Classifications

• • 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

• 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.
• 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.
• 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.
• 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 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 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 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, -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 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 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 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.
• 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.
• 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.
• 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 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.
• 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 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 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 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 (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 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
• 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
• 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 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
• 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 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 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 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 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
• 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 (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
• 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 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 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)
• 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
• 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.
• 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 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.
• 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
• 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 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 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 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 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 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 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 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 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 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 (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 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 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 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 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.

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