 2.28 (m, 2H), 2.15 - 1.81 (m, 3H), 1.50 - 1.38 (m, 9H) [0567] Step 6: tert-butyl ((2S)-4-amino-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3- yl)butan-2-yl)carbamate
Figure imgf000149_0002
[0568] To a solution of tert-butyl ((2S)-1-cyano-1-hydroxy-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)carbamate (200 mg, 705.91 μmol) in DMSO (2 mL) was added K2CO3 (97 mg, 705.91 μmol). H2O2 (140 mg, 1.24 mmol, 119 uL, 30% purity) was added to the above mixture at 10 °C dropwise. Then the mixture was stirred at 25°C for 2 hrs. Saturated Na2SO3 (2 mL) was added to the mixture. The reaction mixture was filtered. The combined filtrate was concentrated under reduce pressure. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C1875 x 30mm x 3μm; mobile phase: [water (0.05%HCl)-ACN]; B%: 0%-25%, 40min) to give the title compound (200 mg, 94.02% yield) as a white solid. ESI- MS [M+H]+ calc’d for C13H23N3O5, 302.2, found 302.4. [0569] Step 7: (3S)-3-amino-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide
Figure imgf000150_0001
[0570] To a solution of tert-butyl N-[(1S)-3-amino-2-hydroxy-3-oxo-1-[[(3S)-2- oxopyrrolidin-3-yl] methyl]propyl]carbamate (150 mg, 497.78 μmol) in MeOH (4 mL) was added HCl/dioxane (4 M, 124.44 μL). The resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduce pressure to give a residue. The product (118 mg, 99.73% yield, HCl) as a white solid was used for next step directly without further purification. [0571] Step 8: (1R,2S,5S)-N-((2S)-4-amino-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3- yl)butan-2-yl)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000150_0002
[0572] To a solution of (3S)-3-amino-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide (118 mg, 496.46 μmol, HCl) in DCM (2 mL) was added DIEA (192 mg, 1.49 mmol) and (1R,2S,5S)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (146 mg, 397.17 µmol) slowly at 25°C. And then a solution of HATU (377 mg, 992.92 μmol) in DCM (2 mL) was added dropwise at 0°C. The resulting mixture was stirred at 25°C for 16 hrs. The reaction mixture was concentrated under reduce pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C1875 x 30mm x 3μm; mobile phase: [water (0.05%HCl)-ACN]; B%: 10%-40%, 40 min) to give the title compound (60 mg, 21.95% yield) as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 4.33 - 4.22 (m, 2H), 4.09 - 3.89 (m, 3H), 3.30 - 3.17 (m, 2H), 2.70 - 2.54 (m, 1H), 2.47 - 2.10 (m, 2H), 1.89 - 1.50 (m, 3H), 1.49 - 1.30 (m, 2H), 1.29 - 1.22 (m, 9H), 1.08 - 1.03 (m, 3H), 1.03 - 0.95 (m, 9H), 0.95 - 0.90 (m, 3H). [0573] Step 9: (1R, 2S, 5S)-N-((S)-4-amino-3, 4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan- 2-yl)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide [0574] To a solution of (1R,2S,5S)-N-((2S)-4-amino-3-hydroxy-4-oxo-1-((S)-2- oxopyrrolidin-3-yl)butan-2-yl)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (60 mg, 108.95 μmol) in DCM (1 mL) was added Dess-Martin (139 mg, 326.86 μmol). Then the mixture was stirred at 25°C for 16 h. The reaction was concentrated under reduce pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C1875 x 30mm x 3μm; mobile phase: [water (0.05%HCl)-ACN]; B%: 10%-50%, 40min) to give Compound 50 (13.9 mg, 23.25% yield) as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 4.38 - 4.18 (m, 3H), 4.07 - 3.88 (m, 2H), 3.28 - 3.14 (m, 2H), 2.65 - 2.52 (m, 1H), 2.44 - 2.25 (m, 1H), 2.15 - 1.96 (m, 1H), 1.81 - 1.42 (m, 4H), 1.29 - 1.22 (m, 9H), 1.07 - 0.93 (m, 15H). ESI-MS [M+H]+ calc’d for C27H44N6O6, 549.3, found 549.5. [0575] Example 51: (S)-1-(4-Fluoro-1H-indole-2-carbonyl)-4,4-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 51)
Figure imgf000151_0001
[0576] Compound 51 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.28 - 7.23 (m, 1H), 7.21 - 7.12 (m, 1H), 7.07 - 6.88 (m, 1H), 6.81 - 6.66 (m, 1H), 4.58 (s, 1H), 4.50 - 4.28 (m, 1H), 4.06 - 3.76 (m, 2H), 3.73 - 3.41 (m, 1H), 2.96 - 2.63 (m, 1H), 2.46 - 1.98 (m, 3H), 1.94 - 1.52 (m, 3H), 1.42 - 1.29 (m, 1H), 1.27 - 1.00 (m, 6H). ESI-MS [M+H]+ calc’d for C23H27FN4O4, 443.20, found 443.1. [0577] Example 52: (1R,2S,5S)-6,6-dimethyl-3-(2-(4-methylcyclohexyl)acetyl)-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 52)
Figure imgf000152_0001
[0578] Step 1: (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(2-(4-methylcyclohexyl)acetyl)-3- azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000152_0002
[0579] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (165 mg, 458.53 μmol, HCl), 2-(4- methylcyclohexyl)acetic acid (72 mg, 458.53 μmol,) and DIEA (178 mg, 1.38 mmol) in DCM (3 mL) was added HATU (349 mg, 917.06 μmol) slowly at 0°C. The resulting mixture was stirred at 25°C for 10 hr. The resulting suspension was diluted with DCM (10 mL). The mixure was washed with sat.aq.NH4Cl (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (Eluent of 0~100% EtOAc in PE). The title compound (267 mg, 30.78% yield) was obtained as a yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 10.83 - 10.31 (m, 1H), 8.81 - 7.31 (m, 1H), 4.64 - 4.37 (m, 1H), 4.35 - 4.07 (m, 1H), 3.95 - 3.79 (m, 1H), 3.79 - 3.70 (m, 3H), 3.70 - 3.62 (m, 1H), 3.56 - 3.44 (m, 1H), 3.42 - 3.30 (m, 1H), 2.65 - 2.40 (m, 2H), 2.38 - 2.28 (m, 1H), 2.25 - 2.08 (m, 3H), 2.06 - 1.97 (m, 1H), 1.93 - 1.81 (m, 1H), 1.76 - 1.58 (m, 3H), 1.57 - 1.54 (m, 5H), 1.39 - 1.15 (m, 3H), 1.09 - 0.81 (m, 9H). [0580] Step 2: (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6- dimethyl-3-(2-(4-methylcyclohexyl)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000153_0001
[0581] To a solution of (S)-methyl 2-((1R,2S,5S)-6,6-dimethyl-3-(2-(4- methylcyclohexyl)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin- 3-yl)propanoate (260 mg, 563.27 μmol) in THF (3 mL) was added LiBH4 (70 mg, 3.21 mmol) at 0°C. The mixture was stirred at 25°C for 1h. The reaction was quenched with water (10 mL) drop-wise. The resulting mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 μm; mobile phase: [water (0.05%NH3H2O+10 mM NH4HCO3)-ACN]; B%: 21%-61%, 11 min). The title compound (30 mg, 7.92% yield) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 8.15 - 7.98 (m, 1H), 4.38 - 4.18 (m, 1H), 4.07 - 3.84 (m, 2H), 3.76 - 3.45 (m, 4H), 3.29 - 3.20 (m, 1H), 2.71 - 2.56 (m, 1H), 2.40 - 2.14 (m, 3H), 2.08 - 1.87 (m, 2H), 1.81 - 1.39 (m, 11H), 1.37 - 1.22 (m, 2H), 1.07 (s, 3H), 0.97 - 0.83 (m, 6H). [0582] Step 3: (1R,2S,5S)-6,6-dimethyl-3-(2-(4-methylcyclohexyl)acetyl)-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0583] To a solution of (1R,2S,5S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-6,6-dimethyl-3-(2-(4-methylcyclohexyl)acetyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (20 mg, 46.13 μmol) in DCM (4 mL) was added DMP (59 mg, 138.38 μmol). The mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 26%-56%, 10 min). Compound 52 (7.0 mg, 34.87% yield, 99.156% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 4.54 - 4.33 (m, 1H), 4.32 - 4.20 (m, 1H), 4.08 - 3.66 (m, 2H), 3.65 - 3.50 (m, 1H), 3.29 - 3.20 (m, 1H), 2.68 - 1.81 (m, 6H), 1.80 - 1.62 (m, 4H), 1.61 - 1.38 (m, 5H), 1.36 - 1.17 (m, 2H), 1.12 - 0.83 (m, 11H). ESI-MS [M+H]+ calc’d for C24H37N3O4, 432.28; found, 432.4. [0584] Example 53: (1R,2S,5S)-3-(2-cyclohexylacetyl)-6,6-dimethyl-N-((S)-1-oxo-3-((S)- 2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 53)
Figure imgf000154_0001
[0585] Step 1: (S)-methyl 2-((1R,2S,5S)-3-(2-cyclohexylacetyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000154_0002
[0586] To a solution of 2-cyclohexylacetic acid (101 mg, 708.63 μmol) and DIEA (367 mg, 2.83 mmol) in DCM (4 mL) was added T3P (677 mg, 1.06 mmol, 50% purity in EtOAc) dropwise at 0°C. After addition, the mixture was stirred at 0°C for 20 mins. Then (S)-methyl- 2-((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2- oxopyrrolidin-3-yl)propanoate (255 mg, 708.63 μmol, HCl) in DCM (4 mL) was added in one portion at 0°C. The mixture was stirred at 25°C for 10 hr. The reaction mixture was poured into water (20 mL). The resulting mixture was extracted with DCM (15 mL x3). The combined organic phase was washed with 5% H3PO4 (15 mL x2), sat.aq.NaHCO3 (15 mL x2) and brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: Xtimate C18150×40 mm×10 μm; mobile phase: [water (0.05%HCl)-ACN]; B%: 30%-60%, 10 min). The title compound (175 mg, 37.16% yield) was obtained as colorless oil.1H NMR (400 MHz, CDCl3) δ ppm 8.41 - 7.43 (m, 1H), 6.28 - 5.67 (m, 1H), 4.61 - 4.38 (m, 1H), 4.33 - 4.15 (m, 1H), 3.86 - 3.77 (m, 1H), 3.75 - 3.67 (m, 3H), 3.49 (d, J = 10.4 Hz, 1H), 3.41 - 3.28 (m, 2H), 2.58 - 2.36 (m, 2H), 2.19 - 2.09 (m, 2H), 1.91 - 1.79 (m, 2H), 1.76 - 1.59 (m, 8H), 1.58 - 1.45 (m, 2H), 1.38 - 1.08 (m, 4H), 1.07 - 1.01 (m, 3H), 0.93 - 0.89 (m, 3H). [0587] Step 2: (1R,2S,5S)-3-(2-cyclohexylacetyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000155_0001
[0588] To a solution of (S)-methyl 2-((1R,2S,5S)-3-(2-cyclohexylacetyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (85 mg, 189.92 μmol) in THF (6 mL) was added LiBH4 (12 mg, 569.75 μmol) at 0°C. The mixture was stirred at 0°C for 1 hr. H2O (10 mL) was added. The resulting mixture was extracted with DCM (15 mL x3). The combined organic phase was washed with brine (25 mL), water (25 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 22%-52%, 10 min). The title compound (45 mg, 29.91% yield, 52.95% purity) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 7.82 - 7.44 (m, 1H), 6.34 - 6.00 (m, 1H), 4.27 - 4.16 (m, 1H), 4.14 - 3.95 (m, 1H), 3.93 - 3.81 (m, 1H), 3.77 - 3.67 (m, 1H), 3.63 - 3.43 (m, 3H), 3.39 - 3.27 (m, 2H), 2.58 - 2.32 (m, 2H), 2.20 - 1.98 (m, 3H), 1.90 - 1.54 (m, 8H), 1.53 - 1.37 (m, 2H), 1.31 - 1.08 (m, 3H), 1.07 - 0.79 (m, 8H). [0589] Step 3: (1R,2S,5S)-3-(2-cyclohexylacetyl)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [0590] To a solution of (1R,2S,5S)-3-(2-cyclohexylacetyl)-N-((S)-1-hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (40 mg, 95.34 μmol) in DCM (3 mL) was added DMP (81 mg, 190.68 μmol) at 25°C. The reaction mixture was stirred at 25°C for 0.5 hr. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30 mm×3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 25%-55%, 10 min). Compound 53 (5 mg, 12.08% yield, 96.212% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 4.52 - 4.33 (m, 1H), 4.30 - 3.61 (m, 3H), 3.60 - 3.53 (m, 1H), 3.29 - 3.26 (m, 1H), 2.66 - 2.27 (m, 2H), 2.23 - 1.89 (m, 3H), 1.83 - 1.62 (m, 7H), 1.61 - 1.39 (m, 3H), 1.33 - 1.13 (m, 3H), 1.11 - 0.81 (m, 8H). ESI-MS [M+H]+ calc’d for C23H35N3O4, 418.26 found 418.4. [0591] Example 54: (1R,2S,5S)-3-(2-Cyclohexylacetyl)-6,6-dimethyl-N-((S)-1-oxo-3-((S)- 2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 54)
Figure imgf000156_0001
[0592] Compound 54 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.53 - 7.23 (m, 2 H), 7.12 - 6.85 (m, 1 H), 4.53 - 4.38 (m, 1 H), 4.33 - 4.23 (m, 1 H), 4.06 – 3.91 (m, 2 H), 3.85 - 3.70 (m, 1 H), 3.28 - 3.23 (m, 1 H), 2.74 - 2.57 (m, 1 H), 2.52 - 2.27 (m, 1 H), 2.08 – 1.83 (m, 1 H), 1.80 - 1.67 (m, 2 H), 1.63 - 1.50 (m, 2 H), 1.48 - 1.36 (m, 1 H), 1.17 – 0.93 (m, 6 H). ESI-MS [M+H]+ calc’d for C24H26F2N4O4, 473.19, found 473.2. [0593] Example 55: (1R,2S,5S)-3-(2-(Azepan-1-yl)acetyl)-6,6-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 55)
Figure imgf000156_0002
[0594] Compound 55 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 4.53 - 4.45 (m, 1H), 4.32 - 3.83 (m, 3H), 3.76 - 3.35 (m, 3H), 3.28 - 2.99 (m, 2H), 2.81 - 2.69 (m, 3H), 2.67 - 2.27 (m, 3H), 2.07 - 1.93 (m, 1H), 1.72 - 1.42 (m, 11H), 1.11 - 0.96 (m, 6H). ESI-MS [M+H]+ calc’d for C23H36N4O4, 451.27, found 451.3. [0595] Example 56: (1R,2S,5S)-3-(6-Methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 56)
Figure imgf000157_0001
[0596] Compound 56 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.55 - 7.34 (m, 1H), 7.03 - 6.82 (m, 2H), 6.71 (ddd, J = 2.4, 8.8, 11.2 Hz, 1H), 4.52 - 4.38 (m, 1H), 4.30 - 3.93 (m, 2H), 3.82 (d, J = 3.6 Hz, 3H), 3.79 - 3.73 (m, 1H), 3.29 - 3.23 (m, 1H), 2.95 - 2.23 (m, 2H), 2.04 - 1.86 (m, 1H), 1.80 - 1.25 (m, 5H), 1.15 - 0.93 (m, 6H). ESI-MS [M+H]+ calc’d for C25H30N4O5, 467.22, found 467.4. [0597] Example 57: (S)-1-(1H-Indole-2-carbonyl)-4,4-dimethyl-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamid (Compound 57)
Figure imgf000157_0002
[0598] Compound 57 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CDCl3) δH = 9.56 - 9.43 (m, 2H), 8.57 - 8.38 (m, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.33 - 7.27 (m, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.93 (s, 1H), 5.87 - 5.67 (m, 1H), 4.80 (t, J = 9.2 Hz, 1H), 4.43 - 4.29 (m, 1H), 3.89 - 3.82 (m, 1H), 3.80 - 3.73 (m, 1H), 3.39 - 3.25 (m, 2H), 2.69 - 2.51 (m, 1H), 2.48 - 2.32 (m, 1H), 2.23 - 1.90 (m, 5H), 1.26 - 1.20 (m, 3H), 1.05 (s, 3H). ESI-MS [M+H]+ calc’d for C23H28N4O4, 425.21, found 425.1. [0599] Example 58: (S)-1-(7-Cyano-1H-indole-2-carbonyl)-4,4-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 58)
Figure imgf000157_0003
[0600] Compound 58 was synthesized by the same procedure as Compound 2. H NMR (400 MHz, CD3OD) δ ppm 8.02 - 7.83 (m, 1H), 7.69 - 7.60 (m, 1H), 7.27 - 6.96 (m, 2H), 5.16 - 4.87 (m, 1H), 4.76 - 4.66 (m, 1H), 4.51 - 4.28 (m, 1H), 4.07 - 3.41 (m, 3H), 3.01 - 2.62 (m, 1H), 2.41 - 2.26 (m, 1H), 2.14 - 2.00 (m, 1H), 1.93 - 1.80 (m, 1H), 1.79 - 1.67 (m, 1H), 1.65 - 1.50 (m, 1H), 1.46 - 1.27 (m, 1H), 1.26 - 0.98 (m, 6H). ESI-MS [M+H]+ calc’d for C24H27N5O4, 450.21, found 450.4. [0601] Example 59: (1R,2S,5S)-3-(4-Cyano-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 59)
Figure imgf000158_0001
[0602] Compound 59 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.81 - 7.71 (m, 1H), 7.59 - 7.46 (m, 1H), 7.41 - 7.30 (m, 1H), 7.18 - 6.93 (m, 1H), 4.85 - 4.69 (m, 1H), 4.55 - 4.29 (m, 1H), 4.09 - 3.66 (m, 3H), 3.30 - 3.23 (m, 1H), 2.97 - 2.58 (m, 1H), 2.48 - 2.29 (m, 1H), 2.10 - 1.73 (m, 2H), 1.66 - 1.25 (m, 3H), 1.20 - 0.95 (m, 6H). ESI-MS [M+H]+ calc’d for C25H27N5O4, 462.2, found 462.3. [0603] Example 60: (1R,2S,5S)-3-(1H-Indole-2-carbonyl)-6,6-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 60)
Figure imgf000158_0002
[0604] Compound 60 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.66 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.46 - 7.40 (m, 1H), 7.22 (q, J = 7.2 Hz, 1H), 7.10 - 6.99 (m, 2H), 6.94 - 6.88 (m, 1H), 5.03 - 4.90 (m, 1H), 4.65 - 4.63 (m, 1H), 4.52 - 4.38 (m, 1H), 4.35 - 4.27 (m, 1H), 4.07 - 3.94 (m, 2H), 3.80 - 3.67 (m, 1H), 2.91 - 2.80 (m, 1H), 2.70 - 2.57 (m, 1H), 2.42 - 2.29 (m, 1H), 2.26 - 2.14 (m, 1H), 2.10 - 1.98 (m, 1H), 1.95 - 1.79 (m, 1H), 1.74 - 1.68 (m, 1H), 1.64 - 1.53 (m, 1H), 1.44 - 1.26 (m, 1H), 1.17-1.06 (m, 4H), 0.99-0.96 (m, 1H). ESI-MS [M+H]+ calc’d for C24H28N4O4, 437.21, found 437.0. [0605] Example 61: (2S,4S)-4-Cyclohexyl-1-(1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)- 2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 61)
Figure imgf000159_0001
[0606] Compound 61 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.71 - 7.49 (m, 1H), 7.48 - 7.39 (m, 1H), 7.28 - 7.15 (m, 1H), 7.12 - 6.83 (m, 2H), 5.10 (d, J = 6.0 Hz, 1H), 4.75 - 4.53 (m, 1H), 4.39 (d, J = 3.2 Hz, 1H), 4.20 - 3.89 (m, 1H), 3.86 - 3.54 (m, 1H), 3.07 - 2.55 (m, 1H), 2.51 - 2.25 (m, 2H), 2.25 - 1.86 (m, 4H), 1.77 (d, J = 10.0 Hz, 4H), 1.71 - 1.54 (m, 2H), 1.53 - 1.39 (m, 1H), 1.38 - 1.18 (m, 4H), 1.15 - 0.94 (m, 2H). ESI-MS [M+H]+ calc’d for C27H34N4O4, 479.26, found 479.4. [0607] Example 62: (S)-1-(7-Fluoro-1H-indole-2-carbonyl)-4,4-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 62)
Figure imgf000159_0002
[0608] Compound 62 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.43 - 7.17 (m, 1H), 7.01 - 6.74 (m, 3H), 4.40 - 4.18 (m, 1H), 3.97 - 3.80 (m, 1H), 3.75 - 3.31 (m, 3H), 2.85 - 2.53 (m, 1H), 2.35 - 1.88 (m, 3H), 1.84 - 1.70 (m, 1H), 1.70 - 1.58 (m, 1H), 1.56 - 1.39 (m, 1H), 1.27 - 1.17 (m, 1H), 1.15 - 0.92 (m, 6H.. ESI-MS [M+H]+ calc’d for C23H27FN4O4, 443.20, found 443.1 [0609] Example 63: (1S,3aR,6aS)-2-(2-(2,4-Dichlorophenoxy)acetyl)-N-((S)-1-oxo-3-((S)- 2-oxopyrrolidin-3-yl)propan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide (Compound
Figure imgf000160_0001
[0610] Compound 63 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.34 - 7.28 (m, 1H), 7.16 - 7.08 (m, 1H), 6.89 - 6.81 (m, 1H), 4.41 - 4.10 (m, 2H), 3.90 - 3.68 (m, 2H), 3.45 - 3.34 (m, 1H), 3.08 - 2.73 (m, 3H), 2.67 - 2.37 (m, 2H), 2.10 - 2.00 (m, 1H), 1.95 - 1.76 (m, 3H), 1.75 - 1.15 (m, 7H). ESI-MS [M+H]+ calc’d for C23H27Cl2N3O5, 496.13, found 496.1. [0611] Example 64: (1R,2S,5S)-3-(2-(2,2-Difluorocyclohexyl)acetyl)-6,6-dimethyl-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 64)
Figure imgf000160_0002
[0612] Compound 64 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 4.66 - 4.15 (m, 3H), 3.91 - 3.57 (m, 2H), 3.55 - 3.43 (m, 1H), 2.68 - 2.29 (m, 2H), 2.27 - 2.13 (m, 2H), 1.98 - 1.86 (m, 2H), 1.81 - 1.31 (m, 10H), 1.28 - 1.03 (m, 2H), 1.00 - 0.96 (m, 3H), 0.90 - 0.84 (m, 3H). ESI-MS [M+H]+ calc’d for C23H33F2N3O4, 454.24, found 454.5. [0613] Example 65: (1R,2S,5S)-3-(4-Methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 65)
Figure imgf000161_0001
[0614] Compound 65 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 9.66 - 9.24 (m, 1H), 8.32 (d, J = 9.6 Hz, 1H), 7.22 - 6.91 (m, 3H), 6.55 - 6.37 (m, 1H), 5.09 - 4.90 (m, 1H), 4.83 - 4.59 (m, 1H), 4.52 - 4.26 (m, 1H), 4.05 - 3.74 (m, 5H), 3.30 - 3.22 (m, 1H), 2.46 - 2.19 (m, 1H), 2.10 - 1.91 (m, 1H), 1.86 - 1.49 (m, 3H), 1.48 - 1.22 (m, 2H), 1.18 - 0.94 (m, 6H). ESI-MS [M+H]+ calc’d for C25H30N4O5, 467.2, found 467.4 [0615] Example 66: (1R,2S,5S)-3-(4-Isopropoxy-1H-indole-2-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 66)
Figure imgf000161_0002
[0616] Compound 66 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.07 - 6.98 (m, 1H), 6.97 - 6.90 (m, 1H), 6.89 - 6.80 (m, 1H), 6.37 (d, J = 7.6 Hz, 1H), 4.70 - 4.62 (m, 1H), 4.61 - 4.38 (m, 3H), 4.32 - 4.16 (m, 1H), 3.98 - 3.86 (m, 1H), 3.70 - 3.56 (m, 1H), 3.19 - 3.14 (m, 1H), 2.73 - 2.46 (m, 1H), 2.31 - 1.79 (m, 2H), 1.72 - 1.38 (m, 3H), 1.36 - 1.20 (m, 6H), 1.20 - 0.97 (m, 5H), 0.87 (s, 1H). ESI-MS [M+H]+ calc’d for C27H34N4O5, 495.25; found, 495.3. [0617] Example 67: (1R,2S,5S)-3-((R)-2-Cyclohexylpropanoyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 67)
Figure imgf000162_0001
[0618] Compound 67 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 4.60 - 4.48 (m, 1H), 4.40 - 4.26 (m, 1H), 4.06 - 3.88 (m, 2H), 3.70 - 3.63 (m, 1H), 3.31 - 3.27 (m, 1H), 2.70 - 2.56 (m, 1H), 2.50 - 2.27 (m, 2H), 2.09 - 1.96 (m, 1H), 1.95 - 1.73 (m, 3H), 1.71 - 1.42 (m, 7H), 1.32 - 1.15 (m, 3H), 1.09 (s, 3H), 1.07 - 0.88 (m, 8H). ESI-MS [M+H]+ calc’d for C24H37N3O4, 432.28; found, 432.5. [0619] Example 68: (1R,2S,5S)-3-(5-Methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 68)
Figure imgf000162_0002
[0620] Compound 68 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.35 - 7.28 (m, 1H), 7.14 - 6.98 (m, 1H), 6.98 - 6.83 (m, 2H), 5.02 - 4.89 (m, 1H), 4.64 - 4.39 (m, 1H), 4.32 - 3.92 (m, 2H), 3.80 (d, J = 10.8 Hz, 3H), 3.78 - 3.69 (m, 1H), 3.29 - 3.22 (m, 1H), 2.92 - 2.57 (m, 1H), 2.40 - 2.17 (m, 1H), 2.06 - 1.90 (m, 1H), 1.79 - 1.68 (m, 1H), 1.62 - 1.52 (m, 1H), 1.50 - 1.24 (m, 2H), 1.17 - 0.88 (m, 6H). ESI- MS [M+H]+ calc’d for C25H30N4O5, 467.22; found, 467.4. [0621] Example 69: (1R,2S,5S)-3-(5-Chloro-7-methyl-1H-indole-2-carbonyl)-6,6- dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane- 2-carboxamide (Compound 69)
Figure imgf000163_0001
[0622] Compound 69 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.51 - 7.33 (m, 1H), 7.06 - 6.82 (m, 2H), 4.99 - 4.88 (m, 1H), 4.54 - 4.38 (m, 1H), 4.32 - 3.96 (m, 2H), 3.95 - 3.73 (m, 1H), 2.99 - 2.58 (m, 1H), 2.50 (s, 3H), 2.44 - 2.29 (m, 1H), 2.07 - 1.82 (m, 1H), 1.80 - 1.70 (m, 1H), 1.64 - 1.50 (m, 2H), 1.40 - 1.29 (m, 1H), 1.19 - 0.89 (m, 7H). ESI-MS [M+H]+ calc’d for C25H29ClN4O4, 485.19; found, 485.4. [0623] Example 70: (1R,2S,5S)-3-(4-Ethoxy-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 70)
Figure imgf000163_0002
[0624] Compound 70 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.17 - 6.94 (m, 3H), 6.53 - 6.40 (m, 1H), 4.68 - 4.55 (m, 1H), 4.52 - 4.26 (m, 1H), 4.23 - 4.07 (m, 2H), 4.06 - 3.94 (m, 1H), 3.83 - 3.63 (m, 1H), 3.37 - 3.32 (m, 1H), 3.28 - 3.22 (m, 1H), 2.81 - 2.30 (m, 2H), 2.21 - 1.91 (m, 2H), 1.83 - 1.67 (m, 1H), 1.62 - 1.27 (m, 5H), 1.17 - 0.91 (m, 6H). ESI-MS [M+H]+ calc’d for C26H32N4O5, 481.24; found, 481.1. [0625] Example 71: (2S,4S)-4-cyclohexyl-1-(7-fluoro-1H-indole-2-carbonyl)-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 71)
Figure imgf000164_0001
[0626] Step 1: (2S,4S)-1-tert-butoxycarbonyl-4-cyclohexyl-pyrrolidine-2-carboxylic acid
Figure imgf000164_0002
[0627] To a solution of (2S,4S)-4-cyclohexylpyrrolidine-2-carboxylic acid (2.0 g, 10.14 mmol) and K2CO3 (4.9 g, 35.49 mmol) in THF (15 mL) was added H2O (15 mL). After addition, the mixture was stirred at 0°C for 5 min, and then tert-butoxycarbonyl tert-butyl carbonate (4.43 g, 20.28 mmol) was added dropwise at 0°C. The resulting mixture was stirred at 25°C for 12 h. Water (10 mL) was added to the reaction mixture. The reaction mixture was then adjusted to pH~5 by aq. HCl (2M). The resulting mixture was extracted with EtOAc (20 mL x3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The title compound (3.9 g, crude) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 4.45 - 4.22 (m, 1H), 3.80 - 3.52 (m, 1H), 3.02 - 2.87 (m, 1H), 2.43 - 2.11 (m, 1H), 2.06 - 1.86 (m, 1H), 1.78 - 1.57 (m, 6H), 1.48 - 1.36 (m, 9H), 1.24 - 1.06 (m, 4H), 1.04 - 0.85 (m, 2H). [0628] Step 2: (2S,4S)-tert-butyl 4-cyclohexyl-2-(((S)-1-methoxy-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)pyrrolidine-1-carboxylate
Figure imgf000164_0003
[0629] To a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-cyclohexylpyrrolidine-2- carboxylic acid (1 g, 3.36 mmol) and DIEA (1.74 g, 13.45 mmol) in DCM (10 mL) was added dropwise T3P (3.21 g, 5.04 mmol, 50% purity in EtOAc) at 0°C. After addition, the mixture was stirred at the same temperature for 30 min, and then (S)-methyl 2-amino-3-((S)- 2-oxopyrrolidin-3-yl)propanoate (748.7 mg, 3.36 mmol, HCl) was added dropwise at 25°C. The resulting mixture was stirred at 25°C for 10 h. Water (10 mL) was added and the reaction was extracted with DCM (10 mL x3). The combined organic phase was washed with 5% H3PO4 (5 mL x2) and sat aq. NaHCO3 (5 mL x2), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (1.89 g, 73.65% yield) was obtained as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 7.92 - 7.36 (m, 1H), 6.90 - 6.19 (m, 1H), 4.64 - 4.41 (m, 1H), 4.37 - 4.15 (m, 1H), 3.77 - 3.65 (m, 3H), 3.64 - 3.52 (m, 1H), 3.40 - 3.24 (s, 2H), 3.08 - 2.82 (m, 1H), 2.49 - 2.12 (m, 4H), 1.92 - 1.75 (m, 3H), 1.74 - 1.57 (m, 6H), 1.49 - 1.37 (m, 9H), 1.30 - 1.05 (m, 4H), 0.95 (s, 2H). [0630] Step 3: (S)-methyl 2-((2S,4S)-4-cyclohexylpyrrolidine-2-carboxamido)-3-((S)-2- oxopyrrolidin-3-yl)propanoate hydrochloride
Figure imgf000165_0001
[0631] A solution of (2S,4S)-tert-butyl 4-cyclohexyl-2-(((S)-1-methoxy-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)pyrrolidine-1-carboxylate (300 mg, 644.36 μmol) in HCl/dioxane (3 mL) was stirred at 25°C for 1 h. The reaction mixture was concentrated directly. The title compound (258 mg, crude, HCl) was obtained as a yellow solid, which was used to next step without further purification. [0632] Step 5: (S)-methyl 2-((2S,4S)-4-cyclohexyl-1-(7-fluoro-1H-indole-2- carbonyl)pyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000166_0001
[0633] To a mixture of (S)-methyl 2-((2S,4S)-4-cyclohexylpyrrolidine-2-carboxamido)-3- ((S)-2-oxopyrrolidin-3-yl)propanoate (258 mg, 641.91 μmol HCl) and 7-fluoro-1H-indole-2- carboxylic acid (115 mg, 641.91 μmol) in DCM (5 mL) was added DIEA (248 mg, 1.93 mmol) and HATU (488 mg, 1.28 mmol) at 0°C. The mixture was stirred at 25°C for 12 hrs. The mixture was diluted with DCM (20 mL), and washed with sat.aq. NH4Cl (10 mL x2). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30mm×3μm; mobile phase: [water (0.05%NH3H2O+10mM NH4HCO3) - ACN]; B%: 30%-70%, 11min). The solvent after prep-HPLC purification was extracted with DCM (30 mL x3). The combined organic layer was dried over Na2SO4, filtered and concentrated to dryness. The title compound (60 mg, 13.14% yield) was obtained as a yellow oil. ESI-MS [M+H]+ calc’d for C28H35FN4O5, 527.26; found, 527.2. [0634] Step 6: (2S,4S)-4-cyclohexyl-1-(7-fluoro-1H-indole-2-carbonyl)-N-((S)-1-hydroxy- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide
Figure imgf000166_0002
[0635] To a mixture of (S)-methyl 2-((2S,4S)-4-cyclohexyl-1-(7-fluoro-1H-indole-2- carbonyl)pyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (60 mg, 113.94 μmol) in THF (3 mL) was added LiBH4 (50 mg, 2.30 mmol, 2.30 mL) at 0°C under N2. The mixture was stirred at 0°C for 1hr. The mixture was quenched with H2O (10 mL), and extracted with DCM (5 mL x3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The title compound (60 mg, 68.65% yield) was obtained as a white solid. ESI-MS [M+H] calc d for C27H35FN4O4, 499.26; found, 499.3. [0636] Step 7: (2S,4S)-4-cyclohexyl-1-(7-fluoro-1H-indole-2-carbonyl)-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide [0637] To a mixture of (2S,4S)-4-cyclohexyl-1-(7-fluoro-1H-indole-2-carbonyl)-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (50 mg, 100.28 μmol) in DCM (2 mL) was added DMP (85 mg, 200.57 μmol). The mixture was stirred at 25 °C for 0.5 hr. The mixture was quenched with H2O (3 mL), and extracted with DCM:MeOH (10:1, 5 mL x3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30mm×3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 27%-67%, 11min). Compound 71 (8.3 mg, 15.18% yield, 91.1% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.60 - 7.28 (m, 1H), 7.17 - 6.88 (m, 3H), 4.73 (br d, J = 8.8 Hz, 1H), 4.55 - 4.37 (m, 1H), 4.32 - 4.10 (m, 1H), 4.05 - 3.72 (m, 1H), 3.67 - 3.47 (m, 1H), 3.11 - 2.93 (m, 1H), 2.69 - 2.52 (m, 1H), 2.48 - 2.23 (m, 2H), 2.22 - 1.90 (m, 3H), 1.88 - 1.57 (m, 6H), 1.55 - 1.17 (m, 5H), 1.16 - 0.95 (m, 2H). ESI-MS [M+H]+ calc’d for C27H33FN4O4, 497.25; found, 497.3. [0638] Example 72: (1R,2S,5S)-6,6-Dimethyl-3-(6-methyl-1H-indole-2-carbonyl)-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 72)
Figure imgf000167_0001
[0639] Compound 72 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.58 - 7.37 (m, 1H), 7.28 - 7.18 (m, 1H), 7.07 - 6.89 (m, 1H), 6.89 - 6.81 (m, 1H), 4.54 - 4.37 (m, 1H), 4.32 - 3.93 (m, 2H), 3.83 - 3.67 (m, 1H), 3.29 - 3.21 (m, 1H), 2.94 - 2.56 (m, 1H), 2.42 (d, J = 5.2 Hz, 3H), 2.39 - 2.18 (m, 1H), 2.10 - 1.66 (m, 3H), 1.64 - 1.25 (m, 3H), 1.19 - 0.92 (m, 6H). ESI-MS [M+H]+ calc’d for C25H30N4O4, 451.23; found, 451.4. [0640] Example 73: (1R,2S,5S)-3-(4,4-Dimethylpentanoyl)-6,6-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 73)
Figure imgf000168_0001
[0641] Compound 73 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 4.53 - 4.44 (m, 1H), 4.35 - 4.24 (m, 1H), 4.02 - 3.66 (m, 2H), 3.64 - 3.47 (m, 1H), 3.29 - 3.24 (m, 1H), 2.62 - 2.08 (m, 4H), 2.06 - 1.94 (m, 1H), 1.87 - 1.65 (m, 1H), 1.61 - 1.38 (m, 5H), 1.10 - 0.95 (m, 6H), 0.93 - 0.86 (m, 9H). ESI-MS [M+H]+ calc’d for C22H35N3O4, 406.26; found, 406.4. [0642] Example 74: (1R,2S,5S)-3-(6-Cyano-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 74)
Figure imgf000168_0002
[0643] Compound 74 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.87 - 7.68 (m, 2H), 7.37 - 7.25 (m, 1H), 7.21 - 6.96 (m, 1H), 4.53 - 4.38 (m, 1H), 4.35 - 4.00 (m, 1H), 4.00 - 3.92 (m, 1H), 3.80 - 3.66 (m, 1H), 3.30 - 3.21 (m, 1H), 3.00 - 2.57 (m, 1H), 2.41 - 2.23 (m, 1H), 2.11 - 1.77 (m, 1H), 1.77 - 1.69 (m, 1H), 1.68 - 1.54 (m, 2H), 1.54 - 1.23 (m, 2H), 1.16 - 0.96 (m, 6H). ESI-MS [M+H]+ calc’d for C25H27N5O4, 462.21; found, 462.4. [0644] Example 75: (2S,4S)-1-(7-cyano-1H-indole-2-carbonyl)-4-cyclohexyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 75)
Figure imgf000169_0001
[0645] Step 1: methyl 7-bromo-1H-indole-2-carboxylate
Figure imgf000169_0002
[0646] To a solution of 7-bromo-1H-indole-2-carboxylic acid (1.00 g, 4.17 mmol) in MeOH (12 mL) was added SOCl2 (1.5 g, 12.50 mmol) at 0°C. The mixture was stirred at 50°C for 12 hr. The reaction mixture was concentrated in vacuo. The residue was dissolved in water (20 mL) and then extracted with EtOAc (40 mL x3). The combined organic phase was washed with water (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The title compound (1.17 g, crude) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.97 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 3.97 (s, 3H). [0647] Step 2: methyl 7-cyano-1H-indole-2-carboxylate
Figure imgf000169_0003
[0648] A mixture of methyl 7-bromo-1H-indole-2-carboxylate (500 mg, 1.97 mmol) and CuCN (352 mg, 3.94 mmol, 859.76 μL) in NMP (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 180°C for 2 hr under microwave. Water (15 mL) was added and the reaction mixture was adjusted to pH~10 by aq. NaOH (6 M). The resulting mixture was extracted with EtOAc (30 mL x3). The combined organic phase was washed with aq. NH4Cl (20 mL x3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The title compound (420 mg, crude) was obtained as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 9.49 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.66 (dd, J = 0.8, 7.2 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 3.99 (s, 3H). [0649] Step 3: 7-cyano-1H-indole-2-carboxylic acid
Figure imgf000170_0001
[0650] To a solution of methyl 7-cyano-1H-indole-2-carboxylate (420 mg, 2.10 mmol) in THF (4 mL) and H2O (4 mL) was added LiOH.H2O (352 mg, 8.39 mmol). The mixture was stirred at 25°C for 10 hr. Water (10 mL) was added and the reaction mixture was adjusted to pH~5 by aq. HCl (1 N). The resulting mixture was extracted with EtOAc (30 mL x3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The title compound (310 mg, crude) was obtained as a yellow solid.1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J =8.4 Hz, 1H), 7.68 (d, J =7.6 Hz, 1H), 7.28 (s, 1H), 7.25 - 7.16 (m, 1H). [0651] Step 4: (S)-methyl 2-((2S,4S)-1-(7-cyano-1H-indole-2-carbonyl)-4- cyclohexylpyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000170_0002
[0652] To a solution of compound (S)-methyl 2-((2S,4S)-4-cyclohexylpyrrolidine-2- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (648 mg, 1.61 mmol, HCl), 7-cyano- 1H-indole-2-carboxylic acid (300 mg, 1.61 mmol,) and DIEA (625 mg, 4.83 mmol) in DCM (10 mL) was added slowly HATU (1.23 g, 3.22 mmol) at 0°C. The resulting mixture was stirred at 25°C for 3 hr. Sat.aq.NH4Cl (30 mL) was added. The resulting mixture was extracted with DCM (50 mL x3). The combined organic phase was washed with water (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (Eluent of 0~96% EtOAc in PE). The title compound (500 mg, 26.72% yield) was obtained as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 11.55 (brs, 1H), 9.05 (brs, 1H), 8.05 - 7.81 (m, 1H), 7.66 - 7.47 (m, 1H), 7.24 - 6.94 (m, 2H), 5.17 - 4.69 (m, 1H), 4.65 - 4.17 (m, 1H), 4.09 - 3.96 (m, 1H), 3.79 - 3.73 (m, 3H), 3.60 - 3.37 (m, 3H), 2.79 - 2.24 (m, 8H), 2.16 - 2.07 (m, 1H), 1.96 - 1.56 (m, 5H), 1.23 - 0.79 (m, 5H). [0653] Step 5: (2S,4S)-1-(7-cyano-1H-indole-2-carbonyl)-4-cyclohexyl-N-((S)-1-hydroxy- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide
Figure imgf000171_0001
[0654] To a solution of (S)-methyl 2-((2S,4S)-1-(7-cyano-1H-indole-2-carbonyl)-4- cyclohexylpyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (500 mg, 937.00 μmol) in THF (5 mL) was added LiBH4 (70 mg, 3.21 mmol) at 0°C. The mixture was stirred at 25°C for 1 h. The reaction was quenched with water (15 mL) drop-wise. The resulting mixture was extracted with DCM (30 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex C1875×30mm×3μm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 27%-57%, 10 min). The title compound (30 mg, 4.88% yield) was obtained.1H NMR (400 MHz, CDCl3) δ ppm 11.87 (brs, 1H), 9.01 (d, J = 3.6 Hz, 1H), 7.97 - 7.61 (m, 1H), 7.61 - 7.36 (m, 1H), 7.19 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 5.12 - 4.82 (m, 1H), 4.68 - 4.37 (m, 1H), 4.13 - 3.99 (m, 1H), 3.96 - 3.84 (m, 1H), 3.79 - 3.56 (m, 2H), 3.53 - 3.28 (m, 2H), 3.05 (t, J = 9.6 Hz, 1H), 2.59 - 2.45 (m, 1H), 2.43 - 2.27 (m, 1H), 2.08 - 1.46 (m, 10H), 1.34 - 1.03 (m, 5H), 1.00 - 0.80 (m, 2H). [0655] Step 6: (2S,4S)-1-(7-cyano-1H-indole-2-carbonyl)-4-cyclohexyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide [0656] To a solution of (2S,4S)-1-(7-cyano-1H-indole-2-carbonyl)-4-cyclohexyl-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (20 mg, 39.56 μmol) in DCM (4 mL) was added DMP (50 mg, 118.67 μmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was filtered. The filtrate was concentrated. The residue was purified by prep-HPLC (column: Phenomenex C1875×30mm×3μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 28%-58%, 10 min). Compound 75 (4.3 mg, 20.48% yield, 94.895% purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 8.11 - 7.81 (m, 1H), 7.75 - 7.57 (m, 1H), 7.34 - 6.91 (m, 2H), 4.72 (br d, J = 8.8 Hz, 1H), 4.54 - 4.35 (m, 1H), 4.29 - 4.10 (m, 1H), 4.07 - 3.72 (m, 1H), 3.67 - 3.45 (m, 1H), 3.29 - 3.02 (m, 1H), 2.73 - 2.51 (m, 1H), 2.48 - 1.92 (m, 4H), 1.81 - 0.99 (m, 14H). ESI-MS [M+H] calc d for C28H33N5O4, 504.25; found, 504.4. [0657] Example 76: (S)-5-(4-Cyano-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (Compound 76)
Figure imgf000172_0001
[0658] Compound 76 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.80 - 7.73 (m, 1H), 7.55 - 7.47 (m, 1H), 7.39 - 7.31 (m, 1H), 7.12 - 6.94 (m, 1H), 4.84 - 4.78 (m, 1H), 4.51 - 4.36 (m, 1H), 4.06 - 3.93 (m, 1H), 3.89 (dd, J = 6.0, 10.0 Hz, 1H), 3.85 - 3.66 (m, 1H), 2.71 - 2.51 (m, 1H), 2.47 - 2.34 (m, 1H), 2.28 - 2.18 (m, 1H), 2.13 - 1.98 (m, 2H), 1.95 - 1.36 (m, 3H), 0.83 - 0.59 (m, 4H). ESI-MS [M+H]+ calc’d for C24H25N5O4, 448.19; found, 448.4. [0659] Example 77: (1R,2S,5S)-3-(7-Fluoro-4-methyl-1H-indole-2-carbonyl)-6,6- dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane- 2-carboxamide (Compound 77)
Figure imgf000172_0002
[0660] Compound 77 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.14 - 6.73 (m, 3H), 4.56 - 3.93 (m, 3H), 3.83 - 3.64 (m, 1H), 2.94 - 2.59 (m, 1H), 2.56 - 2.45 (m, 3H), 2.42 - 1.98 (m, 2H), 1.91 - 1.26 (m, 6H), 1.20 - 0.99 (m, 6H). ESI-MS [M+H]+ calc’d for C25H29FN4O4, 469.22; found, 469.4. [0661] Example 78: (1R,2S,5S)-3-(4H-Furo[3,2-b]pyrrole-5-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 78)
Figure imgf000173_0001
[0662] Compound 78 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.65 - 7.42 (m, 1H), 6.83 - 6.35 (m, 2H), 4.56 - 4.39 (m, 1H), 4.17 (m, 1H), 3.99 - 3.76 (m, 2H), 3.11 - 2.74 (m, 1H), 2.67 - 2.54 (m, 1H), 2.44 - 2.24 (m, 1H), 2.11 - 1.96 (m, 1H), 1.81 - 1.42 (m, 5H), 1.11 - 0.93 (m, 6H). ESI-MS [M+H]+ calc’d for C22H26N4O5, 427.19; found, 427.4. [0663] Example 79: (1R,2S,5S)-3-(2-Cyclohexylacetyl)-6,6-dimethyl-N-((S)-1-oxo-3-((S)- 2-oxopiperidin-3-yl)propan-2-yl)-3-azabicyclo[310]hexane-2-carboxamide (Compound 79)
Figure imgf000173_0002
[0664] Compound 79 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 4.82 (m, 1H), 4.55 - 4.22 (m, 2H), 4.07 - 3.65 (m, 2H), 3.62 - 3.54 (m, 1H), 3.29 - 3.23 (m, 2H), 2.43 (m, 1H), 2.22 - 2.05 (m, 3H), 1.85 - 1.62 (m, 8H), 1.56 - 1.38 (m, 3H), 1.32 - 1.13 (m, 3H), 1.13 - 0.79 (m, 8H). ESI-MS [M+H]+ calc’d for C24H37N3O4, 432.28; found, 432.4. [0665] Example 80: (1R,2S,5S)-6,6-Dimethyl-3-(5-(methylsulfonyl)-1H-indole-2- carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane- 2-carboxamide (Compound 80)
Figure imgf000173_0003
[0666] Compound 80 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 8.40 - 8.19 (m, 1H), 7.76 – 7.68 (m, 1H), 7.67 - 7.59 (m, 1H), 7.31 - 7.05 (m, 1H), 4.64 - 4.38 (m, 1H), 4.36 - 3.94 (m, 2H), 3.82 - 3.68 (m, 1H), 3.36 - 3.32 (m, 1H), 3.28 - 3.23 (m, 1H), 3.15 (d, J = 18.4 Hz, 3H), 3.00 - 2.58 (m, 1H), 2.50 - 2.29 (m, 1H), 2.12 - 1.75 (m, 1H), 1.72 - 1.30 (m, 4H), 1.19 - 0.96 (m, 6H). ESI-MS [M+H]+ calc’d for C25H30N4O6S, 515.19; found, 515.1. [0667] Example 81: (2S,4S)-1-(7-chloro-1H-indole-2-carbonyl)-4-cyclohexyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 81)
Figure imgf000174_0001
[0668] Step 1: (S)-methyl 2-((2S,4S)-4-cyclohexylpyrrolidine-2-carboxamido)-3-((S)-2- oxopyrrolidin-3-yl)propanoate
Figure imgf000174_0002
[0669] To a mixture of (2S,4S)-tert-butyl 4-cyclohexyl-2-(((S)-1-methoxy-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)pyrrolidine-1-carboxylate (350 mg, 751.75 μmol) in dioxane (4 mL) was added HCl/dioxane (4M, 4 mL). The mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated to dryness. The title compound (300 mg, crude, HCl) was obtained as a white solid. [0670] Step 2: (S)-methyl 2-((2S,4S)-1-(7-chloro-1H-indole-2-carbonyl)-4- cyclohexylpyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate
Figure imgf000175_0001
[0671] To a solution of (S)-methyl 2-((2S,4S)-4-cyclohexylpyrrolidine-2-carboxamido)-3- ((S)-2-oxopyrrolidin-3-yl)propanoate (300 mg, 746.40 μmol, HCl), 7-chloro-1H-indole-2- carboxylic acid (146 mg, 746.40 μmol) and DIEA (289 mg, 2.24 mmol) in DCM (5 mL) was added HATU (567 mg, 1.49 mmol) slowly at 0°C. The mixture was stirred at 25°C for 3 hr. Sat.aq.NH4Cl (20 mL) was added. The resulting mixture was extracted with DCM (20 mL x3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash silica gel chromatography (Eluent of 0~88% EtOAc in PE). The title compound (400 mg, 58.54% yield) was obtained as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 9.78 - 9.38 (m, 1H), 8.80 - 7.92 (m, 1H), 7.69 - 7.54 (m, 1H), 7.53 - 7.28 (m, 1H), 7.16 - 7.02 (m, 1H), 6.94 (s, 1H), 6.13 - 5.99 (m, 1H), 4.98 - 4.72 (m, 1H), 4.64 - 4.27 (m, 1H), 4.25 - 3.94 (m, 1H), 3.80 - 3.65 (m, 3H), 3.46 - 3.28 (m, 3H), 2.41 - 2.24 (m, 3H), 1.97 - 1.73 (m, 5H), 1.69 - 1.63 (m, 2H), 1.30 - 0.92 (m, 9H). [0672] Step 3: (2S,4S)-1-(7-chloro-1H-indole-2-carbonyl)-4-cyclohexyl-N-((S)-1-hydroxy- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide
Figure imgf000175_0002
[0673] To a solution of (S)-methyl 2-((2S,4S)-1-(7-chloro-1H-indole-2-carbonyl)-4- cyclohexylpyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (400 mg, 736.58 μmol) in THF (4 mL) was added LiBH4 (140 mg, 6.43 mmol) at 0°C. The mixture was stirred at 25 °C for 1 hr. The reaction was quenched with water (10 mL) dropwise. The resulting mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: Xtimate C18150×40mm×10μm; mobile phase: [water (0.05%NH3H2O)-ACN]; B%: 35%-65%, 10 min). The title compound (106 mg, 27.25% yield,) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.85 - 9.46 (m, 1H), 8.37 - 7.94 (m, 1H), 7.64 - 7.44 (m, 1H), 7.31 - 7.27 (m, 1H), 7.10 - 7.03 (m, 1H), 7.00 - 6.77 (m, 1H), 5.92 - 5.59 (m, 1H), 4.94 - 4.65 (m, 1H), 4.22 (t, J = 8.4 Hz, 1H), 4.09 - 3.91 (m, 1H), 3.82 - 3.73 (m, 1H), 3.63 - 3.52 (m, 1H), 3.42 (t, J = 9.2 Hz, 1H), 3.35 - 3.24 (m, 2H), 2.60 - 2.24 (m, 5H), 2.08 - 2.02 (m, 1H), 1.91 - 1.74 (m, 3H), 1.69 - 1.57 (m, 3H), 1.30 - 0.91 (m, 7H). [0674] Step 4: (2S,4S)-1-(7-chloro-1H-indole-2-carbonyl)-4-cyclohexyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide [0675] To a solution of (2S,4S)-1-(7-chloro-1H-indole-2-carbonyl)-4-cyclohexyl-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (100 mg, 194.16 μmol) in DCM (5 mL) was added DMP (165 mg, 388.32 μmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 32%-62%, 10 min). Compound 81 (20.6 mg, 38.88 μmol, 20.03% yield, 96.84 purity) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.71 - 7.42 (m, 1H), 7.32 - 7.21 (m, 1H), 7.15 - 6.87 (m, 2H), 4.71 (br d, J = 8.4 Hz, 1H), 4.55 - 4.34 (m, 1H), 4.28 - 4.10 (m, 1H), 4.06 - 3.71 (m, 1H), 3.63 - 3.43 (m, 1H), 3.29 - 2.95 (m, 1H), 2.67 - 2.52 (m, 1H), 2.43 - 2.17 (m, 2H), 2.13 - 1.90 (m, 2H), 1.88 - 0.92 (m, 14H) ESI-MS [M+H]+ calc’d for C27H33ClN4O4, 513.22; found, 513.2. [0676] Example 82: (S)-5-(6-Cyano-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (Compound 82)
Figure imgf000176_0001
[0677] Compound 82 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.86 (s, 1H), 7.83 - 7.68 (m, 1H), 7.36 - 7.27 (m, 1H), 7.13 - 6.95 (m, 1H), 4.84 - 4.75 (m, 2H), 4.51 - 4.35 (m, 1H), 4.10 - 3.93 (m, 1H), 3.89 - 3.81 (m, 1H), 3.78 - 3.68 (m, 1H), 3.12 - 2.62 (m, 1H), 2.59 - 2.37 (m, 1H), 2.27 - 1.97 (m, 2H), 1.90 - 1.71 (m, 1H), 1.67 - 1.39 (m, 2H), 0.80 - 0.60 (m, 4H). ESI-MS [M+H]+ calc’d for C24H25N5O4, 448.19; found, 448.3. [0678] Example 83: (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-(1H-pyrrolo[3,2-b]pyridine-2-carbonyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 83)
Figure imgf000177_0001
[0679] Step 1: (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoic acid
Figure imgf000177_0002
[0680] To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin- 3-yl)propanoate (5 g, 17.46 mmol) in THF (25 mL) and H2O (25 mL) was added LiOH·H2O (1.5 g, 34.93 mmol) at 25°C. The mixture was stirred at 25°C for 1 h. Water (15 mL) was added to the reaction mixture. The resulting mixture was extracted with EtOAc:PE (1:5) ( 10 mL). The water phase was then adjusted to pH~6 by aq. HCl (1 M) and then lyophilized. The
Figure imgf000177_0003
title compound (6.1 g, crude,) was obtained as a white solid.1H NMR (400MHz, DMSO-d6) δ ppm 7.56 (s, 1H), 6.11 (d, J = 7.2 Hz, 1H), 3.70 - 3.62 (m, 1H), 3.16 - 3.07 (m, 2H), 2.31 - 2.10 (m, 2H), 1.95 - 1.83 (m, 1H), 1.67 - 1.51 (m, 2H), 1.36 (s, 9H) [0681] Step 2: tert-butyl ((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)carbamate
Figure imgf000177_0004
[0682] To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3- yl)propanoic acid (5 g, 18.36 mmol) in DCM (40 mL) was added DIEA (9.5 g, 73.45 mmol, 12.79 mL) and T3P (17.5 g, 27.54 mmol, 16.38 mL, 50% purity) at 0°C. After addition, the mixture was stirred at 0°C for 5 min, and then N,O-dimethylhydroxylamine (2.7 g, 27.54 mmol, 1.5 eq, HCl) was added dropwise at 0°C. The resulting mixture was stirred at 25 °C for 12 hr. The reaction mixture was poured into water (20 mL). The resulting mixture was extracted with DCM (30 mL x 2). The combined organic phase was washed with 5% H3PO4 (50 mL), sat.aq.NaHCO3 (50mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The title compound (3.2 g, 53.39% yield) was obtained as a light yellow solid.1H NMR (400MHz, CDCl3) δ ppm 5.95 (s, 1H), 5.39 (d, J = 8.8 Hz, 1H), 4.75 - 4.62 (m, 1H), 3.77 (s, 3H), 3.40 - 3.30 (m, 2H), 3.20 (s, 3H), 2.57 - 2.43 (m, 2H), 2.16 - 2.05 (m, 1H), 1.92 - 1.62 (m, 2H), 1.42 (s, 9H). [0683] Step 3: (S)-2-amino-N-methoxy-N-methyl-3-((S)-2-oxopyrrolidin-3- yl)propanamide
Figure imgf000178_0001
[0684] A mixture of tert-butyl ((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)carbamate (1.2 g, 3.81 mmol) in HCl/dioxane (12 mL) was stirred at 25°C for 2 hrs. The reaction mixture was concentrated directly. The title compound (960 mg, 90.21% yield, HCl) was obtained as a white solid. [0685] Step 4: (1R,2S,5S)-tert-butyl 2-(((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3- carboxylate
Figure imgf000178_0002
[0686] To a mixture of (1R,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (950 mg, 3.72 mmol) in DCM (10 mL) was added T3P (3.55 g, 5.58 mmol, 3.32 mL, 50% purity) and DIEA (1.92 g, 14.88 mmol, 2.59 mL) at 0°C. After addition, the reaction mixture was stirred at the same temperature for 5 min. To the above solution was added a solution of (S)-2-amino-N-methoxy-N-methyl-3-((S)-2- oxopyrrolidin-3-yl)propanamide (936.61 mg, 3.72 mmol, HCl) in DCM (4 mL) at 0°C. Then the resulting mixture was degassed and purged with N2 for 3 times, and the mixture was stirred at 25°C for 10 hrs under N2 atmosphere.5% phosphoric acid solution (10 mL) was added to the reaction mixture. The aqueous phase was extracted with DCM (10 mL x3). Then the combined organic phase was washed with sat.aq NaHCO3 (20 mL), brine (20mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product used into the next step without further purification. The title compound (1.2 g, 64.14% yield) was obtained as a white solid.1H NMR (400MHz, CDCl3) δ ppm 7.17 - 6.95 (m, 1H), 5.99 - 5.43 (m, 1H), 5.05 - 4.89 (m, 1H), 4.15 - 3.99 (m, 1H), 3.79 (d, J = 9.6 Hz, 3H), 3.67 - 3.58 (m, 1H), 3.58 - 3.40 (m, 1H), 3.37 - 3.26 (m, 2H), 3.19 (d, J = 5.6 Hz, 3H), 2.58 - 2.35 (m, 2H), 2.24 - 2.10 (m, 1H), 1.88 - 1.69 (m, 2H), 1.47 - 1.34 (m, 11H), 1.04 - 0.90 (m, 6H) [0687] Step 5: (1R,2S,5S)-N-((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000179_0001
[0688] To a solution of (1R,2S,5S)-tert-butyl 2-(((S)-1-(methoxy(methyl)amino)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 3-carboxylate (300 mg, 662.92 µmol) in dioxane (6 mL) was added HCl/dioxane (4 M, 6 mL). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was concentrated directly. The title compound (280 mg, crude, HCl) was obtained as a white solid. [0689] Step 6: (1R,2S,5S)-N-((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-(1H-pyrrolo[3,2-b]pyridine-2-carbonyl)-3- azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000180_0001
[0690] To a solution of 1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (115 mg, 709.37 µmol) and DIEA (275 mg, 2.13 mmol, 370.67 uL) in DCM (5 mL) was added (1R,2S,5S)-N- ((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (250 mg, 709.37 µmol). After addition, HATU (540 mg, 1.42 mmol) was added at 0°C. The mixture was stirred at 25 °C for 3 hr. The reaction mixture was poured into sat.aq.NH4Cl (20 mL). The resulting mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30mm×3μm;mobile phase: [water(0.05%NH3H2O+10mM NH4HCO3)-ACN];B%: 5%-45%,11min). The title compound (150 mg, 284.44 µmol, 40.10% yield) was obtained as a white solid.1H NMR (400MHz, CDCl3) δ ppm 9.88 - 8.99 (m, 1H), 8.53 - 8.20 (m, 1H), 7.73 - 7.33 (m, 2H), 7.16 - 6.83 (m, 2H), 5.92 - 5.69 (m, 1H), 4.97 - 4.77 (m, 1H), 4.62 - 4.49 (m, 1H), 4.25 - 3.89 (m, 2H), 3.87 - 3.70 (m, 4H), 3.19 - 3.10 (m, 4H), 2.55 - 2.08 (m, 4H), 1.83 - 1.74 (m, 1H), 1.07 - 0.77 (m, 8H). [0691] - Step 7: (1R,2S,5S)-6,6-dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-(1H-pyrrolo[3,2-b]pyridine-2-carbonyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide [0692] To a solution of (1R,2S,5S)-N-((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-(1H-pyrrolo[3,2-b]pyridine-2-carbonyl)-3- azabicyclo[3.1.0]hexane-2-carboxamide (70 mg, 140.97 µmol) in THF (3 mL) was added LiAlH4 (2 M, 105 uL) at 0°C. The mixture was stirred at 25°C for 12 hr. The reaction was quenched with sat.aq.NH4Cl (1 mL) drop-wise, filtered and concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3μm;mobile phase: [water(0.05%NH3H2O+10mM NH4HCO3)-ACN];B%: 0%- 40%,15min). Compound 83 (4 mg, 8.67 µmol, 6.15% yield, 94.80% purity) was obtained as a white solid.1H NMR (400MHz, CD3OD) δ ppm 8.45 - 8.33 (m, 1H), 7.94 - 7.84 (m, 1H), 7.33 - 7.22 (m, 1H), 7.19 - 6.95 (m, 1H), 4.53 - 3.70 (m, 4H), 3.29 - 3.23 (m, 1H), 2.95 - 2.58 (m, 1H), 2.45 - 2.29 (m, 1H), 2.13 - 1.96 (m, 1H), 1.89 - 1.68 (m, 2H), 1.67 - 1.47 (m, 2H), 1.34 - 0.97 (m, 7H). ESI-MS [M+H]+ calc’d. for C23H27N5O4438.21, found 456.2. [0693] Example 84: (S)-N-((S)-1-Oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6-(1- phenylcyclopropanecarbonyl)-6-azaspiro[3.4]octane-7-carboxamide (Compound 84)
Figure imgf000181_0001
[0694] Compound 84 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.40 - 7.16 (m, 5H), 4.86 - 4.43 (m, 2H), 4.35 (t, J = 8.0 Hz, 1H), 4.04 - 3.88 (m, 1H), 3.57 (d, J = 10.8 Hz, 1H), 3.26 - 3.16 (m, 1H), 2.78 - 2.57 (m, 1H), 2.47 - 2.23 (m, 2H), 2.10 - 1.98 (m, 1H), 1.95 - 1.67 (m, 7H), 1.67 - 1.49 (m, 3H), 1.35 - 1.12 (m, 3H). ESI-MS [M+H]+ calc’d for C25H31N3O4, 438.23; found, 438.4. [0695] Example 85: (1R,2S,5S)-6,6-Dimethyl-3-(4-methyl-1H-indole-2-carbonyl)-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 85)
Figure imgf000181_0002
[0696] Compound 85 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.29 - 7.21 (m, 1H), 7.16 - 7.10 (m, 1H), 7.09 - 6.89 (m, 1H), 6.89 - 6.80 (m, 1H), 4.67 - 4.61 (m, 1H), 4.52 - 4.30 (m, 1H), 4.03 - 3.66 (m, 2H), 3.29 - 3.23 (m, 1H), 2.82 - 2.59 (m, 1H), 2.58 - 2.45 (m, 3H), 2.39 - 1.82 (m, 2H), 1.81 - 1.66 (m, 2H), 1.64 - 1.19 (m, 3H), 1.18 - 0.94 (m, 6H). ESI-MS [M+H]+ calc’d for C25H30N4O4, 451.23; found, 451.2. [0697] Example 86: (1R,2S,5S)-6,6-Dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-(2-(tetrahydro-2H-pyran-4-yl)acetyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 86)
Figure imgf000182_0001
[0698] Compound 86 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 4.56 - 4.43 (m, 1H), 4.37 - 4.25 (m, 1H), 4.03 - 3.66 (m, 4H), 3.64 - 3.55 (m, 1H), 3.45 - 3.35 (m, 2H), 3.28 - 3.22 (m, 1H), 2.72 - 2.51 (m, 1H), 2.44 - 2.14 (m, 3H), 2.07 - 1.96 (m, 2H), 1.91 - 1.40 (m, 6H), 1.37 - 1.17 (m, 2H), 1.13 - 0.92 (m, 6H). ESI-MS [M+H]+ calc’d for C22H33N3O5, 420.24; found, 420.2. [0699] Example 87: (S)-5-(7-Fluoro-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (Compound 87)
Figure imgf000182_0002
[0700] Compound 87 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.53 - 7.29 (m, 1H), 7.12 - 6.86 (m, 3H), 4.65 - 4.31 (m, 2H), 4.12 - 3.64 (m, 3H), 2.72 - 2.34 (m, 2H), 2.30 - 2.15 (m, 1H), 2.14 - 1.91 (m, 2H), 1.90 - 1.72 (m, 1H), 1.70 - 1.52 (m, 1H), 1.51 - 1.26 (m, 1H), 0.85 - 0.56 (m, 4H). ESI-MS [M+H]+ calc’d for C23H25FN4O4, 441.19; found, 441.1. [0701] Example 88: (1R,2S,5S)-3-(7-Chloro-4-isopropyl-1H-indole-2-carbonyl)-6,6- dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane- 2-carboxamide (Compound 88)
Figure imgf000183_0001
[0702] Compound 88 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.29 - 6.83 (m, 3H), 4.70 - 4.65 (m, 1H), 4.41 - 4.26 (m, 1H), 4.11 - 3.94 (m, 1H), 3.93 - 3.70 (m, 1H), 3.51 - 3.34 (m, 1H), 3.28 - 3.22 (m, 1H), 2.97 - 2.52 (m, 1H), 2.44 - 2.28 (m, 1H), 2.24 - 1.96 (m, 1H), 1.85 - 1.67 (m, 2H), 1.66 - 1.44 (m, 2H), 1.42 - 1.24 (m, 7H), 1.22 - 0.90 (m, 6H). ESI-MS [M+H]+ calc’d for C27H33ClN4O4, 513.22; found, 513.1. [0703] Example 89: (1R,2S,5S)-3-(5-Chloro-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 89)
Figure imgf000183_0002
[0704] Compound 89 was synthesized by the same procedure as Compound 83.1H NMR (400 MHz, CD3OD) δ ppm 7.69 - 7.48 (m, 1H), 7.45 - 7.37 (m, 1H), 7.23 - 7.15 (m, 1H), 7.07 - 6.83 (m, 1H), 5.04 - 4.94 (m, 1H), 4.53 - 4.38 (m, 1H), 4.32 - 3.95 (m, 2H), 3.80 - 3.64 (m, 1H), 2.99 - 2.56 (m, 1H), 2.43 - 2.28 (m, 1H), 2.10 - 1.91 (m, 1H), 1.90 - 1.75 (m, 1H), 1.74 - 1.67 (m, 1H), 1.64 - 1.30 (m, 3H), 1.19 - 0.85 (m, 6H). ESI-MS [M+H]+ calc’d for C24H27ClN4O4, 471.17; found, 471.4. [0705] Example 90: (1R,2S,5S)-3-(5-Chloro-1-methyl-1H-indole-2-carbonyl)-6,6- dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane- 2-carboxamide (Compound 90)
Figure imgf000184_0001
[0706] Compound 90 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.63 - 7.50 (m, 1H), 7.45 - 7.38 (m, 1H), 7.26 - 7.18 (m, 1H), 6.85 - 6.60 (m, 1H), 4.77 - 4.60 (m, 1H), 4.54 - 4.33 (m, 1H), 4.11 - 3.94 (m, 1H), 3.81 - 3.73 (m, 3H), 3.72 - 3.64 (m, 1H), 3.59 - 3.37 (m, 1H), 3.09 - 2.56 (m, 2H), 2.45 - 1.97 (m, 1H), 1.82 - 1.61 (m, 1H), 1.61 - 1.54 (m, 2H), 1.41 - 1.25 (m, 2H), 1.23 - 1.03 (m, 6H). ESI-MS [M+H]+ calc’d for C25H29ClN4O4, 485.19; found, 485.4. [0707] Example 91: (1R,2S,5S)-3-(7-Methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 91)
Figure imgf000184_0002
[0708] Compound 91 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.28 - 7.09 (m, 1H), 7.07 - 6.84 (m, 2H), 6.79 - 6.68 (m, 1H), 5.02 - 4.93 (m, 1H), 4.65 - 4.56 (m, 1H), 4.54 - 4.37 (m, 1H), 4.33 - 4.01 (m, 1H), 3.98 - 3.94 (m, 3H), 3.83 - 3.68 (m, 1H), 2.97 - 2.53 (m, 1H), 2.42 - 2.26 (m, 1H), 2.12 - 1.82 (m, 1H), 1.81 - 1.67 (m, 2H), 1.65 - 1.28 (m, 3H), 1.20 - 0.93 (m, 6H). ESI-MS [M+H]+ calc’d for C25H30N4O5, 467.22; found, 467.4. [0709] Example 92: (1R,2S,5S)-3-((S)-2-Cyclohexylpropanoyl)-6,6-dimethyl-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 92)
Figure imgf000185_0001
[0710] Compound 92 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 4.52 - 4.39 (m, 1H), 4.33 - 4.07 (m, 1H), 4.04 - 3.67 (m, 2H), 3.64 - 3.51 (m, 1H), 3.28 - 3.24 (m, 1H), 2.70 - 1.93 (m, 4H), 1.89 - 1.61 (m, 6H), 1.60 - 1.37 (m, 4H), 1.29 - 1.11 (m, 3H), 1.10 - 1.05 (m, 3H), 1.05 - 0.79 (m, 8H). ESI-MS [M+H]+ calc’d for C24H37N3O4, 432.57; found, 432.4. [0711] Example 93: (1R,2S,5S)-6,6-Dimethyl-3-(5-methyl-1H-indole-2-carbonyl)-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 93)
Figure imgf000185_0002
[0712] Compound 93 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.45 - 7.27 (m, 2H), 7.10 - 7.02 (m, 1H), 6.99 - 6.80 (m, 1H), 5.02 - 4.89 (m, 1H), 4.82 - 4.61 (m, 1H), 4.52 - 4.25 (m, 1H), 4.06 - 3.95 (m, 1H), 3.79 - 3.43 (m, 1H), 3.29 - 3.19 (m, 1H), 2.89 - 2.55 (m, 1H), 2.39 (d, J = 14.4 Hz, 3H), 2.35 - 2.13 (m, 1H), 2.09 - 1.88 (m, 1H), 1.78 - 1.66 (m, 1H), 1.63 - 1.52 (m, 1H), 1.46 - 1.22 (m, 2H), 1.16 - 0.94 (m, 6H). ESI-MS [M+H]+ calc’d for C25H30N4O4, 451.23; found, 451.4. [0713] Example 94: (1R,2S,5S)-3-(1-Hydroxycyclohexanecarbonyl)-6,6-dimethyl-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 94)
Figure imgf000186_0001
[0714] Compound 94 was synthesized by the same procedure as Compound 1. [0715] 1H NMR (400 MHz, CD3OD) δ ppm 4.54 - 4.45 (m, 1H), 4.39 - 4.34 (m, 1H), 4.08 - 3.72 (m, 3H), 3.29 - 3.26 (m, 1H), 2.67 - 2.20 (m, 2H), 2.05 - 1.83 (m, 2H), 1.76 - 1.47 (m, 11H), 1.43 - 1.19 (m, 2H), 1.09 - 0.90 (m, 6H). ESI-MS [M+H]+ calc’d for C22H33N3O5, 420.24; found, 420.4. [0716] Example 95: (1R,2S,5S)-3-(3,3-Dimethylbutanoyl)-6,6-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 95)
Figure imgf000186_0002
[0717] Compound 95 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 4.57 - 4.35 (m, 1H), 4.34 - 4.21 (m, 1H), 4.05 - 3.88 (m, 2H), 3.71 - 3.54 (m, 1H), 3.29 - 3.22 (m, 1H), 2.71 - 2.29 (m, 2H), 2.28 - 2.08 (m, 2H), 2.07 - 1.67 (m, 2H), 1.63 - 1.34 (m, 3H), 1.12 - 0.94 (m, 15H). ESI-MS [M+H]+ calc’d for C21H33N3O4, 392.25; found, 392.3. [0718] Example 96: (1R,2S,5S)-3-(1,4-Dimethylindole-2-carbonyl)-N-[(1S)-1-formyl-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 96)
Figure imgf000186_0003
[0719] Compound 96 was synthesized by the same procedure as Compound 1. H NMR (400 MHz, CD3OD) δ ppm 7.94 - 7.66 (m, 2H), 7.37 - 7.23 (m, 1H), 7.20 - 6.96 (m, 1H), 4.66 - 4.49 (m, 1H), 4.46 - 4.22 (m, 1H), 4.09 - 3.70 (m, 2H), 2.98 - 2.58 (m, 1H), 2.53 - 2.26 (m, 1H), 2.23 - 1.95 (m, 1H), 1.92 - 1.69 (m, 2H), 1.67 - 1.49 (m, 2H), 1.47 - 1.21 (m, 2H), 1.18 - 0.94 (m, 6H). ESI-MS [M+H]+ calc’d for C25H27F3N4O4, 505.20; found, 505.4. [0720] Example 97: (1R,2S,5S)-3-(4,6-Dichloro-1H-indole-2-carbonyl)-6,6-dimethyl-N- ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 97)
Figure imgf000187_0002
[0721] Compound 97 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.45 - 7.39 (m, 1H), 7.15 - 7.09 (m, 1H), 7.08 - 6.87 (m, 1H), 4.65 - 4.57 (m, 1H), 4.53 - 4.39 (m, 1H), 4.35 - 3.92 (m, 2H), 3.83 - 3.68 (m, 1H), 3.02 - 2.55 (m, 1H), 2.43 - 2.26 (m, 1H), 2.06 - 1.90 (m, 1H), 1.85 - 1.72 (m, 1H), 1.72 - 1.51 (m, 2H), 1.50 - 1.26 (m, 2H), 1.20 - 0.91 (m, 6H). ESI-MS [M+H]+ calc’d for C24H26Cl2N4O4, 505.13; found, 505.4. [0722] Example 98: (2S,4R)-4-fluoro-1-(1H-Indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 98)
Figure imgf000187_0001
[0723] Compound 98 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.68 - 7.52 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.11 - 7.04 (m, 1H), 7.04 - 6.89 (m, 1H), 5.52 - 5.20 (m, 1H), 4.36 - 3.57 (m, 4H), 3.29 - 3.23 (m, 1H), 2.84 - 2.57 (m, 2H), 2.39 - 2.00 (m, 3H), 1.85 - 1.54 (m, 2H), 1.39 - 1.16 (m, 1H). ESI-MS [M+H]+ calc’d for C21H23FN4O4, 415.43; found, 415.0. [0724] Example 99: (1R,2S,5S)-N-((S)-4-(Cyclopropylamino)-3,4-dioxo-1-((S)-2- oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-(1-phenylcyclopentanecarbonyl)-3- azabicyclo[3.1.0]hexane-2-carboxamide (Compound 99)
Figure imgf000188_0001
[0725] Compound 99 was synthesized by the same procedure as Compound 119.1H NMR (400 MHz, CD3OD) δ ppm 7.39 - 7.29 (m, 2H), 7.29 - 7.15 (m, 3H), 4.65 - 4.12 (m, 2H), 3.50 - 3.34 (m, 2H), 3.30 - 3.16 (m, 1H), 3.02 - 2.86 (m, 1H), 2.84 - 2.59 (m, 2H), 2.54 - 2.35 (m, 2H), 2.34 - 2.17 (m, 2H), 2.15 - 1.73 (m, 5H), 1.71 - 1.46 (m, 3H), 1.37 - 1.18 (m, 2H), 0.92 (d, J = 3.6 Hz, 3H), 0.82 - 0.65 (m, 2H), 0.65 - 0.50 (m, 5H). ESI-MS [M+H]+ calc’d for C31H40N4O5, 549.30; found, 549.5. [0726] Example 100: (1R,2S,5S)-3-(4-Fluoro-1-methyl-1H-indole-2-carbonyl)-6,6- dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane- 2-carboxamide (Compound 1
Figure imgf000188_0002
[0727] Compound 100 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.29 - 7.13 (m, 2H), 6.93 - 6.64 (m, 2H), 4.83 - 4.73 (m, 1H), 4.55 - 4.32 (m, 1H), 4.14 - 3.98 (m, 1H), 3.84 - 3.74 (m, 3H), 3.73 - 3.47 (m, 2H), 3.29 - 3.19 (m, 1H), 3.07 - 2.79 (m, 1H), 2.69 - 2.31 (m, 1H), 2.13 - 1.68 (m, 1H), 1.64 - 1.49 (m, 3H), 1.42 - 1.28 (m, 1H), 1.22 - 1.13 (m, 3H), 1.12 - 1.03 (m, 3H). ESI-MS [M+H]+ calc’d for C25H29FN4O4, 469.22; found, 469.4. [0728] Example 101: (1R,2S,5S)-3-(5-Fluoro-6-methoxy-1H-indole-2-carbonyl)-6,6- dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane- 2-carboxamide (Compound 101)
Figure imgf000189_0001
[0729] Compound 101 was synthesized by the same procedure as Compound 83.1H NMR (400 MHz, CD3OD) δ ppm 7.35 - 7.14 (m, 1H), 7.08 - 6.80 (m, 2H), 4.59 - 4.37 (m, 1H), 4.30 - 3.93 (m, 2H), 3.89 (d, J = 3.6 Hz, 3H), 3.82 - 3.67 (m, 1H), 3.29 - 3.22 (m, 2H), 2.64 - 2.34 (m, 1H), 2.10 - 1.67 (m, 3H), 1.66 - 1.35 (m, 3H), 1.17 - 0.89 (m, 6H). ESI-MS [M+H]+ calc’d for C25H29FN4O5, 485.21; found, 485.1. [0730] Example 102: (2S,4S)-1-(1H-Indole-2-carbonyl)-4-methoxy-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 102)
Figure imgf000189_0002
[0731] Compound 102 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.72 - 7.52 (m, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.27 - 7.16 (m, 1H), 7.13 - 6.84 (m, 2H), 4.76 (s, 1H), 4.52 - 4.31 (m, 1H), 4.22 - 3.75 (m, 4H), 3.36 - 3.30 (m, 3H), 2.67 - 2.18 (m, 4H), 2.08 - 1.34 (m, 4H). ESI-MS [M+H]+ calc’d for C22H26N4O5, 427.19; found, 427.1. [0732] Example 103: (2S,4R)-4-cyclohexyl-1-(1H-Indole-2-carbonyl)-N-((S)-1-oxo-3-((S)- 2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 103)
Figure imgf000189_0003
[0733] Compound 103 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.70 - 7.49 (m, 1H), 7.47 - 7.30 (m, 1H), 7.26 - 7.16 (m, 1H), 7.11 - 6.79 (m, 2H), 4.66 - 4.52 (m, 2H), 4.37 - 4.17 (m, 1H), 4.12 - 3.84 (m, 1H), 3.78 - 3.56 (m, 1H), 3.43 - 3.33 (m, 1H), 2.90 - 2.60 (m, 1H), 2.55 - 2.34 (m, 1H), 2.24 - 1.98 (m, 2H), 1.90 - 1.72 (m, 5H), 1.71 - 1.55 (m, 3H), 1.39 - 1.26 (m, 4H), 1.23 - 0.99 (m, 3H). ESI-MS [M+H]+ calc’d for C27H34N4O4, 479.26; found, 479.1. [0734] Example 104: (1R,2S,5S)-6,6-Dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-((S)-2-phenylpropanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 104)
Figure imgf000190_0001
[0735] Compound 104 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.54 - 6.91 (m, 5H), 4.57 - 4.30 (m, 1H), 4.21 - 3.84 (m, 2H), 3.82 - 3.62 (m, 1H), 3.59 - 3.34 (m, 2H), 3.27 - 3.10 (m, 1H), 2.68 - 2.22 (m, 2H), 2.10 - 1.52 (m, 3H), 1.52 - 1.37 (m, 2H), 1.37 - 1.27 (m, 3H), 1.13 - 0.30 (m, 6H). ESI-MS [M+H]+ calc’d for C24H31N3O4, 426.23; found, 426.4. [0736] Example 105: (1R,2S,5S)-N-((S)-4-(Cyclopropylamino)-3,4-dioxo-1-((S)-2- oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-(2-(4-methylcyclohexyl)acetyl)-3- azabicyclo[3.1.0]hexane-2-carboxamide (Compound 105)
Figure imgf000190_0002
[0737] Compound 105 was synthesized by the same procedure as Compound 119.1H NMR (400 MHz, CD3OD) δ ppm 4.65 - 4.09 (m, 2H), 3.99 - 3.83 (m, 1H), 3.69 - 3.53 (m, 1H), 3.40 - 3.32 (m, 1H), 3.30 - 3.16 (m, 2H), 2.81 - 2.39 (m, 2H), 2.37 - 1.83 (m, 5H), 1.80 - 1.57 (m, 4H), 1.54 - 1.37 (m, 5H), 1.35 - 1.21 (m, 2H), 1.13 - 1.04 (m, 3H), 1.00 - 0.84 (m, 7H), 0.82 - 0.66 (m, 2H), 0.65 - 0.50 (m, 2H). ESI-MS [M+H]+ calc’d for C28H42N4O5, 515.32; found, 515.5. [0738] Example 106: (1S,3S,4R,6S)-6-Fluoro-2-(1H-indole-2-carbonyl)-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (Compound 106)
Figure imgf000191_0001
[0739] Compound 106 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.76 - 7.39 (m, 2H), 7.30 - 7.17 (m, 1H), 7.14 - 6.78 (m, 2H), 5.17 - 4.96 (m, 1H), 4.53 - 4.27 (m, 1H), 4.12 - 3.33 (m, 2H), 3.18 - 2.78 (m, 2H), 2.65 - 2.36 (m, 1H), 2.35 - 2.09 (m, 2H), 2.08 - 1.57 (m, 5H), 1.57 - 1.28 (m, 2H). ESI-MS [M+H]+ calc’d for C23H25FN4O4, 441.19; found, 441.2. [0740] Example 107: (2S,4R)-1-(1H-Indole-2-carbonyl)-4-methyl-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 107)
Figure imgf000191_0002
[0741] Compound 107 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.68 - 7.50 (m, 1H), 7.44 (br d, J = 8.0 Hz, 1H), 7.26 - 7.18 (m, 1H), 7.10 - 6.84 (m, 2H), 4.85 - 4.66 (m, 1H), 4.65 - 4.46 (m, 1H), 4.40 - 4.18 (m, 1H), 4.16 - 3.89 (m, 1H), 3.84 - 3.50 (m, 1H), 2.98 - 2.53 (m, 2H), 2.45 - 2.16 (m, 2H), 2.14 - 1.71 (m, 3H), 1.67 - 1.33 (m, 2H), 1.13 (d, J = 6.4 Hz, 3H). ESI-MS [M+H]+ calc’d for C22H26N4O4, 411.2; found, 411.0. [0742] Example 108: (S)-1-(1H-Indole-2-carbonyl)-4-methylene-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 108)
Figure imgf000192_0001
[0743] Compound 108 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.71 - 7.52 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.13 - 6.87 (m, 2H), 5.27 - 5.08 (m, 2H), 4.75 - 4.64 (m, 1H), 4.48 - 4.36 (m, 1H), 4.05 - 3.68 (m, 1H), 3.29 - 3.23 (m, 1H), 3.09 - 2.91 (m, 1H), 2.87 - 2.57 (m, 2H), 2.53 - 2.26 (m, 1H), 2.05 - 1.89 (m, 1H), 1.80 - 1.35 (m, 3H). ESI-MS [M+H]+ calc’d for C22H24N4O4, 409.18; found, 409.0. [0744] Example 109: (2S,4R)-4-(2-Chlorobenzyl)-1-(1H-indole-2-carbonyl)-N-((S)-1-oxo- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 109)
Figure imgf000192_0002
[0745] Compound 109 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.69 - 7.52 (m, 1H), 7.50 - 7.30 (m, 3H), 7.29 - 7.17 (m, 3H), 7.11 - 6.87 (m, 2H), 4.49 - 4.16 (m, 1H), 4.06 - 3.89 (m, 1H), 3.85 - 3.71 (m, 1H), 3.58 - 3.44 (m, 1H), 3.34 - 3.25 (m, 2H), 3.04 - 2.84 (m, 3H), 2.78 - 2.56 (m, 1H), 2.44 - 2.27 (m, 1H), 2.14 - 1.71 (m, 3H), 1.61 - 1.29 (m, 2H). ESI-MS [M+H]+ calc’d for C28H29ClN4O4, 521.19; found, 521.3. [0746] Example 110: (1R,2S,5S)-6,6-Dimethyl-3-(3-methylcyclobutanecarbonyl)-N-((S)-1- oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 110)
Figure imgf000193_0001
[0747] Compound 110 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 4.60 - 4.44 (m, 1H), 4.35 - 4.15 (m, 1H), 4.03 - 3.88 (m, 1H), 3.85 - 3.75 (m, 1H), 3.74 - 3.47 (m, 1H), 3.18 - 2.96 (m, 1H), 2.68 - 2.48 (m, 1H), 2.45 - 2.21 (m, 4H), 2.13 - 1.79 (m, 3H), 1.77 (s, 2H), 1.59 - 1.48 (m, 2H), 1.48 - 1.40 (m, 1H), 1.14 (d, J = 6.4 Hz, 1H), 1.11 - 0.99 (m, 5H), 0.95 - 0.90 (m, 3H). ESI-MS [M+H]+ calc’d for C21H31N3O4, 390.23; found, 390.4. [0748] Example 111: (1R,2S,5S)-3-(5-Ethoxy-1H-indole-2-carbonyl)-6,6-dimethyl-N-((S)- 1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 111)
Figure imgf000193_0002
[0749] Compound 111 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.31 (dd, J = 6.8, 8.8 Hz, 1H), 7.13 - 6.97 (m, 1H), 6.96 - 6.81 (m, 2H), 4.59 (s, 1H), 4.52 - 4.38 (m, 1H), 4.31 - 3.92 (m, 4H), 3.83 - 3.72 (m, 1H), 3.28 - 3.20 (m, 1H), 2.94 - 2.55 (m, 1H), 2.41 - 2.20 (m, 1H), 2.03 - 1.86 (m, 1H), 1.77 - 1.68 (m, 1H), 1.66 - 1.48 (m, 2H), 1.40 (dt, J = 0.8, 6.8 Hz, 3H), 1.37 - 1.30 (m, 1H), 1.16 - 0.95 (m, 6H). ESI-MS [M+H]+ calc’d for C26H32N4O5, 481.24; found, 481.5. [0750] Example 112: (2S,4R)-4-Cyano-1-(1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 112)
Figure imgf000194_0001
[0751] Compound 112 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.77 - 7.49 (m, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.13 - 6.82 (m, 2H), 4.56 (s, 1H), 4.50 - 4.35 (m, 1H), 4.33 - 4.13 (m, 1H), 3.97 (s, 1H), 3.86 - 3.56 (m, 1H), 3.53 - 3.34 (m, 1H), 3.02 - 2.20 (m, 4H), 2.12 - 1.69 (m, 2H), 1.68 - 1.16 (m, 2H). ESI-MS [M+H]+ calc’d for C22H23N5O4, 422.18; found, 422.4. [0752] Example 113: (2S,3aS,7aS)-1-(1H-Indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)octahydro-1H-indole-2-carboxamide (Compound 113)
Figure imgf000194_0002
[0753] Compound 113 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.69 - 7.47 (m, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.20 (br t, J = 7.6 Hz, 1H), 7.08 - 6.99 (m, 1H), 6.98 - 6.79 (m, 1H), 5.21 - 4.99 (m, 1H), 4.80 - 4.66 (m, 1H), 4.51 - 4.32 (m, 1H), 4.30 - 4.19 (m, 1H), 4.05 - 3.59 (m, 1H), 2.86 - 2.63 (m, 1H), 2.49 - 2.33 (m, 2H), 2.27 - 2.14 (m, 2H), 2.12 - 2.03 (m, 1H), 1.85 - 1.74 (m, 4H), 1.60 - 1.50 (m, 2H), 1.46 - 1.19 (m, 4H).. ESI-MS [M+H]+ calc’d for C25H30N4O4, 451.23; found, 451.4. [0754] Example 114: (1R,2S,5S)-3-(5,6-dimethoxy-1H-Indole-2-carbonyl)-6,6-dimethyl- N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2- c
Figure imgf000194_0003
[0755] Compound 114 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.18 - 6.73 (m, 3H), 5.01 - 4.88 (m, 1H), 4.65 - 4.22 (m, 2H), 4.05 - 3.94 (m, 1H), 3.89 - 3.79 (m, 6H), 3.29 - 3.17 (m, 1H), 2.95 - 2.56 (m, 1H), 2.40 - 2.21 (m, 1H), 2.14 - 1.83 (m, 2H), 1.81 - 1.26 (m, 4H), 1.16 - 0.93 (m, 6H). ESI-MS [M+H]+ calc’d for C26H32N4O6, 497.24; found, 497.4. [0756] Example 115: (S)-4,4-difluoro-1-(1H-Indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 115)
Figure imgf000195_0001
[0757] Compound 115 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.77 - 7.51 (m, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.12 - 6.83 (m, 2H), 3.87 - 3.86 (m, 1H), 4.51 - 3.66 (m, 4H), 2.95 - 2.25 (m, 4H), 2.08 - 1.32 (m, 4H). ESI-MS [M+H]+ calc’d for C21H22F2N4O4, 433.16; found, 433.3. [0758] Example 116: N-((S)-1-((1R,2S,5S)-2-(((S)-4-amino-3,4-dioxo-1-((S)-2- oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3- dimethyl-1-oxobutan-2-yl)-1H-indole-2-carboxamide (Compound 116)
Figure imgf000195_0002
[0759] Step 1: (1R,2S,5S)-methyl 3-((S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
Figure imgf000195_0003
[0760] To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (1 g, 4.32 mmol) in DCM (15 mL) was added DIPEA (2.24 g, 17.29 mmol, 3.01 mL), and then T3P (4.13 g, 6.49 mmol, 3.86 mL, 50% purity) was added at 0°C. The mixture was stirred at 0°C for 1 hr. Then (1R,2S,5S)-methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (889 mg, 4.32 mmol, HCl) was added, the resulting mixture was stirred at 25°C for 10 hr. The reaction mixture was diluted with EtOAc (50 mL) and 5% H3PO4 (50 mL) for 30 min. The aqueous phase was extracted with EtOAc (50 mL). The combined organic layer was washed with 5% H3PO4 (50 mL x3), sat.aq.NaHCO3 (50 mL x4), water (50 mL x 2) and brine (50 mL), and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12g, SepaFlash® Silica Flash Column, eluent of 0~20% EtOAc/PE@ 30 mL/min). The title compound (630 mg, 37.40% yield) was obtained as colorless oil.1H NMR (400 MHz, DMSO-d6) δ ppm 6.71 (d, J = 9.2 Hz, 1H), 4.20 (s, 1H), 4.07 - 4.00 (m, 1H), 3.92 (d, J = 10.0 Hz, 1H), 3.82 - 3.75 (m, 1H), 3.70 - 3.62 (m, 3H), 1.55 - 1.48 (m, 1H), 1.43 - 1.39 (m, 1H), 1.39 - 1.30 (m, 9H), 1.00 (s, 3H), 0.93 (s, 9H), 0.84 (s, 3H). [0761] Step 2: (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid
Figure imgf000196_0001
[0762] To a solution of (1R,2S,5S)-methyl 3-((S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (630 mg, 1.65 mmol) in THF (3 mL) and H2O (3 mL) was added LiOH.H2O (138 mg, 3.29 mmol). The resulting mixture was stirred at 25 °C for 1 hr. To the reaction mixture was added 2M HCl until pH was adjusted to 5-6. The aqueous layer was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (550 mg, 90.62% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 5.14 (d, J = 10.4 Hz, 1H), 4.48 (s, 1H), 4.24 (d, J = 10.4 Hz, 1H), 3.82 (dd, J = 5.6, 10.4 Hz, 1H), 1.75 (d, J = 7.6 Hz, 1H), 1.53 - 1.47 (m, 1H), 1.40 (s, 9H), 1.26 (t, J = 7.2 Hz, 1H), 1.06 (s, 3H), 1.00 (s, 9H), 0.90 (s, 3H). [0763] Step 3: tert-butyl ((2S)-1-((1R,2S,5S)-2-(((2S)-4-amino-3-hydroxy-4-oxo-1-((S)-2- oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3- dimethyl-1-oxobutan-2-yl)carbamate
Figure imgf000197_0001
[0764] To a solution of (3S)-3-amino-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide hydrochloride (100 mg, 496.96 mmol) in DCM (4 mL) was added DIEA (178 mg, 1.38 mmol, 240 uL) and (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (135 mg, 366.75 mmol) slowly at 25 °C. And then a solution of HATU (349 mg, 916.87 mmol) was added dropwise at 0°C. The resulting mixture was stirred at 25 °C for 16 hrs. The mixture was concentrated under reduce pressure to give a residue. The residue was purified by prep- HPLC (column: 3_Phenomenex Luna C1875 x 30 mm x 3mm; mobile phase: [water (0.05%HCl)-ACN]; B%: 10%-60%, 40 min ) to give the title compound (80 mg, 31.63% yield) as a white solid. ESI-MS [M+H]+ calc’d for C27H45N5O7, 552.3; found, 552.5. [0765] Step 4: (1R, 2S, 5S)-3-((S)-2-amino-3, 3-dimethylbutanoyl)-N-((2S)-4-amino-3- hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000197_0002
[0766] To a solution of tert-butyl ((2S)-1-((1R,2S,5S)-2-(((2S)-4-amino-3-hydroxy-4-oxo- 1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3- yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (135 mg, 244.71 mmol) in MeOH (4 mL) was added HCl/dioxane (4 M, 3 mL). Then the mixture was stirred at 25°C for 1h. The reaction was concentrated under reduced pressure to give a residue. The title compound (119 mg, 99.65% yield, HCl) was obtained as a white solid. [0767] Step 5: N-((2S)-1-((1R,2S,5S)-2-(((2S)-4-amino-3-hydroxy-4-oxo-1-((S)-2- oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3- dimethyl-1-oxobutan-2-yl)-1H-indole-2-carboxamide
Figure imgf000198_0001
[0768] To a solution of (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-N-((2S)-4- amino-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride (119 mg, 243.84 mmol, HCl) in DCM (2 mL) was added DIEA (95 mg, 731.53 mmol, 127 uL) and 1H-indole-2-carboxylic acid (31 mg, 195.07 mmol) slowly at 25 °C. And HATU (185 mg, 487.69 mmol) was added to the above mixture dropwise at 0°C. The resulting mixture was stirred at 25 °C for 16 hrs. Water (10 mL) was added to the mixture. The aqueous layer was extracted with DCM (50 mL x 2). The combined organic layers were concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1880 x 30mm x 5mm; mobile phase: [water (0.05%HCl)-ACN]; B%: 35%-65%, 10 min) to give the title compound (80 mg, 55.17% yield) as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 7.61 (d, J = 8.0 Hz, 1H), 7.47 - 7.34 (m, 1H), 7.27 - 7.13 (m, 2H), 7.10 - 7.01 (m, 1H), 4.82 - 4.75 (m, 1H), 4.51 - 4.26 (m, 2H), 4.16 - 3.84 (m, 3H), 3.79 - 3.53 (m, 1H), 3.29 - 3.21 (m, 1H), 2.79 - 2.10 (m, 3H), 1.97 - 1.53 (m, 3H), 1.51 - 1.36 (m, 3H), 1.36 - 1.24 (m, 1H), 1.13 - 1.04 (m, 9H), 1.03 - 0.86 (m, 3H). [0769] Step 6: N-((S)-1-((1R,2S,5S)-2-(((S)-4-amino-3,4-dioxo-1-((S)-2-oxopyrrolidin-3- yl)butan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1- oxobutan-2-yl)-1H-indole-2-carboxamide [0770] To a solution of N-((2S)-1-((1R,2S,5S)-2-(((2S)-4-amino-3-hydroxy-4-oxo-1-((S)- 2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)- 3,3-dimethyl-1-oxobutan-2-yl)-1H-indole-2-carboxamide (50 mg, 84.08 µmol) in DCM (3 mL) was added NaHCO3 (14 mg, 168.15 µmol, 6.54 uL). Then the mixture was stirred at 25 C for 1 h. Dess-Martin (107 mg, 252.23 µmol, 78 uL) was added to the above mixture. Then the mixture was stirred at 25 °C for 1 hrs. Water (20 mL) was added to the mixture. The aqueous layer was extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini- NX C1875 x 30mm x 3μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 21%- 61%, 4 min) to Compound 116 (6.0 mg, 12.04% yield) as an off-white dolid.1H NMR (400 MHz, CD3OD) δ ppm 7.61 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.17 - 7.13 (m, 1H), 7.10 - 7.02 (m, 1H), 4.82 - 4.78 (m, 1H), 4.44 - 4.15 (m, 2H), 4.15 - 3.92 (m, 2H), 3.31 - 3.24 (m, 2H), 2.85 - 1.69 (m, 4H), 1.66 - 1.25 (m, 3H), 1.16 - 1.01 (m, 12H), 0.98 - 0.87 (m, 3H). ESI-MS [M+H]+ calc’d for C31H40N6O6, 593.3; found, 593.5. [0771] Example 117: (1R,2S,5S)-3-(5-Chloro-4-fluoro-1H-indole-2-carbonyl)-6,6- dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane- 2-carboxamide (Compound 117)
Figure imgf000199_0001
[0772] Compound 117 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.30 - 7.18 (m, 2H), 7.13 - 6.88 (m, 1H), 4.97 - 4.88 (m, 1H), 4.53 - 4.39 (m, 1H), 4.34 - 4.01 (m, 1H), 4.00 - 3.74 (m, 2H), 3.28 - 3.22 (m, 1H), 3.04 - 2.29 (m, 2H), 2.07 - 1.86 (m, 1H), 1.77 - 1.53 (m, 3H), 1.47 - 1.29 (m, 1H), 1.18 - 0.93 (m, 6H). ESI-MS [M+H]+ calc’d for C24H26ClFN4O4, 489.17; found, 489.3. [0773] Example 118: (1R,2S,5S)-3-(1,4-Dimethylindole-2-carbonyl)-N-[(1S)-1-formyl-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 118)
Figure imgf000200_0001
[0774] Compound 118 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.27 - 7.09 (m, 2H), 6.95 - 6.65 (m, 2H), 4.53 - 4.32 (m, 1H), 4.17 - 4.02 (m, 1H), 3.83 - 3.62 (m, 4H), 3.56 - 3.46 (m, 1H), 2.99 - 2.87 (m, 1H), 2.69 - 2.58 (m, 1H), 2.55 - 2.44 (m, 3H), 2.12 - 1.71 (m, 1H), 1.67 - 1.53 (m, 3H), 1.28 - 1.04 (m, 8H), 0.98 - 0.83 (m, 1H). ESI-MS [M+H]+ calc’d for C26H32N4O4, 465.24; found, 465.4. [0775] Example 119: (1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2- oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-(1-phenylcyclopropanecarbonyl)-3- azabicyclo[3.1.0]hexane-2-carboxamide (Compound 119)
Figure imgf000200_0002
[0776] Step 1: tert-butyl ((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)carbamate
Figure imgf000200_0003
[0777] To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin- 3-yl)propanoate (10 g, 34.93 mmol) in THF (100 mL) was added LiBH4 (2.28 g, 104.78 mmol) and LiBH4 (2.57 g, 117.98 mmol) at 0°C. And then the mixture was stirred at 25°C for 1 hr. The reaction was quenched with water (30 mL) drop-wise. The resulting mixture was extracted with DCM (100 ml x3). The combined organic phase was washed with water (50 mL) dried over anhydrous Na2SO4, filtered and concentrated. The title compound (9.19 g, crude) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 6.42 (s, 1H), 3.78 - 3.66 (m, 1H), 3.66 - 3.53 (m, 2H), 3.40 - 3.28 (m, 2H), 3.27 - 3.06 (m, 1H), 2.57 - 2.33 (m, 2H), 2.02 - 1.90 (m, 1H), 1.88 - 1.75 (m, 1H), 1.67 - 1.54 (m, 1H), 1.43 (s, 9H). [0778] Step 2: tert-butyl ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate
Figure imgf000201_0001
[0779] To a solution of tert-butyl ((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)carbamate (2 g, 7.74 mmol) in DCM (30 mL) was added SO3.Py (7.39 g, 46.46 mmol), TEA (4.70 g, 46.46 mmol, 6.47 mL) and DMSO (6.05 g, 77.43 mmol, 6.05 mL) at 25°C. Then the mixture was stirred at 25 °C for 1 hr. The mixture was diluted with Water (100 mL), extracted with DCM (200 mL x3). The organic layer was dried over Na2SO4, filtered and concentrated to give crude product. The title compound (2 g, crude) was obtained as yellow oil. [0780] Step 3: isocyanocyclopropane
Figure imgf000201_0002
[0781] To a solution of cyclopropanamine (5 g, 87.57 mmol, 6.07 mL) in DCM (40 mL) was added a solution of NaOH (21.02 g, 525.45 mmol) in H2O (40 mL). Then benzyl(triethyl)ammonium;chloride (399 mg, 1.75 mmol) and CHCl3 (62.73 g, 525.45 mmol, 42.38 mL) were added respectively. The mixture was stirred at 25 °C for 12 hr. The organic layer was extracted with a syringe. The residue was directly purified by flash silica gel chromatography (Eluent of 0% MeOH in DCM). Eluent in a test tube with most pungent odour was used directly in the next step. Isocyanocyclopropane (6.6 g, crude) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 2.69 (tt, J = 3.6, 7.6 Hz, 1H), 1.02 - 0.93 (m, 2H), 0.91 - 0.80 (m, 2H). [0782] Step 4: (3S)-3-((tert-butoxycarbonyl)amino)-1-(cyclopropylamino)-1-oxo-4-((S)-2- oxopyrrolidin-3-yl)butan-2-yl acetate
Figure imgf000201_0003
[0783] To a solution of tert-butyl ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)carbamate (2 g, 7.80 mmol) and isocyanocyclopropane (523.52 mg, 7.80 mmol) in DCM (25 mL) was added AcOH (937 mg, 15.61 mmol). Then the mixture was stirred at 25 C for 12 hr. The reaction mixture was diluted with EtOAc (50 mL). The combined organic layer was washed with sat.aq. NaHCO3 (20 mL), 1 M Na2CO3 (20 mL) and brine (20 mL), and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep- HPLC (column: YMC Triart 30×150mm×7μm; mobile phase: [water (NH3H2O+NH4HCO3)- ACN]; B%: 2%-32%, 27 min). The title compound (120 mg, 3.76% yield) was obtained as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 6.58 - 6.31 (m, 1H), 6.12 (s, 1H), 5.61 - 4.98 (m, 2H), 4.30 - 3.97 (m, 1H), 3.44 - 3.19 (m, 2H), 2.67 (s, 1H), 2.50 - 2.29 (m, 2H), 2.20 - 2.11 (m, 3H), 2.07 - 1.91 (m, 1H), 1.90 - 1.74 (m, 1H), 1.61 - 1.49 (m, 1H), 1.41 (s, 9H), 0.86 - 0.66 (m, 2H), 0.51 (s, 2H). [0784] Step 5: (3S)-3-amino-1-(cyclopropylamino)-1-oxo-4-((S)-2-oxopyrrolidin-3- yl)butan-2-yl acetate
Figure imgf000202_0001
[0785] To a solution of (3S)-3-((tert-butoxycarbonyl)amino)-1-(cyclopropylamino)-1-oxo- 4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl acetate (60 mg, 156.48 μmol) in DCM (1 mL) was added TFA (0.1 mL). The mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated directly. The title compound (60 mg, crude, TFA) was obtained as yellow oil. [0786] Step 6: (3S)-1-(cyclopropylamino)-3-((1R,2S,5S)-6,6-dimethyl-3-(1- phenylcyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)-1-oxo-4-((S)-2- oxopyrrolidin-3-yl)butan-2-yl acetate
Figure imgf000202_0002
[0787] To a solution of (3S)-3-amino-1-(cyclopropylamino)-1-oxo-4-((S)-2-oxopyrrolidin- 3-yl)butan-2-yl acetate (45.20 mg, 151.00 μmol), (1R,2S,5S)-6,6-dimethyl-3-(1- phenylcyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (60 mg, 151.00 μmol, TFA) and DIEA (59 mg, 453.01 μmol, 78.90 uL) in DCM (3 mL) was added slowly HATU (115 mg, 302.00 μmol) at 0°C. The resulting mixture was stirred at 25°C for 3 hr. The reaction mixture was concentrated. Sat.aq.NH4Cl (5 mL) was added to the residue. The resulting mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with water (5 mL) dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 0~25% MeOH in DCM). The title compound (75 mg, 71.50% yield) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 7.38 - 7.27 (m, 2H), 7.24 - 7.09 (m, 3H), 5.34 - 5.11 (m, 1H), 4.57 - 4.22 (m, 1H), 3.43 - 3.21 (m, 3H), 2.91 - 2.77 (m, 2H), 2.55 - 2.30 (m, 2H), 2.23 - 2.10 (m, 2H), 2.09 - 2.05 (m, 1H), 2.04 (s, 3H), 1.93 - 1.73 (m, 1H), 1.62 - 1.55 (m, 6H), 1.14 - 1.02 (m, 1H), 1.01 - 0.91 (m, 3H), 0.78 - 0.67 (m, 4H), 0.65 - 0.46 (m, 2H). [0788] Step 7: (1R,2S,5S)-N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2- oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-(1-phenylcyclopropanecarbonyl)-3- azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000203_0001
[0789] To a solution of (3S)-1-(cyclopropylamino)-3-((1R,2S,5S)-6,6-dimethyl-3-(1- phenylcyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)-1-oxo-4-((S)-2- oxopyrrolidin-3-yl)butan-2-yl acetate (75 mg, 132.82 μmol) in MeOH (3 mL) was added K2CO3 (37 mg, 265.64 μmol) at 0°C. And then the mixture was stirred at 25°C for 12 hr. The reaction mixture was concentrated. Sat.aq.NH4Cl (5 mL) was added to the residue. The resulting mixture was extracted with DCM (10 mL x3). The combined organic phase was washed with water (5 mL), dried over anhydrous Na2SO4, filtered and concentrated. The title compound (50 mg, crude) was obtained as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 7.37 - 7.27 (m, 2H), 7.25 - 7.09 (m, 3H), 6.50 - 5.78 (m, 1H), 4.53 - 4.33 (m, 1H), 4.29 - 4.13 (m, 1H), 3.52 - 3.22 (m, 3H), 3.01 - 2.78 (m, 2H), 2.65 - 2.34 (m, 2H), 2.27 - 1.76 (m, 3H), 1.75 - 1.56 (m, 4H), 1.39 - 1.04 (m, 5H), 1.02 - 0.86 (m, 3H), 0.81 - 0.66 (m, 4H), 0.61 - 0.49 (m, 1H) [0790] Step 8: (1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3- yl)butan-2-yl)-6,6-dimethyl-3-(1-phenylcyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide [0791] To a solution of (1R,2S,5S)-N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)- 2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-(1-phenylcyclopropanecarbonyl)-3- azabicyclo[3.1.0]hexane-2-carboxamide (50 mg, 95.67 μmol) in DCM (5 mL) was added Dess-Martin (122 mg, 287.01 μmol). The mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered and concentrated. The residue was purified by prep-HPLC (column: YMC Triart 30×150mm×7μm; mobile phase: [water (NH4HCO3)-ACN];B%: 29%- 59%,15min). Compound 119 (3.2 mg, 6.07 μmol, 6.34% yield) was obtained as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.43 - 7.12 (m, 5H), 4.38 - 3.73 (m, 2H), 3.69 - 3.53 (m, 1H), 3.39 - 3.35 (m, 1H), 3.29 - 3.22 (m, 1H), 2.82 - 2.44 (m, 2H), 2.42 - 2.14 (m, 1H), 2.12 - 1.60 (m, 3H), 1.48 - 1.20 (m, 6H), 1.15 - 1.02 (m, 1H), 1.01 - 0.86 (m, 3H), 0.81 - 0.64 (m, 5H), 0.63 - 0.50 (m, 2H). ESI-MS [M+H]+ calc’d for C29H36N4O5, 521.27, found 521.5. [0792] Example 120: (1R,2S,5S)-3-(5H-[1,3]dioxolo[4,5-f]indole-6-carbonyl)-N-[(1S)-1- formyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 120)
Figure imgf000204_0001
[0793] Step 1: tert-butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)carbamate
Figure imgf000204_0002
[0794] A mixture of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (5.00 g, 17.46 mmol) in NH3/MeOH (7 M, 50 mL) was purged with N2 for 3 times, and then the mixture was stirred at 50°C for 96 hours under N2 atmosphere. The reaction mixture was concentrated directly. Crude product was used in the next step directly, no purification needed. Crude product (5.20 g, 13.42 mmol, 76.83% yield) was obtained as a yellow solid. H NMR (400 MHz, CDCl3) δ ppm 7.13 (s, 1H), 6.20 - 5.92 (m, 2H), 5.67 (s, 1H), 4.37 (s, 1H), 3.44 - 3.30 (m, 2H), 2.58 - 2.48 (m, 1H), 2.44 - 2.34 (m, 1H), 2.13 - 2.02 (m, 1H), 1.94 - 1.88 (m, 1H), 1.79 - 1.71 (m, 1H), 1.44 (s, 9H). [0795] Step 2: tert-butyl ((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)carbamate
Figure imgf000205_0001
[0796] To a solution of tert-butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)carbamate (1.00 g, 3.69 mmol) in THF (10 mL) was added TEA (372 mg, 3.69 mmol, 513 uL) at 0°C. Then TFAA (774 mg, 3.69 mmol, 512.67 uL) was added dropwise to the mixture. The reaction was stirred at 25°C for 2 hr. The mixture was concentrated under reduced pressure. The residue was poured into ice-water (20 mL). The aqueous phase was extracted with ethyl acetate (50 mL x3). The combined organic phase was washed with sat.aq.NaHCO3 (30 mL) and brine (30 mL), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was triturated with n-hexane (10 mL) at 25 °C for 30 minutes. The solid was filtered and dried under reduced pressure. The title compound (700 mg, 1.69 mmol, 45.74% yield) was obtained as a yellow solid which was used in the next step without further purification.1H NMR (400 MHz, CD3OD) δ ppm 4.75 - 4.67 (m, 1H), 3.37 - 3.32 (m, 2H), 2.57 - 2.44 (m, 1H), 2.41 - 2.30 (m, 1H), 2.27 - 2.13 (m, 1H), 1.94 - 1.76 (m, 2H), 1.47 (s, 9H). [0797] Step 3: (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanenitrile
Figure imgf000205_0002
[0798] To a solution of tert-butyl ((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)carbamate (300 mg, 1.18 mmol) in DCM (6 mL) was added TFA (3 mL) in one portion at 25°C. The mixture was stirred for 1 hr and then concentrated under reduce pressure. The title compound (300 mg, crude, TFA) was obtained as a yellow oil. [0799] Step 4: (1R,2S,5S)-tert-butyl 2-(((S)-1-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure imgf000206_0001
[0800] To a solution of (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanenitrile (300 mg, 1.12 mmol, TFA) and (1R,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (286 mg, 1.12 mmol) in DCM (2 mL) was added DIEA (435 mg, 3.37 mmol, 586 uL) at 0°C. Then HATU (853 mg, 2.25 mmol) was added in one portion at 0°C. The mixture was stirred at 25°C for 2 hours. The mixture was poured into water (10 mL). The aqueous phase was extracted with DCM (30 mL x3). The combined organic phase was washed with NH4Cl (20 mL x2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=0:1). The title compound (150 mg, 13.69% yield) was obtained as a white solid.1H NMR (400 MHz, CD3OD) δ ppm 5.10 - 4.98 (m, 1H), 4.05 - 4.01 (m, 1H), 3.71 (dt, J = 5.6, 11.2 Hz, 1H), 3.44 - 3.33 (m, 2H), 3.29 - 3.19 (m, 1H), 2.66 - 2.21 (m, 3H), 2.00 - 1.75 (m, 2H), 1.47 - 1.40 (m, 9H), 1.37 - 1.33 (m, 2H), 1.09 - 0.92 (m, 6H). [0801] Step 5: (1R,2S,5S)-tert-butyl 2-(((S)-1-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure imgf000206_0002
[0802] To a solution of (1R,2S,5S)-tert-butyl 2-(((S)-1-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (140 mg, 358.54 µmol) in DCM (5 mL) and TFA (0.5 mL) was stirred at 25°C for 10 hr. The mixture was concentrated under reduce pressure. The title compound (145 mg, crude, TFA) was obtained as a yellow oil which was used in the next step without further purification. [0803] Step 6: (1R,2S,5S)-3-(5H-[1,3]dioxolo[4,5-f]indole-6-carbonyl)-N-[(1S)-1-formyl- 2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [0804] To a solution of (R)-2-(m-tolyl)propanoic acid (21 mg, 126.12 μmol), (1R,2S,5S)- N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (51 mg, 126.12 μmol TFA) and DIEA (49 mg, 378.35 μmol, 66.00 μL) in DCM (1 mL) was added HATU (96 mg, 252.24 μmol) at 0°C. The resulting mixture was stirred at 25°C for 10 hr. The reaction mixture was concentrated. Sat.aq.NH4Cl (10 mL) was added to the residue. The resulting mixture was extracted with DCM (20 mL x3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (column: Phenomenex C1875×30mm×3μm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 26%-60%, 11 min). Compound 120 (8.1 mg, 14.71% yield, 100% purity) was obtained.1H NMR (400 MHz, DMSO-d6) δ ppm 9.38 - 8.74 (m, 1H), 7.87 - 7.64 (m, 1H), 7.28 - 6.88 (m, 4H), 5.12 - 4.80 (m, 1H), 4.48 - 3.95 (m, 1H), 3.91 - 3.53 (m, 2H), 3.22 - 3.07 (m, 3H), 2.45 - 2.36 (m, 1H), 2.25 (s, 3H), 2.21 - 2.07 (m, 2H), 1.86 - 1.62 (m, 2H), 1.47 - 1.12 (m, 5H), 1.07 - 0.28 (m, 6H).ESI-MS [M+H]+ calc’d for C25H32N4O3, 437.55; found, 437.4. [0805] Example 121: (2S,4R)-1-(1H-Indole-2-carbonyl)-4-methoxy-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 121)
Figure imgf000207_0001
[0806] Compound 121 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.68 - 7.50 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.27 - 7.17 (m, 1H), 7.12 - 6.83 (m, 2H), 4.77 - 4.63 (m, 1H), 4.50 - 4.28 (m, 1H), 4.21 - 4.07 (m, 2H), 4.04 - 3.89 (m, 1H), 3.85 - 3.56 (m, 1H), 3.46 - 3.31 (m, 3H), 3.30 - 3.23 (m, 1H), 2.84 - 2.62 (m, 1H), 2.49 - 2.34 (m, 1H), 2.24 - 1.98 (m, 2H), 1.91 - 1.50 (m, 2H), 1.43 - 1.15 (m, 1H). ESI-MS [M+H]+ calc’d for C22H26N4O5, 427.19; found, 427.4. [0807] Example 122: (1R,2S,5S)-6,6-Dimethyl-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-(3-phenyl-1H-indole-2-carbonyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 122)
Figure imgf000208_0001
[0808] Compound 122 was synthesized by the same procedure as Compound 1.1H NMR (400 MHz, CD3OD) δ ppm 7.72 - 7.41 (m, 6H), 7.39 - 7.29 (m, 1H), 7.28 - 7.17 (m, 1H), 7.15 - 6.97 (m, 1H), 4.83 - 4.67 (m, 1H), 4.54 - 4.26 (m, 1H), 4.10 - 3.95 (m, 1H), 3.93 - 3.82 (m, 1H), 3.53 - 3.37 (m, 2H), 3.25 - 2.79 (m, 2H), 2.71 - 2.35 (m, 1H), 2.12 - 1.64 (m, 1H), 1.49 - 1.37 (m, 2H), 1.34 - 1.25 (m, 1H), 0.96 - 0.86 (m, 3H), 0.67 - 0.40 (m, 3H). ESI-MS [M+H]+ calc’d for C30H32N4O4, 513.24; found, 513.5. [0809] Example 123: (1R,2S,5S)-3-(1-(3-Chlorophenyl)cyclopropanecarbonyl)-N-((S)-1- cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 123)
Figure imgf000208_0002
[0810] Compound 123 was synthesized by the same procedure as Compound 120.1H NMR (400 MHz, DMSO-d6) δ ppm 9.18 - 8.90 (m, 1H), 7.86 - 7.64 (m, 1H), 7.42 - 7.01 (m, 4H), 5.09 - 4.79 (m, 1H), 4.25 - 3.75 (m, 1H), 3.67 - 3.40 (m, 1H), 3.25 - 3.05 (m, 3H), 2.45 - 2.34 (m, 1H), 2.31 - 2.05 (m, 2H), 1.87 - 1.64 (m, 2H), 1.47 - 1.22 (m, 4H), 1.21 - 1.06 (m, 2H), 1.02 - 0.86 (m, 3H), 0.79 - 0.47 (m, 3H).. ESI-MS [M+H]+ calc’d for C25H29ClN4O3, 469.98; found, 469.4. [0811] Example 124: (1R,2S,5S)-3-(Cyclopentanecarbonyl)-6,6-dimethyl-N-((S)-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 124)
Figure imgf000209_0001
[0812] Compound 124 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 4.52 - 4.38 (m, 1H), 4.28 (d, J = 2.4 Hz, 1H), 4.03 - 3.57 (m, 3H), 2.95 - 2.80 (m, 1H), 2.65 - 2.48 (m, 1H), 2.38 - 2.25 (m, 1H), 1.95 (s, 1H), 1.92 - 1.65 (m, 6H), 1.65 - 1.22 (m, 7H), 1.09 - 0.95 (m, 6H). ESI-MS [M+H]+ calc’d for C21H31N3O4, 390.23; found, 390.4. [0813] Example 125: (1S,3S,5S)-2-(1H-Indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (Compound 125)
Figure imgf000209_0002
[0814] Compound 125 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CDCl3) δ ppm 9.57 - 9.46 (m, 1H), 9.45 - 9.33 (m, 1H), 8.27 - 8.12 (m, 1H), 7.72 - 7.61 (m, 1H), 7.46 - 7.37 (m, 1H), 7.33 - 7.28 (m, 1H), 7.24 - 7.19 (m, 1H), 7.17 - 7.11 (m, 1H), 5.74 - 5.57 (m, 1H), 5.20 (dd, J = 3.2, 10.4 Hz, 1H), 4.44 - 4.30 (m, 1H), 3.95 - 3.84 (m, 1H), 3.29 - 3.13 (m, 2H), 2.63 - 2.44 (m, 2H), 2.40 - 2.25 (m, 2H), 2.06 - 1.89 (m, 2H), 1.83 - 1.78 (m, 1H), 1.33 - 1.24 (m, 1H), 1.14 - 1.02 (m, 1H), 0.93 - 0.77 (m, 1H). ESI-MS [M+H]+ calc’d for C22H24N4O4, 409.18; found, 409.3. [0815] Example 126: (S)-5-(2-Cyclohexylacetyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (Compound 126)
Figure imgf000209_0003
[0816] Compound 126 was synthesized by the same procedure as Compound 2. H NMR (400 MHz, CDCl3) δ ppm 9.60 - 9.45 (m, 1H), 9.06 - 8.24 (m, 1H), 6.59 - 5.69 (m, 1H), 4.99 - 4.58 (m, 1H), 4.57 - 4.25 (m, 1H), 3.75 - 3.49 (m, 1H), 3.44 - 3.21 (m, 3H), 2.56 - 2.36 (m, 2H), 2.28 - 2.08 (m, 3H), 2.06 - 1.81 (m, 8H), 1.79 - 1.72 (m, 2H), 1.31 - 1.20 (m, 2H), 1.20 - 1.03 (m, 1H), 1.02 - 0.85 (m, 2H), 0.69 - 0.40 (m, 4H). ESI-MS [M+H]+ calc’d for C22H33N3O4, 404.25; found, 404.1. [0817] Example 127: (S)-N-((S)-1-(benzo[d]thiazol-2-yl)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-5-(1H-indole-2-carbonyl)-5-azaspiro[2.4]heptane-6-carboxamide (Compound 127)
Figure imgf000210_0001
[0818] Example 128: (1R,2S,5S)-3-(7-Chloro-4-fluoro-1H-indole-2-carbonyl)-N-((S)-1- cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (Compound 128)
Figure imgf000210_0002
[0819] Compound 128 was synthesized by the same procedure as Compound 120.1H NMR (400 MHz, CD3OD) δ ppm 77.30 - 6.72 (m, 3H), 5.09 (dd, J = 5.6, 10.2 Hz, 1H), 4.86 (br d, J = 6.8 Hz, 1H), 4.37 - 4.00 (m, 1H), 3.98 - 3.79 (m, 1H), 3.32 - 3.27 (m, 1H), 3.32 - 3.03 (m, 1H), 2.86 - 2.61 (m, 1H), 2.42 - 2.03 (m, 2H), 2.00 - 1.52 (m, 4H), 1.25 - 0.93 (m, 6H). ESI- MS [M+H]+ calc’d for C24H25ClFN5O3, 485.16; found, 486.4. [0820] Example 129: (2S,3aS,6aS)-1-(1H-Indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)octahydrocyclopenta[b]pyrrole-2-carboxamide (Compound 129)
Figure imgf000211_0001
[0821] Compound 129 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CDCl3) δ ppm 9.61-9.46 (m, 2H), 8.35-8.12 (m, 1H), 7.50-7.14 (m, 1H), 7.12- 7.10 (m, 1H), 7.09-7.04 (m, 1H), 7.00-6.92 (m,1H), 6.89-6.80 (m, 1H), 5.62 – 5.83 (m, 1H), 4.63-4.91 (m, 2H), 4.35 - 4.25 (m, 1H), 3.32-3.05 (m, 4H), 2.86 - 2.63 (m, 1H), 2.49 - 2.03 (m, 8H) 1.39-1.15 (m, 3H). ESI-MS [M+H]+ calc’d for C24H28N4O4, 437.21; found, 437.2. [0822] Example 130: (1S,2S,5R)-3-(1H-Indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 130)
Figure imgf000211_0002
[0823] Compound 130 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, MeOD) δ ppm 7.65 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.27 - 7.17 (m, 1H), 7.09 - 6.98 (m, 1H), 6.90 (d, J = 6.0 Hz, 1H), 4.25 - 4.12 (m, 1H), 4.02 - 3.73 (m, 2H), 3.35 - 3.32 (m, 1H), 3.26 - 3.15 (m, 1H), 2.95 - 2.87 (m, 1H), 2.57 (m, 1H), 2.36 - 2.26 (m, 1H), 2.10 - 1.29 (m, 6H), 0.90 (m, 1H), 0.46 - 0.16 (m, 1H) ESI-MS [M+H]+ calc’d for C22H24N4O4, 409.18; found, 409.1. [0824] Example 131: (1R,2S,5S)-N-((S)-1-Cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-(7- fluoro-4-isopropyl-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- c
Figure imgf000211_0003
[0825] Compound 131 was synthesized by the same procedure as Compound 120.1H NMR (400 MHz, CD3OD) δ ppm 7.17 (d, J = 3.2 Hz, 1H), 6.95 - 6.83 (m, 2H), 5.11 - 4.91 (m, 1H), 4.34 (dd, J = 5.6, 10.8 Hz, 1H), 4.04 - 3.80 (m, 2H), 3.43 - 3.34 (m, 1H), 2.76 - 2.61 (m, 1H), 2.45 - 2.24 (m, 2H), 2.09 - 1.66 (m, 4H), 1.64 - 1.46 (m, 2H), 1.40 - 1.28 (m, 6H), 1.17 - 0.95 (m, 6H). ESI-MS [M+H]+ calc’d for C27H32FN5O3, 494.25; found, 494.4. [0826] Example 132: (1R,2S,5S)-3-(7-Chloro-1H-indole-2-carbonyl)-N-((S)-1-cyano-2- ((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 132)
Figure imgf000212_0001
[0827] Compound 132 was synthesized by the same procedure as Compound 120.1H NMR (400 MHz, CD3OD) δ ppm 7.58 - 7.10 (m, 2H), 7.09 - 6.74 (m, 2H), 4.97 (dd, J = 5.6, 10.2 Hz, 1H), 4.20 (dd, J = 5.6, 10.6 Hz, 1H), 4.03 - 3.60 (m, 2H), 2.64 - 2.47 (m, 1H), 2.31 - 2.19 (m, 1H), 1.99 - 1.69 (m, 2H), 1.68 - 1.45 (m, 2H), 1.43 - 1.28 (m, 1H), 1.27 - 1.17 (m, 1H), 1.08 - 0.88 (m, 8H). ESI-MS [M+H]+ calc’d for C24H26ClN5O3, 468.17; found, 468.3. [0828] Example 133: (2S,4R)-1-(1H-Indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-4-phenoxypyrrolidine-2-carboxamide (Compound 133)
Figure imgf000212_0002
[0829] Compound 133 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CDCl3) δ ppm 9.54 (s, 1H), 8.54 (d, J = 4.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.33 - 7.26 (m, 3H), 7.12 (t, J = 7.6 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.93 - 6.85 (m, 3H), 5.94 - 5.70 (m, 1H), 5.17 (s, 1H), 4.96 (t, J = 7.6 Hz, 1H), 4.45 - 4.32 (m, 2H), 4.31 - 4.23 (m, 1H), 3.37 - 3.21 (m, 2H), 2.71 - 2.47 (m, 3H), 2.42 - 2.27 (m, 1H), 2.07 - 1.92 (m, 2H), 1.90 - 1.74 (m, 2H). ESI-MS [M+H]+ calc’d for C27H28N4O5, 489.54; found, 489.2. [0830] Example 134: (2S,4S)-1-(1H-Indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-4-phenoxypyrrolidine-2-carboxamide (Compound 134)
Figure imgf000213_0001
[0831] Compound 134 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CDCl3) δ ppm 9.76 - 9.53 (m, 1H), 9.52 - 9.41 (m, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.33 - 7.27 (m, 3H), 7.16 - 7.10 (m, 1H), 7.02 - 6.95 (m, 2H), 6.87 - 6.70 (m, 3H), 5.70 - 5.31 (m, 1H), 5.21 - 5.10 (m, 1H), 5.07 - 4.83 (m, 1H), 4.35 - 4.12 (m, 3H), 3.38 - 2.99 (m, 2H), 2.97 - 2.81 (m, 1H), 2.69 - 2.08 (m, 4H), 1.96 - 1.80 (m, 2H). ESI- MS [M+H]+ calc’d for C27H28N4O5, 489.21; found, 489.4. [0832] Example 135: (1R,2S,5S)-N-((S)-1-Cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6- dimethyl-3-(1-phenylcyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 135)
Figure imgf000213_0002
[0833] Compound 135 was synthesized by the same procedure as Compound 120.1H NMR (400 MHz, DMSO-d6) δ ppm 9.21 - 8.82 (m, 1H), 7.87 - 7.63 (m, 1H), 7.39 - 7.07 (m, 5H), 5.11 - 4.77 (m, 1H), 4.29 - 3.77 (m, 1H), 3.27 - 3.03 (m, 4H), 2.45 - 2.35 (m, 1H), 2.31 - 2.06 (m, 2H), 1.89 - 1.63 (m, 2H), 1.44 - 1.05 (m, 6H), 0.99 - 0.83 (m, 3H), 0.76 - 0.37 (m, 3H). ESI-MS [M+H]+ calc’d for C25H30N4O3, 435.53; found, 435.4. [0834] Example 136: (1R,2S,5S)-N-((S)-1-Cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6- dimethyl-3-(1-phenylcyclopentanecarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 136)
Figure imgf000214_0001
[0835] Compound 136 was synthesized by the same procedure as Compound 120.1H NMR (400 MHz, DMSO-d6) δ ppm 7.37 - 7.20 (m, 5H), 5.13 - 4.97 (m, 1H), 4.30 - 4.23 (m, 1H), 3.50 - 3.33 (m, 3H), 3.00 - 2.86 (m, 1H), 2.80 - 2.63 (m, 1H), 2.46 - 2.30 (m, 3H), 2.30 - 2.19 (m, 2H), 1.96 - 1.72 (m, 5H), 1.68 - 1.53 (m, 2H), 1.38 - 1.30 (m, 1H), 1.27 - 1.17 (m, 1H), 0.98 - 0.87 (m, 3H), 0.66 - 0.50 (m, 3H). ESI-MS [M+H]+ calc’d for C27H34N4O3, 463.26; found, 463.4. [0836] Example 137: (2S,4R)-4-(3-Chlorobenzyl)-1-(1H-indole-2-carbonyl)-N-((S)-1-oxo- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 137)
Figure imgf000214_0002
[0837] Compound 137 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.69 - 7.49 (m, 1H), 7.48 - 7.39 (m, 1H), 7.32 - 7.13 (m, 5H), 7.10 - 6.83 (m, 2H), 4.47 - 4.16 (m, 1H), 4.09 - 3.88 (m, 1H), 3.83 - 3.66 (m, 1H), 3.49 - 3.37 (m, 0.5 H), 3.00 - 2.90 (m, 0.5 H), 2.88 - 2.76 (m, 2H), 2.74 - 2.53 (m, 2H), 2.46 - 2.15 (m, 2H), 2.15 - 1.85 (m, 3H), 1.83 - 1.22 (m, 4H). ESI-MS [M+H]+ calc’d for C28H29ClN4O4, 521.19; found, 521.4. [0838] Example 138: (S)-1-(3,3-Dimethylbutanoyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidin- 3-yl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 138)
Figure imgf000215_0001
[0839] Compound 138 was synthesized by the same procedure as Compound 2.1H NMR (400 MHz, CD3OD) δ ppm 7.74 - 7.52 (m, 1H), 7.51 -7.40 (m, 1H), 7.30 - 7.18 (m, 1H), 7.16 – 6.82 (m, 2H), 5.04 – 5.24 (m, 1H), 4.61 – 3.72 (m, 1H), 4.24 -3.71 (m, 4H), 3.04 - 2.63 (m, 1H), 2.60 - 2.31 (m, 2H), 2.30 – 2.16 (m, 2H), 2.14 - 1.88 (m, 2H), 1.85 - 1.54 (m, 1H), 1.50 - 1.27 (m, 1H). ESI-MS [M+H]+ calc’d for C21H24N4O4, 397.18; found, 397.4. EVALUATION OF THE ACTIVITY OF COMPOUNDS AGAINST SARS-COV-2 MPRO [0840] Materials [0841] The hCoV Mpro are cloned, expressed in E. coli and purified by WuXi AppTec Co., Ltd. The substrate are synthesized by Genscript Biotech. [0842] Methods [0843] Compounds are 3 fold serially diluted for 10 doses and added to an assay plate (384w format) using ECHO, in duplicate wells. The test concentration of test compounds is defined by sponsor. For 100% inhibition control (HPE, hundred percent effect), 2 μM of GC376 is added. For no inhibition control (ZPE, zero percent effect), DMSO is added. [0844] 25 μL of Mpro proteins are added to the assay plates containing compounds, respectively, using Multidrop. The compounds and Mpro proteins are pre-incubated at room temperature for 30 min. Then 5 μL of Mpro substrates are added to the related assay plates, respectively. Each activity testing point has a relevant background control to normalize the fluorescence interference of compound. The test concentrations of the Mpro protein and substrate are shown in Table 4. Table 4 The final test concentrations of Mpro protein in enzymatic assay
Figure imgf000215_0002
_ .
Figure imgf000216_0001
[0845] After 60 min incubation at 30oC, the fluorescence signal (RFU) is detected using a microplate reader M2e (SpectraMax) at Ex/Em=340nm/490nm. [0846] The inhibition activity is calculated using the formula below, IC50 values will be calculated using the Inhibition% data. Inhibition% = [(CPD-BGCPD)-(ZPE -BGZPE)/ (HPE-BGHPE)-(ZPE -BGZPE)] × 100% CPD: Signal of test compounds wells, containing compound + enzyme + substrate. ZPE: Average of signals of zero percent effective control wells, containing enzyme + substrate, no compound. HPE: Average of signals of hundred percent effect control wells, containing GC376 + enzyme + substrate. BG: Compound background control wells, containing compound + substrate, no enzyme [0847] IC50 values of compounds are calculated with the GraphPad Prism software using the nonlinear regression model of log(inhibitor) vs. response -- Variable slope (four parameters). [0848] The mean IC50 (nM) values of compounds are provided in Table 5. Table 5
Figure imgf000216_0002
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001

Claims

CLAIMS 1. A compound of formula I:
Figure imgf000220_0002
or a pharmaceutically acceptable salt thereof, wherein: R1 is (a) -C1-6alkyl, (b) -C1-6haloalkyl, (c) -C1-6alkylene-NHCO-C1-6haloalkyl, (d) -C0-6alkylene-(saturated cycloalkyl), (e) -C0-6alkylene-heterocycloalkyl, (f) -C0-6alkylene-(tricyclic heteroaryl), (g) -heteroarylene-cycloalkyl, (h) -heteroarylene-aryl, (i)
Figure imgf000220_0001
, or , wherein RA is halo, -OH, -CN, -NH2, -NO2, -C1-6alkyl, alkenyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; p is 0, 1, 2, 3, 4, or 5; and q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; (j)
Figure imgf000221_0001
, wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2; or (
Figure imgf000221_0002
or , wherein R11 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, or -SO2(C1-6alkyl); and r is 0 or 1; R3, R4, and R5 are each independently -H, halo, -OH, -CN, -NH2, -NO2, alkylenyl, -C1-6alkyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; or R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; or R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R4 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; R2 is H; or R2 and R3 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R2 and R5 together with the pyrrolidine ring to which they are attached form a bridged 6 to 8 membered heterocycloalkyl; R
Figure imgf000221_0003
6 is ; R7 and R8 are each independently H or C1-6alkyl; and n is 1, 2, or 3; wherein at each occurrence, cycloalkyl, saturated cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl); provided that where n is 1; R , R , and R are H; R and R or R and R together with the carbon atom to which they are attached form a 3 membered or 5 membered-cycloalkyl; then R1 is not
Figure imgf000222_0001
or . 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is (a) -C1-6alkyl, (b) -C1-6alkylene-NHCO-C1-6haloalkyl, (c) -C0-6alkylene-(saturated cycloalkyl), (d) -C0-6alkylene-heterocycloalkyl, (e) -C0-6alkylene-(tricyclic heteroaryl), (f) -heteroarylene-cycloalkyl, (
Figure imgf000222_0002
, or , wherein R is halo, -OH, -CN, -NH2, -NO2, -C1-6alkyl, alkenyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; p is 0, 1, 2, 3, 4, or 5, and q is 0, 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; (h)
Figure imgf000222_0003
or , wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2; and (i)
Figure imgf000223_0001
, wherein R11 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, or -SO2(C1-6alkyl); and r is 0 or 1; wherein at each occurrence, cycloalkyl, heterocycloalkyl, aryl, phenyl, and heteroaryl are each independently substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, -CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl).
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is (a) -C1-6alkyl, (b) -C1-6alkylene-NHCO-C1-6haloalkyl, (c) -C0-6alkylene-(saturated cycloalkyl), wherein cycloalkyl is substituted with 0 or 1 phenyl, (d) -C0-6alkylene-(3-7 membered heterocycloalkyl), (e) -C0-6alkylene-(8-12 membered tricyclic heteroaryl), wherein the tricyclic heteroaryl is substituted with 0 or 1 substituents selected from the group consisting of C3-6cycloalkyl and phenyl, (f) -(5-12 membered heteroarylene)-C3-6cycloalkyl, (g) -(5-12 membered heteroarylene)-phenyl, (h) (
Figure imgf000223_0002
or , wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2; and (j)
Figure imgf000224_0001
, wherein R11 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, or -SO2(C1-6alkyl); and r is 0 or 1; wherein at each occurrence, the cycloalkyl, heterocycloalkyl, aryl, phenyl, and heteroaryl are each independently substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, -CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl).
4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1 is -C0-6alkylene-(C3-6 saturated cycloalkyl), wherein the cycloalkyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, -CN, -C1-6alkyl, -C1-6haloalkyl, and -C1-6alkoxy.
5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of
Figure imgf000224_0002
.
6. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1 is
Figure imgf000224_0003
or , wherein R1 is substituted with 0, 1, or 2 RA substituents independently selected from the group consisting of halo, -OH, -CN, -C1-6alkyl, -C1-6haloalkyl, and -C1-6alkoxy; and p is 0, 1, or 2.
7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R1 is halo or -C1-6alkyl; and p is 0 or 1.
8. The compound of claim 1 or 7, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of
Figure imgf000225_0001
.
9. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1 is -C0-6alkylene-(3-7 membered heterocycloalkyl), wherein the heterocycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo, -OH, -CN, -C1-6alkyl, -C1-6haloalkyl, and -C1-6alkoxy.
10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R1 is -C0-3alkylene-(5-7 membered heterocycloalkyl).
11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of
Figure imgf000225_0002
.
12. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1 is
Figure imgf000225_0003
, or , wherein RA is halo, -OH, -CN, -C1-6alkyl, -C1-6haloalkyl, or -C1-6alkoxy.
13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of
Figure imgf000226_0001
.
14. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1 is (a) -C0-6alkylene-(8-12 membered tricyclic heteroaryl), wherein the tricyclic heteroaryl is substituted with 0 or 1 substituents selected from the group consisting of C3-6cycloalkyl and phenyl, (b) -C0-6alkylene-(8-12 membered tricyclic heteroaryl), wherein the tricyclic heteroaryl is substituted with 0 or 1 substituents selected from the group consisting of C3-6cycloalkyl and phenyl, or (c) -(5-12 membered heteroarylene)-phenyl.
15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is a
Figure imgf000226_0002
, , , or , wherein R10 or R11 is independently halo, -CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, or -SO2(C1-6alkyl).
16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R1 is
Figure imgf000226_0003
, wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, or -SO2(C1-6alkyl); and m is 0, 1, or 2.
17. The compound of any one of claims 1 or 14-16, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of
Figure imgf000227_0001
Figure imgf000228_0001
.
18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from any of the following moieties
Figure imgf000228_0002
, ,
Figure imgf000229_0001
Figure imgf000230_0001
.
19. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is H; R3 and R4 are each independently -H, halo, -OH, -CN, -NH2, -NO2, methylenyl, -C1-6alkyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; R5 is -H, halo, -C1-6alkyl, or -C1-6haloalkyl; or R3 and R4 together with the carbon atom to which they are attached form a C3-C6cycloalkyl; or R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R4 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R2 and R3 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R2 and R5 together with the pyrrolidine ring to which they are attached form a bridged 6 to 8 membered heterocycloalkyl; wherein at each occurrence, the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, or 3 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl).
20. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is H; R3 and R4 are each independently -H, halo, -OH, -CN, methylenyl, -C1-6alkyl, -C1-6alkoxy, phenyl, phenoxy, benzyl, C3-C6cycloalkyl, 5-7 membered heterocycloalkyl, or 5-9 membered heteroaryl; R5 is -H, halo, -C1-6alkyl, or -C1-6haloalkyl; or R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; or R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R4 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R2 and R3 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R2 and R5 together with the pyrrolidine ring to which they are attached form a bridged 6 to 8 membered heterocycloalkyl; wherein at each occurrence, the cycloalkyl, heterocycloalkyl, phenyl, phenoxy, benzyl, and heteroaryl are each independently substituted with 0, 1, or 2 substituents selected from the group consisting of halo, -OH, -CN, -C1-6alkyl, -C1-6haloalkyl, and -C1-6alkoxy.
21. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is H; R3 and R4 are each independently -H, halo, -OH, -CN, methylenyl, -C1-6alkyl, -C1-6alkoxy, phenyl, phenoxy, benzyl, or C3-C6cycloalkyl; R5 is -H, halo, or -C1-6alkyl; or R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; or R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R2 and R3 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R2 and R5 together with the pyrrolidine ring to which they are attached form a bridged 6 to 8 membered heterocycloalkyl; wherein at each occurrence, the cycloalkyl, heterocycloalkyl, phenyl, phenoxy, and benzyl are each independently substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C1-6alkyl.
22. The compound of any one of claims 19-21, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are each independently -H, halo, -OH, -CN, methylenyl, -C1-6alkyl, -C1-6alkoxy, phenyl, phenoxy, benzyl, or C3-C6cycloalkyl, wherein the phenyl, phenoxy, and benzyl are each independently substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C1-6alkyl.
23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein R3 is -H, halo, -OH, -CN, methylenyl, -C1-6alkyl, -C1-6alkoxy, phenyl, phenoxy, benzyl, or C3-C6cycloalkyl, wherein the phenyl, phenoxy, and benzyl are each independently substituted with 0 or 1 substituent selected from the group consisting of halo and -C1-6alkyl; and R4 is -H, halo, or -C1-6alkyl.
24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein R3 is -H, -F, -Me, -Et, -OH, -CN, methylenyl, -OMe, phenyl, phenoxy,
Figure imgf000232_0001
, , or cyclohexyl; and R4 is -H, -F, -Me, or –Et.
25. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is H and R5 is -H or -C1-6alkyl.
26. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein R2 and R5 are H.
27. The compound of claim 19-22, or a pharmaceutically acceptable salt thereof, wherein R3 is -H, halo, -OH, -CN, methylenyl, -C1-6alkyl, -C1-6alkoxy, phenyl, phenoxy, benzyl, or C3-C6cycloalkyl, wherein the phenyl, phenoxy, and benzyl are each independently substituted with 0 or 1 substituent selected from the group consisting of halo and -C1-6alkyl; R4 is -H, halo, or -C1-6alkyl; R2 is -H; and R5 is -H or -C1-6alkyl.
28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein R3 is -H, -F, -Me, -Et, -OH, -CN, methylenyl, -OMe, phenyl, phenoxy,
Figure imgf000233_0001
, , or cyclohexyl; R4 is -H, -F, -Me, or -Et; and R2 and R5 are -H.
29. The compound of claim 19-21, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C1-6alkyl.
30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; R2 is H; and R5 is -H or -C1-6alkyl.
31. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 together with the carbon atom to which they are attached, form a C3-C4cycloalkyl; and R2 and R5 are –H.
32. The compound of claim 19-21, or a pharmaceutically acceptable salt thereof, wherein R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C1-6alkyl.
33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents which is -C1-6alkyl; R2 is H; and R4 is -H or -C1-6alkyl.
34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R3 and R5 together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents which is -Me; and R2 and R4 are -H.
35. The compound of claim 19-21, or a pharmaceutically acceptable salt thereof, wherein R4 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C1-6alkyl.
36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein R4 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents which is -C1-6alkyl; R2 is H; and R3 is -H or -C1-6alkyl.
37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein R4 and R5 together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents which is - Me; and R2 and R3 are -H.
38. The compound of any one of claims 19-21, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C1-6alkyl.
39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; and R4 and R5 are each independently -H or -C1-6alkyl.
40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; and R4 and R5 are -H.
41. The compound of any one of claims 19-21, or a pharmaceutically acceptable salt thereof, wherein R2 and R5 together with the pyrrolidine ring to which they are attached form a bridged 6 to 8 membered heterocycloalkyl, wherein the heterocycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C1-6alkyl.
42. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein R2 and R5 together with the pyrrolidine ring to which they are attached form a bridged 6 to 7 membered heterocycloalkyl, wherein the heterocycloalkyl is substituted with 0 or 1 substituent selected from the group consisting of halo and -C1-6alkyl; and R3 and R4 are each independently -H or -C1-6alkyl.
43. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein R2 and R5 together with the pyrrolidine ring to which they are attached form a bridged 7 membered heterocycloalkyl, wherein the heterocycloalkyl is substituted with -F; and R3 and R4 are -H.
44. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein R2 and R5 together with the pyrrolidine ring to which they are attached form a bridged 8 membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted; and R and R are -H.
45. The compound of any one of the the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein R7 and R8 are H.
46. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.
47. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein n is 1.
48. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula A .
Figure imgf000236_0001
A
49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R1 is (a) -C1-6alkyl, (b) -C1-6alkylene-NHCO-C1-6haloalkyl, (c) -C0-6alkylene-(saturated cycloalkyl), (d) -C0-6alkylene-heterocycloalkyl, (e) -heteroarylene-cycloalkyl, or (f) -heteroarylene-aryl; (
Figure imgf000236_0002
, , , ,
Figure imgf000237_0001
, wherein RA is halo, -OH, -CN, -NH2, -NO2, -C1-6alkyl, alkenyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; p is 0, 1, 2, 3, 4, or 5; and q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11;
Figure imgf000237_0004
, wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2; (i)
Figure imgf000237_0002
or , wherein R11 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, or -SO2(C1-6alkyl); and r is 0 or 1; R3 and R4 are each independently -H, halo, -OH, -CN, -NH2, -NO2, methylenyl, -C1-6alkyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; R5 is -H, halo, -C1-6alkyl, or -C1-6haloalkyl; or R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; or R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R4 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; and
Figure imgf000237_0003
R6 is ; wherein at each occurrence, the cycloalkyl, saturated cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, or 3 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl).
50. The compound of claim 49, or a pharmaceutically acceptable salt thereof, wherein R is (a) -C1-6alkylene-NHCO-C1-6haloalkyl, (b) -C0-6alkylene-(saturated cycloalkyl), (c) -C0-6alkylene-(tricyclic heteroaryl), (d) -C0-6alkylene-heterocycloalkyl, (e)
Figure imgf000238_0003
, , , ,
Figure imgf000238_0004
, ; wherein RA is halo, -OH, -CN, -NH2, -NO2, -C1-6alkyl, alkenyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; (f)
Figure imgf000238_0001
or , wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2; and (g)
Figure imgf000238_0002
or , wherein R is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, or -SO2(C1-6alkyl); and r is 0 or 1; wherein at each occurrence, the cycloalkyl, saturated cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, or 3 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl).
51. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of
Figure imgf000239_0001
, .
52. The compound of claim 49, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are each independently -H, halo, -OH, -CN, methylenyl, -C1-6alkyl, -C1-6alkoxy, phenyl, phenoxy, benzyl, or C3-C6cycloalkyl, wherein the phenyl, phenoxy, and benzyl are each independently substituted with 0 or 1 substituent selected from the group consisting of halo and -C1-6alkyl; and R5 is -H or -C1-6alkyl.
53. The compound of claim 52, or a pharmaceutically acceptable salt thereof, wherein R3 is -H -F -Me -Et -OH, -CN, methylenyl, -OMe, phenyl, phenoxy,
Figure imgf000239_0002
, , or cyclohexyl; R4 is -H, -F, -Me, or -Et; and R2 and R5 are -H.
54. The compound of claim 49, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; and R5 is H.
55. The compound of claim 49, or a pharmaceutically acceptable salt thereof, wherein R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C1-6alkyl; and R4 is H.
56. The compound of any one of claims 48-51, or a pharmaceutically acceptable salt thereof, wherein the compound of formula A is a compound of formula B
Figure imgf000240_0001
. B
57. The compound of claim 56, or a pharmaceutically acceptable salt thereof, wherein the compound of formula B is a compound of formula B-1
Figure imgf000240_0002
. B-1
58. The compound of any one of claims 48-51, or a pharmaceutically acceptable salt thereof, wherein the compound of formula A is a compound of formula C
.
Figure imgf000241_0003
59. The compound of claim 58, or a pharmaceutically acceptable salt thereof, wherein the compound of formula C is a compound of formula C-1
Figure imgf000241_0001
. C-1
60. The compound of any one of claims 56-59, or a pharmaceutically acceptable salt thereof, wherein R1 is (a) -C1-6alkylene-NHCO-C1-6haloalkyl, (b) -C0-6alkylene-(saturated cycloalkyl), (c) -C0-6alkylene-heterocycloalkyl, (d) -C0-6alkylene-(tricyclic heteroaryl), (e)
Figure imgf000241_0002
, or ; RA is halo, -OH, -CN, -NH2, -NO2, -C1-6alkyl, alkenyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; (f)
Figure imgf000242_0001
, wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2; and (g)
Figure imgf000242_0004
or , wherein R11 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, or -SO2(C1-6alkyl); and r is 0 or 1; wherein at each occurrence, the cycloalkyl, saturated cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, or 3 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl); and R
Figure imgf000242_0002
is .
61. The compound of claim 60, or a pharmaceutically acceptable salt thereof, wherein R1 is (a) -C1-6alkylene-NHCO-C1-6haloalkyl, (b) -C0-6alkylene-(saturated cycloalkyl), (c) -C0-6alkylene-(tricyclic heteroaryl), (d)
Figure imgf000242_0003
, or ; wherein RA is halo, -OH, -CN, -NH2, -NO2, -C1-6alkyl, alkenyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; (e)
Figure imgf000243_0001
, wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2; and (f)
Figure imgf000243_0003
, wherein R11 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, or -SO2(C1-6alkyl); and r is 0 or 1; wherein at each occurrence, the cycloalkyl, saturated cycloalkyl, heterocycloalkyl, aryl, phenyl, and heteroaryl are each independently substituted with 0, 1, or 2 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl); and R
Figure imgf000243_0002
is .
62. The compound of any one of claims 48-61, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of
Figure imgf000244_0001
; and R6 is
Figure imgf000244_0002
63. A compound of formula II
Figure imgf000244_0003
:
Figure imgf000244_0004
or a pharmaceutically acceptable salt thereof, wherein: R1A is H, -C1-6alkylene-NHCONH-C1-6alkyl, -C1-6alkylene-NHCO(heteroaryl), -C1-6alkylene-cycloalkyl, ,
Figure imgf000245_0001
, wherein RA is halo, -OH, -CN, -NH2, -NO2, -C1-6alkyl, alkenyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; p is 0, 1, 2, 3, 4, or 5; , wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2; R3, R4, and R5 are each independently -H, halo, -OH, -CN, -NH2, -NO2, alkylenyl, -C1-6alkyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; or R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; or R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; or R4 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl; R2 is H; or R2 and R3 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl;
Figure imgf000245_0002
R6 is or -COR12; R7 and R8 are each independently H or C1-6alkyl; each R9 is independently H, C1-6alkyl, cycloalkyl, or heteroaryl; and R12 is heterocyclyl or heteroaryl; wherein at each occurrence, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, -OH, -CN, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NO2, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkoxy, -SO2(C1-6alkyl), and -CO(C1-6alkyl).
64. The compound of claim 63, or a pharmaceutically acceptable salt thereof, wherein R1A is -C1-6alkylene-NHCONH-C1-6alkyl.
65. The compound of claim 63 or 64, or a pharmaceutically acceptable salt thereof, 1A
Figure imgf000246_0001
wherein R is of the formula: .
66. The compound of claim 63, or a pharmaceutically acceptable salt thereof, wherein R1A is -C1-6alkylene-NHCO(heteroaryl).
67. The compound of claim 66, or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000246_0002
R1A is of the formula: .
68. The compound of claim 63, or a pharmaceutically acceptable salt thereof, wherein R1A is -C1-6alkylene-cycloalkyl, wherein the cycloalkyl is optionally substituted by halo, -C1-6alkyl, -OH, -CN, -NH2, or -NO2.
69. The compound of claim 68, or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000246_0003
R1A is of the formula: .
70. The compound of claim 63, or a pharmaceutically acceptable salt thereof, wherein R1A is of the formula:
Figure imgf000247_0001
RA is halo, -OH, -CN, -NH2, -NO2, -C1-6alkyl, alkenyl, -C1-6alkoxy, -C1-6haloalkyl, -O-C0-6alkylene-aryl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; and p is 0, 1, 2, or 3.
71. The compound of claim 63, or a pharmaceutically acceptable salt thereof, wherein R1A is of the formula:
Figure imgf000247_0002
or .
72. The compound of claim 63, or a pharmaceutically acceptable salt thereof, wherein R1A is of the formula:
Figure imgf000247_0003
; wherein R10 is halo, CN, -C1-6alkyl, -C1-6haloalkyl, -O(C1-6 branched alkyl), or -SO2(C1-6alkyl); and m is 0, 1, or 2.
73. The compound of claim 72, or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000247_0004
R1A is of the formula: .
74. The compound of any one of claims 63-73, or a pharmaceutically acceptable salt thereof, wherein R2 is H.
75. The compound of any one of claims 63-73, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 together with the carbon atom to which they are attached, form a C3-C6cycloalkyl; and R5 is H.
76. The compound of any one of claims 63-73, or a pharmaceutically acceptable salt thereof, wherein R3 and R5 together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo and -C1-6alkyl; and R4 is H.
77. The compound of any one of claims 63-76, or a pharmaceutically acceptable salt thereof, wherein R6 is of the formula:
Figure imgf000248_0001
; an each R9 is independently H, C1-6alkyl, or cycloalkyl.
78. The compound of any one of claims 63-77, or a pharmaceutically acceptable salt thereof, wherein R6 is of the formula:
Figure imgf000248_0002
or .
79. The compound of any one of claims 63-78, or a pharmaceutically acceptable salt 6
Figure imgf000248_0003
thereof, wherein R is of the formula: .
80. The compound of any one of claims 63-79, or a pharmaceutically acceptable salt thereof, wherein the compound of formula II is a compound of formula II-A or II-B:
Figure imgf000248_0004
(II-A) or (II-B).
81. The compound of any one of claims 63-80, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:
Figure imgf000249_0001
, ,
Figure imgf000250_0001
, or a pharmaceutically acceptable salt thereof.
82. The compound of any one of claims 1-81 selected from:
Figure imgf000250_0002
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
or a pharmaceutically acceptable salt thereof.
83. A pharmaceutical composition for treating a coronavirus infection in a human in need thereof, comprising a compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof.
84. A method of treating a viral infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-82, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 88.
85. The method of claim 84, wherein the viral infection is caused by a coronavirus.
86. The method of claim 85, wherein the viral infection is a coronavirus infection caused by SARS-CoV-2, SARS-CoV, MERS-CoV, 229E, NL63, OC43, or HKUl.
87. The method of claim 86, wherein the coronavirus infection is caused by SARS-CoV- 2.
88. The method of any one of claims 84-87, wherein the patient is suffering from COVID-19.
89. The method of claim 86, wherein the coronavirus infection is caused by SARS-CoV.
90. The method of claim 86, wherein the coronavirus infection is caused by MERS-CoV.
91. The method of any one of clams 84-90, wherein the method inhibits Mpro.
92. The method of any one of the preceding claims 84-91, wherein the compound or a pharmaceutically acceptable salt thereof is administered orally.
93. The method of claim 92, wherein the compound or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, or three times a day.
94. The method of any one of claims 84-93, wherein the therapeutically effective amount is from 0.5 mg to 100 mg, 1 mg to 80 mg, or from 1 mg to 60 mg.
95. The method of any one of claims 84-94, wherein the compound is in a solid dosage form.
96. A compound of any one of claims 1-82 or a pharmaceutically acceptable salt or ester thereof, for use in treating a coronavirus infection in a human.
97. A compound of any one of claims 1-82 or a pharmaceutically acceptable salt or ester thereof, for use in treating SARS-CoV-2 infection in a human.
98. Use of a compound of any one of claims 1-82 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a coronavirus infection.
PCT/US2023/032564 2022-09-13 2023-09-12 3-(1h-indole-2-carbonyl)-6,6-dimethyl-n-((s)-1-oxo-3-((s)-2-oxopyrrolidin-3-yl)p ropan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide derivatives as mpro inhibitors for the treatment of coronavirus infections WO2024059087A1 (en)

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