WO2012085501A1 - Composés 8-sulfo-imidazotétrazin-4-one et leur utilisation en tant que médicament anticancéreux - Google Patents

Composés 8-sulfo-imidazotétrazin-4-one et leur utilisation en tant que médicament anticancéreux Download PDF

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WO2012085501A1
WO2012085501A1 PCT/GB2011/001739 GB2011001739W WO2012085501A1 WO 2012085501 A1 WO2012085501 A1 WO 2012085501A1 GB 2011001739 W GB2011001739 W GB 2011001739W WO 2012085501 A1 WO2012085501 A1 WO 2012085501A1
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independently
compound according
compound
alkyl
optionally substituted
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PCT/GB2011/001739
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Marc Geoffery Hummersone
David Cousin
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Pharminox Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention pertains generally to the field of therapeutic compounds, and more specifically to 3-substituted-8-sulfo-3H-imidazo[5,1-d][1 ,2,3,5]tetrazin-4-one compounds.
  • the present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit cell proliferation, and in the treatment of proliferative disorders such as cancer, etc., and methods of preparing such compounds.
  • Ranges are often expressed herein as from “about” one particular value, and/or to "about” another particular value. When such a range is expressed, another embodiment includes from the one particular value andfor to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent "about,” it will be understood that the particular value forms another embodiment.
  • Temozolomide also known as 3,4-dihydro-3-methyl-4-oxoimidazo[5, 1-d]-1 ,2,3,5-tetrazine-8- carboxamide; 8-carbamoyl-3-methylimidazo[5, 1 -d]-1 ,2,3,5-tetrazin-4(3H)-one; methazolastone; M & B 39831 ; CCRG-81045; NSC-362856; Temodal; Temodar
  • Temozolomide is a well known antineoplastic agent that acts as an alkylating agent. Its primary application is in the treatment of brain cancer (e.g., glioma).
  • Temozolomide is a prodrug, being cleaved in a multi-step pathway firstly to liberate an unstable monomethyltriazene (MTIC), which then suffers proteolytic fragmentation to generate a highly- reactive methylating agent (methanediazonium ion) and 5-aminoimidazole-4-carboxamide (see, e.g., Arrowsmith et al., 2002, J. Med. Chem., Vol. 45, pp. 5458-5470). Support for this process comes from the isolation of MTIC from the degradation of temozolomide in aqueous sodium carbonate solution (see, e.g., Stevens et al., 1984, J. Med. Chem.. Vol. 27, pp. 196-201). There is only a small pH window around physiological pH where ring-opening of temozolomide is accompanied by fragmentation of MTIC in a methylating mode.
  • MTIC monomethyltriazene
  • the methanediazonium active species derived from MTIC is believed to covalently methylate guanine residues of DNA in tracts of three or more guanines (see, e.g., Hartley et al., 1988, Carcinogenesis. Vol. 9, pp. 669-674; Clark et al., 1995, J. Med. Chem., Vol. 38, pp. 1493-1504).
  • MGMT DNA repair protein 0(6)-methylguanine methyltransferase
  • 0-6 guanine methylation is a cytotoxic (antitumour) lesion since it provokes base mis-pairing with thymine during DNA replication. Unless repaired by MGMT, mis-pairing on the daughter strand is recognised by mismatch repair proteins which trigger futile cycles of thymine excision and re-insertion leading to persistent DNA strand breaks.
  • a new strategy to overcome these deficiencies proposes that compounds structurally related in structure to temozolomide and retaining the drug's favourable pharmaceutical profile - such as ease of synthesis, acid stability, oral bioavailability, freedom from metabolic complications, transmission across the blood-brain barrier, and an acceptable toxicological profile - could be developed which create an alternative anti-tumour lesion at 0-6 residues of guanines in DNA (i.e., not methylation) which cannot be repaired by MGMT.
  • Such compounds would be likely to retain useful therapeutic activity against all brain tumours, but also those major killer tumour types (e.g., lung, breast, ovarian, colorectal, renal, pancreatic, melanoma) which are currently inherently resistant to temozolomide.
  • Temozolomide is the subject of granted claim 13 of US Patent No 5,260,291 to Lunt et al. granted 09 November 1993.
  • PCT/GB2008/004140 filed 16 December 2008 (published as WO 2009/077741 on 25 June 2009).
  • Mitozolomide is a compound related to temozolomide, which is characterised by the presence of a 3-chloroethyl group.
  • the compounds of Lunt et al may have elicited their effects on cancer cells because the ⁇ /-3 chloroethyl group cross-links DNA, although the authors of Lunt et al. were not aware of this at the time of publishing.
  • This mode of action means that the ⁇ /-3 chloroethyl compounds may potentially be toxic to normal cells, as well as cancerous ones.
  • One aspect of the invention pertains to certain 8-sulfo-3H-imidazo[5,1-d][1 ,2,3,5] tetrazin-4-one compounds, as described herein.
  • compositions e.g., a pharmaceutical compositions
  • a pharmaceutical compositions comprising a compound of the invention as described herein and a pharmaceutically acceptable carrier or diluent.
  • compositions e.g., a pharmaceutical composition
  • methods of preparing a composition comprising the step of admixing a compound of the invention as described herein and a pharmaceutically acceptable carrier or diluent.
  • Another aspect of the present invention pertains to methods of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of the invention as described herein.
  • cell proliferation e.g., proliferation of a cell
  • cell cycle progression e.g., proliferation of a cell
  • promoting apoptosis e.g., apoptosis
  • Another aspect of the present invention pertains to methods of treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound of the invention as described herein, preferably in the form of a pharmaceutical composition.
  • Another aspect of the present invention pertains to a compound of the invention as described herein for use in a method of treatment of the human or animal body by therapy.
  • Another aspect of the present invention pertains to use of a compound of the invention as described herein, in the manufacture of a medicament for use in treatment.
  • the treatment is treatment of a proliferative disorder.
  • the treatment is treatment of cancer.
  • the treatment is treatment of: lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, renal cancer, prostate cancer, esophageal cancer, squamous carcinoma of the head or neck, or glioma.
  • the treatment is treatment of: glioma.
  • kits comprising (a) a compound of the invention as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the compound.
  • Another aspect of the present invention pertains to certain methods of synthesis, as described herein.
  • Another aspect of the present invention pertains to a compound (e.g., a compound of the invention) obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to a compound (e.g., a compound of the invention) obtained by a method of synthesis as described herein, or by a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to certain novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
  • Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
  • Temozolomide also known as 3-methyl-4-oxo-3,4-dihydro-imidazo[5,1- d][1 ,2,3,5]tetrazine-8-carboxylic acid amide
  • the compounds may be described as 3-substituted-8-sulfo-3H-imidazo[5,1-d] [1 ,2,3,5]tetrazin- 4-one compounds and are based on the imidazotetrazine core shown below: 7 3H-lmidazo[5,1 -d][1 ,2,3,5]tetrazin- -one
  • one aspect of the present invention pertains to compounds selected from compounds of formula (I) and salts, hydrates, and solvates thereof (e.g., pharmaceutically acceptable salts, hydrates, and solvates thereof)
  • X is independently selected from -X 1 , -X 2 ; and -X 3
  • X 1 is independently saturated aliphatic Cvealkyl, C 3 . 6 cycloalkyl, aryl or aryl-C n-4 alkyl and is optionally substituted;
  • X 2 is independently amino, d-ea'kyl-amino, C 3 - 6 cycloalkyl-amino, arylamino, or aryl-Ci. 4 alkyl-amino, and is optionally substituted;
  • X 3 is independently N-heterocyclo, and is optionally substituted
  • Y is independently -H or saturated aliphatic C 1- alkyl
  • B is independently selected from:
  • B 1 is independently saturated aliphatic C 1-6 alkyl
  • B 2 is independently aliphatic C 2 . 6 alkynyl
  • B 3 is independently mercapto-C ⁇ alkyl, sulfanyl-C 1- alkyl, sulfinyl-C 1-4 alkyl, sulfonyI-C 1-4 alkyl and is optionally substituted;
  • B 4 is independently hydroxy-Ci. 4 alkyl or ether-C 1-4 alkyl, and is optionally substituted;
  • B 5 is independently phenyl-Ci. 6 alkyl, Cs-eheteroaryl-Cvealkyl,
  • phenyl-C 3 -6cycloalkyl or C 5 . 6 heteroaryl-C 3 . 6 cycloalkyl, and is optionally substituted;
  • B 6 is independently acyl-Ci. 6 alkyl, carboxy-Ci. 6 alkyl, oxyacyl-Ci -6 alkyl, or acyloxy-C ⁇ alkyl;
  • B 7 is independently amido-Ci.4alkyl or substituted amido-Ci. 4 alkyl;
  • B 8 is independently C 3-6 cycloalkyl, C 3 . 6 cycloalkyl-C 1-4 alkyl, C 3-6 heterocyclyl, or
  • B 9 is independently trifluoromethyl-Cvealkyl
  • B 10 is independently nitro-C 1-6 alkyl
  • B 11 is independently cyano-d-ealkyl
  • B 12 is independently phosphate-Ci. 6 alkyl
  • B 13 is independently carbamate-Ci -6 alkyl
  • B 14 is independently oxime-Ci -6 alkyl.
  • X is independently selected from -X 1 -X 2 and -X 3 wherein:
  • X 1 is independently saturated aliphatic C ⁇ alkyl, C 3 . 6 cycloalkyl, aryl or aryl-C ⁇ alkyl and is optionally substituted;
  • X 2 is independently amino, Ci. 6 alkyl-amino, C 3-6 cycloalkyl-amino, arylamino, or aryl-
  • Ci-4alkyl-amino and is optionally substituted;
  • X 3 is independently /V-heterocyclo, and is optionally substituted.
  • (X1-2) A compound as described in paragraph (X-1), wherein X 1 is independently saturated aliphatic Ci -6 alkyl, C 3 . 6 cycloalkyl, aryl or aryl-Ci -4 alkyl and is optionally substituted.
  • (X1-3) A compound as described in paragraph (X1-1) or (X1-2), wherein X 1 is independently saturated aliphatic Ci. 6 alkyl or C 3-6 cycloalkyl and is optionally substituted.
  • (X1-6) A compound as described in paragraph (X1-5), wherein X 1 is independently selected from -Me, -Et, -nPr, -iPr, -nBu, -iBu, and -tBu.
  • (X1-7) A compound as described in paragraph (X1-5), wherein X 1 is independently -Me or -Et.
  • X1-17 A compound as described in paragraph (X1-16) wherein X 1 is independently selected from furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
  • X 1 is independently selected from furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
  • each -R is independently saturated aliphatic C 1-4 alkyl, saturated C 3 . 6 cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C 3 -6cycloalkyl and -Ph is optionally substituted with one or more substituents selected from -F, -CI, -Br, -I, -R , -CF 3 , -OH, -OR', and -OCF 3 , wherein each -R ' is independently saturated aliphatic C ⁇ alkyl.
  • X1-20 A compound as described in paragraph (X1-19), wherein X 1 is independently a group of formula -L 1x1 -Ar 1x1 wherein L 1X1 is independently saturated aliphatic Ci. 4 alkylene and Ar 1X1 is an aryl group, which may optionally be substituted.
  • (X1-22) A compound as described in paragraph (X1-20), wherein L 1 is independently -CH , -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH(CH 2 CH 3 )-.
  • (X1-26) A compound as described in any one of paragraphs (X1- 9) to (X1-25), wherein Ar 1x1 is independently an aryl group selected from phenyl or C 5-6 heteroaryl, and is optionally substituted.
  • C 5- 6 heteroaryl selected from furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazoiyi, isoxazoiyi, ihiazolyl, isothiazolyi, pyridyl, pyrimidinyl, or pyridaziny!, and is optionally substituted.
  • each -R is independently saturated aliphatic C ⁇ alkyl, saturated C 3 . 6 cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C 3 . 6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from -F, -CI, -Br, -I, -R ' , -CF 3 , -OH, -OR', and -OCF 3 , wherein each - R is independently saturated aliphatic C n-4 alkyl.
  • X2-3) A compound as described in paragraph (X2-1 ) or (X2-2), wherein X 2 is a group of general formula -NR 1X2 R 2X2 , wherein R X2 and R 2X2 are each independently selected from -H, Ci. 6 alkyl, C 3-B cycloalkyl, aryl, and aryl-C ⁇ alkyl, and are optionally substituted.
  • (X2-8) A compound as described in any one of paragraphs (X2-3), (X2-4) or (X2-7), wherein R 2X2 is independently selected from d. 6 alkyl, C 3-6 cycloalkyl, aryl, and aryl-d ⁇ alkyl.
  • (X2-1 1 ) A compound as described in any one of paragraphs (X2-3), (X2-5), or (X2-7) to (X2-10) wherein R 1X2 is independently Cvealkyl or C 3 . 6 cycloalkyl, and is optionally substituted.
  • (X2-12) A compound as described in any one of paragraphs (X2-3), (X2-5), or (X2-7) to (X2-10) wherein R X2 is independently d-ealkyl, and is optionally substituted.
  • Ci. 4 alkyl and is optionally substituted.
  • R 1X2 is independently selected from -Me, -Et, -nPr, -iPr, -nBu, -I ' BU, or -tBu, and is optionally substituted.
  • R 2 2 is independently selected from -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu, and is optionally substituted.
  • each -R is independently saturated aliphatic C 1-4 alkyl, saturated C 3 -6cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C 3-6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from -F, -CI, -Br, -I, -R ' , -CF 3I -OH, -OR', and -OCF 3 , wherein each R is independently saturated aliphatic
  • oxazoiyi isoxazoiyi, thiazoiyi, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
  • each -R is independently saturated aliphatic C ⁇ alkyl, saturated C 3 . 6 cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C 3 . 6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from -F, -CI, -Br, -I, -R , -CF 3 , -OH, -OR', and -OCF 3 , wherein each - R ' is independently saturated aliphatic d ⁇ alkyl.
  • R 2 2 is independently C 5 . 6 heteroaryl selected from furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionaWy substituted.
  • each -R is independently saturated aliphatic Ci. 4 alkyl, saturated C 3 . 6 cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C 3 . 6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from -F, -CI, -Br, -I, -R ' , -CF 3 , -OH, -OR', and -OCF 3 , wherein each - R is independently saturated aliphatic C 1-4 alkyl.
  • (X2-45) A compound as described in paragraph (X2-44), wherein R X2 is independently a group of formula -L 1X2 -Ar 1X2 wherein L 1X2 is independently saturated aliphatic Ci. 4 alkylene and Ar 1 2 is independently an aryl group and is optionally substituted.
  • (X2-46) A compound as described in paragraph (X2-45), wherein L is independently saturated aliphatic d. alkylene.
  • Ar 1X2 is independently C 5 . 6 heteroaryl selected from furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
  • each -R is independently saturated aliphatic C h alky!, saturated C 3 .6cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C 3-6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from -F, -CI, -Br, -I, -R , -CF 3 , -OH, -OR', and -OCF 3l wherein each -R is independently saturated aliphatic
  • R 2X2 is independently a group of formula -L 2X2 -Ar 2X2 wherein L 2X2 is independently saturated aliphatic Ci- alkylene and Ar ⁇ 2 is independently an aryl group and is optionally substituted.
  • r ⁇ 2 is independently C*e heteroaryl selected from furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
  • each -R is independently saturated aliphatic C 1-4 alkyl, saturated C 3 . 6 cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C 3 . 6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from -F, -CI, -Br, -I, -R ' , -CF 3l -OH, -OR', and -OCF 3 , wherein each - R is independently saturated aliphatic
  • X3-4 A compound as described in paragraph (X3-3) wherein X 3 is a /V-linked saturated C 5-6 nitrogen-containing heterocycle independently selected from aziridino, azetidino, pyrrolidino, piperidino, piperizino, morpholino, azepano, diazepano, and oxazepano, and is optionally substituted.
  • X3-5 A compound as described in paragraph (X3-3) wherein X 3 is a /V-linked saturated C 5 - 6 nitrogen-containing heterocycle independently selected from pyrrolidino, piperidino, piperizino, and morpholino, and is optionally substituted.
  • each -R is independently saturated aliphatic C ⁇ alkyl, saturated C 3 . 6 cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C 3-6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from -F, -CI, -Br, -I, -R , -CF 3 , -OH, -OR', and -OCF 3 , wherein each - R is independently saturated aliphatic C 1-4 alkyl.
  • Y is independently selected from -H and -Me.
  • (Y-1) A compound of formula (I) as defined herein, for example as described in any one of paragraphs (X1-1) to (X1-31), (X2-1) to (X2-76), or (X3-1) to (X3-9), wherein Y is -H.
  • (Y-2) A compound of formula (I) as defined herein, for example as described in any one of paragraphs (X1-1) to (X1-31), (X2-1) to (X2-76), or (X3-1) to (X3-9), wherein Y is -Me.
  • B is independently selected from -B 1 , -B 2 , -B 3 , -B 4 , -B 5 , -B 6 ,
  • -B 1 is independently saturated aliphatic C 1-6 alkyl
  • -B 2 is independently aliphatic C 2 . 6 alkynyl
  • -B 3 is independently mercapto-C ⁇ alkyl, sulfanyl-C 1-4 alkyl, sulfinyl-C ⁇ alkyl,
  • -B 4 is independently hydroxy-C ⁇ alkyl or ether-Ci. 4 alkyl, and is optionally substituted;
  • -B 5 is independently phenyl-Ci. 6 alkyl, Cs-eheteroaryl-C ealkyl, phenyl-C 3 . 6 cycloalkyl, or C 5 -6heteroaryl-C3. 6 cycloalkyl, and is optionally substituted;
  • or -B 11 is independently cyano-Ci. 6 alkyl
  • -B 12 is independently phosphate-d. 6 a1kyl
  • -B 3 is independently carbamate-Ci -6 alkyl
  • -B 14 is independently oxime-Ci-ealkyl.
  • (B1 -1 ) A compound of formula (I) as defined herein, for example as described in any one of paragraphs (X1-1 ) to (X1-31 ), (X2-1 ) to (X2-76), (X3-1) to (X3-9), or (Y-1 ) to (Y-2), wherein -B is independently -B 1 .
  • (B1-6) A compound as described in paragraph (B1-2), wherein -B 1 is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • (B1-7) A compound as described in paragraph (B1-2), wherein -B 1 is independently -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • (B2-1 ) A compound of formula (I) as defined herein, for example as described in any one of paragraphs (X1-1) to (X1-31 ), (X2-1 ) to (X2-76), (X3-1 ) to (X3-9), or (Y-1 ) to (Y-6), wherein -B is independently -B 2 .
  • alkynyl relates to an aliphatic hydrocarbyl group (i.e., a group having only carbon atoms and hydrogen atoms) having at least one carbon-carbon triple bond.
  • (B3-1) A compound of formula (I) as defined herein, for example as described in any one of paragraphs (X1-1) to (X1-31), (X2-1) to (X2-76), (X3-1) to (X3-9), or (Y-1) to (Y-6), wherein -B is independently -B 3 .
  • -L Y3 - is independently saturated aliphatic Ci. alkylene
  • R Y3 is independently saturated aliphatic C 1- alkyl, saturated C 3 . 6 cycloalkyl,
  • Ci. 4 alkyl, C 3 . 6 cycloalkyl, C 3-6 heteroaryl, and -Ph is optionally substituted.
  • (B3-11) A compound as described in any one of paragraphs (B3-3) to (B3-9), wherein -L Y3 - is independently -CH , -CH 2 CH 2 -, -CH 2 CH 2 CH , -CH(CH 3 )-, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH(CH 2 CH 3 )-.
  • (B3-12) A compound as described in any one of paragraphs (B3-3) to (B3-9), wherein -L Y3 - is independently -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • (B3-13) A compound as described in any one of paragraphs (B3-3) to (B3-9), wherein -L Y3 - is independently -CH 2 - or -CH 2 CH 2 -.
  • (B3-16) A compound as described in any one of paragraphs (B3-3) to (B3-15), wherein -R Y3 , if present, is independently saturated aliphatic d ⁇ alkyl, saturated C 3 . 6 cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C h alky!, C 3 . 6 cycloalkyl, and -Ph is optionally substituted.
  • (B3-17) A compound as described in any one of paragraphs (B3-3) to (B3-15) wherein -R Y3 , if present, is independently saturated aliphatic Ci. 4 alkyl, saturated C 3-6 cycloalkyl, C 5-6 heteroaryl, -CH 2 -C5.6heteroaryl, -Ph, or -CH 2 -Ph, and wherein each of said C ⁇ alkyl, C 3 . 6 cycloalkyl,
  • each -R Y3A is independently saturated aliphatic saturated
  • C 3 . 6 cycloalkyl, -Ph, or -CH 2 -Ph wherein each of said C 3 . 6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from -F, -CI, -Br, -I, -R Y3B , -CF 3 , -OH, -OR Y3B , and -OCF 3 , wherein each -R Y3B is independently saturated aliphatic Ci- 4 alkyl.
  • (B3-18) A compound as described in any one of paragraphs (B3-3) to (B3-15), wherein -R Y3 , if present, is independently saturated aliphatic C ⁇ alkyl, saturated C 3 . 6 cycloalkyl, C 5 . 6 heteroaryl, -ChVCs-eheteroaryl, -Ph, or -CH 2 -Ph, wherein each of said C 3- 6cycloalkyl,
  • Cs-eheteroaryl, and -Ph is optionally substituted with one or more groups selected from:
  • (B3-19) A compound as described in any one of paragraphs (B3-3) to (B3-15), wherein -R Y3 , if present, is independently saturated aliphatic d- 4 alkyl, saturated C 3 . 6 cycloalkyl, C 5 . 6 heteroaryl, -CH 2 -C 5 . 6 heteroaryl, -Ph, or -CH 2 -Ph, wherein each of said Ci. 4 alkyl, C 3- 6cycloalkyl,
  • C 5-6 heteroaryl, and -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R Y3A , -CF 3 , -OH, -0R Y3A , and -OCF 3 .
  • (B3-20) A compound as described in any one of paragraphs (B3-3) to (B3-15), wherein -R Y3 , if present, is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said Ci. 4 alkyl, C 3-6 cycloalkyl, and -Ph is optionally substituted with one or more groups selected from:
  • (B3-21) A compound as described in any one of paragraphs (B3-3) to (B3-15), wherein -R , if present, is independently saturated aliphatic C 1-4 alkyl, saturated C 3 . 6 cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C 3 . 6 cycloalkyl, and -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R Y3A , -CF 3 , -OH, -OR Y3A , and -OCF 3 .
  • (B3-22) A compound as described in any one of paragraphs (B3-3) to (B3-15), wherein -R Y3 , if present, is independently -Ph or -CH 2 -Ph, wherein said -Ph is optionally substituted.
  • (B3-23) A compound as described in any one of paragraphs (B3-3) to (B3-15), wherein -R Y3 , if present, is independently -Ph or -CH 2 -Ph, wherein said -Ph is optionally substituted with one or more groups selected from:
  • (B3-24) A compound as described in any one of paragraphs (B3-3) to (B3-15), wherein -R Y3 , if present, is independently -Ph, or -CH 2 -Ph, wherein said -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R Y3A , -CF 3 , -OH, -OR Y3A , and -OCF 3 .
  • (B3-27) A compound as described in any one of paragraphs (B3-3) to (B3-15), wherein -R Y3 , if present, is independently saturated aliphatic C ⁇ alkyl, optionally substituted with one or more groups selected from -CF 3 , -OH, -OR Y3A , and -OCF 3 .
  • R Y3 is a group of formula -L 23 - R Z3 wherein L Z3 is a C 1-4 alkylene group and R Z3 is selected from -F, -CI, -Br, -I, -CF 3 , -OH, -OR Y3A , and -OCF 3 .
  • (B3-30) A compound as described in paragraph (B3-29) wherein L Z3 is independently -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • (B3-31) A compound as described in paragraph (B3-29) wherein L is independently -CH 2 - or -CH 2 CH 2 -.
  • (B3-33) A compound as described in any one of paragraphs (B3-28) to (B3-32) wherein R 23 is selected from -F, -CI, -CF 3 , -OH, -O e, and -OCF 3 .
  • (B3-35) A compound as described in any one of paragraphs (B3-3) to (B3-15), wherein -R Y3 , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, or -tBu.
  • (B3-36) A compound as described in any one of paragraphs (B3-3) to (B3-15), wherein -R YS , if present, is independently -Me, -Et, -nPr, or -iPr.
  • (B4-1 ) A compound of formula (I) as defined herein, for example as described in any one of paragraphs (X1-1) to (X1-31), (X2-1) to (X2-76), (X3-1) to (X3-9), or (Y-1) to (Y-6), wherein -B is independently -B 4 .
  • R Y4 is independently saturated aliphatic C 1-4 alkyl, saturated C 3 . 6 cycloalkyl,
  • each of said C 1- alkyl, C 3 . 6 cycloalkyl, C 5 . 6 heteroaryl, and -Ph is optionally substituted, for example, with one or more groups selected from: ino, morpholino, piperizino,
  • each -R Y A is independently saturated aliphatic d. 4 a!kyl, saturated
  • C 3 . 6 cycloalkyl, -Ph, or -CH 2 -Ph wherein each of said C 3 . 6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from -F, -CI, -Br, -I, -R Y4B , -CF 3 , -OH, -OR Y4B , and -OCF 3 , wherein each -R Y4B is independently saturated aliphatic Ci. 4 alkyl.
  • (B4-7) A compound as described in any one of paragraphs (B4-3) to (B4-5), wherein -L Y4 - is independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH(CH 2 CH 3 )-.
  • (B4-8) A compound as described in any one of paragraphs (B4-3) to (B4-5), wherein -L Y4 - is independently -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • (B4-9) A compound as described in any one of paragraphs (B4-3) to (B4-5), wherein -L Y4 - is independently -CH 2 - or -CH 2 CH 2 -.
  • (B4-12) A compound as described in any one of paragraphs (B4-3) to (B4-11), wherein -R Y4 , if present, is independently saturated aliphatic C ⁇ alkyl, saturated C 3 - 6 cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C 1-4 alkyl, C3 -6 cycloalkyl, and -Ph is optionally substituted.
  • (B4-13) A compound as described in any one of paragraphs (B4-3) to (B4-1 1 ), wherein -R Y4 , if present, is independently saturated aliphatic C ⁇ alkyl, -Ph, or -CH 2 -Ph, wherein said C 1-4 alkyl or -Ph is optionally substituted.
  • (B4-14) A compound as described in any one of paragraphs (B4-3) to (B4-1 1 ), wherein -R Y4 , if present, is independently saturated aliphatic C -4 alkyl, saturated C 3 . 6 cycloalkyl, C 5 -6heteroaryl, -CH 2 -C 5- 6heteroaryl, -Ph, or -CH 2 -Ph, wherein each of said Ci. 4 alkyl, C 3 - 6 cycloalkyl,
  • Ci -4 alkyl, C 3 . 6 cycloalkyl, and -Ph is optionally substituted with one or more groups selected from:
  • (B4-16) A compound as described in any one of paragraphs (B4-3) to (B4-1 1 ), wherein -R , if present, is independently saturated aliphatic d. 4 alkyl, -Ph, or -CH 2 -Ph, wherein said Ci. alkyl or -Ph is optionally substituted with one or more groups selected from:
  • (B4-17) A compound as described in any one of paragraphs (B4-3) to (B4-11), wherein -R , if present, is independently saturated aliphatic C 1- alkyl, saturated C 3 . 6 cycloalkyl, Cs-eheteroaryl, -CH 2 -C 5 . 6 heteroaryl, -Ph, or -CH 2 -Ph, wherein each of said Ci. 4 alkyl, C 3 . 6 cycloalkyl,
  • C 5 . 6 heteroaryl, and -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R Y4A , -CF 3 , -OH, -OR Y A , -SR Y A , and -OCF 3 .
  • (B4-18) A compound as described in any one of paragraphs (B4-3) to (B4-11), wherein -R , if present, is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said Ci. 4 alkyl, C 3 . 6 cycloalkyl, and -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R Y A , -CF 3 , -OH, -OR Y4A , -SR Y4A , and -OCF 3 .
  • (B4-19) A compound as described in any one of paragraphs (B4-3) to (B4-11), wherein -R Y4 , if present, is independently saturated aliphatic C ⁇ alkyl, -Ph, or -CH 2 -Ph, wherein said d. 4 alkyl or -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R Y A , -CF 3 , -OH, -OR Y A , -SR Y4A , and -OCF 3 .
  • (B4-20) A compound as described in any one of paragraphs (B4-3) to (B4-11), wherein -R , if present, is independently saturated aliphatic C ⁇ alkyl, and is optionally substituted.
  • R Y4 is a group of formula -L Z -R Z4 wherein L 4 is a C 1-4 alkylene group and R Z4 is selected from -F, -CI, -Br, -I, -CF 3 , -SR Y4A , -OH, -OR Y A , and -OCF 3 .
  • R Z4 is selected from -F, -CI, -CF 3 , -S e, -OH, -OMe, and -OCF 3 .
  • (B4-31) A compound as described in any one of paragraphs (B4-3) to (B4-11), wherein -R Y4 , if present, is independently -Me or -Et.
  • (B5-1) A compound of formula (I) as defined herein, for example as described in any one of paragraphs (X1-1) to (X1-31), (X2-1) to (X2-76), (X3-1) to (X3-9), or (Y-1) to (Y-6), wherein -B is independently -B 5 .
  • phenyl-Ci-ealkyl C 5- 6heteroaryl-Ci. 5 alkyl, phenyl-C 3-6 cycloalkyl, or C 5 .6heteroaryl-C 3 .6cycloalkyl and is optionally substituted.
  • -L Y5 - is independently saturated aliphatic Ci. 4 alkylene, or saturated aliphatic
  • -Ar Y5 is independently C 5-6 heteroaryl or -Ph
  • each of said C 5 . 6 heteroaryl and -Ph is optionally substituted, for example, with one or more groups selected from:
  • each -R Y5A is independently saturated aliphatic Ci -4 alkyl, saturated
  • each of said C 3-6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from -F, -CI, -Br, -I, -R Y5B , -CF 3l -OH, -OR Y and -OCF3, wherein each -R Y5B is independently saturated aliphatic C ⁇ alkyl.
  • (B5-4) A compound as described in any one of paragraphs (B5-3) to (B5-5), wherein -L Y5 - is independently saturated aliphatic d. 4 alkylene.
  • (B5-5) A compound as described in any one of paragraphs (B5-3) to (B5-4), wherein -L Y5 - is independently saturated aliphatic C 1-3 alkylene.
  • (B5-9) A compound as described in any one of paragraphs (B5-3) to (B5-6), wherein -L YS - is independently -CH 2 -, -CH(CH 3 )-, or -CH(CH 2 CH 3 )-.
  • (B5-10) A compound as described in any one of paragraphs (B5-3) to (B5-6), wherein -L Y5 - is independently -CH(CH 3 )- or -CH(CH 2 CH 3 )-.
  • (B5-13) A compound as described in any one of paragraphs (B5-3) to (B5-6), wherein -L Y5 - is independently -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, or -CH 2 CH(CH 3 )-.
  • (B5-15) A compound as described in any one of paragraphs (B5-3) to (B5-5), wherein -L Y5 - is independently saturated aliphatic C 3- e cycloalkylene.
  • -L Y5 - is independently saturated aliphatic C 3- e cycloalkylene.
  • 'C 3 . 6 cycloalkylene' denotes a divalent moiety obtained by removing two hydrogen atoms from the same carbon atom of a saturated aliphatic cyclic hydrocarbon compound having from 3 to 6 carbon atoms, which may optionally be substituted.
  • each -R is independently saturated aliphatic d ⁇ alkyl, saturated C 3 . 6 cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C 3- 6cycloalkyl and -Ph is optionally substituted with one or more substituents selected from -F, -CI, -Br, -I, -R ' , -CF 3 , -OH, -OR', and -0CF 3 , wherein each - R is independently saturated aliphatic
  • each of said furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, and -Ph is optionally substituted,
  • (B5-22) A compound as described in any one of paragraphs (B5-3) to (B5-18), wherein -Ar Y5 is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, or -Ph,
  • each of said furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, and -Ph is optionally substituted with one or more groups selected from: ino, morpholino, piperizino,
  • (B5-24) A compound as described in any one of paragraphs (B5-3) to (B5-18), wherein -Ar Y5 is independently C 5 . 6 heteroaryl, or -Ph, wherein each of said C 5 . 6 heteroaryl and -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R Y5A , -CF 3 , -OH, -OR Y5A , and
  • (B5-25) A compound as described in any one of paragraphs (B5-3) to (B5-18), wherein -Ar Y5 is independently -Ph, wherein said -Ph is optionally substituted with one or more groups selected from. -F, -CI, -Br, -I, -R Y5A , -CF 3 , -OH, -OR YSA , and -OCF 3 .
  • (B5-31) A compound as described in paragraph (B5-3), wherein -B 5 is -CH(CH 3 )-Ph, wherein said -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, and -OMe.
  • (B6-1) A compound of formula (I) as defined herein, for example as described in any one of paragraphs (X1-1) to (X1-31), (X2-1) to (X2-76), (X3-1) to (X3-9), or (Y-1) to (Y-6), wherein -B is independently -B 6 .
  • acyl-Ci. 6 alkyl carboxy-Ci. 6 alkyl, oxyacyl-Ci. 6 alkyl, or acyloxy-Ci -6 alkyl.
  • R Y6 is independently saturated aliphatic C 1-4 alkyl, saturated C 3 . 6 cycloalkyl,
  • each of said C 3 - 6 cycloalkyl, C 5-6 heteroaryl, and -Ph is optionally substituted, for example, with one or more groups selected from:
  • each -R Y6A is independently saturated aliphatic C ⁇ alkyl, saturated
  • C 3 . 6 cycloalkyl, -Ph, or -CH 2 -Ph wherein each of said C 3 . 6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from -F, -CI, -Br, -I, -R Y6B , -CF 3 , -OH, -OR Y6B , and -OCF 3 , wherein each -R Y6B is independently saturated aliphatic d. 4 alkyl.
  • (B6-1 1 ) A compound as described in any one of paragraphs (B6-3) to (B6-9), wherein -L Y6 - is independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - -CH(CH 3 )-, -CH(CH 3 )CH 2 -, -CH2CH(CH 3 )-, or -CH(CH 2 CH 3 )-.
  • (B6-12) A compound as described in any one of paragraphs (B6-3) to (B6-9), wherein -L Y6 - is independently -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • (B6-16) A compound as described in any one of paragraphs (B6-3) to (B6-15), wherein -R YB , if present, is independently saturated aliphatic C -4 alkyl, saturated C 3 . 6 cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C 3-6 cycloalkyl and -Ph is optionally substituted.
  • (B6-18) A compound as described in any one of paragraphs (B6-3) to (B6-15), wherein -R Y6 , if present, is independently saturated aliphatic Chalky!, saturated C 3-6 cycloalkyl, Cs-eheteroaryl, -CH 2 -C 5 . 6 heteroaryl, -Ph, or -CH 2 -Ph, wherein each of said C 3 -ecycloalkyl, Cs-eheteroaryl, and -Ph is optionally substituted with one or more groups selected from:
  • (B6-20) A compound as described in any one of paragraphs (B6-3) to (B6-15), wherein -R Y6 , if present, is independently saturated aliphatic Ci. 4 alkyl, -Ph, or -CH 2 -Ph, wherein said -Ph is optionally substituted with one or more groups selected from:
  • (B6-21) A compound as described in any one of paragraphs (B6-3) to (B6-15), wherein -R Ye , if present, is independently saturated aliphatic C alkyl, saturated C 3-6 cycloalkyl, Cs-eheteroaryl, -CH 2 -C5.6heteroaryl, -Ph, or -CH 2 -Ph, wherein each of said C 3-6 cycloalkyl, C 5 .
  • -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R Y6A , -CF 3 , -OH, -OR Y6A , and -OCF 3 .
  • (B6-22) A compound as described in any one of paragraphs (B6-3) to (B6-15), wherein -R Y6 , if present, is independently saturated aliphatic C alkyl, saturated C 3 .6cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C 3 . 6 cycloalkyl and -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R Y6A , -CF 3 , -OH, -OR Y6A , and -OCF 3 .
  • (B6-23) A compound as described in any one of paragraphs (B6-3) to (B6-15), wherein -R Y6 , if present, is independently saturated aliphatic C 1-4 alkyl, -Ph, or -CH 2 -Ph, wherein said -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R Y6A , -CF 3 , -OH, -OR Y6A , and -OCF 3 .
  • (B6-24) A compound as described in any one of paragraphs (B6-3) to (B6-15), wherein -R Ye , if present, is independently saturated aliphatic C alkyl, saturated C 3 . 6 cycloalkyl, C 5 . 6 heteroaryl, -CH C 5 . 6 heteroaryl, -Ph, or -CH 2 -Ph.
  • (B7-1) A compound of formula (I) as defined herein, for example as described in any one of paragraphs (X1-1) to (X1-31), (X2-1) to (X2-76), (X3-1) to (X3-9), or (Y-1) to (Y-6), wherein -B is independently -B 7 .
  • (B7-2) A compound as described in paragraph (B7-1 ), wherein -B 7 is independently amido- C 1-4 alkyl or substituted amido-C 1-4 alkyl.
  • -L Y7 - is independently saturated aliphatic C 1-4 alkylene
  • -R Y7 is independently saturated aliphatic Ci. 4 alkyl, saturated C 3 . 6 cycioalkyl,
  • each of said C 3 . 6 cycloalkyl, C 5 . 6 heteroaryl, and -Ph is optionally substituted, for example, with one or more groups selected from:
  • each -R is independently saturated aliphatic d ⁇ alkyl, saturated
  • each of said C 3 . 6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from -F, -CI, -Br, -I, -R , -CF 3 , -OH, -OR , and -OCF 3 , wherein each -RTM is independently saturated aliphatic Ci -4 alkyl.
  • (B7-7) A compound as described in any one of paragraphs (B7-3) to (B7-6), wherein -L 7 - is independently saturated aliphatic Ci -3 alkylene.
  • (B7-8) A compound as described in any one of paragraphs (B7-3) to (B7-6), wherein -L - is independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH(CH 3 )CH i -CH 2 CH(CH 3 )-, or -CH(CH 2 CH 3 )-.
  • (B7-9) A compound as described in any one of paragraphs (B7-3) to (B7-6), wherein -I 7 - is independently -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • (B7-10) A compound as described in any one of paragraphs (B7-3) to (B7-6), wherein -I 7 - is independently -CH 2 - or -CH 2 CH 2 -.
  • (B7-13) A compound as described in any one of paragraphs (B7-3) to (B7-12), wherein -FT 7 , if present, is independently saturated aliphatic C M alkyl, saturated C 3 . 6 cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C 3 . 6 cycloalkyl and -Ph is optionally substituted.
  • (B7-15) A compound as described in any one of paragraphs (B7-3) to (B7-12), wherein -R ⁇ , if present, is independently saturated aliphatic C 1-4 alkyl, saturated C 3 -6cycloalkyl, C 5 . 6 heteroaryl, -CH 2 -C 5-6 heteroaryl, -Ph, or -CH 2 -Ph, wherein each of said C 3 . 6 cycloalkyl, C s . 6 heteroaryl, and -Ph is optionally substituted with one or more groups selected from:
  • each of said C 3 . 6 cycloalkyl and -Ph is optionally substituted with one or more groups selected from:
  • (B7-18) A compound as described in any one of paragraphs (B7-3) to (B7-12), wherein -R , if present, is independently saturated aliphatic C 1- alkyl, saturated C 3 . 6 cycloalkyl, C 5-6 heteroaryl, -CH 2 -C 5 - 6 heteroaryl, -Ph, or -CH 2 -Ph, wherein each of said C 3 - 6 cycloalkyl, C 5 .
  • -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R Y7A , -CF 3 , -OH, -OR , and -OCF 3 .
  • (B7-19) A compound as described in any one of paragraphs (B7-3) to (B7-12), wherein -R , if present, is independently saturated aliphatic C alkyl, saturated C 3-6 cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C 3-6 cycloalkyl and -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -RTM, -CF 3 , -OH, -ORTM, and -OCF 3 .
  • (B7-20) A compound as described in any one of paragraphs (B7-3) to (B7-12), wherein -R ⁇ , if present, is independently saturated aliphatic C ⁇ alkyl, -Ph, or -CH 2 -Ph, wherein said -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -RTM, -CF 3 , -OH, -OR Y7A and -OCF 3 .
  • (B7-21 ) A compound as described in any one of paragraphs (B7-3) to (B7-12), wherein -R ⁇ , if present, is independently saturated aliphatic C 1-4 alkyl, -Ph, or -CH 2 -Ph.
  • (B7-23) A compound as described in any one of paragraphs (B7-3) to (B7-12), wherein -R 7 , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, or -tBu.
  • (B8-1) A compound of formula (I) as defined herein, for example as described in any one of paragraphs (X1 -1 ) to (X1-31 ), (X2-1) to (X2-76), (X3-1) to (X3-9), or (Y-1 ) to (Y-6), wherein -B is independently -B 8 .
  • C 3 .6cycloalkyl C 3 . 6 cycloalkyl-C alkyl, C 3 . 6 heterocyclyl, or C 3 . 6 heterocyclyl-Ci- 4 alkyl, and is optionally substituted.
  • -L Ya - is independently saturated aliphatic Ci. alkylene
  • R Y8 is independently saturated C 3 . 6 cycloalkyl or saturated C 3-6 heterocyclyl
  • each of said C 3 . 6 cycloalkyl and C 3-6 heterocyclyl is optionally substituted, for example, with one or more groups selected from:
  • each -R Y8A is independently saturated aliphatic d. alkyl, saturated
  • (B8-6) A compound as described in any one of paragraphs (B8-3) to (B8-5), wherein -L YB -, if present, is independently saturated aliphatic C 1-3 alkylene.
  • (B8-7) A compound as described in any one of paragraphs (B8-3) to (B8-5), wherein -L Y8 -, if present, is independently -CH 2 -, -CH 2 CH , -CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH(CH 2 CH 3 )-.
  • (B8-8) A compound as described in any one of paragraphs (B8-3) to (B8-5), wherein -L Y8 -, if present, is independently -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • (B8-9) A compound as described in any one of paragraphs (B8-3) to (B8-5), wherein -L Y8 -, if present, is independently -CH 2 - or -CH 2 CH 2 -.
  • (B8-15) A compound as described in any one of paragraphs (B8-3) to (B8-11), wherein and -R is independently saturated C 3 . 6 cycloalkyl or saturated C 3-6 heterocyclyl, wherein each of said C 3 . 6 cycloalkyl and C 3 . 6 heterocyclyl is optionally substituted, for example, with one or more groups selected from: -F, -CI, -Br, -I, -R Y8A , -CF 3 , -OH, -OR Y8A , and -OCF 3 .
  • (B8-16) A compound as described in any one of paragraphs (B8-3) to (B8-11), wherein and -R ' is independently saturated C 3 . 6 cycloalk l, wherein said C 3 . 6 cycloalkyl is optionally substituted, for example, with one or more groups selected from: -F, -CI, -Br, -I, -R Y8A , -CF 3 , -OH, -OR Y8A , and -OCF 3 .
  • (B8-18) A compound as described in any one of paragraphs (B8-3) to (B8-11), wherein and -R is independently saturated pyrrolidinyl, piperidinyl, piperizinyl, or morpholinyl, wherein each of said pyrrolidinyl, piperidinyl, piperizinyl, and morpholinyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R Y8A , -CF 3 , -OH, -OR Y8A , and -OCF 3 .
  • (B8-20) A compound as described in any one of paragraphs (B8-3) to (B8-11), wherein and -R is independently saturated C 3-6 heterocyclyl.
  • (B8-21) A compound as described in any one of paragraphs (B8-3) to (B8-11), wherein and -R Y8 is independently pyrrolidinyl, piperidinyl, piperizinyl, or morpholinyl.
  • (B9-1) A compound of formula (I) as defined herein, for example as described in any one of paragraphs (X1-1 ) to (X1-31), (X2-1 ) to (X2-76), (X3-1) to (X3-9), or (Y-1) to (Y-6), wherein -B is independently -B 9 .
  • (B10-1) A compound of formula (I) as defined herein, for example as described in any one of paragraphs (X1-1) to (X1-31), (X2-1 ) to (X2-76), (X3-1) to (X3-9), or (Y-1) to (Y-6), wherein -B is independently -B 10 .
  • (B10-2) A compound as described in paragraph (B10-1 ), wherein -B 10 is independently nitro-C 1-6 alkyl.
  • (B10-4) A compound as described in paragraph (B10-3), wherein -L Y1 °- is independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH(CH 2 CH 3 )-.
  • (B1 1-1) A compound of formula (I) as defined herein, for example as described in any one of paragraphs (X1-1 ) to (X1-31 ), (X2-1 ) to (X2-76), (X3-1 ) to (X3-9), or (Y-1 ) to (Y-6), wherein -B is independently -B 11 .
  • (B1 1-4) A compound as described in paragraph (B1 1-3), wherein -L Y11 - is independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH(CH 2 CH 3 )-.
  • (B12-1 ) A compound of formula (I) as defined herein, for example as described in any one of paragraphs (X1-1 ) to (X1-31), (X2-1 ) to (X2-76), (X3-1 ) to (X3-9), or (Y-1 ) to (Y-6), wherein -B is independently -B 12 .
  • (B12-2) A compound as described in paragraph (B12-1), wherein -B 12 is independently phosphate-Ci. 6 alkyl.
  • each -R Y12 is independently saturated aliphatic C h alky!, saturated C 3 . 6 cycloalkyl, C 5 . 6 heteroaryl, -CH 2 -C 5 - 6 heteroaryl, -Ph, or -CH 2 -Ph,
  • each of said C 3 .6cycloalkyl, C ⁇ eheteroaryl, and -Ph is optionally substituted, for example, with one or more groups selected from:
  • each -R Y12A is independently saturated aliphatic Ci. 4 alkyl, saturated
  • each of said C 3-6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from -F, -CI, -Br, -I, -R Y12B , -CF 3 , -OH, -OR Y12B , and -OCF 3 , wherein each -R Y12B is independently saturated aliphatic d. 4 alkyl.
  • (B12-7) A compound as described in any one of paragraphs (B12-3) to (B12-6), wherein -L Y12 - is independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH(CH 2 CH 3 )-.
  • (B12-8) A compound as described in any one of paragraphs (B12-3) to (B12-6), wherein -
  • each -R Y 2 is independently saturated aliphatic C ⁇ alkyl, saturated C 3-6 cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C 3 . 6 cycloalkyl and -Ph is optionally substituted.
  • each -R Y12 if present, is independently saturated aliphatic C n-4 alkyl, -Ph, or -CH 2 -Ph, wherein said -Ph is optionally substituted.
  • C 5 .6heteroaryl, and -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R Y 2A , -CF 3 , -OH, -OR Y12A , and -OCF 3 .
  • each -R Y12 if present, is independently saturated aliphatic C 1- alkyl, saturated C 3 . 6 cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C 3 . 6 cycloalkyl and -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R Y12A , -CF 3 , -OH, -OR Y12A , and -OCF 3 .
  • each -R Y12 if present, is independently saturated aliphatic C 1-4 alkyl, -Ph, or -CH 2 -Ph, wherein said -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R V12A , -CF 3 , -OH, -OR Y12A , and -OCF 3 .
  • each -R Y12 is independently -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, or -tBu.
  • (B12- 1) A compound as described in any one of paragraphs (B12-3) to (B12-10), wherein each -R Y12 , if present, is independently -Et.
  • (B13-1) A compound of formula (I) as defined herein, for example as described in any one of paragraphs (X1-1) to (X1-31), (X2-1) to (X2-76), (X3-1) to (X3-9), or (Y-1) to (Y-6), wherein -B is independently -B 3 .
  • -i_ Y13 - is independently saturated aliphatic C ⁇ a!ky!ene
  • each -R Y ' 3 is independently saturated aliphatic saturated C 3 . 6 cycloalkyl, C 5 - 6 heteroaryl, -CH2-C 5 .6heteroaryl, fluorenyl, -CH 2 -fluorenyl, -Ph, or -CH 2 -Ph,
  • each of said C 3-6 cycloalkyl, C 5-6 heteroaryl, fluorenyl and -Ph is optionally substituted, for example, with one or more groups selected from:
  • each -R Y 3A is independently saturated aliphatic C ⁇ alkyl, saturated
  • each of said C 3 . 6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from -F, -CI, -Br, -I, -R Y13B , -CF 3 , -OH, -OR Y13B , and -OCF 3 , wherein each -R Y13B is independently saturated aliphatic C alkyl.
  • (B13-7) A compound as described in any one of paragraphs (B13-3) to (B13-6), wherein -L Y 3 - is independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH(CH 2 CH 3 )-.
  • each -R Y13 is independently saturated aliphatic CMalkyl, saturated C 3 . 6 cycloalkyl, fluorenyl, -CHrfluorenyl, -Ph, or -CH 2 -Ph, wherein each of said C 3 . 6 cycloalkyl, fluorenyl and -Ph is optionally substituted.
  • each -R Y13 is independently fluorenyl or -CH 2 -fluorenyl, wherein said fluorenyl is optionally substituted.
  • each -R Y13 is independently saturated aliphatic CMalkyl, -Ph, or -CH 2 -Ph, wherein said -Ph is optionally substituted.
  • each -R Y13 is independently saturated aliphatic CMalkyl, saturated C 3 . 6 cycloalkyl, fluorenyl, -CH 2 -fluorenyl, -Ph, or -CH 2 -Ph, wherein each of said C 3 . 6 cycloalkyl, C 5 .
  • fluorenyl and -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R Y12A , -CF 3 , -OH, -OR Y12A , and -OCF 3 .
  • each -R Y13 is independently fluorenyl or -CH 2 -fluorenyl, wherein said fluorenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R Y1 A , -CF 3 , -OH, -OR Y12A , and -OCF 3 .
  • B13-16 A compound as described in any one of paragraphs (B13-3) to (B13-10), wherein each -R Y13 , if present, is independently saturated aliphatic Ci.
  • (B14-1) A compound of formula (I) as defined herein, for example as described in any one of paragraphs (X1-1) to (X1-31), (X2-1) to (X2-76), (X3-1) to (X3-9), or (Y-1) to (Y-6), wherein -B is independently -B 14 .
  • -L Y14 - is independently saturated aliphatic C 1-4 alkylene
  • each -R Y14 is independently saturated aliphatic C 1- alkyl, saturated C 3 . 6 cycloalkyl,
  • each of said C 3 . 6 cycloalkyl, C s . 6 heteroaryl, and -Ph is optionally substituted, for example, with one or more groups selected from:
  • each -R Y14A is independently saturated aliphatic C ⁇ alkyl, saturated
  • C 3 . 6 cycloalkyl, -Ph, or -CH 2 -Ph wherein each of said C 3 . 6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from -F, -CI, -Br, -I, -R Y14B , -CF 3 , -OH, -0R Y1 B , and -0CF 3 , wherein each -R Y1 B is independently saturated aliphatic C -4 alkyl.
  • (B14-6) A compound as described in any one of paragraphs (B14-3) to (B14-5), wherein -L Y14 - is independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH(CH 2 CH 3 )-.
  • (B14-7) A compound as described in any one of paragraphs (B14-3) to (B1 -5), wherein -L Y14 - is independently -CH 2 - or -CH 2 CH 2 -.
  • each -R Y14 is independently saturated aliphatic C 1-4 alkyl, saturated C 3 . 6 cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C 3 . 6 cycloalkyl and -Ph is optionally substituted.
  • each -R Y14 is independently saturated aliphatic C 1-4 alkyl, -Ph, or -CH 2 -Ph, wherein said -Ph is optionally substituted.
  • C 5 . 6 heteroaryl C 5 . 6 heteroaryl, -CH 2 -C 5 . 6 heteroaryl, -Ph, or -CH 2 -Ph, wherein each of said C 3 . 6 cycloalkyl, C 5 . 6 heteroaryl, and -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R Y14A , -CF 3 , -OH, -OR Y14A , and -OCF 3 .
  • each -R Y14 if present, is independently saturated aliphatic d. 4 alkyl, saturated C 3-6 cycloalkyl, -Ph, or -CH 2 -Ph, wherein each of said C 3-6 cycloalkyl and -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R Y14A , -CF 3 , -OH, -OR Y1 A , and -OCF 3 .
  • each -R Y14 if present, is independently saturated aliphatic C 1-4 alkyl : -Ph, or -CH 2 -Ph, wherein said -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R Y14A , -CF 3 , -OH, -OR Y1 A , and -OCF 3 .
  • each -R Y14 is independently -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, or -tBu.

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  • Organic Chemistry (AREA)
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Abstract

L'invention concerne des composés de formule (I) et des sels, hydrates ou solvates pharmaceutiquement acceptables de ceux-ci, où B, X et Y sont tels que définis présentement. Les composés sont utiles dans des méthodes de régulation de la prolifération cellulaire, d'inhibition de la progression du cycle cellulaire et/ou de promotion de l'apoptose, et dans le traitement de troubles prolifératifs.
PCT/GB2011/001739 2010-12-20 2011-12-19 Composés 8-sulfo-imidazotétrazin-4-one et leur utilisation en tant que médicament anticancéreux WO2012085501A1 (fr)

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