NZ758381B2 - Secondary amine-substituted coumarin compounds and their uses as fluorescent labels - Google Patents

Secondary amine-substituted coumarin compounds and their uses as fluorescent labels Download PDF

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Publication number
NZ758381B2
NZ758381B2 NZ758381A NZ75838118A NZ758381B2 NZ 758381 B2 NZ758381 B2 NZ 758381B2 NZ 758381 A NZ758381 A NZ 758381A NZ 75838118 A NZ75838118 A NZ 75838118A NZ 758381 B2 NZ758381 B2 NZ 758381B2
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New Zealand
Prior art keywords
optionally substituted
compound
so3h
4alkyl
co2h
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NZ758381A
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NZ758381A (en
Inventor
Carole Anastasi
Niall Hynes
Patrick Mccauley
Nikolai Nikolaevich Romanov
Xiaolin Wu
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Illumina Cambridge Limited
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Priority claimed from GBGB1716931.9A external-priority patent/GB201716931D0/en
Application filed by Illumina Cambridge Limited filed Critical Illumina Cambridge Limited
Publication of NZ758381A publication Critical patent/NZ758381A/en
Publication of NZ758381B2 publication Critical patent/NZ758381B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/44—Amides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/14—Pyrrolo-pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2563/00—Nucleic acid detection characterized by the use of physical, structural and functional properties
    • C12Q2563/107—Nucleic acid detection characterized by the use of physical, structural and functional properties fluorescence

Abstract

The present application relates to secondary amine-substituted coumarin compounds and their uses as fluorescent labels. The compounds may be used as fluorescent labels for nucleotides in nucleic acid sequencing applications.

Claims (52)

WHAT IS CLAIMED IS:
1. A compound of Formula (I) or a salt thereof: wherein: 5 X is O, S, Se, or NRn, where Rn is H or kyl; R is H, halo, -CN, amino, -OH, C-amido, N-amido, -NO2, -SO3H, -SO2NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aminoalkyl, optionally substituted yclyl, optionally substituted heterocyclyl, optionally substituted 10 aryl, or optionally substituted heteroaryl; R1 is H, halo, -CN, -CO2H, amino, -OH, C-amido, N-amido, -NO2, -SO3H, -SO2NH2, optionally tuted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aminoalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted 15 aryl; R2 and R4 are each independently H, halo, -CN, -CO2H, amino, -OH, C-amido, N-amido, -NO2, -SO3H, -SO2NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted l, optionally substituted alkoxy, optionally substituted aminoalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, 20 optionally substituted aryl, or optionally substituted heteroaryl; ; R3 is C2-6alkyl substituted with –CO2H or –SO2H, ally tuted heterocyclyl, or R3 is linked to R2 or R4 to form an ally substituted ring; each R5 is independently halo, -CN, -CO2H, amino, -OH, C-amido, N-amido, -NO2, -SO3H, -SO2NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted 25 alkynyl, optionally tuted , optionally substituted aminoalkyl, optionally tuted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and m is 0, 1, 2, 3, or 4. 30
2. The nd of claim 1, wherein R2 and R4 are each independently H, halo, -CN, -CO2H, amino, -OH, C-amido, N-amido, -NO2, -SO3H, -SO2NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, ally substituted alkoxy, optionally substituted aminoalkyl, ally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and neither of R2 and R4 is linked to R3 to form an optionally substituted heterocyclic ring.
3. The compound of claim 1 or claim 2, wherein X is O or S.
4. The compound of any one of claims 1-3, wherein X is NRn, where Rn is H or C1-6alkyl. 10
5. The compound of any ing claim, wherein R3 is nCOOH, where n is 2, 3, 4, 5 or
6. The compound of any preceding claim wherein R3 is -(CH2)nSO3H where n is 2, 3, 4, 5 or 6. 15
7. The nd of any preceding claim, wherein m is 0, 1, or 2.
8. The compound of any preceding claim, wherein each R5 is independently optionally substituted C1-6alkyl, halo, -CN, -CO2H, amino, -OH, -SO3H, or -SO2NH2. 20
9. The compound of claim 8, wherein each R5 is halo, -CN, -CO2H, -SO3H, -SO2NH2, or ally substituted C1-6alkyl.
10. The compound of claim 9, wherein R5 is C2-6alkyl substituted with -CO2H, -SO3H, or -SO2NH2.
11. The compound of claim 10, wherein R5 is -(CH2)xCOOH, where x is 2, 3, 4, 5 or 6.
12. The compound of claim 1, wherein R5 is -SO3H or -SO2NH2. 30
13. The compound of any one of claims 1-11, wherein R1 is H, halo, or C1-6alkyl.
14. The compound of claim 13, wherein R1 is H or Cl.
15. The nd of any one of claims 1-14, wherein R is H, halo, C1-6alkyl, or Cl.
16. The compound of any preceding claim, wherein R2 is H, optionally substituted alkyl, C1- 4alkyl optionally substituted with -CO2H or -SO3H, or -SO3H. 5
17. The nd of claim 16, wherein R2 is H or -SO3H.
18. The compound of any one of claims 1 or 3 to 15, wherein R2 is linked to R3 to form an ally substituted heterocyclic ring, or a pyrrolidine or a piperidine, wherein the pyrrolidine or the piperidine are optionally substituted with one or more alkyl groups.
19. The nd of any one of claims 1-17, wherein R4 is H, optionally substituted alkyl, C1- 4alkyl optionally substituted with -CO2H or -SO3H, or -SO3H.
20. The compound of any one of claims 1 or 3 to 17, wherein R4 is linked to R3 to form an 15 optionally substituted heterocyclic ring, or a pyrrolidine or a piperidine, n the pyrrolidine or the piperidine are optionally substituted with one or more alkyl groups.
21. The compound of claim 1, wherein X is O or S; R is H; R1 is H; R3 is -(CH2)nCOOH where n is 2, 3, 4, 5, or 6; R5 is H, -SO3H, or -SO2NH2; R2 is H or -SO3H; and R4 is H or -SO3H.
22. The compound of claim 21, wherein R3 is -(CH2)2COOH.
23. The compound of claim 21, wherein R3 is -(CH2)5COOH. 25
24. A compound of Formula (II) or a salt thereof: wherein: X’ is selected from O, S, and NRp, where Rp is H or kyl; R6 is H or C1-4alkyl; R7 is H, halo, -CN, -OH, optionally substituted C1-4alkyl, optionally tuted C1-4alkenyl, optionally substituted C2-4alkynyl, -CO2H, -SO3H, -SO2NH2, -SO2NH(C1-4alkyl), -SO2N(C1- 4alkyl)2, and optionally substituted C1-4alkoxy; R8 and R10 are each ndently H, halo, -CN, -CO2H, amino, -OH, -SO3H, -SO2NH2, 5 -SO2NH(C1-4alkyl), -SO2N(C1-4alkyl)2, optionally substituted C1-6alkyl, optionally substituted C1-6alkenyl, optionally substituted kynyl, or optionally tuted C1- 6alkoxy; or one of R8 and R10 is H, halo, -CN, -CO2H, amino, -OH, -SO3H, -SO2NH2, -SO2NH(C1-4alkyl), -SO2N(C1-4alkyl)2, optionally tuted C1-6alkyl, optionally substituted C1-6alkenyl, 10 optionally substituted C2-6alkynyl, or optionally substituted C1-6alkoxy, and the other of R8 and R10 is taken with R9 to form an optionally substituted 4- to 7-membered heterocyclic ring; R9 is kyl tuted with -CO2H, -CO2C1-4alkyl, -CONH2, -CONH(C1-4alkyl), -CON(C1-4alkyl)2, -CN, -SO3H, -SO2NH2, -SO2NH(C1-4alkyl), or -SO2N(C1-4alkyl)2; 15 each R11 is independently halo, -CN, carboxy, amino, -OH, C-amido, N-amido, nitro, -SO3H, -SO2NH2, -SO2NH(C1-4alkyl), -SO2N(C1-4alkyl)2, optionally substituted alkyl, optionally substituted l, optionally substituted alkynyl, and ally substituted koxy; and q is 0, 1, or 2. 20
25. The compound of claim 24, wherein X’ is O or X’ is S.
26. The compound of claim 24, wherein X’ is NRp, where Rp is H or C1-6alkyl.
27. The compound of any one of claims 24-26, wherein R6 is H or R6 is C1-4alkyl.
28. The compound of any one of claims 24-27, wherein R7 is H or R7 is optionally substituted C1-4alkyl, -CO2H, -SO3H, -SO2NH2, -SO2NH(C1-4alkyl), or -SO2N(C1-4alkyl)2.
29. The compound of claim 28, wherein R7 is C1-4alkyl optionally substituted with -CO2H.
30. The compound of any one of claims 24-29, wherein R8 is H or R8 is -CO2H, -SO3H, or - SO2NH2.
31. The compound of any one of claims 24-30, wherein R10 is H or is -CO2H, -SO3H, or 35 -SO2NH2.
32. The compound of any one of claims 24-29, wherein (a) R8 is H and R10 is -SO3H or (b) R8 is -SO3H and R10 is H. 5
33. The compound of any one of claims 24-29, wherein one of R8 and R10 is H, halo, -CN, - CO2H, amino, -OH, -SO3H, -SO2NH2, -SO2NH(C1-4alkyl), -SO2N(C1-4alkyl)2, optionally substituted C1-6alkyl, optionally substituted C1-6alkenyl, optionally substituted C2-6alkynyl, or optionally substituted koxy, and the other of R8 and R10 is taken with R9 to form an optionally substituted 4- to 7-membered heterocyclic ring.
34. The compound of claim 24, wherein R9 is C2-6alkyl tuted with -CO2H, or where R9 is –(CH2)y-CO2H, where y is 2, 3, 4, or 5.
35. The compound of any one of claims 24-34, wherein each R11 is independently halo, -CO2H, 15 -SO3H, -SO2NH2, -SO2NH(C1-4alkyl), -SO2N(C1-4alkyl)2, or ally substituted alkyl.
36. A compound of claim 1 selected from the group consisting of: and salts thereof.
37. A nucleotide or oligonucleotide labeled with a compound according to any one of claims 1- 5 36.
38. The labeled nucleotide or oligonucleotide according to claim 37 wherein the compound according to claims 1-6 is attached via R3 of Formula (I) or R9 of Formula (II). 10
39. The labeled nucleotide or oligonucleotide of claim 38, wherein R3 of Formula (I) is nCOOH where n is 2, 3, 4, 5, or 6, or R9 of Formula (II) is -(CH2)yCOOH where y is 2, 3, 4, 5, or 6, and the attachment forms an amide using the -COOH group.
40. The labeled nucleotide or oligonucleotide of any one of claims 37 to 39, n the label is 15 attached to the C5 position of a pyrimidine base or the C7 position of a a purine base through a linker moiety.
41. The labeled nucleotide or oligonucleotide according to any one of claims 37 to 40, further comprising a 3’ OH blocking group covalently attached to the ribose or deoxyribose sugar of the 20 nucleotide.
42. A kit comprising a first labeled nucleotide according to any one of claims 38 to 41 and a second labeled tide. 25
43. The kit of claim 42, wherein the second labeled nucleotide is labeled with a different compound that the first d nucleotide or is unlabeled.
44. The kit of claim 43, wherein the first and second labeled nucleotides are excitable using a single laser wavelength.
45. The kit of claim 42 or 43, further comprising a third nucleotide and a fourth nucleotide, wherein each of the , third, and fourth nucleotides is labeled with a different compound or is unlabeled, wherein each label has a distinct absorbance maximum that is distinguishable from the other labels.
46. The kit of claim 42, n the kit comprises four nucleotides, wherein a first of the four 5 nucleotides is a labeled nucleotide according to any one of claims 37 to 41, a second of the four nucleotides carries a second label, a third nucleotide carries a third label, and a fourth nucleotide is led (dark).
47. The kit of claim 42, wherein the kit comprises four nucleotides, wherein a first of the four 10 nucleotides is a labeled nucleotide according to any one of claims 37 to 41, a second of the four nucleotides s a second label, a third nucleotide carries a mixture of two labels, and a fourth tide is unlabeled (dark).
48. Use of a nucleotide according to any one of claims 1 to 36, an oligonucleotide ing to 15 claims 37 to 41, or a kit according to any one of claims 42 to 47 in sequencing, expression is, hybridization analysis, genetic analysis, RNA analysis, or a protein binding assay.
49. Use according to claim 48 on an automated sequencing instrument, wherein said automated sequencing instrument comprises two lasers operating at ent wavelengths.
50. A method of sequencing sing incorporating a nucleotide according to any one of claims 37 to 41 in a sequencing assay.
51. The method of claim 50, further comprising detecting the nucleotide.
52. The method of claim 50 or 51, wherein the cing assay is performed on an automated sequencing instrument, and wherein the automated sequencing instrument comprises two light sources operating at different wavelengths. 1.1"? FIG. 'E A HG. EB HA2
NZ758381A 2018-10-16 Secondary amine-substituted coumarin compounds and their uses as fluorescent labels NZ758381B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB1716931.9A GB201716931D0 (en) 2017-10-16 2017-10-16 New fluorescent compounds and their use as biomarkers
PCT/GB2018/052971 WO2019077331A1 (en) 2017-10-16 2018-10-16 Secondary amine-substituted coumarin compounds and their uses as fluorescent labels

Publications (2)

Publication Number Publication Date
NZ758381A NZ758381A (en) 2023-11-24
NZ758381B2 true NZ758381B2 (en) 2024-02-27

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