# US 12,600,699 B2 · Thiosemicarbazates and uses thereof

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- Number: US 12,600,699 B2
- Document ID: US12600699B2
- Status: Granted
- Kind: B2
- Application number: 18/073,689
- Filed: 2022-12-02
- Published: 2023-04-13
- Granted: 2026-04-14
- 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/US12600699B2

## 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 H;
Y is a NR1;
X is NR5;
D is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R1 is H; or
R1 and R5 are joined together by —(CH2—CH2—CH2)—; 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 a natural or unnatural amino acid, which is 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 unsubstituted, and wherein, when said amino acid is a natural amino acid, the natural amino acid is selected from the group consisting of aspartic acid, phenylalanine, alanine, histidine, glutamic acid, tryptophan, valine, leucine, lysine, methionine, tyrosine, isoleucine, arginine, asparagine, and glutamine.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 and R5 are joined together by —(CH2—CH2—CH2)—.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R5 is a side chain radical of a natural amino acid, which is unsubstituted.

### Claim 4 (depends on 3)

The compound of claim 3, wherein the natural amino acid is selected from the group consisting of aspartic acid, alanine, phenylalanine, histidine, glutamic acid, tryptophan, methionine, tyrosine, arginine, asparagine, and glutamine.

### Claim 5 (depends on 4)

The compound of claim 4, wherein the natural amino acid is phenylalanine.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein the natural amino acid is selected from the group consisting of aspartic acid, phenylalanine, alanine, histidine, glutamic acid, tryptophan, valine, leucine, lysine, methionine, tyrosine, isoleucine, arginine, asparagine, and glutamine, which is 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 alkyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the side chain radical is a residue from an unnatural amino acid.

### Claim 8 (depends on 7)

The compound of claim 7, wherein the residue from the unnatural amino acid is unsubstituted.

### Claim 9 (depends on 7)

The compound of claim 7, wherein R5 is a side chain radical of an unnatural amino acid, and the unnatural amino acid is selected from the group consisting of a β-amino acid, an aliphatic amino acid, β-cyclohexyl-L-alanine, 6-aminohexanoic acid, L-α,β-diaminopropionic acid, L-propargylglycinel, L-α,β-diaminopropionic acid, α-aminoisobutyric acid, β-(2-pyridyl)-L-alanine, β-(3-pyridyl)-L-alanine, β-cyclopropyl-L-alanine, β-t-butyl-L-alanine, (2,4-dinitrophenyl))-L-α,β-diaminopropionic acid, (allyloxycarbonyl)-L-α,β-diaminopropionic acid, D-α,β-diaminopropionic acid, L-α,β-diaminopropionic acid, (N-γ-1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl)-L-α,γ-diaminobutyric acid, (N-γ-4-methyltrityl)-L-α,γ-diaminobutyric acid, L-α,γ-diaminobutyric acid, 4-fluoro-L-phenylglycine, 5,5,5-trifluoro-DL-leucine, epsilon-aminohexanoic-OH, L-α-t-butylglycine, L-2-amino-3-(dimethylamino)propionic acid, L-2-aminocaproic acid, L-allylglycine, lysine azide, (N-8-4-methyltrityl)-L-ornithine, Arg(Me)(Pbf)-OH, dimethyl-L-arginine (symmetrical and unsymmetrical), L-2-amino-3-guanidinopropionic acid, L-citrulline, ε-acetyl-L-lysine, Lys(ivDde)-OH, Lys(Me)2-OH·HCl, Lys(Me3)-OHchloride, α-methyl-DL-glutamic acid, γ-carboxy-L-glutamic acid γ,γ-di-t-butyl ester, (N-γ-ethyl)-L-glutamine, 2,6-diaminopimelic acid, Glu(OAll)-OH, L-cysteic acid, α-methyl-DL-methionine, DL-buthionine, L-cysteic acid, L-selenomethionine, S-[2-(4-pyridyl)ethyl]-L-cysteine, S-[2-(4-pyridyl)ethyl]-L-cysteine, S-diphenylmethyl-L-cysteine, S-trityl-L-homocysteine, S-trityl-L-penicillamine, (Se-p-methoxybenzyl)-L-selenocysteine, β-hydroxyphenylalanine, 2-cyano-L-phenylalanine, L-thyroxine, O-methyl-L-tyrosine, β-methyl-DL-phenylalanine, 2-cyano-L-phenylalanine, L-thyroxine, O-methyl-L-tyrosine, β-methyl-DL-phenylalanine, 2-cyano-L-phenylalanine, 3,4-dichloro-L-phenylalanine, 3,4-difluoro-L-phenylalanine, 3,4-dihydroxy-L-phenylalanine, 3,4-dihydroxy-phenylalanine, 3-amino-L-tyrosine, 3-chloro-L-tyrosine, 3-fluoro-DL-tyrosine, 3-nitro-L-tyrosine, 4-amino-L-phenylalanine, 4-aminomethyl-L-phenylalanine, 4-(phosphonomethyl)-phenylalanine, 4-benzoyl-D-phenylalanine, 4-bis(2-chloroethyl) amino-L-phenylalanine, 4-cyano-L-phenylalanine, 4-fluoro-L-phenylalanine, 4-iodo-L-phenylalanine, DL-m-tyrosine, 2,6-dimethyl-tyrosine, L-homophenylalanine, O-methyl-L-tyrosine, Phe(4-guanidino)-OH, O-benzyl-L-phosphotyrosine, (2S,3R)-3-phenylpyrrolidine-2-carboxylic acid, (2S,4S)-4-phenyl-pyrrolidine-2-carboxylic acid, (2S,3aS,7aS)-Octahydro-1H-indole-2-carboxylic acid, (2S,3R)-3-phenylpyrrolidine-2-carboxylic acid, (2S,4R)-(−)-4-t-butoxypyrrolidine-2-carboxylic acid, trans-4-fluoro-L-proline, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, 4-amino-3-hydroxybutanoic acid, L-a-methylserine, (2S,3S)-2-amino-3-methoxybutanoic acid, Thr(β-D-GlcNAc(Ac) 3)-OH, O-benzyl-L-phosphoserine, O-benzyl-D-phosphothreonine, O-benzyl-L-phosphothreonine, 4-methyl-DL-tryptophan, 6-fluoro-DL-tryptophan, 6-methyl-DL-tryptophan, DL-7-azatryptophan, (R)-7-Azatryptophan, 5-benzyloxy-DL-tryptophan, 5-bromo-DL-tryptophan, 5-chloro-DL-tryptophan, 5-fluoro-DL-tryptophan, 5-hydroxy-L-tryptophan, 5-methoxy-L-tryptophan, 6-chloro-L-tryptophan, 6-methyl-DL-tryptophan, 7-methyl-DL-tryptophan, DL-7-azatryptophan, 5-azido-pentanoic acid, 2-amino-N-(3-azidopropyl)-3-mercaptopropionamide, 2-amino-N-(3-azidopropyl)-3-mercaptopropionamide, Azidohomoalanine, L-propargylglycine·DCHA, azidolysine, p-azidophenylalanine, Azidohomoalanine, D-propargylglycine, L-propargylglycine, azidolysine, tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine, 2-(7′-octenyl) alanine, 2-(4′-pentenyl) alanine, 2-(4′-pentenyl) glycine, 2-(7′-octenyl) alanine, [5-((2-aminoethyl)amino)naphthalene-1-sulfonic acid], L-glutamic acid-γ-[2-(1-sulfonyl-5-naphthyl)-aminoethylamide], N-8-(5-carboxyfluorescein)-L-lysine, N-ε-(5/6-carboxyfluorescein)-L-lysine, N-ε-(4,4-dimethylazobenzene-4′carbonyl)-L-lysine, N-8-2,4-dinitrophenyl-L-lysine, N-ε-[(7-methoxycoumarin-4-yl)-acetyl-L-lysine, glycosylated amino acids (e.g., Ser(β-D-GlcNAc (Ac) 3)-OH, Thr(β-D-GlcNAc(Ac)3)-OH), 3-azabicyclo[3.1.0]hexane-2-carboxylic acid, 4-amino-(1-carboxymethyl) piperidine, 4-phenylpiperidine-4-carboxylic acid, Nα-methyl-N-im-trityl-L-histidine, Nα-methyl-O-benzyl-L-serine dicyclohexylammonium salt, N-alpha-methyl-N-omega-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-L-arginine, N-alpha-methyl-L-leucine, Nalpha-methyl-L-norvaline, N-alpha-methyl-L-phenylalanine, N-alpha-methyl-N-im-trityl-L-histidine, N-alpha-methyl-O-t-butyl-L-serine, N-alpha-methylglycine, 21-amino-4,7,10,13,16,19-hexaoxaheneicosanoic acid, {2-[2-(amino)-ethoxy]-ethoxy}acetic acid, 6-amino-4-oxahexanoic acid, 5-amino-3-oxapentamoic acid, NH-(PEG)10-CH2CH2COOH, NH-(PEG) 12-CH2CH2COOH, 9-Amino-4; 7-dioxanonanoic acid, 9-amino-4; 7-dioxanonanoic acid, 12-amino-4,7,10-trioxadodecanoic acid, 15-amino-4,7,10,13-tetraoxapentadecacanoic acid, 18-amino-4,7,10,13,16-pentaoxaoctadecanoic acid, 21-amino-4,7,10,13,16,19-hexaoxaheneicosanoic acid, NH-(PEG) 8-CH2CH2COOH, 11-amino-3,6,9-trioxaundecanoic acid, N-(Fmoc-8-amino-3,6-dioxa-octyl) succinamic acid, —N-ε-acetyl-L-lysine, L-citrulline, Arg(Me)(Pbf)-OH, N-ω,ω-dimethyl-L-arginine, Lys(Me) 2-OH chloride, N-8,8-t-methyl-L-lysine, Lys(Me3)-OH chloride, O-benzyl-L-phosphoserine, O-benzyl-D-phosphothreonine and O-benzyl-L-phosphothreonine, and O-benzyl-L-phosphotyrosine, 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 10 (depends on 9)

The compound of claim 9, wherein the unnatural amino acid is a β-amino acid or an aliphatic amino acid, which is unsubstituted or 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 alkyl.

### Claim 11 (depends on 10)

The compound of claim 10, wherein the β-amino acid is selected from the group consisting of L-β-homotyrosine, β-alanine, L-β-homoasparagine, L-β-homoalanine, L-β-homophenylalanine, homotryptophan, homoserine, homocysteine, L-β-homoproline, L-β-homoolysine, L-β-homorarginine, and L-β-proline.

### Claim 12 (depends on 10)

The compound of claim 10, wherein the aliphatic amino acid is selected from the group consisting of 6-aminohexanoic acid, 2-amino-3-methoxybutanoic acid, 1-aminocyclopentane-1-carboxylic acid, 2-(aminooxy) acetic acid, and 6-aminohaxanoic acid, 2-[2-(amino)-ethoxy]-ethoxy}acetic acid.

### Claim 13 (depends on 1)

The compound of claim 1, wherein D is H, alkyl, or aryl, wherein said alkyl or aryl are unsubstituted or 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, and C1-C6 haloalkyl, wherein R is alkyl.

### Claim 14

A compound of the Formula (I):
wherein
A is H;
Y is a NR1;
X is NR5;
D is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R1 is H; and
R5 is a side chain radical of a natural amino acid selected from the group consisting of aspartic acid, phenylalanine, alanine, histidine, glutamic acid, tryptophan, valine, leucine, lysine, methionine, tyrosine, isoleucine, arginine, asparagine, and glutamine, which is unsubstituted or 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 alkyl.

### Claim 15 (depends on 14)

The compound of claim 14, wherein the natural amino acid is unsubstituted.

### Claim 16 (depends on 15)

The compound of claim 15, wherein the natural amino acid is selected from the group consisting of aspartic acid, phenylalanine, alanine, histidine, glutamic acid, tryptophan, valine, leucine, methionine, tyrosine, isoleucine, arginine, asparagine, and glutamine.

### Claim 17

A compound of the Formula (I):
wherein
A is H;
Y is a NR1;
X is NR5;
D is a substituted or unsubstituted alkyl,
R1 is H; and
R5 is a side chain radical of a natural amino acid selected from the group consisting of aspartic acid, phenylalanine, alanine, histidine, glutamic acid, tryptophan, valine, leucine, lysine, methionine, tyrosine, isoleucine, arginine, asparagine, and glutamine, which is unsubstituted or 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.