# US 12,595,233 B2 · Thiosemicarbazates and uses thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,595,233 B2 - Document ID: US12595233B2 - Status: Granted - Kind: B2 - Application number: 17/831,504 - Filed: 2022-06-03 - Published: 2022-09-29 - Granted: 2026-04-07 - Earliest claimed: 2019-05-09 - Assignees: The Feinstein Institutes for Medical Research - Applicants: The Feinstein Institutes for Medical Research - Inventors: Yousef Al-Abed; Ahmad Altiti - Web page: https://patentgrep.com/patent/US12595233B2 ## CPC - C07D 209/48: with oxygen atoms in positions 1 and 3, e.g. phthalimide - C07D 403/12: linked by a chain containing hetero atoms as chain links - Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS ## Abstract Thioesters, thiocarbamates, thiocarbazates, semithiocarbazates, peptides, aza-amino acid conjugates, and azapeptides; and a chemoselective and site-specific functionalization protocol of protected thiocarbazates and semithiocarbazates are described. The protocol features the use of Mitsunobu reaction to alkylate specifically the nitrogen atom close to the acylthiol moiety with alcohols to produce protected mono-substituted thiocarbazates that can be stored for months, activated under mild conditions at low temperature using halonium reagents and integrated orthogonally to make substituted semicarbazides that can be used, e.g., as synthons in synthesis of aza-amino acid conjugates, azapeptides and other peptidomimetics. Methods for preparing and using ureases, carbazides, semicarbazides, beta-peptides, azapeptides, and other peptidomimetics and azapeptide conjugates, and uses of ureases, carbazides, semicarbazides, beta-peptides, azapeptides in drug discovery, diagnosis, inhibition, prevention and treatment of diseases are also described. ## Claims ### Claim 1 A compound of the Formula (I): wherein A is a protecting group selected from the group consisting of tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, carboxybenzyl, 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl, 2,2,4,6,7,-pendamethyl-dihydrobenzofuran-5-sulfonyl, triphenylmethyl, tert-butylcarbonyl, t-butoxy, allyloxycarbonyl, methoxytrimethylbenzene sulfonyl, 4,4-dimethoxy benzhydryl, 2,2,5,7,8-pentamethylchroman-6-sulfonyl, 2,4,6-trimethoxybenzyl, allylcarbonyl, and acetamidomethyl; Y is NR1; X is NR5; D is H, Cl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is unsubstituted or substituted; and R5 is H, an unsubstituted alkyl, unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is substituted or unsubstituted, or an alkyl substituted one or more times by one or more substituents selected from the group consisting of halo, C1-C6 alkyl, —COOR, —COR, methoxy, ethoxy, propoxy, C1-C6 haloalkyl, and a protecting group, wherein R is an alkyl; or R1 and R5 are together joined by —(CH2—CH2—CH2)—. ### Claim 2 (depends on 1) The compound according to claim 1, wherein A is selected from the group consisting of tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, and carboxybenzyl. ### Claim 3 A compound of the Formula (I): wherein A is a protecting group selected from the group consisting of tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, carboxybenzyl, 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl, 2,2,4,6,7,-pendamethyl-dihydrobenzofuran-5-sulfonyl, triphenylmethyl, tert-butylcarbonyl, t-butoxy, allyloxycarbonyl, methoxytrimethylbenzene sulfonyl, 4,4-dimethoxy benzhydryl, 2,2,5,7,8-pentamethylchroman-6-sulfonyl, 2,4,6-trimethoxybenzyl, allylcarbonyl, and acetamidomethyl; Y is NR1; X is NR5; D is H, Cl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1 is a radical of an amino acid, wherein the amino acid is selected from the group consisting of aspartic acid, phenylalanine, alanine, histidine, glutamic acid, tryptophan, valine, leucine, lysine, methionine, tyrosine, isoleucine, arginine, glycine, asparagine, serine, and glutamine, which are unsubstituted or substituted by one or more substituents selected from the group consisting of halo, C1-C6 alkyl, —COOR, —COR, methoxy, ethoxy, propoxy, C1-C6 haloalkyl, and a protecting group, wherein R is alkyl; and R5 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is substituted or unsubstituted. ### Claim 4 A compound of the Formula (I): wherein A is a protecting group selected from the group consisting of tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, carboxybenzyl, 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl, 2,2,4,6,7,-pendamethyl-dihydrobenzofuran-5-sulfonyl, triphenylmethyl, tert-butylcarbonyl, t-butoxy, allyloxycarbonyl, methoxytrimethylbenzene sulfonyl, 4,4-dimethoxy benzhydryl, 2,2,5,7,8-pentamethylchroman-6-sulfonyl, 2,4,6-trimethoxybenzyl, allylcarbonyl, and acetamidomethyl; Y is NR1; X is NR5; D is H, Cl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is unsubstituted or substituted; and R5 is a radical of an amino acid wherein the amino acid is selected from the group consisting of aspartic acid, phenylalanine, alanine, histidine, glutamic acid, tryptophan, valine, leucine, lysine, methionine, tyrosine, isoleucine, arginine, glycine, asparagine, serine, and glutamine, which are unsubstituted or substituted by one or more substituents selected from the group consisting of halo, a C1-C6 alkyl, —COOR, —COR, methoxy, ethoxy, propoxy, C1-C6 haloalkyl, and a protecting group, wherein R is alkyl. ### Claim 5 A compound of the Formula (I): wherein A is a protecting group selected from the group consisting of tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, carboxybenzyl, 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl, 2,2,4,6,7,-pendamethyl-dihydrobenzofuran-5-sulfonyl, triphenylmethyl, tert-butylcarbonyl, t-butoxy, allyloxycarbonyl, methoxytrimethylbenzene sulfonyl, 4,4-dimethoxy benzhydryl, 2,2,5,7,8-pentamethylchroman-6-sulfonyl, 2,4,6-trimethoxybenzyl, allylcarbonyl, and acetamidomethyl; Y is NR1; X is NR5; D is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and the substituents are selected from the group consisting of halo, C1-C6 alkyl, —COOR, —COR, methoxy, ethoxy, propoxy, and C1-C6 haloalkyl, wherein R is alkyl, R1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is unsubstituted or substituted; and R5 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is substituted or unsubstituted. ### Claim 6 (depends on 1) The compound according to claim 1, A compound of the Formula (I): wherein A is a protecting group selected from the group consisting of tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, carboxybenzyl, 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl, 2,2,4,6,7,-pendamethyl-dihydrobenzofuran-5-sulfonyl, triphenylmethyl, tert-butylcarbonyl, t-butoxy, allyloxycarbonyl, methoxytrimethylbenzene sulfonyl, 4,4-dimethoxy benzhydryl, 2,2,5,7,8-pentamethylchroman-6-sulfonyl, 2,4,6-trimethoxybenzyl, allylcarbonyl, and acetamidomethyl; Y is NR1; X is NR5; D is H, Cl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R1 is a radical of an amino acid wherein the amino acid is an unnatural amino acid, and R5 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is substituted or unsubstituted. ### Claim 7 (depends on 1) The compound according to claim 1, A compound of the Formula (I): wherein A is a protecting group selected from the group consisting of tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, carboxybenzyl, 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl, 2,2,4,6,7,-pendamethyl-dihydrobenzofuran-5-sulfonyl, triphenylmethyl, tert-butylcarbonyl, t-butoxy, allyloxycarbonyl, methoxytrimethylbenzene sulfonyl, 4,4-dimethoxy benzhydryl, 2,2,5,7,8-pentamethylchroman-6-sulfonyl, 2,4,6-trimethoxybenzyl, allylcarbonyl, and acetamidomethyl; Y is NR1; X is NR5; D is H, Cl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is unsubstituted or substituted; and R5 is a radical of an amino acid wherein the amino acid is an unnatural amino acid. ### Claim 8 (depends on 1) The compound according to claim 1, which is of the formula: ### Claim 9 (depends on 8) The compound according to claim 8, wherein A is selected from the group consisting of tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, and carboxybenzyl. ### Claim 10 (depends on 1) The compound according to claim 1, which is of the formula: wherein R9 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is substituted or unsubstituted. ### Claim 11 A compound of the Formula (V): wherein A is a protecting group selected from the group consisting of tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, carboxybenzyl, 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl, 2,2,4,6,7,-pendamethyl-dihydrobenzofuran-5-sulfonyl, triphenylmethyl, tert-butylcarbonyl, t-butoxy, allyloxycarbonyl, methoxytrimethylbenzene sulfonyl, 4,4-dimethoxy benzhydryl, 2,2,5,7,8-pentamethylchroman-6-sulfonyl, 2,4,6-trimethoxybenzyl, allylcarbonyl, and acetamidomethyl; D is H, Cl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R10 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is substituted or unsubstituted. ### Claim 12 (depends on 1) The compound according to claim 1, wherein R1 is a radical of an amino acid, wherein the amino acid is selected from the group consisting of aspartic acid, phenylalanine, alanine, histidine, glutamic acid, tryptophan, valine, leucine, lysine, methionine, tyrosine, isoleucine, arginine, glycine, asparagine, serine, and glutamine, which are unsubstituted or substituted by one or more substituents selected from the group consisting of halo, C1-C6 alkyl, —COOR, —COR, methoxy, ethoxy, propoxy, C1-C6 haloalkyl, and a protecting group, wherein R is alkyl. ### Claim 13 (depends on 12) The compound according to claim 12, wherein R5 is a radical of an amino acid, wherein the amino acid is selected from the group consisting of aspartic acid, phenylalanine, alanine, histidine, glutamic acid, tryptophan, valine, leucine, lysine, methionine, tyrosine, isoleucine, arginine, glycine, asparagine, serine, and glutamine, which are unsubstituted or substituted by one or more substituents selected from the group consisting of halo, C1-C6 alkyl, —COOR, —COR, methoxy, ethoxy, propoxy, C1-C6 haloalkyl, and a protecting group, wherein R is alkyl. ### Claim 14 (depends on 1) A process for synthesizing an aza-peptide comprising activating an acyl thiol with TCCA or a combination of TCCA and TBACl to form an acyl chloride and coupling the acyl chloride with an amine, wherein the acyl thiol is a compound according to claim 1. ### Claim 15 (depends on 1) A process for preparing a compound according to claim 1, which comprises forming the compound by reacting a semi-protected hydrazine with chlorothioformate to form an S-alkylthiocarbazate, and alkylating the resulting S-alkylthiocarbazate selectively via Mitsunobu reaction, a direct alkylation with a combination of NaH or Barton's base and an alkyl halide. ### Claim 16 (depends on 1) The compound according to claim 1, wherein: R1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is unsubstituted or substituted; and R5 is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is substituted or unsubstituted. ### Claim 17 (depends on 1) The compound according to claim 1, wherein: R1 is H, substituted or unsubstituted alkyl, or a side chain radical of an amino acid, which is unsubstituted or substituted; and R5 is substituted or unsubstituted alkyl, or a side chain radical of an amino acid, which is substituted or unsubstituted. ### Claim 18 (depends on 1) The compound according to claim 1, wherein A is fluorenylmethoxycarbonyl. ### Claim 19 (depends on 1) The compound according to claim 1, wherein D is ethyl. ### Claim 20 (depends on 1) The compound according to claim 1, wherein A is fluorenylmethoxycarbonyl, and D is ethyl. ### Claim 21 (depends on 1) The compound according to claim 1, wherein A is 9-fluorenylmethoxycarbonyl, R1 is H; and D is ethyl.