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WO2024158872A1 - Inhibiteurs 1,3-indole-propanamides de la plpro/nsp3 du sars-cov-2 et leurs dérivés - Google Patents

Inhibiteurs 1,3-indole-propanamides de la plpro/nsp3 du sars-cov-2 et leurs dérivés Download PDF

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WO2024158872A1
WO2024158872A1 PCT/US2024/012712 US2024012712W WO2024158872A1 WO 2024158872 A1 WO2024158872 A1 WO 2024158872A1 US 2024012712 W US2024012712 W US 2024012712W WO 2024158872 A1 WO2024158872 A1 WO 2024158872A1
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methyl
optionally substituted
indol
hydrocarbon
umol
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Thomas Tuschl
Cindy Meyer
Aitor Garcia
J. Fraser Glickman
Michael W. Miller
David John HUGGINS
Nigel John LIVERTON
Shan Sun
Mayako MICHINO
Melissa Egbertson
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Rockefeller University
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Rockefeller University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the compounds are generally 1,3- indole-propanamides and derivatives thereof.
  • Coronaviruses are readily transmitted enveloped, non-segmented positive-sense single-stranded RNA viruses. They have a 30-kb RNA genome encoding as many as 14 open reading frames (ORFs).
  • ORF1a and 1ab encode polyproteins that are processed by two essential viral proteases, papain-like protease (PLpro/NSP3) and 3C-like main protease (3CLpro/NSP5), which in concert auto-excise and then cleave the polyprotein into 16 non-structural proteins (NSP2).
  • the NSPs, including PLpro are essential for replication.
  • PLpro recognizes an LXGG amino acid motif and cleaves the peptide bonds after the second glycine between the NSP1/2, 2/3, and 3/4 boundaries of the SARS-CoV-2 polyprotein. It is a cysteine protease involving a nucleophilic cysteine thiol residing in a catalytic amino acid triad. The development of cysteine-reactive compounds can be challenging in terms of specificity, stability, and toxicity. PLpro is essential for SARS-CoV-2 replication and can therefore be used as a target to develop treatments for COVID-19.
  • the disclosure is directed to compounds, pharmaceutical compositions and methods for inhibiting SARS-CoV-2 viral protease papain-like protease (PLpro/NSP3) and thereby treating SARS-CoV-2 and COVID-19.
  • PLpro/NSP3 SARS-CoV-2 viral protease papain-like protease
  • the disclosure relates to compounds of formula (I): wherein X 4 , X 5 , X 6 , X 7 , and are each independently chosen from C or N, with the proviso that when X 10 is N, R 6 is not H; and R 1 is chosen from H, (C 1 -C 3 )hydrocarbon, or heterocycle optionally substituted with oxo; and R 2 is chosen from S(O) 2 -R 8 , H, halogen, cyano, (C 1 -C 3 )alkoxy, C(O)N(R 9 )(R 10 ), heterocycle, phenylthio, , or optionally substituted (C1-C3)hydrocarbon, wherein said optionally substituted is optionally substituted with one or more aliphatic heterocycle or halogen; and X 11 is NH or NCH3; and R 3 is chosen from H, halogen, C(O)N(R 9 )(R 10 ), cyan
  • the disclosure relates to a method of inhibiting SARS-CoV-2 PLpro/NSP3 protein in a patient comprising administering a compound as disclosed herein.
  • the disclosure relates to a method of treating Covid-19 in a patient comprising administering a compound as disclosed herein.
  • the disclosure relates to a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a compound as disclosed herein.
  • the disclosure relates to compounds of formula (I): wherein X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , and X 10 are each independently chosen from C or N, with the proviso that when X 10 is N, R 6 is not H; and R 1 is chosen from H, (C 1 -C 3 )hydrocarbon, or heterocycle optionally substituted with oxo; and R 2 is chosen from S(O)2-R 8 , H, halogen, cyano, (C1-C3)alkoxy, C(O)N(R 9 )(R 10 ), heterocycle, phenylthio, , or optionally substituted (C 1 -C 3 )hydrocarbon, wherein said optionally substituted is optionally substituted with one or more aliphatic heterocycle or halogen; and X 11 is NH or NCH 3 ; and R 3 is chosen from H,
  • X 4 is C. In some embodiments X 4 is N. In some embodiments, X 5 is C. In some embodiments X 5 is N. In some embodiments, X 6 is C. In some embodiments X 6 is N. In some embodiments, X 7 is C. In some embodiments X 7 is N. In some embodiments, X 8 is C. In some embodiments X 8 is N. In some embodiments, X 9 is C. In some embodiments X 9 is N. In some embodiments, X 10 is C.
  • X 10 is N.
  • R 6 is not H.
  • R 1 is H.
  • R 1 is hydrocarbon.
  • R 1 is methyl.
  • R 1 is ethyl.
  • R 1 is isopropyl.
  • R 1 is heterocycle optionally substituted with oxo.
  • R 1 is nitrogen-containing heterocycle optionally substituted with oxo.
  • R 1 is pyrrolidinone.
  • R 1 is pyrrolyl.
  • R 2 is S(O)2-R 8 .
  • R 2 is hydrogen.
  • R 2 is halogen (e.g., F, Cl, and the like). In some embodiments, R 2 is cyano. In some embodiments, R 2 is (C 1 -C 3 )alkoxy (e.g., methoxy, ethoxy, or propoxy). In some embodiments, R 2 is C(O)N(R 9 )(R 10 ). In some embodiments, R 2 is heterocycle. In some embodiments, R 2 is phenylthiol. In some embodiments, R 2 is phenyloxo. In some embodiments, some embodiments, R 2 is (C 1 -C 3 )hydrocarbon optionally substituted with heterocycle or halogen.
  • R 2 is halogen (e.g., F, Cl, and the like). In some embodiments, R 2 is cyano. In some embodiments, R 2 is (C 1 -C 3 )alkoxy (e.g., methoxy, ethoxy, or propoxy). In some embodiments, R 2 is C(
  • R 2 is (C1-C3)hydrocarbon optionally substituted with one or more halogen or nitrogen-containing aliphatic heterocycle. In some embodiments, R 2 is nitrogen-containing monocycle optionally substituted with one or more halogen or aliphatic heterocycle. In some embodiments, R 2 is nitrogen-containing monocycle optionally substituted with one or more halogen or nitrogen-containing aliphatic heterocycle. In some embodiments R 2 is triazolyl, piperidinylmethyl, piperidinylethyl, or trifluoromethyl. [0015] In some embodiments, X 11 is NH. In some embodiments, X 11 is NCH3. [0016] In some embodiments, R 3 is H.
  • R 3 is halogen (e.g., F, Cl, and the like). In some embodiments, R 3 is C(O)N(R 9 )(R 10 ). In some embodiments, R 3 is cyano. In some embodiments, R 3 is (C1-C3)alkoxy (e.g., methoxy, ethoxy, or propoxy). In some embodiments, R 3 is S(O) 2 -R 8 . In some embodiments, R 3 is haloalkyl. In some embodiments, R 3 is (C1-C3)hydrocarbon optionally substituted with one or more halogen. In some embodiments, R 3 is trifluoromethyl. [0017] In some embodiments, R 4 is H.
  • R 4 is (C 1 -C 3 )hydrocarbon. In some embodiments, R 4 is halogen (e.g., Cl, F, and the like). [0018] In some embodiments, R 11 is H. In some embodiments, R 11 is hydroxy. In some embodiments, R 11 is N(R 9 )(R 10 ). In some embodiments, R 11 is heterocycle. In some embodiments, R 11 is nitrogen-containing monocycle. In some embodiments, R 11 is (C 1 - C3)hydrocarbon optionally substituted with one or more N(R 9 )(R 10 ). In some embodiments, R 11 is piperazinyl, methyl, aminomethyl, or aminoethyl.
  • R 5 is H. In some embodiments, R 5 is N(R 9 )(R 10 ). In some embodiments, R 5 is methyl. In some embodiments, R 5 is (C 2 -C 3 )hydrocarbon optionally substituted with one or more N(R 9 )(R 10 ) or (C1-C3)alkyl. In some embodiments, R 5 is heterocycle optionally substituted with one or more N(R 9 )(R 10 ) or (C 1 -C 3 )alkyl.
  • R 5 is nitrogen-containing monocycle optionally substituted with one or more N(R 9 )(R 10 ) or (C1-C3)alkyl.
  • R 5 is (C1-C3)alkoxy optionally substituted with one or more N(R 9 )(R 10 ) or (C1-C3)alkyl.
  • R 5 is hydroxy.
  • R 5 is cyano.
  • R 5 is halogen (e.g., Cl, F, and the like).
  • R 5 may be aminomethyl, aminoethyl, aminopropyl, piperazinyl, pyrazolyl, pyrazolylmethyl, or aminoalkoxy.
  • R 6 is H. In some embodiments, R 6 is 2-oxopiperizine, In some embodiments, R 6 is 2-oxoimidazoline. In some embodiments, R 6 is heterocycle optionally substituted with one or more morpholinyl, azetadine, hydroxy, (C1-C3)alkoxy, (C1-C3)alkyl, oxo, N(R 9 )(R 10 ), or optionally substituted pyrrolidinyl (e.g., pyrrolidinyl optionally substituted with one or more methyl or halogen).
  • R 6 is nitrogen-containing monocycle optionally substituted with one or more morpholinyl, azetadine, hydroxy, (C1-C3)alkoxy, (C1- C3)alkyl, oxo, N(R 9 )(R 10 ), or optionally substituted pyrrolidinyl (e.g., pyrrolidinyl optionally substituted with one or more methyl or halogen).
  • R 6 is N(R 9 )(R 10 ).
  • R 6 is carboxamide.
  • R 6 is (C 1 -C 3 )hydrocarbon optionally substituted with one or more morpholinyl, pyrrolidinyl, or N(R 9 )(R 10 ). In some embodiments, R 6 is (C1-C3)alkoxy. In some embodiments, R 6 is hydroxy. In some embodiments, R 6 may be carboxamidyl, piperazinyl, piperidinyl, pyridinyl, morpholinyl, 2-oxopiperizine, 2- oxoimidazoline, morpholinylethyl, pyrrolidinylpropyl, hydroxy, methoxy, or aminopyrrolidinyl.
  • R 6 is -O-R 14 . In some embodiments, R 6 is -O-CH2-R 14 . [0021] In some embodiments, R 14 is heterocycle optionally substituted with one or more (C 1 - C 3 )alkyl. In some embodiments, R 14 is nitrogen-containing heterocycle optionally substituted with one or more (C1-C3)alkyl. In some embodiments, R 14 is pyrrolidine optionally substituted with one or more (C1-C3)alkyl. In some embodiments, R 14 is pyrrolidine substituted with methyl.
  • R 11 and R 5 taken together with the atoms to which they are attached form heterocycle optionally substituted with one or more N(R 9 )(R 10 ) or azetidinylmethyl. In some embodiments, R 11 and R 5 taken together with the atoms to which they are attached form nitrogen-containing monocycle optionally substituted with one or more N(R 9 )(R 10 ) or azetidinylmethyl. In some embodiments, R 11 and R 5 taken together with the atoms to which they are attached form aliphatic carbocycle optionally substituted with one or more N(R 9 )(R 10 ) or azetidinylmethyl.
  • R 11 and R 5 taken together with the atoms to which they are attached form aminocyclopentanyl, piperidinyl, pyrazolyl, pyrrolyl, pyrrolidinyl, aminopyrrolidinyl, triazolyl, or pyrazole substituted with azetidinylmethyl.
  • R 5 and R 6 taken together with the atoms to which they are attached form heterocycle optionally substituted with one or more aminoethyl or azetidinylmethyl.
  • R 5 and R 6 taken together with the atoms to which they are attached form nitrogen-containing monocycle optionally substituted with one or more aminoethyl or azetidinylmethyl.
  • R 5 and R 6 taken together with the atoms to which they are attached form carbocycle optionally substituted with one or more N(R 9 )(R 10 ). In some embodiments, R 5 and R 6 taken together with the atoms to which they are attached form (i) cyclopentyl substituted with one or more N(R 9 )(R 10 ), (ii) pyrazolyl substituted with one or more azetidinyl, aminoethyl, or azetidinylmethyl, or (iii) pyrrolidinyl substituted with one or more aminoethyl. [0024] In some embodiments, R 7 is H. In some embodiments, R 7 is (C1-C3)hydrocarbon.
  • R 7 is methyl.
  • R 8 is N(R 9 )(R 10 ). In some embodiments, R 8 is (C1- C6)hydrocarbon. In some embodiments, R 8 is heterocycle optionally substituted with one or more N(R 9 )(R 10 ) or halogen. In some embodiments, R 8 is nitrogen-containing monocycle optionally substituted with one or more N(R 9 )(R 10 ) or halogen. In some embodiments, R 8 may be methyl, phenyl, piperidine, pyrrolidine, or aminopyrrolidinyl. [0026] In some embodiments, R 9 is H.
  • R 9 is (C 1 -C 6 )hydrocarbon (e.g., methyl, ethyl, isopropyl, cyclopropyl, and the like). In some embodiments, R 9 is heterocycle. In some embodiments, R 9 is nitrogen-containing monocycle. In some embodiments, R 9 is (C1-C6)oxoalkyl). In some embodiments, R 9 is azetidinylmethyl. [0027] In some embodiments, R 10 is H. In some embodiments, R 10 is (C 1 -C 6 )hydrocarbon (e.g., methyl, ethyl, isopropyl, cyclopropyl, and the like).
  • R 10 is heterocycle. In some embodiments, R 10 is nitrogen-containing monocycle. In some embodiments, R 10 is (C 1 -C 6 )oxoalkyl). In some embodiments, R 10 is azetidinylmethyl. [0028] In some embodiments, R 12 is methyl. In some embodiments R 12 is ethyl. [0029] In some embodiments, R 13 is H. [0030] In some embodiments R 12 and R 13 together with the C to which they are attached form a (C 1 -C 6 )hydrocarbon. [0031] In some embodiments, L is direct bond. In some embodiments, L is CH2.
  • the disclosure relates to a method of inhibiting coronavirus PLpro/NSP3 protein with a compound described above.
  • the coronavirus is SARS-CoV-2.
  • the disclosure relates to a method of treating a Covid-19 patient with a compound described above.
  • the disclosure relates to treating the disease associated with coronavirus generally.
  • the disclosure relates to a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a compound described above.
  • a “patient” or “subject,” as used herein, includes both humans and other animals, particularly mammals. Thus, the methods are applicable to both human therapy and veterinary applications.
  • the patient is a mammal, for example, a primate.
  • the patient is a human.
  • substituents retain their definitions.
  • “hydrocarbon” or hydrocarbyl (as a substituent) means any substituent comprised of hydrogen and carbon as the only elemental constituents.
  • (C1-Cn)hydrocarbon wherein n may be any integer from 1 to 20 or higher, is intended to include alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl, and combinations thereof.
  • Non-limiting examples of a hydrocarbon include cyclopropylmethyl, benzyl, phenethyl, cyclohexylmethyl, adamantyl, camphoryl, naphthylethyl, etc.
  • Hydrocarbyl refers to any substituent comprised of hydrogen and carbon as the only elemental constituents.
  • Aliphatic hydrocarbons are hydrocarbons that are not aromatic; they may be saturated or unsaturated, cyclic, linear, or branched.
  • Non-limiting examples of aliphatic hydrocarbons include isopropyl, 2-butenyl, 2-butynyl, cyclopentyl, norbornyl, etc.
  • Non-limiting examples of aromatic hydrocarbons include benzene (phenyl), naphthalene (naphthyl), anthracene, etc.
  • (C 1 -C 10 )hydrocarbon includes all combination therein, i.e., (C 1 -C 2 )hydrocarbon, (C 1 - C3)hydrocarbon, (C1-C4)hydrocarbon, (C1-C5)hydrocarbon, (C1-C6)hydrocarbon, (C1- C7)hydrocarbon, (C1-C8)hydrocarbon, (C1-C9)hydrocarbon, (C1-C10)hydrocarbon, (C2- C 3 )hydrocarbon, (C 2 -C 4 )hydrocarbon, (C 2 -C 5 )hydrocarbon, (C 2 -C 6 )hydrocarbon, (C 2 - C7)hydrocarbon, (C2-C8)hydrocarbon, (C2-C9)hydrocarbon, (C2-C10)hydrocarbon, (C3- C4)hydrocarbon, (C3-C5)hydrocarbon, (C3-C6)hydrocarbon, (C3-C7)hydrocarbon, (C3- C8)
  • alkyl (or alkylene) is intended to include linear or branched hydrocarbon structures.
  • alkyl refers to alkyl groups from 1 to 20 or higher carbon atoms, in some instances 1 to 10 carbon atoms, in some instances 1 to 6 carbon atoms, in some instances 1 to 4 carbon atoms, and in some instances 1 to 3 carbon atoms.
  • Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, n- butyl, s-butyl, t-butyl, and the like.
  • (C1-C10)alkyl includes all combinations therein, i.e., (C1- C 2 )alkyl, (C 1 -C 3 )alkyl, (C 1 -C 4 )alkyl, (C 1 -C 5 )alkyl, (C 1 -C 6 )alkyl, (C 1 -C 7 )alkyl, (C 1 -C 8 )alkyl, (C 1 - C 9 )alkyl, (C 2 -C 3 )alkyl, (C 2 -C 4 )alkyl, (C 2 -C 5 )alkyl, (C 2 -C 6 )alkyl, (C 2 -C 7 )alkyl, (C 2 -C 8 )alkyl, (C 2 - C9)alkyl, (C2-C10)alkyl, (C3-C4)alkyl, (C3-C5)alkyl, (C3-C6)alkyl, (C
  • oxoalkyl is intended to include alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen.
  • Non- limiting examples include methoxypropoxy, 3,6,9-trioxadecyl and the like.
  • the term oxoalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 196, but without the restriction of 127(a)], i.e., it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds); it does not refer to doubly bonded oxygen, as would be found in carbonyl groups.
  • (C1-C10)oxoalkyl includes all combinations therein, i.e., (C1- C2)oxoalkyl, (C1-C3)oxoalkyl, (C1-C4)oxoalkyl, (C1-C5)oxoalkyl, (C1-C6)oxoalkyl, (C1- C7)oxoalkyl, (C1-C8)oxoalkyl, (C1-C9)oxoalkyl, (C2-C3)oxoalkyl, (C2-C4)oxoalkyl, (C2- C 5 )oxoalkyl, (C 2 -C 6 )oxoalkyl, (C 2 -C 7 )oxoalkyl, (C 2 -C 8 )oxoalkyl, (C 2 -C 9 )oxoalkyl, (C 2 - C10)oxoalkyl, (C3-C4)oxoal
  • azaalkyl is intended to include alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by nitrogen.
  • Non- limiting examples include ethylaminoethyl and the like.
  • (C1-C10)azaalkyl includes all combinations therein, i.e., (C1-C2)azaalkyl, (C1-C3)azaalkyl, (C1-C4)azaalkyl, (C1-C5)azaalkyl, (C 1 -C 6 )azaalkyl, (C 1 -C 7 )azaalkyl, (C 1 -C 8 )azaalkyl, (C 1 -C 9 )azaalkyl, (C 2 -C 3 )azaalkyl, (C 2 - C 4 )azaalkyl, (C 2 -C 5 )azaalkyl, (C 2 -C 6 )azaalkyl, (C 2 -C 7 )azaalkyl, (C 2 -C 8 )azaalkyl, (C 2 - C9)azaalkyl, (C2-C10)azaalkyl, (C3-C4)azaalkyl, (C3-C5)azaalkyl, (C3-
  • thiaalkyl is intended to include alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by sulfur.
  • Non-limiting examples include methylthiopropyl and the like.
  • (C1-C10)thiaalkyl includes all combinations therein, i.e., (C1-C2)thiaalkyl, (C1-C3)thiaalkyl, (C1-C4)thiaalkyl, (C1-C5)thiaalkyl, (C1- C 6 )thiaalkyl, (C 1 -C 7 )thiaalkyl, (C 1 -C 8 )thiaalkyl, (C 1 -C 9 )thiaalkyl, (C 2 -C 3 )thiaalkyl, (C 2 - C4)thiaalkyl, (C2-C5)thiaalkyl, (C2-C6)thiaalkyl, (C2-C7)thiaalkyl, (C2-C2-C2-C
  • “carbocycle” is intended to include ring systems in which the ring atoms are all carbon but of any oxidation state. If not otherwise limited, “carbocycle” is intended to include both non-aromatic and aromatic systems. In addition, unless otherwise specified herein, “carbocycle” is intended to include monocycles, bicycles, spirocycles, and polycycles.
  • (C 3 -C 10 )carbocycle may refer to cyclopropane, cyclohexane, benzene, phenyl, cyclopentadiene, cyclohexene, norbornane, decalin, naphthalene, indane, and the like.
  • (C3-C10)carbocycle includes all combinations therein, i.e., (C 3 -C 4 )carbocycle, (C 3 -C 5 )carbocycle, (C 3 -C 6 )carbocycle, (C 3 -C 7 )carbocycle, (C 3 - C 8 )carbocycle, (C 3 -C 9 )carbocycle, (C 3 -C 10 )carbocycle, (C 4 -C 5 )carbocycle, (C 4 -C 6 )carbocycle, (C4-C7)carbocycle, (C4-C8)carbocycle, (C4-C9)carbocycle, (C4-C10)carbocycle, (C5- C 6 )carbocycle, (C 5 -C 7 )carbocycle, (C 5 -C 8 )carbocycle, (C 5 -C 9 )carbocycle, (C 5 -C 10
  • cycloalkyl is a subset of hydrocarbyl and is intended to include cyclic hydrocarbon structures. If not otherwise limited, “cycloalkyl” may include cyclic alkyl groups of from 3 to 8 carbon atoms or from 3 to 6 carbon atoms. Non- limiting examples of cycloalkyl include cy-propyl, cy-butyl, cy-pentyl, norbornyl, and the like.
  • (C3-C10)cycloalkyl includes all combinations therein, i.e., (C3-C4)cycloalkyl, (C3-C5)cycloalkyl, (C3-C6)cycloalkyl, (C3-C7)cycloalkyl, (C3-C8)cycloalkyl, (C3-C9)cycloalkyl, (C3-C10)cycloalkyl, (C 4 -C 5 )cycloalkyl, (C 4 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkyl, (C 4 -C 8 )cycloalkyl, (C 4 -C 9 )cycloalkyl, (C4-C10)cycloalkyl, (C5-C6)cycloalkyl, (C5-C7)cycloalkyl, (C5-C8)cycloalkyl, (C5-C9)cycloalkyl, (C5-C10)cycloalkyl,
  • Heterocycle means a cycloalkyl or aryl carbocycle residue in which from 1 to 4 carbon atoms (and their associated hydrogens) is replaced by a heteroatom selected from the group consisting of N, O and S.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • a heterocycle may be non-aromatic or aromatic. Heterocycle, if not otherwise limited, refers to monocycles, bicycles, spirocycles, and polycycles.
  • 3- to 11-member heterocycle includes all combinations therein, e.g., 3-member heterocycle, 4-member heterocycle, 5-member heterocycle, 6-member heterocycle, 7-member heterocycle, 8-member heterocycle, 9-member heterocycle, 10-member heterocycle, 11-member heterocycle, 5:5 bicyclic heterocycle, 5:6 bicyclic heterocycle, 6:6 bicyclic heterocycle, 6:7 bicyclic heterocycle, 5:3 spiro heterocycle, and the like.
  • heterocycles that fall within the scope of the disclosure include pyrrolidine, pyrazole, pyrazine, pyrrole, indole, indazole, indoline, indolin-2-one, dihydroindene, dihydrocyclopentapyridine, dihydrofuropyridine, imidazole, quinoline, dihydroquinolinone, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, dihydrobenzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), benzoimidazole, dihydrobenzodioxepine, dihydropyrrolotriazole, triazole, tetrazole, morpholine, thiazole, pyridine, triazolopyridine, pyrazolopyridine, dihydropyrrolotriazo
  • Cycloazaalkyl is a subset of heterocycle in which at least 1 carbon atom (and its associated hydrogens) is replaced by N.
  • Non-limiting examples of cycloaazaalkyl include azetidine, pyrrolidine, pyrazole, pyrrole, piperidine, pyridazine, pyrimidine and the like.
  • (C 3 - C10)cycloazaalkyl includes all combinations therein, i.e., (C3-C4)cycloazaalkyl, (C3- C5)cycloazaalkyl, (C3-C6)cycloazaalkyl, (C3-C7)cycloazaalkyl, (C3-C8)cycloazaalkyl, (C3- C 9 )cycloazaalkyl, (C 3 -C 10 )cycloazaalkyl, (C 4 -C 5 )cycloazaalkyl, (C 4 -C 6 )cycloazaalkyl, (C 4 - C7)cycloazaalkyl, (C4-C8)cycloazaalkyl, (C4-C9)cycloazaalkyl, (C4-C10)cycloazaalkyl, (C5- C6)cycloazaalkyl, (C5-C7)cycloazaalkyl, (C5-C8)cycloazaalkyl, (C5-C9)cycloaza
  • Cyclooxoalkyl is a subset of heterocycle in which at least 1 carbon atom (and its associated hydrogens) is replaced by O.
  • Non-limiting examples of cyclooxoalkyl include furan, morpholine, chromane, oxazole and the like.
  • (C 3 -C 10 )cyclooxoalkyl includes all combinations therein, i.e., (C 3 -C 4 )cyclooxoalkyl, (C 3 -C 5 )cyclooxoalkyl, (C 3 -C 6 )cyclooxoalkyl, (C 3 - C7)cyclooxoalkyl, (C3-C8)cyclooxoalkyl, (C3-C9)cyclooxoalkyl, (C3-C10)cyclooxoalkyl, (C4- C5)cyclooxoalkyl, (C4-C6)cyclooxoalkyl, (C4-C7)cyclooxoalkyl, (C4-C8)cyclooxoalkyl, (C4- C 9 )cyclooxoalkyl, (C 4 -C 10 )cyclooxoalkyl, (C 5 -C 6 )cyclooxoal
  • Cyclothiaalkyl is a subset of heterocycle in which at least 1 carbon atom (and its associated hydrogens) is replaced by S.
  • Non-limiting examples of cyclothiaalkyl include thiophene and the like.
  • (C3-C10)cyclothiaalkyl includes all combinations therein, i.e., (C3- C4)cyclothiaalkyl, (C3-C5)cyclothiaalkyl, (C3-C6)cyclothiaalkyl, (C3-C7)cyclothiaalkyl, (C3- C 8 )cyclothiaalkyl, (C 3 -C 9 )cyclothiaalkyl, (C 3 -C 10 )cyclothiaalkyl, (C 4 -C 5 )cyclothiaalkyl, (C 4 - C6)cyclothiaalkyl, (C4-C7)cyclothiaalkyl, (C4-C8)cyclothiaalkyl, (
  • Heteroaryl is a subset of heterocycle in which the heterocycle is aromatic. In some instances, the heteroaryl contains 4, 5, 6, or 7 ring members. In some instances, the heteroaryl is bicyclic and contains 8, 9, 10, or 11 total ring members.
  • Non-limiting examples include furan, benzofuran, isobenzofuran, pyrrole, indole, isoindole, thiophene, benzothiophene, imidazole, benzimidazole, purine, pyrazole, indazole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, triazole, tetrazole, pyridine, quinoline, isoquinoline, pyrazine, quinoxaline, acridine, pyrimidine, quinazoline, pyridazine, cinnoline, phthalazine, and triazine.
  • heterocyclyl residues additionally include piperazinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxo-pyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone,
  • Aryl and heteroaryl mean (i) a phenyl group (or benzene) or a monocyclic 5- or 6- member heteroaromatic ring containing 1-4 heteroatoms selected from O, N, or S; (ii) a bicyclic 9- or 11-member aromatic or heteroaromatic ring system containing 0-4 heteroatoms selected from O, N, or S; or (iii) a tricyclic 13- or 14-member aromatic or heteroaromatic ring system containing 0-5 heteroatoms selected from O, N, or S.
  • Non-limiting examples of the aromatic 6- to 14-member carbocyclic rings include benzene, naphthalene, indane, tetralin, and fluorene.
  • Non-limiting examples of the 5- to 10-member aromatic heterocyclic rings include imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
  • aryl and heteroaryl refer to residues in which one or more rings are aromatic, but not all need be.
  • alkoxy refers to groups of from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms of a straight, branched, or cyclic configuration, and combinations thereof, attached to the parent structure through an oxygen.
  • Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy cyclopropyloxy, cyclohexyloxy, methylenedioxy, ethylenedioxy, and the like.
  • (C1-C10)alkoxy includes all combinations therein, i.e., (C1-C2)alkoxy, (C1-C3)alkoxy, (C1-C4)alkoxy, (C1-C5)alkoxy, (C1- C 6 )alkoxy, (C 1 -C 7 )alkoxy, (C 1 -C 8 )alkoxy, (C 1 -C 9 )alkoxy, (C 2 -C 3 )alkoxy, (C 2 -C 4 )alkoxy, (C 2 - C5)alkoxy, (C2-C6)alkoxy, (C2-C7)alkoxy, (C2-C8)alkoxy, (C2-C9)alkoxy, (C2-C10)alkoxy, (C3- C4)alkoxy, (C3-C5)alkoxy, (C3-C6)alkoxy, (C3-C7)alkoxy, (C3-C8)alkoxy, (C3-C9)alkoxy,
  • acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms of a straight, branched, or cyclic configuration, saturated or unsaturated, and aromatic, and combinations thereof, attached to the parent structure through a carbonyl functionality.
  • One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl.
  • Non-limiting examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl, and the like.
  • the double bonded oxygen, when referred to as a substituent itself is called “oxo”.
  • Arylalkyl refers to a substituent in which an aryl residue is attached to the parent structure through alkyl.
  • Non-limiting examples include benzyl, phenethyl and the like.
  • Heteroarylalkyl refers to a substituent in which a heteroaryl residue is attached to the parent structure through alkyl.
  • the alkyl group of an arylalkyl or a heteroarylalkyl is an alkyl group of from 1 to 6 carbons.
  • Non-limiting examples include pyridinylmethyl, pyrimidinylethyl, and the like.
  • An oxygen heterocycle is a heterocycle containing at least one oxygen in the ring; it may contain additional oxygens, as well as other heteroatoms.
  • a sulphur heterocycle is a heterocycle containing at least one sulphur in the ring; it may contain additional sulphurs, as well as other heteroatoms.
  • Oxygen heteroaryl is a subset of oxygen heterocycle; non-limiting examples include furan and oxazole.
  • Sulphur heteroaryl is a subset of sulphur heterocycle; non- limiting examples include thiophene and thiazine.
  • a nitrogen heterocycle is a heterocycle containing at least one nitrogen in the ring; it may contain additional nitrogens, as well as other heteroatoms.
  • Non-limiting examples include piperidine, piperazine, morpholine, pyrrolidine and thiomorpholine.
  • Nitrogen heteroaryl is a subset of nitrogen heterocycle; non-limiting examples include pyridine, pyrrole and thiazole.
  • halogen means fluorine, chlorine, bromine, or iodine atoms. In one embodiment, halogen may be a fluorine or chlorine atom.
  • haloalkyl and “haloalkoxy” mean alkyl or alkoxy, respectively, substituted with one or more halogen atoms.
  • optionally substituted may be used interchangeably with “unsubstituted or substituted”.
  • substituted refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical. For example, unless otherwise specified, substituted alkyl, aryl, cycloalkyl, heterocyclyl, etc.
  • Oxo is also included among the substituents referred to in “optionally substituted”; it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g., on phenyl).
  • 1, 2, or 3 hydrogen atoms are replaced with a specified radical.
  • more than three hydrogen atoms can be replaced by fluorine; indeed, all available hydrogen atoms could be replaced by fluorine.
  • substituents are halogen, haloalkyl, alkyl, acyl, hydroxyalkyl, hydroxy, alkoxy, haloalkoxy, aminocarbonyl oxoalkyl, carboxy, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, arylsulfonyl, arylsulfonylamino, and benzyloxy.
  • any alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl moiety described herein can also be an aliphatic group, an alicyclic group or a heterocyclic group.
  • An “aliphatic group” is non-aromatic moiety that may contain any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contain one or more units of unsaturation, e.g., double and/or triple bonds.
  • An aliphatic group may be straight chained, branched or cyclic and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms.
  • aliphatic groups include, for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Such aliphatic groups may be further substituted. It is understood that aliphatic groups may be used in place of the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylene groups described herein.
  • Substituents R n are generally defined when introduced and retain that definition throughout the specification and in all independent claims.
  • the terms "subject” or “subject in need thereof” are used interchangeably herein. These terms refer to a patient who has been diagnosed with the underlying disorder to be treated.
  • a "subject in need thereof” may be a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological systems of a disease, even though a diagnosis of this disease may not have been made.
  • treatment or “treating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit.
  • Therapeutic benefit includes eradication or amelioration of the underlying disorder being treated; it also includes the eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the term “compound of formula” refers to the compound or a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. When the compounds of the present disclosure are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Suitable pharmaceutically acceptable acid addition salts for the compounds of the present disclosure include acetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic (besylate), benzoic, boric, butyric, camphoric, camphorsulfonic, carbonic, citric, ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, formic, fumaric, glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, oleic, pamoic, pantothenic, phosphoric, pivalic, polygalacturonic, salicylic, stearic, succin
  • suitable pharmaceutically acceptable base addition salts for the compounds of the present disclosure include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations and carboxylate, sulfonate and phosphonate anions attached to alkyl having from 1 to 20 carbon atoms.
  • compositions comprising a compound disclosed above, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The most suitable route may depend upon the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • All methods include the step of bringing into association a compound of formula I or a pharmaceutically acceptable salt thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients.
  • active ingredient a compound of formula I or a pharmaceutically acceptable salt thereof
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
  • a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be
  • Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient.
  • Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents.
  • the formulations may be presented in unit- dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use.
  • a sterile liquid carrier for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • structures depicted herein are also meant to include all stereoisomeric (e.g., enantiomeric, diastereomeric, and cis-trans isomeric) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers.
  • Radiolabeled compounds of the present disclosure can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent.
  • a “pure” or “substantially pure” enantiomer is intended to mean that the enantiomer is at least 95% of the configuration shown and 5% or less of other enantiomers.
  • a “pure” or “substantially pure” diastereomer is intended to mean that the diastereomer is at least 95% of the relative configuration shown and 5% or less of other diastereomers.
  • Typical solvent mixtures include A (water) and B (organic i.e., acetonitrile, methanol, etc.). Additives can also be used in the solvent mixture such as HCl, NH4HCO3, and formic acid.
  • BINAP ([1,1′-Binaphthalene]-2,2′-diyl)bis(diphenylphosphane)
  • BOP benzotriazol-1-yloxytris (dimethylamino)phosphonium hexafluorophosphate
  • C (or °C) Degrees Celsius
  • DAST diethyl
  • Generic-9 contains a protecting group, it can be removed by acidic or basic reaction methods well known to those skilled in the art to give the product Generic -10.
  • Generic Scheme A continued: [0085]
  • Compounds included in the genus may also be prepared by the Scheme outlined in General Scheme B.
  • An appropriately substituted amine Generic-11 can be acylated with 2- bromopropanoyl chloride to give intermediate Generic-12, which can then be reacted with the appropriate intermediate Generic-5 to give intermediate Generic -9 and taken on to product Generic-10.
  • Step 2 General procedure for preparation of 1-[5-(1-piperidylsulfonyl)indolin-1- yl]ethanone
  • piperidine 3.93 g, 46.21 mmol, 4.56 mL, 2 eq
  • Et3N 4.68 g, 46.21 mmol, 6.43 mL, 2 eq
  • the reaction mixture was added H2O (30 mL), the H2O phase was then extracted with DCM (50 mL *2).
  • Step 4 General procedure for preparation of 5-(1-piperidylsulfonyl)-1H-indole
  • Step 5 General procedure for preparation of methyl 2-[5-(1-piperidylsulfonyl)indol- 1-yl]propanoate
  • Cs2CO3 10.35 g, 31.78 mmol, 2 eq
  • methyl 2-bromopropanoate 3.98 g, 23.83 mmol, 2.65 mL, 1.5 eq
  • Step 6 General procedure for preparation of 2-[5-(1-piperidylsulfonyl)indol-1- yl]propanoic acid- Intermediate 1
  • a noate (7 g, 19.98 mmol, 1 eq ) in EtOH (60 mL) was added NaOH (4 M, 14.98 mL, 3 eq) at 0 o C, then the mixture was stirred at 20 o C for 0.5 h.
  • the reaction mixture was concentrated under reduced pressure to remove the solvent.
  • the residue was diluted with H2O (50 mL), and the pH was adjusted to 3 by careful addition of aq. HCl (2 M).
  • the mixture was extracted with EtOAc (40 mL x 3).
  • the combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, and filtered.
  • the filtrate was concentrated under reduced pressure to furnish (racemic)- 2-[3-methyl-5-(1-piperidylsulfonyl)indol-1-yl]propanoic acid as a light orange solid.
  • Step 2 General procedure for preparation of tert-butyl N-[2-[4- (aminomethyl)anilino]ethyl]carbamate [0120] mmol, 1 eq) and Raney-Ni (100 mg, 1.17 mmol, 3.81e-1 eq) in a 7M solution of NH3 in MeOH (10 mL) was hydrogenated at 25°C under 15psi of for 24 h. LCMS showed the starting material was consumed completely and new peak was detected. The reaction mixture was filtered through a pad of Celite and washed with a mixture of MeOH(5mL). The filtrate was evaporated in vacuo to afford the product.
  • Step 3 General procedure for preparation of tert-butyl N-[2-[4-[[2-[5-(1- piperidylsulfonyl)indol-1-yl]propanoylamino]methyl]anilino]ethyl]carbamate [ mg, 392.38 umol, 1.1 eq) and 2-[5-(1-piperidylsulfonyl)indol-1-yl]propanoic acid (120 mg, 356.71 umol, 1 eq) in DCM (2 mL) was added HBTU (162.34 mg, 428.06 umol, 1.2 eq) and DIEA (138.31 mg, 1.07 mmol, 186.40 uL, 3 eq).
  • Step 4 General procedure for preparation of N-[[4-(2- aminoethylamino)phenyl]methyl]-2-[5-(1-piperidylsulfonyl)indol-1-yl]propanamide (A-1) yl]propanoylamino]methyl]anilino]ethyl]carbamate (150 mg, 256.96 umol, 1 eq) in HCl/EtOAc (4 M, 2 mL, 31.13 eq) was stirred at 20°C for 2h. LCMS showed the starting material was consumed and desired ms was detected. The reaction mixture was concentrated to dryness to give the crude.
  • Step 2 General procedure for preparation of N-(5-amino-2-methyl-phenyl)-2-[5-(1- piperidylsulfonyl)indol-1-yl]propanamide
  • Step 2 General procedure for preparation of tert-butyl N-[(3S)-1-indolin-5- ylsulfonylpyrrolidin-3-yl]carbamate
  • 3- yl]carbamate 600 mg, 1.47 mmol, 1eq
  • MeOH MeOH
  • NaOH 4 M, 1.83 mL, 5 eq
  • the reaction mixture was stirred at 70 °C for 2 hr.
  • the reaction mixture was concentrated under reduced pressure to remove EtOH.
  • the residue was added water (3ml), then the residue was filtered and the filter cake concentrated in vacuum.
  • Step 3 General procedure for preparation of tert-butyl N-[(3S)-1-(1H-indol-5- ylsulfonyl)pyrrolidin-3-yl]carbamate [0147] arbamate (470 mg, 1.28 mmol, 1 eq) in THF (18.8 mL), the DDQ (290.35 mg, 1.28 mmol, 1 eq) in THF (5.8 mL) dropwise added to the mixture at 0 °C, then the mixture was stirred at 20 °C for 1 h.
  • Step 4 General procedure for preparation of methyl 2-[5-[(3S)-3-(tert- butoxycarbonylamino)pyrrolidin-1-yl]sulfonylindol-1-yl]propanoate yl]carbamate (220 mg, 602.00 umol, 1 eq) in DMF (2mL) was added Cs 2 CO 3 (294.22 mg, 903.01 umol, 1.5 eq) at 0°C, then the mixture was stirred at 20 °C for 0.5 h, then was added methyl 2-bromopropanoate (150.80 mg, 903.01 umol, 100.54 uL, 1.5 eq) and the mixture was stirred at 20 °C for 2 h.
  • Step 5 General procedure for preparation of 2-[5-[(3S)-3-(tert- butoxycarbonylamino)pyrrolidin-1-yl]sulfonylindol-1-yl]propanoate 1- yl]sulfonylindol-1-yl]propanoate (200 mg, 442.93umol, 1 eq) in EtOH (2.5 mL) was added NaOH (4 M, 332.20 uL, 3 eq) at 0 °C, then the mixture was stirred at 20 °C for 0.5 h.
  • Step 6 General procedure for preparation of tert-butyl N-[(3S)-1-[1-[2-[5-(tert- butoxycarbonylamino)-2-methyl-anilino]-1-methyl-2-oxo-ethyl]indol-5-yl]sulfonylpyrrolidin-3- yl]carbamate yl]sulfonylindol-1-yl]propanoic acid (150 mg, 342.85umol, 1 eq) in DCM (2 mL) was added HATU (156.43 mg, 411.42 umol, 1.2 eq) and DIEA (132.93 mg, 1.03 mmol, 179.15uL, 3 eq).
  • Step 7 General procedure for preparation of N-(5-amino-2-methyl-phenyl)-2-[5- [(3S)-3-aminopyrrolidin-1-yl]sulfonylindol-1-yl]propanamide
  • Step 2 General procedure for preparation of tert-butyl N-[(3R)-1-indolin-5- ylsulfonylpyrrolidin-3-yl]carbamate yl]carbamate (500 mg, 1.22 mmol, 1 eq) in MeOH (5 mL) was added NaOH (244.18 mg, 6.11 mmol, 5 eq). The mixture was stirred at 70 °C for 2 h. LCMS showed the starting material was consumed and desired MS was detected. The mixture was collected by filtration, washed with water (5 mL * 3) and dried under reduced pressure to give the product.
  • Step 3 General procedure for preparation of tert-butyl N-[(3R)-1-(1H-indol-5- ylsulfonyl)pyrrolidin-3-yl]carbamate (370 mg, 1.01 mmol, 1 eq) in THF (3 mL) was added dropwise DDQ (251.43 mg, 1.11 mmol, 1.1 eq) at 0°C.
  • Step 4 General procedure for preparation of methyl 2-[5-[(3R)-3-(tert- butoxycarbonylamino)pyrrolidin-1-yl]sulfonylindol-1-yl]propanoate yl]carbamate (90 mg, 246.27 umol, 1 eq) in DMF (2 mL) was added Cs 2 CO3 (240.72 mg, 738.82 umol, 3 eq) and methyl 2-bromopropanoate (41.13 mg, 246.27 umol, 27.42 uL, 1 eq). The mixture was stirred at 25 °C for 2 hr. LCMS showed the starting material was consumed and desired MS was detected.
  • Step 5 General procedure for preparation of 2-[5-[(3R)-3-(tert- butoxycarbonylamino)pyrrolidin-1-yl]sulfonylindol-1-yl]propanoic acid yl]sulfonylindol-1-yl]propanoate (100 mg, 221.47 umol, 1 eq) in EtOH (2 mL) was added NaOH (4 M, 166.10 uL, 3 eq). The mixture was stirred at 25 °C for 1 hr. LCMS showed the starting material was consumed and desired MS was detected.
  • Step 6 General procedure for preparation of tert-butyl N-[(3R)-1-[1-[2-[5-(tert- butoxycarbonylamino)-2-methyl-anilino]-1-methyl-2-oxo-ethyl]indol-5-yl]sulfonylpyrrolidin-3- yl]carbamate yl]sulfonylindol-1-yl]propanoic acid (70 mg, 160.00 umol, 1 eq) in DCM (1 mL) was added HATU (73.00 mg, 192.00 umol, 1.2 eq) and a solution of tert-butyl N- (3-amino-4-methyl- phenyl)carbamate (35.56 mg, 160.00 umol, 1 eq) in DCM (1 mL) which was basified by DIEA (62.03 mg, 479.99 umol, 83.60 uL, 3 eq
  • Step 7 General procedure for preparation of N-(5-amino-2-methyl-phenyl)-2-[5- [(3R)-3-aminopyrrolidin-1-yl]sulfonylindol-1-yl]propanamide
  • EXAMPLE A-6 anilino]-1-methyl-2-oxo-ethyl]indol-5-yl]sulfonylpyrrolidin-3-yl]carbamate (40 mg, 62.33 umol, 1 eq) in DCM (1 mL) was added TFA (7.11 mg, 62.33 umol, 4.61 uL, 1 eq). The mixture was stirred at 25 °C for 1 h.
  • Step 2 tert-butyl 3-[(6-amino-5-methyl-2H-indazol-2-yl)methyl]azetidine-1- carboxylate (Int-2a) and tert-butyl 3-[(6-amino-5-methyl-1H-indazol-1-yl)methyl]azetidine-1- carboxylate (Int-2b).
  • Step 3 tert-butyl 3-[(5-methyl-6- ⁇ 2-[5-(piperidine-1-sulfonyl)-1H-indol-1- yl]propanamido ⁇ -2H-indazol-2-yl)methyl]azetidine-1-carboxylate (Int-3a) and tert-butyl 3-[(5- methyl-6- ⁇ 2-[5-(piperidine-1-sulfonyl)-1H-indol-1-yl]propanamido ⁇ -1H-indazol-1- yl)methyl]azetidine-1-carboxylate (Int-3b).
  • Step 4 [0187] N- ⁇ 2-[(azetidin-3-yl)methyl]-5-methyl-2H-indazol-6-yl ⁇ -2-[5-(piperidine-1- sulfonyl)-1H-indol-1-yl]propanamide (A-7) and N- ⁇ 1-[(azetidin-3-yl)methyl]-5-methyl-1H- indazol-6-yl ⁇ -2-[5-(piperidine-1-sulfonyl)-1H-indol-1-yl]propanamide (A-8) -7 -8 [0188] tert-buty dol-1-yl]propanamido ⁇ - 2H-indazol-2-yl)methyl]azetidine-1-carboxylate Int-3a (0.07g) was treated with dissolved in dichloromethane and treated with TFA at 25 ⁇ C for 3 hours.
  • Step 2 General procedure for preparation of tert-butyl 4-(3-amino-4-methyl- phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(4- methyl-3-nitro-phenyl)piperazine-1-carboxylate 3 g, 9.34 mmol, 1 eq
  • the mixture was degassed and purged with H 2 for three times, the mixture was stirred at 30°C for 5 h under H2(15 psi).
  • the mixture was filtered and concentrated under reduced pressure to give the crude product.
  • Step 3 General procedure for preparation of tert-butyl 4-[4-methyl-3-[2-[5-(1- piperidylsulfonyl)indol-1-yl]propanoylamino]phenyl]piperazine-1-carboxylate 148.63 umol, 1 eq) in DMF (1 mL) were added tert-butyl 4-(3-amino-4-methyl-phenyl)piperazine-1- carboxylate (56.30 mg, 193.22 umol, 1.3 eq), HATU (84.77 mg, 222.95 umol, 1.5 eq) and DIEA (57.63 mg, 445.89 umol, 77.67 uL, 3 eq), the mixture was stirred at 20°C for 1 h.
  • Step 4 General procedure for preparation of N-(2-methyl-5-piperazin-1-yl-phenyl)-2- [5-(1-piperidylsulfonyl)indol-1-yl]propanamide (A-9) [0199] 1- yl]propanoylamino]phenyl]piperazine-1-carboxylate (90 mg, 147.59 umol, 1 eq) in DCM (1 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 91.51 eq) , the mixture was stirred at 20°C for 3 h. LCMS showed reactant was consumed completely and the desired ms was detected.
  • Step 2 General procedure for preparation of N-(5-amino-2-methyl-phenyl)-2-[3- methyl-5-(1-piperidylsulfonyl)indol-1-yl]propanamide
  • the mixture was stirred at 25°C for 1h. LCMS showed the starting material was consumed and desired ms was detected.30 mL of water was added to the reaction, the reaction mixture was extracted with DCM (15 mL*3). The combined organic layers were washed with brine (15 mL) and dried over Na2SO4. The combined organic layer was concentrated to dryness to give the crude.
  • the crude was purified by flash column (ISCO 20 g silica, 0-60 % ethyl acetate in petroleum ether, gradient over 20 min).
  • the resulting mixture was extracted with CHCl3:i-PrOH ⁇ 3:1 (3 mL*5).
  • the combined organic layers were dried over Na2SO4.
  • the combined organic layer was concentrated to dryness to give the product.
  • Step 2 tert-butyl N-(5-cyanoindan-1-yl)carbamate [0237] To a g, 8.65 mmol, 1 eq) in DMF (30 mL)was added Zn (169.65 mg, 2.59 mmol, 0.3 eq), Zn(CN)2 (1.22 g, 10.38 mmol, 658.72 uL, 1.2 eq)and palladium;tritert-butylphosphane (883.94 mg, 1.73 mmol, 0.2 eq) under N2, Then the mixture was stirred at 110°C for 12 h under N2 atmosphere. LCMS showed the starting material was consumed completely and desired MS was detected.
  • Step 4 tert-butyl N-[5-[[2-[3-methyl-5-(1-piperidylsulfonyl)indol-1- yl]propanoylamino]methyl]indan-1-yl]carbamate [024 g, 285.36 umol, 1 eq) in DCM (2 mL) was added 2-[3-methyl-5-(1-piperidylsulfonyl)indol-1- yl]propanoic acid (100 mg, 285.36 umol, 1 eq), HATU (130.20 mg, 342.43 umol, 1.2 eq) and DIEA (110.64 mg, 856.09 umol, 149.11 uL, 3 eq).
  • Step 5 N-[(1-aminoindan-5-yl)methyl]-2-[3-methyl-5-(1-piperidylsulfonyl)indol-1- yl]propanamide (A-13) yl]propanoylamino]methyl]indan-1-yl]carbamate (100 mg, 168.13 umol, 1 eq) and HCl/EtOAc (4 M, 2 mL) was stirred at 20 °C for 2 hr. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was concentrated to dryness to give the crude product.
  • Step 2 General procedure for preparation of tert-butyl N-[[4-(aminomethyl)-2- methyl-phenyl]methyl]carbamate [0249] To a arbamate (230 mg, 933.80 umol, 1 eq) in NH3/MeOH (2mL) was added Raney-Ni (115.00 mg, 1.34 mmol, 1.44 eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times.
  • Step 3 General procedure for preparation of tert-butylN-[[2-methyl-4-[[2-[3-methyl- 5-(1-piperidylsulfonyl)indol-1-yl]propanoylamino]methyl]phenyl]methyl]carbamate (139.98 mg, 399.46 umol, 1 eq) in DMF (2 mL) was added HATU (182.27 mg, 479.36 umol, 1.2 eq) , tert-butyl N-[[4-(aminomethyl)-2-methyl-phenyl]methyl]carbamate (100mg, 399.46 umol, 1 eq) and DIEA (154.88 mg, 1.20 mmol, 208.73 uL, 3 eq) at 0°C.
  • Step 4 General procedure for preparation of N-[[4-(aminomethyl)-3-methyl- phenyl]methyl]-2-[3-methyl-5-(1-piperidylsulfonyl)indol-1-yl]propanamide – EXAMPLE A-14 [0 l-1- yl]propanoylamino]methyl]phenyl]methyl]carbamate (200 mg, 343.20 umol, 1 eq) in HCl/EtOAc (2 mL) was stirred at 20°Cfor 2h. LC-MS showed Reactant was consumed completely and desired mass was detected. The reaction mixture was concentrated to give the crude product.
  • the crude product was purified by prep-HPLC (Phenomenex C18 75*30mm*3um;mobile phase: [water(HCl)-ACN];B% column; 5-45 % acetonitrile in an a 0.05% hydrochloricacid solution in water, 8 min gradient).
  • Step 2 General procedure for preparation of tert-butyl 3-[4-(aminomethyl)-2-methyl- anilino]azetidine-1-carboxylate (400 mg, 1.39 mmol, 1 eq) in MeOH (4 mL) was added NH3/MeOH (7 M, 198.86 uL, 1 eq) and Raney-Ni (119.25 mg, 1.39mmol, 1eq) . The mixture was stirred at 20 °C for 4hr. LC-MS showed reactant was consumed completely and desired mass was detected. The resultant mixture was filtered and the filter cake was rinsed with DCM (5 mL x 3). Then the combined filtrates were concentrated under reduced pressure.
  • Step 3 General procedure for preparation of tert-butyl 3-[2-methyl-4-[[2-[3-methyl- 5-(1-piperidylsulfonyl)indol-1-yl]propanoylamino]methyl]anilino]azetidine-1-carboxylate [0270] To a solution of tert-butyl 3-[4-(aminomethyl)-2-methyl-anilino]azetidine-1- carboxylate (91.47 mg, 313.90 umol, 1.1 eq) and 2-[3-methyl-5-(1-piperidylsulfonyl)indol-1- yl]propanoic acid (100 mg, 285.36 umol, 1 eq) in DCM (1 mL) was added DIEA(110.64 mg, 856.09 umol, 149.11 uL, 3 eq) and HATU (108.50 mg, 285.36 umol,
  • Step 4 General procedure for preparation of N-[[4-(azetidin-3-ylamino)-3-methyl- phenyl]methyl]-2-[3-methyl-5-(1-piperidylsulfonyl)indol-1-yl]propanamide –
  • Step 2 General procedure for preparation of tert-butyl 4-(3-amino-4-methyl- phenyl)piperazine-1-carboxylate [0278] (200 mg, 622.33 umol, 1 eq) in EtOH (3 mL) and H 2 O (3 mL) was added NH4Cl (332.89 mg, 6.22 mmol, 10 eq) and Fe (278.03 mg, 4.98 mmol, 8 eq). The mixture was stirred at 80°C for 1h. LC- MS showed reactant was consumed completely and one main peak with desired mass was detected.
  • Step 3 General procedure for preparation of tert-butyl4-[3-[2-(5-fluoro-6-methoxy- indol-1-yl)propanoylamino]-4-methyl-phenyl]piperazine-1-carboxylate mg, 171.22 umol, 1 eq) in DMF (2 mL) was added tert-butyl 4-(3-amino-4-methyl- phenyl)piperazine-1-carboxylate (44.90 mg, 154.10 umol, 0.9 eq) ,and was added HATU(78.12 mg, 205.46 umol, 1.2 eq) and DIEA (66.38 mg, 513.65 umol, 89.47 uL, 3 eq), The mixture was stirred at 25°C for 12h.
  • Step 4 General procedure for preparation of N-(2-methyl-5-piperazin-1-yl-phenyl)-2- [3-methyl-5-(1-piperidylsulfonyl)indol-1-yl]propanamide (A-17) 1- yl]propanoylamino]phenyl]piperazine-1-carboxylate (100 mg, 160.31 umol, 1 eq) in DCM (2 mL) and was added TFA (36.56 mg, 320.61 umol, 23.74 uL, 2 eq). The mixture was stirred at 25°C for 2 h. LC-MS and HPLC showed reactant was consumed completely and one main peak with desired mass was detected.
  • the mixture was stirred at 80 °C for 15 hr. LC-MS showed reactant was consumed completely and desired mass was detected.
  • the reaction mixture was cooled to room temperature and diluted by water, extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4, filtered and the reaction mixture was concentrated under reduced pressure to give a residue.
  • Step 2 General procedure for preparation of tert-butyl N-[2-(6-amino-5-methyl- indazol-1-yl)ethyl]carbamate
  • EXAMPLE A-22 In a manner similar to that described for tert-butyl N-[2-(6-nitro-5-methyl-indazol-1- yl)ethyl]carbamate (EXAMPLE A-22,), To a solution of tert-butyl N-[2-(6-nitro-5-methyl- indazol-1-yl)ethyl]carbamate (1 eq) in EtOH (20mL) and H2O was added NH4Cl (3 eq) and Fe (5 eq).
  • Step 3 General procedure for preparation of tert-butyl N-[2-[5-methyl-6-[2-[3- methyl-5-(1-piperidylsulfonyl)indol-1-yl]propanoylamino]indazol-1- yl]ethyl]carbamate (82.86 mg, 285.36 umol, 1 eq) in DCM (1 mL) was added HATU (108.50 mg, 285.36 umol, 1 eq) and a solution of 2-[3-methyl-5-(1-piperidylsulfonyl)indol-1-yl]propanoic acid (100 mg, 285.36 umol, 1 eq) in DCM (1 mL) which was basified by DIEA (110.64 mg, 856.08 umol, 149.11 uL, 3 eq) at 0°C.
  • Step 4 N-[1-(2-aminoethyl)-5-methyl-indazol-6-yl]-2-[3-methyl-5-(1- piperidylsulfonyl)indol-1-yl]propanamide (A-20) [0298] A solution of tert-butyl N-[2-[5-methyl-6-[2-[3-methyl-5-(1-piperidylsulfonyl)indol- 1-yl]propanoylamino]indazol-1-yl]ethyl]carbamate (100.00 mg, 160.57 umol, 1 eq) in HCl/EtOAc (1.5 mL) was stirred at 20°Cfor 2h.
  • the mixture was stirred at 20 °C for 2h. LCMS showed the starting material was consumed completely and desired mass was detected.
  • the reaction mixture was diluted by water (3 mL), extracted with ethyl acetate (3 mL * 2) and washed with brine (5 mL), dried over Na2SO4, filtered and The reaction mixture was concentrated under reduced pressure to give the product.
  • Step 3 N-[2-(2-aminoethyl)-5-methyl-indazol-6-yl]-2-[3-methyl-5-(1- piperidylsulfonyl)indol-1-yl]propanamide (A-21) 1-yl]propanoylamino]indazol-2-yl]ethyl]carbamate (70.00 mg, 112.40 umol, 1 eq) in HCl/EtOAc (1 mL) was stirred at 20 °C for 1 h. LCMS showed the starting material was consumed and desired MS was detected. The reaction mixture was concentrated to dryness to give the crude product.
  • reaction mixture was purified by prep-HPLC (Phenomenex C1875*30mm*3um; 25-65 % acetonitrile in an a 10mM ammonium hydroxide solution in water, 8 min gradient).
  • EXAMPLE A-21 N-[2-(2-aminoethyl)-5-methyl-indazol-6-yl]-2-[3-methyl-5-(1- piperidylsulfonyl)indol-1-yl]propanamide (14.1 mg, 26.79 umol, 99.32% purity) was obtained as a white solid.
  • the mixture was stirred at 80 °C for 15 hr. LC-MS showed reactant was consumed completely and desired mass was detected.
  • the reaction mixture was cooled to room temperature and diluted by water (50 mL), extracted with ethyl acetate (50 mL *3). The combined organics were washed with brine (50 mL), dried over Na2SO4, filtered and the reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in DCM (30 mL), and 20 g of silica gel was added.
  • the mixture was stirred at 80 °C for 2 hr. LC-MS showed reactant was consumed completely and desired mass was detected.
  • the reaction mixture was cooled to room temperature and diluted by water (8 mL), extracted with dichloromethane (8 mL * 2). The combined organics were washed with brine (8 mL), dried over Na2SO4, filtered and The reaction mixture was concentrated under reduced pressure to give a residue.
  • the solid was purified by SFC(column: DAICEL CHIRALPAK AD(250 mm * 30 mm, 10 um); mobile phase: [0.1%NH3H2O IPA];B%: 50%- 50%,14 min).
  • the mixture was stirred at 80 °C for 15 hr. LC-MS showed reactant was consumed completely and desired mass was detected.
  • the reaction mixture was cooled to room temperature and diluted by water (50 mL), extracted with ethyl acetate (50 mL *3). The combined organics were washed with brine (50 mL), dried over Na2SO4, filtered and The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in DCM (30 mL), and 20 g of silica gel was added.
  • Step 2 General procedure for preparation of tert-butyl 3-(6-amino-5-methyl-indazol- 2-yl)azetidine-1-carboxylate (1.3 g, 3.91 mmol, 1 eq) in EtOH (10mL) and H2O (2 mL) was added Fe (1.09 g, 19.56 mmol, 5 eq) and NH4Cl (627.69 mg, 11.73 mmol, 3 eq) . The mixture was stirred at 80 °C for 2 hr. LC- MS showed reactant was consumed completely and desired mass was detected. The resultant mixture was filtered and the filter cake was rinsed with MeOH (5 mL x 3).
  • Step 3 General procedure for preparation of tert-butyl 3-[5-methyl-6-[2-[3-methyl-5- (1-piperidylsulfonyl)indol-1-yl]propanoylamino]indazol-2-yl]azetidine-1-carboxylate (86.29 mg, 285.36 umol, 1 eq) in DCM (2mL) was added DIEA (110.64 mg, 856.09 umol, 149.11 uL, 3 eq) and HATU (108.50 mg, 285.36 umol, 1 eq) and2-[3-methyl-5-(1- piperidylsulfonyl)indol-1-yl]propanoic acid (100 mg, 285.36 umol, 1 eq) . The mixture was stirred at 20 °C for 2 h.
  • Step 4 General procedure for preparation of N-[2-(azetidin-3-yl)-5-methyl-indazol-6- yl]-2-[3-methyl-5-(1-piperidylsulfonyl)indol-1-yl]propanamide
  • EXAMPLE A-25 1- yl]propanoylamino]indazol-2-yl]azetidine-1-carboxylate (150 mg, 236.30 umol, 1 eq) in DCM (0.5 mL) was added TFA (4.62 g, 40.52 mmol, 3.00 mL, 171.47 eq) . The mixture was stirred at 20 °C for 1 h.
  • Step 2 General procedure for preparation N-isoindolin-5-yl-2-[3-methyl-5-(1- piperidylsulfonyl)indol-1-yl]propanamide (A-31) yl]propanoylamino]isoindoline-2-carboxylate (150 mg,264.69 umol, 1 eq) in DCM (3 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 uL, 25.51 eq). The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue.
  • Step 2 General procedure for preparation of of tert-butyl 3-(3-amino-4-methyl- anilino)azetidine-1-carboxylate [0402] . anilino)azetidine-1-carboxylate (see EXAMPLE A-42), a solution of tert-butyl 3-(4-methyl-5- nitro-anilino)azetidine-1-carboxylate (1 eq) Pd/C (10% purity) in MeOH was stirred at 30 °C. LCMS showed the starting material was consumed and desired MS was detected.
  • Step 3 General procedure for preparation of tert-butyl 3-[4-methyl-3-[2-[3-methyl-5- (1-piperidylsulfonyl)indol-1-yl]propanoylamino]anilino]azetidine-1-carboxylate (39.57 mg, 142.68 umol, 1 eq) in DMF (0.5 mL) were added 2-[3-methyl-5-(1- piperidylsulfonyl)indol-1-yl]propanoic acid (50 mg, 142.68 umol, 1 eq), DIEA (92.20 mg, 713.41 umol, 124.26 uL, 5 eq) and HATU (81.38 mg,
  • Step 4 General procedure for preparation of N-[5-(azetidin-3-ylamino)-2-methyl- phenyl]-2-[3-methyl-5-(1-piperidylsulfonyl)indol-1-yl]propanamide (A-35) 1- yl]propanoylamino]anilino]azetidine-1-carboxylate (87 mg, 142.67 umol, 1 eq) in DCM (1 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 94.66 eq), the mixture was stirred at 20 °C for 1 h.
  • Step 2 General procedure for preparation of 1-(4-methyl-3-nitro-phenyl)imidazolidin-2-one [0412] To a (1 g, 5.12 mmol, 1 eq) in THF (10 mL) was added CDI (830.61 mg, 5.12 mmol, 1 eq), the mixture was stirred at 20°C for 1 h.
  • Step 3 General procedure for preparation of 1-(3-amino-4-methyl- phenyl)imidazolidin-2-one
  • Pd/C 20 mg, 90.41 umol, 10% purity, 1 eq
  • the mixture was stirred at 20 °C for 1 h under H2 atmosphere.
  • LCMS showed the reaction was complete.
  • the mixture was filtered under reduced pressure to give 1-(3-amino-4-methyl- phenyl)imidazolidin-2-one (20 mg, crude) as a yellow solid.
  • Step 4 General procedure for preparation of N-[2-methyl-5-(2-oxoimidazolidin-1- yl)phenyl]-2-[3-methyl-5-(1-piperidylsulfonyl)indol-1-yl]propanamide (A-36)
  • reaction was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3um;mobile phase: [water(HCl)-ACN];B%: 5%-40%,8min).
  • EXAMPLE A-37 N-(4-amino-2-methyl- phenyl)-2-[3-methyl-5-(1-piperidylsulfonyl)indol-1-yl]propanamide (65.76 mg, 144.66 umol, 34.89% yield, 100% purity) was obtained as a white solid.
  • Step 2 General procedure for the preparation of 2-methyl-5-morpholino-aniline.
  • EXAMPLE A-39 [0433] 2-[5-(benzenesulfonyl)-3-methyl-indol-1-yl]-N-(2-methyl-5-piperazin-1-yl- phenyl)propanamide 39 [0434] General -3-methyl-indol- 1-yl]propanoate [0435] In a manner similar to that described for EXAMPLE C-1, 5-bromo-3-methyl indole was treated with methyl 2-bromo propanoate to give methyl 2-(5-bromo-3-methylindol-1- yl)propanoate.
  • Step 2 General procedure for preparation of tert-butyl 3-(5-amino-2,4-dimethyl- anilino)azetidine-1-carboxylate [0473] (500 mg, 1.56 mmol, 1 eq) Pd/C (300 mg, 10% purity) in MeOH (2 mL) was stirred at 30 °C for 2 hr. LCMS showed the starting material was consumed and desired MS was detected. The resultant mixture was filtered and the filtrates were concentrated under reduced pressure to give the product. tert-butyl 3-(5-amino-2,4-dimethyl-anilino)azetidine-1-carboxylate (500 mg, crude) was obtained as a yellow oil.
  • Step 3 General procedure for preparation of tert-butyl 3-[2,4-dimethyl-5-[2-[3- methyl-5-(1-piperidylsulfonyl) indol-1-yl]propanoylamino]anilino]azetidine-1-carboxylate d (50 mg, 142.68 umol, 1 eq) tert-butyl 3-(5-amino-2,4-dimethyl-anilino)azetidine-1-carboxylate (41.58 mg, 142.68 umol, 1 eq), DIEA (55.32 mg, 428.04 umol, 74.56 uL, 3 eq), HATU (108.50 mg, 285.36 umol, 2 eq) in DCM (1 mL) was stirred at 20°C for 1h.
  • Step 4 General procedure for preparation of N-[5-(azetidin-3-ylamino)-2,4-dimethyl- phenyl]-2-[3-methyl-5-(1-piperidylsulfonyl)indol-1-yl] propanamide (A-42) indol- 1-yl]propanoylamino] anilino]azetidine-1-carboxylate (100 mg, 160.31 umol, 1 eq) in DCM (1 mL), TFA (1.54 g, 13.51 mmol, 1 mL, 84.25 eq). The mixture was stirred at 20°C for 2h. LCMS showed the starting material was consumed and desired MS was detected.
  • reaction mixture was purified directly by prep-HPLC.
  • the crude was purified by prep-HPLC (column: Phenomenex C1880*30mm*3um;mobile phase: [water(TFA)-ACN];B%: 30%-60%,8min gradient).
  • EXAMPLE A-42 N-[5-(azetidin-3-ylamino)-2,4-dimethyl-phenyl]-2-[3-methyl-5-(1- piperidylsulfonyl)indol-1-yl] propanamide (36.27 mg, 68.61 umol, 42.80% yield, 99.06% purity) was obtained as a white solid.
  • the reaction mixture was purified directly by prep-HPLC.
  • the crude was purified by prep-HPLC (column: Phenomenex C1880*30mm*3um;mobile phase: [water(TFA)-ACN];B%: 30%- 60%,8min).
  • EXAMPLE A-43 N-(2,4-dimethyl-5-piperazin-1-yl-phenyl)-2-[3-methyl-5-(1- piperidylsulfonyl)indol-1-yl]propanamide was obtained as a white solid. (35.14 mg, 65.35 umol, 41.68% yield, 100% purity) was obtained as a white solid.
  • Step 2 General procedure for preparation of N-(5-amino-2,4-dimethyl-phenyl)-2-[3- methyl-5-(1-piperidylsulfonyl)indol-1-yl]propanamide (A-44) [0493] piperidylsulfonyl)indol-1-yl]propanamide (20 mg, 40.11 umol, 1 eq) in MeOH (1 mL) was added Pd/C (40.11 umol, 10% purity, 1 eq), was stirred at 20 °C for 1 h under H 2 15 psi atmosphere. LCMS showed starting material was consumed and desired ms was detected. The mixture was concentrated to dryness to give residue.
  • Step 2 General procedure for preparation of N-(3-amino-2,6-dimethyl-phenyl)-2-[3- methyl-5-(1-piperidylsulfonyl)indol-1-yl]propanamide (A-45) [0499] piperidylsulfonyl)indol-1-yl]propanamide (65 mg, 130.37 umol, 1 eq) in MeOH (2 mL) was added Pd/C (130.37 umol, 10% purity, 1 eq), the reaction was stirred at 20 °C for 1 h under H 2 atmosphere. LCMS showed starting material was consumed and desired ms was detected.
  • Step 3 General procedure for preparation of tert-butyl tert-butyl 3-[2, 4-dimethyl-3- [2-[3-methyl-5-(1-piperidylsulfonyl) indol-1-yl] propanoylamino] anilino] azetidine-1- carboxylate (50 mg, 171.59 umol, 1 eq) in DCM (0.5 mL) were added 2-[3-methyl-5-(1- piperidylsulfonyl)indol-1-yl]propanoic acid (60.13 mg, 171.59 umol, 1 eq), Et3N (86.82 mg, 857.96 umol, 119.42 uL, 5 eq) and 2-chloro-1-methyl-pyridin-1-ium;iodide (87.68 mg, 343.19 umol, 2 eq), the mixture was stirred at 25C for 2 h.
  • Step 4 General procedure for preparation of N-[3-(azetidin-3-ylamino)-2,6-dimethyl- phenyl]-2-[3-methyl-5-(1-piperidylsulfonyl)indol-1-yl]propanamide (A-46) piperidylsulfonyl)indol-1-yl]propanoylamino]anilino]azetidine-1-carboxylate (100 mg, 160.31 umol, 1 eq) in DCM (1 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 84.25 eq), the mixture was stirred at 25°C for 1 h.
  • Step 1 Gene -methyl-4-nitro-2- pyridyl)piperazine-1-carboxylate [0513] To a 1 eq) in dioxane (10 mL) was added tert-butyl piperazine-1-carboxylate (2.16 g, 11.59 mmol, 2 eq), XPhos (276.25 mg, 579.48 umol, 0.1 eq) and K3PO4 (2.46 g, 11.59 mmol, 2 eq).
  • tert-butyl 4-(5-methyl-4-nitro-2-pyridyl)piperazine-1-carboxylate 700 mg, 2.13 mmol, 36.68% yield, 97.89% purity
  • Step 2 General procedure for preparation of tert-butyl 4-(4-amino-5-methyl-2- pyridyl)piperazine-1-carboxylate
  • Pd/C 200 mg, 6.51 mmol, 10% purity, 3 eq).
  • Step 3 General procedure for preparation of tert-butyl 4-[5-methyl-4-[2-[3-methyl-5- (1-piperidylsulfonyl)indol-1-yl]propanoylamino]-2-pyridyl]piperazine-1-carboxylate a tert- (200 mg, 684.05 umol, 1 eq) in DCM (3 mL) was added 2-[3-methyl-5-(1- piperidylsulfonyl)indol-1-yl]propanoic acid (239.71 mg, 684.05 umol, 1 eq) and Et3N (207.66 mg, 2.05 mmol, 285.63 uL, 3 eq).Then the mixture was added CMPI (349.53 mg, 1.37 mmol, 2 eq) and stirred at 25 °C for 1 hr.
  • Step 4 General procedure for preparation of N-(5-methyl-2-piperazin-1-yl-4- pyridyl)-2-[3-methyl-5-(1-piperidylsulfonyl)indol-1-yl]propanamide (A-47) indol- 1-yl]propanoylamino]-2-pyridyl]piperazine-1-carboxylate (200 mg, 320.11 umol, 1 eq) in DCM (3 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 42.19 eq). Then the mixture was stirred at 25 °C for 1 hr.
  • Step 2 General procedure for preparation of 2-(5-fluoro-3-methyl-indol-1- yl)propanoic acid [0525] To a (300 mg, 1.28 mmol, 1 eq) in THF (1.5 mL) and MeOH (1.5 mL) was added NaOH (102.01 mg, 2.55 mmol, 212.54 uL, 2 eq), the mixture was stirred at 20 °C for 1 h.
  • Step 3 General procedure for preparation of tert-butyl 4-[4-methyl-3-[2-(5-fluoro-3- methylindol-1-yl)butanoylamino]phenyl]piperazine-1-carboxylate (131.71 mg, 452.02 umol, 1 eq) and 2-(5-fluoro-3-methyl-indol-1-yl)propanoic acid (100 mg, 452.02 umol, 1 eq) in DMF (1 mL) was added HATU (257.81 mg, 678.04 umol, 1.5 eq) and DIEA (175.26 mg, 1.36 mmol, 236.20 uL, 3 eq), the mixture was stirred at 20 °C for 1 h.
  • Step 4 General procedure for preparation of 2-(5-fluoro-3-methyl-indol-1-yl)-N-(2- methyl-5-piperazin-1-yl-phenyl)propanamide (A-48) -4- methyl-phenyl]piperazine-1-carboxylate (100 mg, 202.18 umol, 1 eq) in TFA (1 mL), the mixture was stirred at 20 °C for 1 h. LCMS and HPLC showed the reaction was complete. The mixture was filtered and the filtrate was purified directly.
  • Step 2 General preparation of tert-butyl 4-(3-amino-4-methylphenyl)piperidine-1- carboxylate
  • I I -methyl-3- nitrophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate was dissolved in methanol and treated with Pd/C under a pressurized atmosphere of hydrogen at 25 deg C for 1 hr.
  • Step 3 and 4 General preparation of N-[2-methyl-5-(piperidin-4-yl)phenyl]-2-[3- methyl-5-(piperidine-1-sulfonyl)-1H-indol-1-yl]propanamide (A-49) methylphenyl)piperidine-1-carboxylate and 2-[5-(1-piperidylsulfonyl)indol-1-yl]propanoic acid where coupled using HATU, DIEA in DMF at 25 deg C for 1 hr.
  • Step 2 General preparation of provide 4-(3-bromoprop-1-ynyl)-1-methyl-2-nitro- benzene [0543] 1 eq) in DCM (20 mL) was added CBr4 (3.95 g, 11.9 mmol, 1.2 eq) at 0 °C.
  • Step 3 General preparation of 1-[3-(4-methyl-3-nitro-phenyl)prop-2-ynyl]pyrrolidine [0545] mmol, 1 eq), pyrrolidine (836 mg, 11.8 mmol, 1.5 eq), Cs2CO3 (5.10 g, 15.7 mmol, 2 eq) in DMF (10 mL) was degassed and purged with N2 (3X). The mixture was stirred at 25 °C for 2 h under a N2 atmosphere. The mixture was poured into water (30 mL), and the mixture was extracted with ethyl acetate (20 mL x 3).
  • Step 4 General preparation of 2-methyl-5-(3-pyrrolidin-1-ylpropyl)aniline [0547] 1.00 g, 4.09 mmol, 1 eq) in MeOH (10 mL) was added Pd/C (1 g, 10% wt% Pd) under a N 2 atmosphere. The suspension was degassed and purged with H2 (3X). The mixture was stirred under H2 (15 Psi) at 25 °C for 2 h. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to furnish 2-methyl-5-(3-pyrrolidin-1-ylpropyl)aniline as a yellow oil. The material was used directly in the next step without further purification.
  • the mixture was stirred at 25 °C for 2 h under a N2 atmosphere.
  • the mixture was poured into water (20 mL), and the mixture was extracted with ethyl acetate (15 mL x 3).
  • the combined organic phase was washed with brine (15 mL), dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum.
  • Step 2 General preparation of 4-[2-(4-methyl-3-nitro-phenyl)ethyl]morpholine HN O
  • morpholine 123 mg, 1.41 mmol, 1.5 eq
  • Cs 2 CO 3 614 mg, 1.88 mmol, 2 eq
  • the mixture was stirred at 25 °C for 2 h.
  • the reaction mixture was quenched with water (15 mL) at 20 °C.
  • the mixture was extracted with ethyl acetate (10 mL x 3).
  • Step 3 General preparation of 2-methyl-5-(2-morpholinoethyl)aniline Pd/C, H 2 (15 psi) O
  • Pd/C 2-methyl-5-(2-morpholinoethyl)aniline
  • Step 4 General Preparation of N-[2-methyl-5-(2-morpholinoethyl)phenyl]-2-[3- methyl-5-(1-piperidylsulfonyl)indol-1-yl]propanamide (A-51) O
  • a mixture of 2-[3-methyl-5-(1-piperidylsulfonyl)indol-1-yl]propanoic acid (90 mg, 0.26 mmol, 1 eq)
  • 2-methyl-5-(2-morpholinoethyl)aniline 68 mg, 0.31 mmol, 1.2 eq
  • HATU 107 mg, 0.28 mmol, 1.1 eq
  • DIPEA 100 mg, 0.770 mmol, 3 eq
  • the mixture was stirred at 20 °C for 3 h under a N2 atmosphere.
  • the mixture was poured into water (5 mL), and the mixture was extracted with ethyl acetate (3 mL x 3).
  • the combined organic layers were washed with brine (5 mL x 3), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure.
  • EXAMPLE A-52 2-[3-methyl-5-(piperidine-1-sulfonyl)-1H-indol-1-yl]-N-[3-methyl-6-(piperazin-1- yl)pyridin-2-yl]propanamide 52 [0562] Step 1: 6-nitropyridin-2- yl)piperazine-1-carboxylate [0563] In a method similar to that described for EXAMPLE A-47 [0564] To a solution of 6-chloro-3-methyl-2-nitropyridine (1 eq) in dioxane was added tert- butyl piperazine-1-carboxylate (2 eq), XPhos (0.1 eq) and K3PO4 (2 eq).
  • Step 2 General procedure for preparation of tert-butyl 4-(6-amino-5-methylpyridin-2- yl)piperazine-1-carboxylate
  • a of tert-butyl tert-butyl 4-(5-methyl-6-nitropyridin-2-yl)piperazine-1-carboxylate (1 eq) in MeOH (3 mL) was added Pd/C (3 eq). Then the mixture was stirred. LC-MS showed reactant was consumed completely and one main peak with desired mass was detected. The resultant mixture was filtered and the filter cake was rinsed with MeOH. Then the combined filtrates were concentrated under reduced pressure to give as brown oil.
  • Step 3 General procedure for preparation of tert-butyl 4-(5-methyl-6- ⁇ 2-[3-methyl-5- (piperidine-1-sulfonyl)-1H-indol-1-yl]propanamido ⁇ pyridin-2-yl)piperazine-1-carboxylate
  • Step 4 General procedure for preparation of 2-[3-methyl-5-(piperidine-1-sulfonyl)- 1H-indol-1-yl]-N-[3-methyl-6-(piperazin-1-yl)pyridin-2-yl]propanamide
  • EXAMPLE A-53 N-(2,6-dimethyl-5-piperazin-1-yl-phenyl)-2-[3-methyl-5-(1-piperidylsulfonyl)indol- 1-yl]propanamide 53 [0573] General 5-nitro- phenyl)piperazine-1-carboxylate [0574] In a manner similar to that described for EXAMPLE A-43, a solution of 1-bromo-2,6- dimethyl-5-nitro-benzene (1 eq), tert-butyl piperazine-1-carboxylate (2 eq), RuPhos (0.2 eq), Pd2(dba)3 (0.1 eq), Cs2CO3 (3 eq) in Toluene was stirred under heat and an nitrogen atmosphere.
  • N-(6-bromo-3-methyl-2- pyridyl)-2-[3-methyl-5-(1-piperidylsulfonyl)indol-1-yl]propanamide 125 mg, crude was obtained as a white solid.
  • Step 2 General preparation of tert-butyl 4-(3-amino-4-methylphenyl)-3- oxopiperazine-1-carboxylate
  • 4-(4-methyl-3- nitrophenyl)-3-oxopiperazine-1-carboxylate was dissolved in methanol and treated with iron and ammonium chloride at 70 deg C for 3 hours. Filtration and evaporation gave tert-butyl 4-(3- amino-4-methylphenyl)-3-oxopiperazine-1-carboxylate.
  • Step 3 and 4 General preparation of N-[2-methyl-5-(2-oxopiperazin-1-yl)phenyl]-2- [3-methyl-5-(piperidine-1-sulfonyl)-1H-indol-1-yl]propanamide (A-55)
  • Step 2 General prep of benzyl 5-(aminomethyl)-2,3-dihydro-1H-isoindole-2- carboxylate.
  • 2- carboxylate was dissolved in HCl/EtOAc and stirred at 25 deg C for 1 hr. Isolation gave benzyl 5-(aminomethyl)-2,3-dihydro-1H-isoindole-2-carboxylate.
  • Step 3 and 4 General preparation of N-[(2,3-dihydro-1H-isoindol-5-yl)methyl]-2-[3- methyl-5-(piperidine-1-sulfonyl)-1H-indol-1-yl]propanamide EXAMPLE A-56
  • EXAMPLE A-57 2-(6-chloro-3-methyl-1H-indol-1-yl)-N-[2-methyl-5-(piperazin-1- yl)phenyl]propanamide [0607] General yl)-N-[2-methyl-5- (piperazin-1-yl)phenyl]propanamide EXAMPLE 1-57 [0608] EXAMPLE A-57 was prepared In a manner similar to that described for EXAMPLE C-1.
  • Step 2 [0625] at 0 deg C, then methyl 2-bromopropionate was added and the solution warmed to 20 deg C for 2.5 hours as described for Intermediate 1 to give methyl 2-[5-(1-piperidylsulfonyl)(3-bromo-indol-1- yl]propanoate.
  • Step 3 with 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane and K2CO3, Pd(dppf)2Cl and water in DMF at 100 deg C for 12 hours to give the acid 2-(5-(piperidin-1-ylsulfonyl)-3-(prop-1-en-2- yl)-1H-indol-1-yl)propanoic acid.
  • Step 4 was dissolved in ethyl acetate and treated with Pd/C under pressurized H2 atmosphere for 12 hours at 25 deg C to give 2-(5-(piperidin-1-ylsulfonyl)-3-(isopropyl)-1H-indol-1-yl)propanoic acid.
  • EXAMPLE A-63 Enantiomer B N-(5-amino-2-methyl-phenyl)-2-[3-methyl-5-(1- piperidylsulfonyl)indol-1-yl]propanamide of unknown absolute stereochemistry
  • A-63 Racemic N- 5-(1-piperidylsulfonyl)indol-1- yl]propanamide (EXAMPLE A-10) was resolved with chiral chromatography to give its two enantiomers of unknown absolute stereochemistry.
  • Step 2 General procedure for preparation of t2-(3-methylindol-1-yl)butanoic acid - Notebook Page: ET58892-6 [0649] To a 1.73 mmol, 1 eq) in MeOH (1.5 mL) and THF (1.5 mL) was added NaOH (2 M, 1.73 mL, 2 eq), the mixture was stirred at 20 °C for 1 h.
  • Step 3 General procedure for preparation of tert-butyl 4-[4-methyl-3-[2-(3- methylindol-1-yl)butanoylamino]phenyl]piperazine-1-carboxylate - Notebook Page: ET58892-8
  • [0651] 134.12 mg, 460.27 umol, 1 eq
  • 2-(3-methylindol-1-yl)butanoic acid 100 mg, 460.27 umol, 1 eq
  • DMF 1 mL
  • HATU 262.51 mg, 690.41 umol, 1.5 eq
  • DIEA 178.46 mg, 1.38 mmol, 240.51 uL, 3 eq
  • Step 4 General procedure for preparation of 2-(3-methylindol-1-yl)-N-(2-methyl-5- piperazin-1-yl-phenyl)butanamide -
  • the mixture was stirred at 20 °C for 1 h.
  • LCMS showed the reaction was complete.
  • the mixture was filtered.
  • Step 2 General procedure for preparation of tert-butyl 3-[4- (aminomethyl)anilino]azetidine-1-carboxylate mmol, 1 eq) in MeOH (30 mL,NH3 in MeOH(7M)) was added Raney-Ni (940.35 mg, 10.98 mmol, 1 eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3times. The mixture was stirred under H2 (15 Psi) at 25°Cfor 4h. LCMS showed the starting material was consumed completely and desired MS was detected. The reaction mixture was filtered through a pad of celite and the celite was rinsed with MeOH (10 mL * 3).
  • Step 3 General procedure for preparation of tert-butyl 3-[4-[(2- bromopropanoylamino)methyl]anilino]azetidine-1-carboxylate uL, 1 eq) in CH2Cl2 (10 mL) was added TEA (729.66 mg, 7.21 mmol, 1.00 mL, 2 eq) at 0 °C and tert- butyl 3-[4-(aminomethyl)anilino]azetidine-1-carboxylate (1 g, 3.61 mmol, 1 eq). The mixture was stirred at 25 °C for 2 h. LCMS showed the starting material was consumed and desired MS was detected.
  • Step 4 General procedure for preparation of tert-butyl tert-butyl 3-[4-[[2-[3-methyl- 5-(1-piperidylsulfonyl)indol-1-yl]propanoylamino]methyl]anilino]azetidine-1-carboxylate 1-carboxylate (100 mg, 242.53 umol, 1 eq) in DMF (2 mL) was added Cs2CO3 (158.04 mg, 485.06 umol, 2 eq) and 3-methyl-5-(1-piperidylsulfonyl)-1H-indole (67.51 mg, 242.53 umol, 1 eq).
  • Step 5 General procedure for preparation of tert-butyl N-[[4-(azetidin-3- ylamino)phenyl]methyl]-2-[3-methyl-5-(1-piperidylsulfonyl)indol-1-yl]propanamide
  • EXAMPLE B-2 [0668] Enantiomer A N-[[4-(azetidin-3-ylamino)phenyl]methyl]-2-[3-methyl-5-(1- piperidylsulfonyl)indol-1-yl]propanamide of unknown absolute stereochemistry
  • EXAMPLE B-2 [0669] 1 H , 1H), 7.46(s, 2H), 7.36(s, 1H), 6.94(d, 2H), 6.44(d, 2H), 5.15(m, 1H), 4.33(m, 1H), 4.15(m, 2H), 3.93(m, 2H), 3.57(m, 2H), 2.93(m, 4H), 2.34(s, 3H), 1.73 (d, 3H), 1.52 (m, 4H), 1.38 (m, 2H).
  • Step 2 General procedure for preparation of 2-[5-[(3R)-3-aminopyrrolidin-1- yl]sulfonyl-3-methyl-indol-1-yl]-N-[[4-(azetidin-3-ylamino)phenyl]methyl]propanamide (B-4) 1-yl]sulfonyl-3-methyl-indol-1-yl]propanoylamino]methyl]anilino]azetidine-1-carboxylate (120 mg, 168.80 umol, 1 eq) in DCM (1.5 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 uL, 40.00 eq) at 0°C.The mixture was stirred at 25°Cfor 1h.
  • Step 2 General procedure for preparation of tert-butyl N-[(3R)-1-(3-methylindolin-5- yl) sulfonylpyrrolidin-3-yl] carbamate
  • sulfonylpyrrolidin-3-yl] carbamate (1.8 g, 4.25 mmol, 1 eq) in MeOH (20 mL) was added K2CO3 (1.76 g, 12.75 mmol, 3 eq). The reaction was stirred at 80°C for 12 hr.
  • Step 3 General procedure for preparation of tert-butyl N-[(3R)-1-[(3-methyl-1H- indol-5-yl) sulfonyl]pyrrolidin-3-yl]carbamate
  • 3-yl] carbamate (1.6 g, 4.19 mmol, 1 eq) in THF (20 mL) was added MnO2 (3.65 g, 41.94 mmol, 10 eq). The mixture was stirred at 70°C for 12 hr. LCMS showed the reaction was complete. The resultant mixture was filtered and the filter cake was rinsed with DCM (5 mL x 3). Then the combined filtrates were concentrated under reduced pressure to give as brown oil.
  • Step 4 General procedure for preparation of tert-butyl 4-[3-(2- bromopropanoylamino)-4-methyl-phenyl]piperazine-1-carboxylate [0688] In a manner similar to that described for tert-butyl 3-[4-[(2- bromopropanoylamino)methyl]anilino]azetidine-1-carboxylate, SEE EXAMPLE B-1, [0689 A (2 eq) at 0 °C and tert-butyl 4-(3-amino-4-methyl-phenyl)piperazine-1-carboxylate (see EXAMPLE A- 9 )(1 eq).
  • Step 5 General procedure for preparation of tert-butyl 4-[3-[2-[5-[(3R)-3-(tert- butoxycarbonylamino) pyrrolidin-1-yl] sulfonyl-3-methyl-indol-1-yl] propanoylamino]-4- methyl-phenyl] piperazine-1-carboxylate - phenyl]piperazine-1-carboxylate (85.97 mg, 263.52 umol, 1 eq) in THF (2 mL) was added NaH (31.62 mg, 790.57 umol, 60% purity, 3 eq) at 0°C. The mixture was stirred at 20 °C for 1hr.
  • Step 6 General procedure for preparation of 2-[5-[(3R)-3-aminopyrrolidin-1-yl] sulfonyl-3-methyl-indol-1-yl]-N-(2-methyl-5-piperazin-1-yl-phenyl) propanamide (B-5) sulfonyl-3-methyl-indol-1-yl] propanoylamino]-4-methyl-phenyl] piperazine-1-carboxylate (100 mg, 137.95 umol, 1 eq) was added HCl/EtOAc (3 mL) and stirred at 20°C for 1hr. LCMS showed the reaction was complete.
  • the reaction mixture was concentrated under reduced pressure to give a residue. Without purification.
  • the residue was purified by preparative HPLC (column: Phenomenex luna C1880*40mm*3 um;mobile phase: [water(HCl)-ACN];B%: 10%- 40%,7min) the HPLC fractions were combined, lyophilized to give the desire comound as a yellow solid.
  • Step 4 General procedure for preparation of tert-butyl 4-[4-methyl-3-[2-[3-methyl-5- (triazol-1-yl)indol-1-yl]propanoylamino]phenyl]piperazine-1-carboxylate THF (10 mL) and purged with N2 three times. Then the reaction was cooled to 0°C and NaH (40.35 mg, 1.01 mmol, 60% purity, 2 eq) was added into the stirring reaction at 0°C.
  • Step 5 General procedure for preparation of N-(2-methyl-5-piperazin-1-yl-phenyl)-2- [3-methyl-5-(triazol-1-yl)indol-1-yl]propanamide (B-7) yl]propanoylamino]phenyl]piperazine-1-carboxylate (100 mg, 183.94 umol, 1 eq) was dissolved into EtOAc (1 mL) and then HCl/EtOAc (4 M, 1 mL, 21.75 eq) was added. The resulting reaction was stirred at 20°C for 1 hr. LCMS showed starting material was consumed completely and main peak with desired mass was detected. The mixture was concentrated in vacuo.
  • Step 2 General procedure for preparation of tert-butyl 4-[3-[2-(6-fluoro-3-methyl- indol-1-yl)propanoylamino]-4-methyl-phenyl]piperazine-1-carboxylate
  • Step 3 General procedure for preparation of 2-(6-fluoro-3-methyl-indol-1-yl)-N-(2- methyl-5-piperazin-1-yl-phenyl)propanamide (B-8) methyl-phenyl]piperazine-1-carboxylate (125.38 mg, 253.50 umol, 1 eq) in TFA (1 mL)the mixture was stirred at 20 °C for 1 h.
  • Step 2 General procedure for preparation of N, N-dimethyl-1H-indole-6-sulfonamide
  • Pd/C 0.5 g, 1.67 mmol, 10% purity
  • Step 3 General procedure for preparation of 3-formyl-N, N-dimethyl-1H-indole-6- sulfonamide eq) was added to the DMF (2 mL) at 0 °C, the mixture was stirred at 0 °C for 0.5 h, then N,N-dimethyl-1H-indole-6-sulfonamide (200 mg, 891.75 umol, 1 eq) in DMF (2 mL) was added to the mixture ,the mixture was stirred at 90 °C for 0.5 h.
  • Step 4 General procedure for preparation of N, N, 3-trimethyl-1H-indole-6- sulfonamide
  • a (0.1 g, 396.37 umol, 1 eq) in THF 15 mL was added LAH (18.05 mg, 475.64 umol, 1.2 eq) in portions at 0 °C .
  • the mixture was stirred at 60 °C for 5 hr.
  • LCMS showed the starting material was consumed completely and approximate 70% of the desired mass was observed.
  • the reaction mixture was cooled to 0 o C, the reaction mixture was quenched by addition of 0.1 mL of H2O, followed by 0.1mL of 15% aqueous NaOH.
  • Step 5 General procedure for preparation of tert-butyl 4-[3-[2-[6- (dimethylsulfamoyl)-3-methyl-indol-1-yl] propanoylamino]-4-methyl-phenyl] piperazine-1- carboxylate phenyl]piperazine-1-carboxylate (see EXAMPLE B-5) (100 mg, 234.55 umol, 1 eq) in THF (20 mL) was added NaH (18.76 mg, 469.10 umol, 60% purity, 2 eq) at 0 °C and N,N,3-trimethyl- 1H-indole-6-sulfonamide (55.89 mg, 234.55 umol, 1 eq).
  • Step 6 General procedure for preparation of 2-[6-(dimethylsulfamoyl)-3-methyl- indol-1-yl]-N-(2-methyl-5-piperazin-1-yl-phenyl) propanamide (B-9) yl]propanoylamino]-4-methyl-phenyl]piperazine-1-carboxylate (50 mg, 85.65 umol, 1 eq) in EtOAc(1 mL) was added HCl/EtOAc (4 M, 2.50 mL, 116.75 eq).
  • Step 2 General procedure for preparation of N-(2-methyl-5-piperazin-1-yl-phenyl)-2- (3- methylpyrrolo [3,2-b] pyridin-1-yl) propanamide (B-11) [0755] To a solution of tert-butyl 4-[4-methyl-3-[2-(3-methylpyrrolo[3,2-b]pyridin-1-yl) propanoylamino]phenyl]piperazine-1-carboxylate (150 mg, 314.07 umol, 1 eq) was added HCl/EtOAc (4 M, 1.67 mL, 21.23 eq) . The mixture was stirred at 20 °C for 1 h.
  • Step 3 General procedure for preparation of tert-butyl 4-[4-methyl-3-[2-(3- methylindol-1-yl)propanoylamino]phenyl]piperazine-1-carboxylate
  • ne-1-carboxylate 172.05 mg, 590.44 umol, 1.2 eq
  • 2-(3-methylindol-1-yl)propanoic acid 100 mg, 492.04 umol, 1 eq
  • HATU 374.17 mg, 984.07 umol, 2 eq
  • DIEA 190.78 mg, 1.48 mmol, 257.11 uL, 3 eq
  • the mixture was stirred at 20°C for 2 hr. LCMS showed the starting material was consumed and desired MS was detected.
  • the reaction mixture was diluted by water (5 mL), extracted with ethyl acetate (5 mL * 2). The combined organics were washed with brine (5 mL), dried over Na2SO4, filtered and the reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in DCM (10 mL), and 2 g of silica gel was added.
  • Step 4 General procedure for preparation of 2-(3-methylindol-1-yl)-N-(2-methyl-5- piperazin-1-yl-phenyl) propanamide (C-1) [0765] yl)propanoylamino]phenyl]piperazine-1-carboxylate (200 mg, 419.63 umol, 1 eq) and HCl/EtOAc (3 mL). The mixture was stirred at 20°C for 2 hr. LCMS showed the starting material was consumed and desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a residue.
  • Step 2 General procedure for preparation of tert-butyl 4-[3-[2-(5-methoxy-3-methyl- indol-1-yl)propanoylamino]-4-methyl-phenyl]piperazine-1-carboxylate 1 eq) in THF (10 mL) was added NaH (93.81 mg, 2.35 mmol, 60% purity, 5 eq) in portions at 0°C, the mixture was stirred at 0°C for 0.5 h, then tert-butyl 4-[3-(2-bromopropanoylamino)-4-methyl- phenyl]piperazine-1-carboxylate (see EXAMPLE B-5) (200 mg, 469.10 umol, 1 eq) was added to the mixture, then mixture was stirred at 20°C for 12 h.
  • Step 3 General procedure for preparation of tert-butyl 4-[3-[2-(5-methoxy-3-methyl- indol-1-yl)propanoylamino]-4-methyl-phenyl]piperazine-1-carboxylate (C-2) - 4-methyl-phenyl]piperazine-1-carboxylate (40 mg, 78.95 umol, 1 eq) in DCM (2 mL) was added TFA (90.02 mg, 789.52 umol, 58.46 uL, 10 eq). The mixture was stirred at 20°C for 1 hr. LCMS and HPLC showed the starting material was consumed completely and approximate 80% of the desired MS was observed.
  • EXAMPLE C-3 [0775] 3-methyl-1-[1-methyl-2-(2-methyl-5-piperazin-1-yl-anilino)-2-oxo-ethyl] indole-6- carboxamide 3 of 3-methyl-1H-indole-6-carboxamide [0777] To a purity, 1 eq) and 3-methyl-1H-indole-6-carboxylic acid (300 mg, 1.71 mmol, 1 eq) in DCM (3 mL) was added HATU (976.71 mg, 2.57 mmol, 1.5 eq) and DIEA (663.98 mg, 5.14 mmol, 894.85 uL, 3 eq) at 0 °C.
  • Step 2 General procedure for preparation of tert-butyl 2-(6-carbamoyl-3-methyl- indol-1-yl)propanoate 4.88 mmol, 1 eq) in DMF (10 mL) was added Cs2CO3 (4.77 g, 14.64 mmol, 3 eq) and tert-butyl 2-bromopropanoate (1.02 g, 4.88 mmol, 1 eq) at 0 °C. The mixture was stirred at 20 °C for 1 h. LCMS showed starting material was consumed completely and main desired MS was detected. The combined reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL * 2).
  • Step 3 General procedure for preparation of 2-(6-carbamoyl-3-methyl-indol-1-yl) propanoic acid (150 mg, 496.09 umol, 1 eq) in TFA (3.08 g, 5.40 mmol, 2 mL, 20% purity, 10.89 eq) was stirred at 20 o C for 1 h. LCMS showed starting material was consumed completely and main desired MS was detected. The mixture was concentrated under reduced pressure to give a crude product.2-(6- carbamoyl-3-methyl-indol-1-yl) propanoic acid (150 mg, crude) was obtained as a pale red oil.
  • Step 4 General procedure for preparation of tert-butyl 4-[3-[2-(6-carbamoyl-3- methyl-indol-1-yl) propanoylamino]-4-methyl-phenyl]piperazine-1-carboxylate
  • the reaction mixture was quenched by addition H2O 3 mL at 20°C, and then extracted with EA 3 mL (1 mL * 3). The combined organic layers were washed with brine 3 mL (1 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Step 5 General procedure for preparation of 3-methyl-1-[1-methyl-2-(2-methyl-5- piperazin-1-yl-anilino)-2-oxo-ethyl] indole-6-carboxamide (C-3) - 4-methyl-phenyl]piperazine-1-carboxylate (200 mg, 384.89 umol, 1 eq) in HCl/EtOAc (4 M, 2 mL, 20.79 eq) was stirred at 20 o C for 1 h. LCMS and HPLC showed starting material was consumed completely and main desired MS was detected. The mixture was concentrated under reduced pressure to give a residue.
  • Step 2 General procedure for preparation of 2-(3-methyl-1H-pyrrolo [2, 3-b] pyridin- 1-yl) propanoic acid [0791] To (600 mg, 2.75 mmol, 1 eq) in THF (6 mL) MeOH (3 mL) H2O (3 mL) was added LiOH.H2O (807.54 mg, 19.24 mmol, 7 eq) at 0 °C. Then the reaction was stirred at 20 °C for 2 h.
  • Step 3 General procedure for preparation of tert-butyl 4-(4-methyl-3-(2-(3-methyl- 1H-pyrrolo [2, 3-b] pyridin-1-yl)propanamido)phenyl)piperazine-1-carboxylate [0793] mg, 979.31 umol, 1 eq) in DCM (4 mL) were added tert-butyl 4-(3-amino-4-methyl- phenyl)piperazine-1-carboxylate (285.36 mg, 979.31 umol, 1 eq) HATU (1.12 g, 2.94 mmol, 3 eq) and DIEA (189.85 mg, 1.47 mmol, 255.87 uL, 1.5 eq) at 0 °C .
  • Step 4 General procedure for preparation of 2-(3-methyl-1H- pyrrolo [2, 3-b] pyridin-1-yl)-N-(2-methyl-5-(piperazin-1-yl) phenyl) propanamide (C-4) 1- yl)propanoylamino]phenyl]piperazine-1-carboxylate (100 mg, 209.38 umol, 1 eq) in HCl/EtOAc (4 M, 52.35 uL, 1 eq) was stirred at 20 °C for 1 h. LC-MS showed starting material were consumed completely and the peak with desired MS was detected. HPLC. The reaction was filtered and the filtrate was purified by prep-HPLC directly.
  • Step 2 General procedure for preparation of 2-(3-methylpyrrolo[2,3-c]pyridin-1- yl)propanoic acid [0801] To a (310 mg, 1.42 mmol, 1 eq) in THF (4 mL) and MeOH (2 mL) and H2O (2 mL) was added LiOH.H2O (417.23 mg, 9.94 mmol, 7 eq), then the mixture was stirred at 20°C for 2 h.
  • Step 3 General procedure for preparation of tert-butyl 4-[4-methyl-3-[2-(3- methylpyrrolo[2,3-c]pyridin-1-yl)propanoylamino]phenyl]piperazine-1-carboxylate [0803] g, 244.83 umol, 1 eq) and tert-butyl 4-(3-amino-4-methyl-phenyl)piperazine-1-carboxylate (71.34 mg, 244.83 umol, 1 eq) in DMF (1 mL) were added DIEA (63.28 mg, 489.66umol, 85.29 uL, 2 eq) and HATU (139.64 mg, 367.24 umol, 1.5 eq) at 0°C, then the mixture was stirred at 20°C for 2h.
  • DIEA 63.28 mg, 489.66umol, 85.29 uL, 2 eq
  • HATU 139.64 mg,
  • Step 4 General procedure for preparation of N-(2-methyl-5-piperazin-1-yl-phenyl)-2- (3-methylpyrrolo[2,3-c]pyridin-1-yl)propanamide (C-5) yl)propanoylamino]phenyl]piperazine-1-carboxylate (100 mg, 209.38 umol, 1 eq) in DCM (1 mL) was added TFA (770.00 mg, 6.75 mmol, 0.5 mL, 32.25 eq), then the mixture was stirred at 20°C for 1h. LC-MS showed starting material were consumed completely and the peak with desired MS was detected.
  • the filtrate was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 1%-25%, 8min).
  • Compound 2-(3-methylpyrrolo [3, 2-c] pyridin-1-yl) propanoic acid (80 mg, 391.73 umol, 35.16% yield) was obtained as a white solid.
  • PLpro catalyzed substrate cleavage and to release the Edans fluorescence signal Small molecule compounds were screened at 16.6 ⁇ M final concentration.
  • the PLpro biochemical cleavage assay at room temperature is carried out in 384-well flat bottom black polypropylene microplates (Greiner, 781076).
  • 1x PLpro reaction buffer 50 mM Tris-HCl, pH 7.3, 1 mM EDTA, 1 mM TCEP, and 0.01% Tween-20
  • 0.1 ⁇ l of serially diluted compounds in DMSO are dispensed into columns 1–22 of the assay microplates with a Janus 384 MDT NanoHead (PerkinElmer). In wells of column 23 and 24, which serve as controls, no compounds are added.
  • PLpro enzyme reaction 10 ⁇ l of 3x PLpro solution (100 nM, high protein version, or 10 nM, low protein version, in 1x PLpro reaction buffer) are added to columns 1-23 followed by incubation for 5 minutes at RT. Column 24 serves as positive control, so no protein is added, just 10 ⁇ l more of 1x PLpro reaction buffer.
  • the PLpro reaction is started by adding 10 ⁇ l of a 3x substrate solution containing FRET-based synthetic peptide (120 ⁇ M) prepared in 1x PLpro reaction buffer. Any addition of reagents is followed by a 30 second centrifugation at 500 ⁇ g to ensure that all liquid was collected at the bottom of the well.
  • the final concentrations of PLpro and peptide are 100 nM (high protein version) or 10 nM (low protein version) and 40 ⁇ M, respectively.
  • the final reaction volume is 30 ⁇ l. Plates are incubated for 1.5 h at room temperature. [0823] Fluorescence signals of each well are recorded in relative fluorescent units (RFUs) using a Biotek Synergy Neo plate reader (BioTek, Winooski, VT).
  • Huh7.5 cells are seeded in 96-well plates (Corning, Product Number 353072) in 10% FBS-containing media at a density of 1.0 ⁇ 10 4 cells per well. Plates are incubated for 24 h at 37 oC, 5% CO 2 . After addition of compounds (100x in DMSO) to cells, plates are transported to the BSL3 facility (laboratory of Dr. Charles Rice, RU), where SARS-CoV-2 (strain USA-WA1/2020 propagated in Vero E6 cells) diluted in assay media is added to achieve ⁇ 30 – 50% infected cells. Plates are incubated for 24 h at 37 oC, 5% CO2, and then fixed with 3.5% formaldehyde.
  • SARS-CoV-2 nucleocapsid protein is analyzed for viral infection by immunostaining for SARS-CoV-2 nucleocapsid protein using SARS-CoV-2 (COVID-19) nucleocapsid antibody (Genetex, GTX135357) as the primary antibody and Alexa Fluor 488-conjugated goat anti-rabbit IgG (H+L, Invitrogen by Thermo Fisher Scientific, A11008) as the secondary antibody, and antifade-46-diamidino-2-phenylindole (DAPI; Thermo Fisher Scientific D1306) to stain DNA, with PBS 0.05% Tween-20 washes in between fixation and subsequent primary and secondary antibody staining.
  • SARS-CoV-2 SARS-CoV-2 (COVID-19) nucleocapsid antibody
  • Alexa Fluor 488-conjugated goat anti-rabbit IgG H+L, Invitrogen by Thermo Fisher Scientific, A110
  • Plates are imaged using the ImageXpress Micro Confocal High-Content Imaging System (Molecular Devices) with a 10 ⁇ objective, with 4 fields imaged per well. Images are analyzed using the Multi-Wavelength Cell Scoring Application Module (MetaXpress), with DAPI staining identifying the host-cell nuclei (the total number of cells in the images) and the SARS-CoV-2 immunofluorescence signal leading to identification of infected cells.
  • MethodaXpress Multi-Wavelength Cell Scoring Application Module
  • the percentage of infection is calculated as the ratio of the number of infected cells stained for coronavirus NP to number of cells stained with DAPI. Treatment of cells with DMSO serves as negative control; treatment of cells with 200 nM Remdesivir serves as positive control.
  • Table 5 (SARS-CoV-2/Huh7.5 screening assay) Cell-based (Viral Cell-based (Viral Cell-based (Cell Cell-based (Viral 50) Cell-base Cell-based (Viral Cell-based (Cell Ex infection EC d (Cell infection + P- viabilit + P- p p g [0829] PLpro docking models were generated using SARS-CoV-2 PLpro structures in complex with inhibitors (PDB IDs 7JIR,7CJM, 7JRN, 7LBS, 7LBR, 7LLF, 7LLZ, 7LOS, 7D6H, 7E35). Docking poses were subjected to refinement by 100ns molecular dynamics simulations followed by absolute FEP calculations.
  • the refined model that validated using FEP+ for affinity prediction came from the structure with PDB ID 7JRN (Discovery of SARS-CoV-2 Papain-like Protease Inhibitors through a Combination of High-Throughput Screening and a FlipGFP-Based Reporter Assay. Ma et al, ACS Cent. Sci.2021).

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Abstract

L'invention concerne des méthodes et des compositions pour le traitement du SARS-CoV-2 et de la COVID-19. Les 1,3-indole propanamides représentés par la formule (I) suivante inhibent la protéine PLpro/NSP3 du SARS-CoV-2 et sont par conséquent utiles pour le traitement du SARS-CoV-2 et de la COVID-19.
PCT/US2024/012712 2023-01-25 2024-01-24 Inhibiteurs 1,3-indole-propanamides de la plpro/nsp3 du sars-cov-2 et leurs dérivés Ceased WO2024158872A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6043257A (en) * 1997-08-18 2000-03-28 E. I. Du Pont De Nemours And Company Amidinoindoles, amidinoazoles, and analogs thereof
WO2008147797A2 (fr) * 2007-05-25 2008-12-04 Vertex Pharmaceuticals Incorporated Modulateurs de canal ionique et leurs procédés d'utilisation
US20090093469A1 (en) * 2004-03-30 2009-04-09 Wyeth Phenylaminopropanol Derivatives and Methods of Their Use
WO2015136463A1 (fr) * 2014-03-11 2015-09-17 Glaxosmithkline Intellectual Property (No.2) Limited Composés chimiques agissant comme inhibiteurs de perk
US11479550B2 (en) * 2017-05-22 2022-10-25 Ono Pharmaceutical Co., Ltd. EP4 antagonist

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6043257A (en) * 1997-08-18 2000-03-28 E. I. Du Pont De Nemours And Company Amidinoindoles, amidinoazoles, and analogs thereof
US20090093469A1 (en) * 2004-03-30 2009-04-09 Wyeth Phenylaminopropanol Derivatives and Methods of Their Use
WO2008147797A2 (fr) * 2007-05-25 2008-12-04 Vertex Pharmaceuticals Incorporated Modulateurs de canal ionique et leurs procédés d'utilisation
WO2015136463A1 (fr) * 2014-03-11 2015-09-17 Glaxosmithkline Intellectual Property (No.2) Limited Composés chimiques agissant comme inhibiteurs de perk
US11479550B2 (en) * 2017-05-22 2022-10-25 Ono Pharmaceutical Co., Ltd. EP4 antagonist

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM COMPOUND 21 October 2014 (2014-10-21), ANONYMOUS: "2-(5-methylindol-1-yl)-Nphenylpropanamide", XP093198812, retrieved from PUBCHEM Database accession no. 84361219 *

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