TECHNICAL FIELD

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.

BACKGROUND

A number of patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

Throughout this specification, including the claims which follow, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and "comprising," will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.

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.

This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

Temozolomide

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) 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

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.

The methanediazonium active species derived from MTIC (or temozolomide) 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). The significant site of DNA methylation is the 0-6 position of guanine residues and tumours which express high levels of the DNA repair protein 0(6)-methylguanine methyltransferase (MGMT; also known as ATase) are inherently resistant to the drug (see, e.g., Wedge et al., 1996, Br. J. Cancer, Vol. 74, pp. 1030-1036; Lee et al., 1994, Br. J. Cancer. Vol. 69, pp. 452-456.) These studies have been reviewed (see, e.g., Stevens and Newlands, 1993, Eur. J. Cancer, Vol. 29A, pp. 1045-1047; Newlands et al., 1997, Cancer Treat. Rev.. Vol. 23, pp. 35-61). 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.

In a significant development in our understanding of the molecular determinants influencing tumour responses to temozolomide, it is now clear that the promoter methylation status (at cytosine C-5 in CpG sequences of the MG Tgene) is a powerful predictor of clinical outcome in glioblastoma patients (see, e.g., Hegi et al., 2004, Clin. Cancer Res. Vol. 10, pp. 1871-1874; Hegi et al., 2005, New England J. Med., Vol. 352, pp. 997-1003). Tumours with the MGMT gene switched off, as in some brain tumours, are unable to repair the 0-6 guanine lesions and are particularly sensitive to temozolomide. Conversely, most common tumours with the MGMT repair gene switched on, leading to high cellular levels of MGMT, can repair the 0-6 guanine lesions and are resistant to the drug. This epigenetic feature considerably restricts the spectrum of action of temozolomide and its penetration of the cancer market.

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.

Certain 3-substituted-4-oxo-3,4-dihydro-imidazo[5,1-d][1 ,2,3,5]tetrazine-8-carboxylic acid amide (3TM) compounds are described in international patent application number

PCT/GB2008/004140 filed 16 December 2008 (published as WO 2009/077741 on 25 June 2009).

Certain 3-substituted-8-substituted-4-oxo-3,4-dihydro-imidazo[5,1-d] [1,2,3,5] tetrazine-8- carboxylic acid amide (38T ) compounds are described in international patent application number PCT/GB2010/001233 filed 23 June 2010. None of the compounds disclosed therein have sulfur containing groups at the 8-position.

Lunt et al. (J. Med. Chem., 1987, 30, pp. 357-366) disclosed anti-tumour imidazotetrazine compounds, including certain 8-sulfonamido mitozolomide derivatives. Mitozolomide is a compound related to temozolomide, which is characterised by the presence of a 3-chloroethyl group.

Without wishing to be bound by theory, the compounds of Lunt et al may have elicited their effects on cancer cells because the Λ/-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 Λ/-3 chloroethyl compounds may potentially be toxic to normal cells, as well as cancerous ones.

The present inventors have now surprisingly found that if certain preferred N-3 groups, which work in a mechanistically desired manner, are combined with a C-8 sulfonamide or sulfone group, the resulting compounds are less toxic and may also have improved pharmacokinetic (PK) and solubility properties, compared to Temozolomide and other analogues thereof.

SUMMARY OF THE INVENTION

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.

Another aspect of the invention pertains to compositions (e.g., a pharmaceutical compositions) comprising a compound of the invention as described herein and a pharmaceutically acceptable carrier or diluent.

Another aspect of the invention pertains to methods of preparing a composition (e.g., a pharmaceutical 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.

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.

In one embodiment, the treatment is treatment of a proliferative disorder.

In one embodiment, the treatment is treatment of cancer.

In one embodiment, 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.

In one embodiment, the treatment is treatment of: glioma.

Another aspect of the present invention pertains to a kit 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.

As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspect of the invention. DETAILED DESCRIPTION OF THE INVENTION

Compounds

One aspect of the present invention pertains to certain compounds that may be considered to be derivatives of Temozolomide (also known as 3-methyl-4-oxo-3,4-dihydro-imidazo[5,1- d][1 ,2,3,5]tetrazine-8-carboxylic acid amide): Temozolomide

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

Thus, 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)

wherein:

X is independently selected from -X ¹ , -X ² ; and -X ³

wherein:

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; and wherein

B is independently selected from:

-B ¹ , -B ² , -B ³ , -B ⁴ , -B ⁵ , -B ⁶ , -B ⁷ , -B ⁸ , -B ⁹ , -B ¹⁰ , -B ¹¹ , B ¹² , -B ¹³ , or -B ¹⁴ ;

wherein:

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

C ₃ . ₆ heterocyclyl-Ci. alkyl, and is optionally substituted;

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; and

B ¹⁴ is independently oxime-Ci _-6 alkyl.

The Group X

In the compounds of the invention 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; and

X ³ is independently /V-heterocyclo, and is optionally substituted.

Some embodiments of the invention include the following:

X1 - 8-Sulfones

(X1-1) A compound of formula (I) as defined herein, wherein X is independently -X ¹ .

(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.

X1.1 Alkyl sulfones

(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.

(X1-4) A compound as described in paragraph (X1-3), wherein X ¹ is independently saturated aliphatic Ci. ₆ alkyl and is optionally substituted.

(X1-5) A compound as described in any one of paragraphs (X1-1) to (X1-3), wherein X ¹ is independently saturated aliphatic

(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.

(X1-8) A compound as described in paragraph (X1-5), wherein X ¹ is independently -Me.

(X1-9) A compound as described in paragraph (X1-3), wherein X ¹ is independently saturated aliphatic C ₃ . ₆ cycloalkyl and is optionally substituted.

(X1-10) A compound as described in paragraph (X1-9), wherein X ¹ is independently selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

(X1-1 1) A compound as described in paragraph (X1-9), wherein X ¹ is independently

cyclopropyl.

(X1-12) A compound as described in any one of paragraphs (X1-1 ) to (X1-11) wherein X ¹ is optionally substituted, for example, with one or more groups selected from:

-F, -CI, -Br, -I,

-NH ₂ , -NHR, -NR ₂ , pyrrolidino piperidino, morpholino, piperizino, (/V-C alky -piperizino. X1.2 Aryl sulfones

(X1-13) A compound as described in paragraph (X1 -1) or (X1-2), wherein X ¹ is independently aryl and is optionally substituted.

(X1-14) A compound as described in paragraph (X1-13), wherein X ¹ is independently phenyl or C _5- 6 heteroaryl and is optionally substituted.

(X1-15) A compound as described in paragraph (X1-14), wherein X ¹ is independently phenyl and is optionally substituted.

(X1-16) A compound as described in paragraph (X1-14), wherein X ¹ is independently C _5-6 heteroaryl, and is optionally substituted.

(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.

(X1-18) A compound as described in any one of paragraphs (X1-13) to (X1-17) wherein X ¹ is optionally substituted, for example with one or more substituents selected from:

-F, -CI, -Br, -I,

-R, -CF ₃ ,

-OH, -OR, -OCF ₃ ,

-NH ₂ , -NHR, -NR ₂ , pyrrolidino piperidino, morpholino, piperizino, ( V-C^alky -piperizino,

-C(=0)OH, -C(=0)OR,

-C(=0)R,

-OC(=0)R,

-C(=0)NH ₂ , -C(=0)NHR, -C(=0)NR _2l -C(=0)-pyrrolidino, -C(=0)-piperidino,

-C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(/V-C _1-4 alkyl)-piperizino,

-NHC(=0)R, -NRC(=0)R,

-S(=0)R, -S(=0) ₂ R, -S(=0) ₂ NR ₂ , and

-CN; wherein 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.

X1.3 Aryl-C^alkyl sulfones

(X1-19) A compound as described in paragraph (X1-1) or (X1-2), wherein X ¹ is independently aryl-Ci- ₄ alkyl and is optionally substituted.

(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.

(X1-21) A compound as described in paragraph (X1-20), wherein L ^{1 1} is independently saturated aliphatic Ci. ₃ alkylene.

(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 )-.

(X1-23) A compound as described in paragraph (X1-20), wherein L ^1X1 is independently -CH ₂ -, -CH ₂ CH ₂ -| or -CH ₂ CH ₂ CH ₂ -.

(X1-24) A compound as described in paragraph (X1-20), wherein L ^X1 is independently -CH ₂ -, or -CH ₂ CH ₂ -.

(X1-25) A compound as described in paragraph (X1-20), wherein L ^1X1 is independently -CH ₂ -.

(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.

(X1-27) A compound as described in paragraph (X1-26), wherein Ar ¹ is independently

C ₅ . ₆ heteroaryl and is optionally substituted.

(X1-28) A compound as described in paragraph (X1-27), wherein Ar ^{1 1} is independently

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.

(X1-29) A compound as described in paragraph (X1-26), wherein Ar ^1X1 is independently phenyl and is optionally substituted.

(X1-30) A compound as described in paragraph (X1-29), wherein Ar ^1X1 is independently phenyl.

(X1-31) A compound as described in any one of paragraphs (X1-20) to (X1-30) wherein Ar ^1X1 is optionally substituted, for example with one or more substituents selected from:

-F, -CI, -Br, -I,

-R, -CF _3l

-OH, -OR, -OCF ₃ ,

-NH ₂ , -NHR, -NR ₂ , pyrrolidino piperidino, morpholino, piperizino, (A/-C _M alkyl)-piperizino, -C(=0)OH, -C(=0)OR, -C(=0)R,

-OC(=0)R,

-C(=0)NH ₂ , -C(=0)NHR, -C(=0)NR ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino,

-C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(N-C ₁ . ₄ alkyl)-piperizino,

-NHC(=0)R, -NRC(=0)R,

-S(=0)R, -S(=0) ₂ R, -S(=0) ₂ NR ₂ , and

-CN;

wherein 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 - 8-Sulfonamides

(X2-1) A compound of formula (I) as defined herein, wherein X is -X ² .

(X2-2) A compound as described in paragraph (X2-1 ), wherein X ² is independently amino, Ci. ₆ alkyl-amino, C ₃ . ₆ cycloalkyl-amino, arylamino, or aryl-Ci _-4 alkyl-amino, and is optionally substituted.

(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.

(X2-4) A compound as described in paragraph (X2-3), wherein R ^1X2 is independently -H.

(X2-5) A compound as described in paragraph (X2-3) or paragraph (X2-4) wherein R ^2X2 is independently -H.

(X2-6) A compound as described in paragraph (X2-3), wherein R ^1X2 and R ^2X2 are each independently -H. In this embodiment, X ² is amino (-NH ₂ ).

(X2-7) A compound as described in paragraph (X2-3) or paragraph (X2-5), wherein R ^1X2 is independently selected from Ci. ₆ alkyl, C _3-6 cycloalkyl, aryl, and aryl-C^alkyl.

(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.

(X2-9) A compound as described in paragraph (X2-3), wherein R ² is -H and R ^X2 is

independently selected from C _h alky!, C _3-6 cycloalkyl, aryl, and aryl-C _1-4 alkyl, and is optionally substituted.

(X2-10) A compound as described in paragraph (X2-3), wherein R ^X2 and R ^2X2 are each independently selected from C ealkyl, C ₃ . ₆ cycloalkyl, aryl, and aryl-C _n-4 alkyl, and are optionally substituted.

X2.1 Alkyl sulfonamides

(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.

(X2-13) A compound as described in paragraph (X2-12), wherein R ^X2 is independently

Ci. ₄ alkyl, and is optionally substituted.

(X2-14) A compound as described in paragraph (X2-13) wherein R ^1X2 is independently selected from -Me, -Et, -nPr, -iPr, -nBu, -I ^' BU, or -tBu, and is optionally substituted.

(X2-15) A compound as described in paragraph (X2-13) wherein R ^1X2 is independently -Me or -Et, and is optionally substituted.

(X2-16) A compound as described in paragraph (X2-13) wherein R ^1X2 is independently -Me, and is optionally substituted.

(X2-17) A compound as described in paragraph (X2-13) wherein R ^{1 2} is independently -Me.

(X2-18) A compound as described in any one of paragraphs (X2-3), (X2-5), or (X2-7) to (X2-10) wherein R ^1X2 is independently C ₃ . ₆ cycloalkyl, and is optionally substituted

(X2-19) A compound as described in paragraph (X2-18), wherein R ^1X2 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

(X1-20) A compound as described in paragraph (X2-19), wherein R ^1X2 is independently cyclopropyl

(X2-21) A compound as described in any one of paragraphs (X2-9) to (X2-20) wherein R ^2X2 is independently Ci _-6 alkyl or C ₃ . ₆ cycloalkyl, and is optionally substituted.

(X2-22) A compound as described in paragraph (X2-21) wherein R ^2X2 is independently C _1-6 alkyl, and is optionally substituted.

(X2-23) A compound as described in paragraph (X2-21), wherein R ^2X2 is independently

C^alkyl, and is optionally substituted.

(X2-24) A compound as described in paragraph (X2-23) wherein R ^{2 2} is independently selected from -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu, and is optionally substituted.

(X2-25) A compound as described in paragraph (X2-23) wherein R ^2X2 is independently -Me or -Et, and is optionally substituted.

(X2-26) A compound as described in paragraph (X2-23) wherein R ^2X2 is independently -Me, and is optionally substituted.

(X2-27) A compound as described in paragraph (X2-23) wherein R ^2X2 is independently -Me.

(X2-28) A compound as described in paragraph (X2-21) wherein R ^2X2 is independently C _3- 6cycloalkyl, and is optionally substituted

(X2-29) A compound as described in paragraph (X2-28), wherein R ^2X2 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. (X2-30) A compound as described in paragraph (X2-29), wherein R ^2X2 is independently cyclopropyl

(X2-31 ) A compound as described in any one of paragraphs (X2-1 1 ) to (X2-30) wherein R ^1X2 and R ^2X2 are each optionally substituted, where appropriate, for example with one or more groups selected from

-F, -CI, -Br, -I,

-CF ₃ ,

-NH _2L -NHR, -NR ₂ , pyrrolidino piperidino, morpholino, piperizino, (A/-Ci. ₄ alkyl)-piperizino,

-C(=0)OH , -C(=0)OR,

-C(=0)R,

-OC(=0)R,

-C(=0)NH ₂ , -C(=0)NHR, -C(=0)NR ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino,

-C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(/V-Ci. alkyl)-piperizino,

-NHC(=0)R, -NRC(=0)R, and

-CN;

wherein 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

X2.2 Aryl sulfonamides

(X2-32) A compound as described in any one of paragraphs (X2-3), (X2-5), or (X2-7) to (X2-10), wherein R ^{1 X2} is independently aryl and is optionally substituted.

(X2-33) A compound as described in paragraph (X2-32), wherein R ^1X2 is independently an aryl group selected from phenyl or C _5-6 heteroaryl, and is optionally substituted.

(X2-34) A compound as described in paragraph (X2-32), wherein R ^1X2 is independently phenyl and is optionally substituted.

(X2-35) A compound as described in paragraph (X2-32), wherein R ^1X2 is independently C ₅ . ₆ heteroaryl and is optionally substituted.

(X2-36) A compound as described in paragraph (X2-35), wherein R ^{1 X2} is independently C _5-6 heteroaryl selected from furany!, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl.

oxazoiyi, isoxazoiyi, thiazoiyi, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.

(X2-37) A compound as described in any one of paragraphs (X2-32) to (X2-36), wherein R ^1X2 is optionally substituted, for example, with one or more groups selected from:

-F, -CI, -Br, -I,

-R, -CF ₃ ,

-OH, -OR, -OCF ₃ ,

-NH ₂ , -NHR, -NR ₂ , pyrrolidino piperidino, morpholino, piperizino, (/V-Ci-4alkyl)-piperizino,

-C(=0)OH, -C(=0)OR,

-C(=0)R,

-OC(=0)R,

-C(=0)NH ₂ , -C(=0)NHR, -C(=0)NR ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino,

-C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(/V-Ci. ₄ alkyl)-piperizino, -NHC(=0)R, -NRC(=0)R,

-S(=0)R, -S(=0) ₂ R, -S(=0) ₂ NR ₂ , and

-CN;

wherein 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.

(X2-38) A compound as described in any one of paragraphs (X2-3), (X2-4), or (X2-7) to (X2-37), wherein R ^2X2 is independently aryl and is optionally substituted.

(X2-39) A compound as described in paragraph (X2-38), wherein R ^2X2 is independently an aryl group selected from phenyl or C ₅ -6 heteroaryl, and is optionally substituted.

(X2-40) A compound as described in paragraph (X2-38), wherein R ^{2 2} is independently phenyl and is optionally substituted.

(X2-41 ) A compound as described in paragraph (X2-38), wherein R ^2X2 is independently C _5-6 heteroaryl and is optionally substituted.

(X2-42) A compound as described in paragraph (X2-41 ), wherein 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.

(X2-43) A compound as described in any one of paragraphs (X2-38) to (X2-42), wherein R ^2X2 is optionally substituted, for example, with one or more groups selected from:

-F, -CI, -Br, -I,

-R, -CF ₃ ,

- NH ₂ , -NHR, -NR ₂ , pyrrolidino piperidino, morpholino, piperizino,

-C(=0)OH, -C(=0)OR,

-C(=0)R,

-OC(=0)R,

-C(=0)NH ₂ , -C(=0)NHR, -C(=0)NR ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino,

-C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(A/-C ₁ . alkyl)-piperizino,

-NHC(=0)R, -NRC(=0)R,

-S(=0)R, -S(=0) ₂ R, -S(=0) ₂ NR ₂ , and

-CN;

wherein 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.

X2.3 Aryl-C talkyl sulfonamides

(X2-44) A compound as described in any one of paragraphs (X2-3), (X2-5), or (X2-7) to (X2-10), wherein R ^{1 2} is independently aryl-Ci. ₄ alkyl and is optionally substituted.

(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.

(X2-47) A compound as described in paragraph (X2-46), wherein L ^1X2 is independently saturated aliphatic Ci. ₃ alkylene.

(X2-48) A compound as described in paragraph (X2-46), wherein L ^{1 2} is independently -CHr, -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 )-.

(X2-49) A compound as described in paragraph (X2-46), wherein L ^{1 2} is independently -CH , -CH2CH ₂ -, or -CH2CH2CH ₂ -.

(X2-50) A compound as described in paragraph (X2-46), wherein L ^1X2 is independently -CH ₂ -, or

(X2-51) A compound as described in paragraph (X2-46), wherein L ^X2 is independently -CH ₂ -.

(X2-52) A compound as described in any one of paragraphs (X2-45) to (X2-51), wherein Ar ^1X2 is independently an aryl group selected from phenyl or C ₅ . ₆ heteroaryl, which may optionally be substituted.

(X2-53) A compound as described in paragraph (X2-52), wherein Ar ^1X2 is independently C _5- 6 heteroaryl and is optionally substituted.

(X2-54) A compound as described in paragraph (X2-53), wherein 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.

(X2-55) A compound as described in paragraph (X2-52), wherein Ar ^{1 2} is independently phenyl and is optionally substituted.

(X2-56) A compound as described in paragraph (X2-52), wherein Ar ² is independently phenyl.

(X2-57) A compound as described in any one of paragraphs (X2-45) to (X2-56), wherein Ar ^X2 is optionally substituted, for example, with one or more groups selected from:

-F, -Ci, -Br, -I,

-R, -CF ₃ ,

-OH, -OR, -OCF ₃ ,

-NH ₂ , -NHR, -NR ₂ , pyrrolidino piperidino, morpholino, piperizino, (/V-d^alkylJ-piperizino,

-C(=0)OH, -C(=0)OR,

-C(=0)R,

-OC(=0)R,

-C(=0)NH ₂ , -C(=0)NHR, -C(=0)NR ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino,

-C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(/V-Ci. ₄ alkyl)-piperizino,

-NHC(=0)R, -NRC(=0)R,

-S(=0)R, -S(=0) ₂ R, -S(=0) ₂ NR ₂ , and

-CN; wherein 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

(X2-58) A compound as described in paragraph (X2-57), wherein Ar ^1X2 is independently phenyl substituted with methoxy (-OMe).

(X2-59) A compound as described in paragraph (X2-57), wherein Ar ^1X2 is independently p-methoxyphenyl.

(X2-60) A compound as described in any one of paragraphs (X2-3), (X2-4), or (X2-7) to (X2-59), wherein R ^2X2 is independently aryl-d. alkyl and is optionally substituted.

(X2-61) A compound as described in paragraph (X2-60), wherein 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.

(X2-62) A compound as described in paragraph (X2-61), wherein L ^2X2 is independently saturated aliphatic Ci. ₄ alkylene.

(X2-63) A compound as described in paragraph (X2-62), wherein L ^2X2 is independently saturated aliphatic Ci. ₃ alkylene.

(X2-64) A compound as described in paragraph (X2-62), wherein L ^2X2 is independently -CH ₂ -, -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 )-.

(X2-65) A compound as described in paragraph (X2-62), wherein L ^2X2 is independently -CH ₂ -, -CH ₂ CH ₂ -, or -CH ₂ CH ₂ CH ₂ -.

(X2-66) A compound as described in paragraph (X2-62), wherein L ^2X2 is independently -CH ₂ - or -CH ₂ CH ₂ -.

(X2-67) A compound as described in paragraph (X2-62), wherein L ^2X2 is independently -CH ₂ -.

(X2-68) A compound as described in any one of paragraphs (X2-61) to (X2-67), wherein Ar ^{2 2} is independently an aryl group, which may optionally be substituted.

(X2-69) A compound as described in paragraph (X2-68), wherein Ar ² ^ is independently an aryl group selected from phenyl or C ₅ . ₆ heteroaryl, and is optionally substituted.

(X2-70) A compound as described in paragraph (X2-69), wherein Ar ² is independently C _5-6 heteroaryl and is optionally substituted.

(X2-71) A compound as described in paragraph (X2-70), wherein 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.

(X2-72) A compound as described in paragraph (X2-69), wherein Ar ² ^ is independently phenyl and is optionally substituted. (X2-73) A compound as described in paragraph (X2-69), wherein Ar ² * ² is independently phenyl.

(X2-74) A compound as described in any one of paragraphs (X2-61) to (X2-72), wherein Ar ² * ² is optionally substituted, for example, with one or more groups selected from:

-F, -CI, -Br, -I,

-R, -CF ₃ ,

-OH, -OR, -OCF ₃ ,

-NH ₂ , -NHR, -NR ₂ , pyrrolidino piperidino, morpholino, piperizino, (/V-C _1-4 alkyl)-piperizino,

-C(=0)OH, -C(=0)OR,

-C(=0)R,

-OC(=0)R,

-C(=0)NH ₂ , -C(=0)NHR, -C(=0)NR ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino,

-C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(A/-Ci. ₄ alkyl)-piperizino,

-NHC(=0)R, -NRC(=0)R,

-S(=0)R, -S(=0) ₂ R, -S(=0) ₂ NR ₂ , and

-CN;

wherein 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

(X2-75) A compound as described in paragraph (X2-74), wherein Ar ² * ² is independently phenyl substituted with methoxy (-O e).

(X2-76) A compound as described in paragraph (X2-75), wherein Ar ² * ² is independently p-methoxyphenyl.

X3- Cyclic Sulfonamides

(X3-1) A compound of formula (I) as defined herein, wherein X is independently -X ³ .

(X3-2) A compound as described in paragraph (X3-1) wherein X ³ is independently

/V-heterocyclo.

(X3-3) A compound as described in paragraph (X3-1) or (X3-2) wherein X ³ is a /V-linked saturated C ₃ . ₇ nitrogen heterocycle, and is optionally substituted.

(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.

(X3-6) A compound as described in paragraph (X3-3) wherein X ³ is independently selected from piperidino, piperizino, and morpholino, and is optionally substituted.

(X3-7) A compound as described in paragraph (X3-3) wherein X ³ is independently morpholino, and is optionally substituted. (X3-8) A compound as described in paragraph (X3-3) wherein X ³ is independently morpholino.

(X3-9) A compound as described in any one of paragraphs (X3-1) to (X3-8) wherein X ³ is optionally substituted, for example, with one or more groups selected from:

-F, -CI, -Br, -I,

-R, -CF ₃ ,

-NH ₂ , -NHR, -NR ₂ , pyrrolidino piperidino, morpholino, piperizino, (A-C _1- alkyl)-piperizino,

-C(=0)OH, -C(=0)OR,

-C(=0)R,

-OC(=0)R,

-C(=0)NH _2l -C(=0)NHR, -C(=0)NR ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino,

-C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(A/-Ci. alkyl)-piperizino,

-NHC(=0)R, -NRC(=0)R, and

-S(=0)R, -S(=0) ₂ R, -S(=0) ₂ NR ₂ , and

-CN;

wherein 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.

The Group Y

In the compounds of the invention Y is independently selected from -H and -Me. Some embodiments of the invention include the following:

(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.

The Group B

In the compounds of the invention B is independently selected from -B ¹ , -B ² , -B ³ , -B ⁴ , -B ⁵ , -B ⁶ ,

-B ⁷ , -B ⁸ , -B ⁹ , -B ¹⁰ , -B ¹¹ , B ¹² , -B ¹³ and -B ⁴

wherein:

-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,

sulfonyl-Ci. ₄ alkyl, and is optionally substituted;

-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; and

-B ¹⁴ is independently oxime-Ci-ealkyl.

Some embodiments of the invention include the following:

B1 - 3-Al yl Compounds

(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 -2) A compound as described in paragraph (B1-1), wherein -B ¹ is independently saturated aliphatic C _h alky!.

(B1-3) A compound as described in paragraph (B1-2), wherein -B ¹ is independently saturated aliphatic C^alkyl, but is not -Me.

(B1-4) A compound as described in paragraph (B1-2), wherein -B ¹ is independently saturated aliphatic C^alkyl.

(B1-5) A compound as described in paragraph (B1-2), wherein -B ¹ is independently saturated aliphatic Ci. ₄ alkyl, but is not -Me.

(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.

(B1-8) A compound as described in paragraph (B1-2), wherein -B ¹ is independently -Me, -Et, -nPr, or -iPr.

(B1-9) A compound as described in paragraph (B1-2), wherein -B is independently -Et, -nPr, or -iPr.

(B1-10) A compound as described in paragraph (B1-2), wherein -B ¹ is independently -Me or -Et. (B1- 1) A compound as described in paragraph (B1-2), wherein -B ¹ is independently -Me. (B1-12) A compound as described in paragraph (B1-2), wherein -B ¹ is independently -Et. 52 - 3-Alkvnyl Compounds

(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 .

(B2-2) A compound as described in paragraph (B2-1), wherein -B ² is independently aliphatic C ₂ - ₆ alkynyl. (B2-3) A compound as described in paragraph (B2-2), wherein -B ² is independently aliphatic C ₃ .5alkynyl.

As used herein, the term "aikynyl" 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.

(B2-4) A compound as described in paragraph (B2-2), wherein -B ² is independently:

-C≡CH,

-C≡C-CH ₃ , -CH ₂ -C=CH,

-C≡C-CH ₂ -CH ₃ , -C≡C-CH=CH ₂ , -C=C-CsCH,

-CH ₂ -CH ₂ -C≡CH, -CH=CH-C≡CH, -C≡C-C≡CH,

-CH ₂ -C≡C-CH ₃ , or

-CH(CH ₃ )-C=CH.

(B2-5) A compound as described in paragraph (B2-2), wherein -B ² is independently

-CH ₂ -C≡CH.

(B2-6) A compound as described in paragraph (B2-2), wherein -B ² is independently

-CH ₂ -C=C-CH ₃ .

B ³ - 3-Sulfur-Alkyl Compounds

(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 .

(B3-2) A compound as described in paragraph (B3-1), wherein -B ³ is independently

mercapto-Ci. ₄ alkyl, sulfanyl-d _-4 alkyl, sulfinyI-Ci _-4 alkyf, or sulfonyi-C^alkyl, and is optionally substituted.

(B3-3) A compound as described in paragraph (B3-1) or (B3-2), wherein -B ³ is independently:

-L ^Y3 -SH, -L ^Y -S-R ^Y3 , -L ^Y3 -S(=0)-R ^Y3 , or -L ^Y3 -S(=0) ₂ -R ^Y3 ,

wherein:

-L ^Y3 - is independently saturated aliphatic Ci. alkylene, and

-R ^Y3 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 _3-6 heteroaryl, and -Ph is optionally substituted.

(B3-4) A compound as described in paragraph (B3-3), wherein -B ³ is independently -L ^Y3 -SH or -L ^Y3 -S-R ^Y3 .

(B3-5) A compound as described in paragraph (B3-3), wherein -B ³ is independently -L ^Y3 -SH.

(B3-6) A compound as described in paragraph (B3-3), wherein -B ³ is independently -L ^Y3 -S-R ^Y3 .

(B3-7) A compound as described in paragraph (B3-3), wherein -B ³ is independently

-L ^Y3 -S(=0)-R ^Y3 or -L ^Y3 -S(=0) ₂ -R ^Y3 .

(B3-8) A compound as described in paragraph (B3-3), wherein -B ³ is independently

-L ^Y3 -S(=0)-R ^Y3 . (B3-9) A compound as described in paragraph (B3-3), wherein -B ³ is independently

-L ^Y3 -S(=0) ₂ -R ^Y3 .

(B3-10) A compound as described in any one of paragraphs (B3-3) to (B3-9), wherein -L ^Y3 - is independently saturated aliphatic C _1-3 alkylene.

(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 -.

(B3-14) A compound as described in any one of paragraphs (B3-3) to (B3-9), wherein -L ^Y3 - is independently -CH ₂ CH ₂ -.

(B3-15) A compound as described in any one of paragraphs (B3-3) to (B3-9), wherein -L ^Y3 - is independently -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,

C5. ₆ heteroaryl, and -Ph is optionally substituted for example, with one or more groups selected from:

-F, -CI, -Br, -I,

-R ^V3A , -CF ₃ ,

-OH, -OR ^Y3A , -OCF ₃ ,

-SR ^Y3A ,

-NH ₂ , -NHR ^Y3A , -NR ^Y3A 2, pyrrolidine piperidino, morpholino, piperizino,

(A/-C alkyl)-piperizino,

-C(=0)OH, -C(=0)OR ^Y3A ,

-C(=0)R ^Y3A ,

-OC(=0)R ^Y3A ,

-C(=0)NH ₂ , -C(=0)NHR ^Y3A , -C(=0)NR ^Y3A ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(/V-Ci. ₄ alkyl)-pipenzino,

-NHC(=0)R ^Y3A , -NR ^Y3A C(=0)R ^Y3A ,

-OC(=0)NH ₂ , -OC(=0)NHR ^Y3A , -OC(=0)NR ^Y3A ₂ , -OC(=0)-pyrrolidino,

-OC(=0)-piperidino, -OC(=0)-morpholino, -OC(=0)-piperizino, (/V-Ci. ₄ alkyl)-piperizino,

-NHC(=0)OH, -NHC(=0)OR ^Y3A , -NR ^Y3A C(=0)OR ^Y3A ,

-NHC(=0)NH ₂ , -NHC(=0)NHR ^Y3A , -NHC(=0)NR ^Y3A ₂ , -NHC(=0)-pyrrolidino,

-NHC(=0)-piperidino, -NHC(=0)-morpholino, -NHC(=0)-piperizino,

-NHC(=0)-(/N/-Ci.4alkyl)-piperizino,

-N0 ₂ , and -CN,

wherein 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:

-F, -CI, -Br, -I,

-R ^Y3A , -CF ₃ ,

-OH, -OR ^Y3A , -OCF ₃ ,

-NH ₂ , -NHR ^Y3A , -NR ^Y3A 2, pyrrolidino piperidino, morpholino, piperizino,

-C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(/V-Ci. ₄ alkyl)-piperizino,

-NHC(=0)R ^Y3A , -NR ^Y3A C(=0)R ^Y3A , and -CN.

(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:

-F, -CI, -Br, -I,

-R ^Y3A , -CF ₃ ,

-OH, -OR ^Y3A , -OCF ₃ ,

-NH ₂ , -NHR ^Y3A , -NR ^Y3A 2, pyrrolidino piperidino, morpholino, piperizino,

(A/-Ci ,alkyl)-piperizino,

-C(=0)OH, -C(=0)OR ^Y3A ,

-C(=0)R ^Y3A ,

-OC(=0)R ^Y3A ,

-C(=0)NH _2; -C(=0)NHR ^Y3A -C(=0)NR ^Y3A _2: -C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(/V-Ci. ₄ alkyl)-piperizino,

-NHC(=0)R ^Y3A , -NR ^Y3A C(=0)R ^Y3A , and

-CN,

(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:

-F, -CI, -Br, -I,

-R ^Y3A , -CF ₃ ,

-OH, -OR ^Y3A , -OCF ₃ ,

-NH ₂ , -NHR ^Y3A , -NR ^Y3A 2, pyrrolidine piperidino, morpholino, piperizino,

(/V-Ci. ₄ alkyl)-piperizino,

-C(=0)OH, -C(=0)OR ^Y3A ,

-C(=0)R ^Y3A ,

-OC(=0)R ^Y3A ,

-C(=0)NH ₂ , -C(=0)NHR ^Y3A , -C(=0)NR ^Y3A ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(A/-Ci _-4 alkyl)-piperizino,

-NHC(=0)R ^Y3A , -NR ^Y3A C(=0)R ^Y3A , and

-CN.

(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 .

(B3-25) 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:

-F, -CI, -Br, -I,

-CF ₃ ,

-OH, -OR ^Y3A , -OCF ₃ ,

-NH ₂ , -NHR ^Y3A , -NR ^Y3A 2, pyrrolidino piperidino, morpholino, piperizino,

(A/-C alkyl)-piperizino,

-C(=0)OH, -C(=0)OR ^Y3A ,

-C(=0)R ^Y3A ,

-OC(=0)R ^Y3A ,

-C(=0)NH ₂ , -C(=0)NHR ^Y3A , -C(=0)NR ^Y3A ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(/V-Ci. ₄ alkyl)-piperizino,

-NHC(=0)R ^Y3A , -NR ^Y3A C(=0)R ^Y3A , and

-CN.

(B3-26) A compound as described in any one of paragraphs (B3-3) to (B3-15), wherein -R ^Y3 , if present, is independently saturated aliphatic C _h alky!, optionally substituted with one or more groups selected from -F, -CI, -Br, -I, -CF ₃₎ -OH, -0R ^Y3A , and -0CF 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 .

(B3-28) A compound as described in paragraph (B3-27) wherein 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 .

(B3-29) A compound as described in paragraph (B3-28) wherein L ^z3 is a C1.3 alkylene group.

(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 -.

(B3-32) A compound as described in paragraph (B3-29) wherein L ^Z3 is independently -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 .

(B3-34) A compound as described in paragraph (B3-33) wherein R ^z3 is selected from -OMe and -CF 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.

(B3-37) A compound as described in any one of paragraphs (B3-3) to (B3-15), wherein -R ^Y3 , if present, is independently -Me or -Et.

(B3-38) A compound as described in any one of paragraphs (B3-3) to (B3-15), wherein -R ^Y3 , if present, is independently -Me.

(B3-39) A compound as described in paragraph (B3-3), wherein -B ³ is independently

-CH ₂ -S-Me, -CH ₂ -S(=0)-Me, or -CH ₂ -S(=0) ₂ -Me.

(B3-40) A compound as described in paragraph (B3-3), wherein -B ³ is independently

-CH ₂ -S-Me.

(B3-41 ) A compound as described in paragraph (B3-3), wherein -B ³ is independently

-CH ₂ -S-CH ₂ -OMe.

(B3-42) A compound as described in paragraph (B3-3), wherein -B ³ is independently

-CH ₂ -S-CH ₂ -CF ₃ .

(B3-43) A compound as described in paragraph (B3-3), wherein -B ³ is independently

-CH ₂ -S(=0)-Me.

(B3-44) A compound as described in paragraph (B3-3), wherein -B ³ is independently

-CH ₂ -S(=0) ₂ -Me.

B ^{4 '} 3-OxyQen-Alkyl Compounds

(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 .

(B4-2) A compound as described in paragraph (B4-1 ), wherein -B ⁴ is independently

hydroxy-d^alkyl or ether-Ci. alkyl, and is optionally substituted.

(B4-3) A compound as described in paragraph (B4-1), wherein -B ⁴ is independently: -L ^Y -OH or -L ^Y4 -0-R ^Y4 ,

wherein:

-L ^Y4 - is independently saturated aliphatic C^alkylene, and

-R ^Y4 is independently saturated aliphatic C _1-4 alkyl, saturated C ₃ . ₆ cycloalkyl,

C ₅ . ₆ heteroaryl, -CH ₂ -C ₅ .6heteroaryl, -Ph, or -CH ₂ -Ph,

wherein 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,

-C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(/V-C ₁ . ₄ alkyl)-piperizino _l

-NHC(=0)R ^Y4A , -NR ^Y4A C(=0)R ^{Y A} ,

-OC(=0)NH ₂ , -OC(=0)NHR ^{Y A} , -OC(=0)NR ^Y4A ₂ , -OC(=0)-pyrrolidino,

-OC(=0)-piperidino, -OC(=0)-morpholino, -OC(=0)-piperizino, (/V-C _1- alkyl)-piperizino,

-NHC(=0)OH, -NHC(=0)OR ^{Y A} , -NR ^Y4A C(=0)OR ^Y4A ,

-NHC(=0)NH ₂ , -NHC(=0)NHR ^Y4A , -NHC(=0)NR ^Y4A ₂ , -NHC(=0)-pyrrolidino,

-NHC(=0)-piperidino, -NHC(=0)-morpholino, -NHC(=0)-piperizino,

-NHC(=0)-(A/-C a1kyl)-piperizino,

-N0 ₂ , and -CN,

wherein 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.

(B4-4) A compound as described in paragraph (B4-3), wherein -B ⁴ is independently -L ^Y -OH.

(B4-5) A compound as described in paragraph (B4-3), wherein -B ⁴ is independently -L ^Y -0-R ^Y4 .

(B4-6) A compound as described in any one of paragraphs (B4-3) to (B4-5), wherein -L ^Y4 - is independently saturated aliphatic Ci. ₃ alkylene.

(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 -.

(B4-10) A compound as described in any one of paragraphs (B4-3) to (B4-5), wherein -L ^Y4 - is independently -CH ₂ CH ₂ -. (B4-11 ) A compound as described in any one of paragraphs (B4-3) to (B4-5), wherein -L ^Y4 - is independently -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,

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 ^Y4A , -OCF ₃ ,

-SR ^Y4A ,

-NH ₂ , -NHR ^Y4A , -NR ^Y4A 2, pyrrolidine piperidino, morpholino, piperizino,

(A/-Ci- ₄ alkyl)-piperizino,

-C(=0)OH, -C(=0)OR ^Y4A ,

-C(=0)R ^{Y A} ,

-OC(=0)R ^Y4A ,

-C(=0)NH ₂ , -C(=0)NHR ^Y4A , -C(=0)NR ^Y4A ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino,

-C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(A/-Ci. ₄ alkyl)-piperizino,

-NHC(=0)R ^Y4A , -NR ^Y4A C(=0)R ^Y4A , and

-CN.

(B4-15) A compound as described in any one of paragraphs (B4-3) to (B4-11), wherein -R ^Y4 , 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 ^Y4A , -CF ₃ ,

-OH, -OR ^{Y A} , -OCF ₃ ,

-SR ^Y4A

-NH ₂ , -NHR ^Y4A , -NR ^Y4A ₂ , pyrro!idino piperidino, morpholino, piperizino,

(/V-Ci- ₄ alkyl)-piperizino,

-C(=0)OH, -C(=0)OR ^Y4A ,

-C(=0)R ^{Y A} ,

-OC(=0)R ^Y4A ,

-C(=0)NH ₂ , -C(=0)NHR ^Y4A , -C(=0)NR ^Y4A ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino,

-C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(/V-Ci. ₄ alkyl)-piperizino,

-NHC(=0)R ^Y4A , -NR ^Y4A C(=0)R ^Y4A , and

-CN.

(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:

-F, -CI, -Br, -I, -OH, -OR , -OCF ₃ ,

-SR ^Y4A ,

-NH ₂ , -NHR ^{Y A} , -NR ^Y4A 2, pyrrolidine piperidino, morpholino, piperizino,

(/V-C^alky -piperizino,

-C(=0)OH, -C(=0)OR ^Y4A ,

-C(=0)R ^Y4A ,

-OC(=0)R ^{Y A} ,

-C(=0)NH _2l -C(=0)NHR ^{Y A} , -C(=0)NR ^Y4A ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(A/-C . ₄ alkyl)-piperizino,

-NHC(=0)R ^Y4A , -NR ^{Y A} C(=0)R ^Y4A , and

-CN.

(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.

(B4-21) A compound as described in paragraph (B4-20) wherein 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 .

(B4-22) A compound as described in paragraph (B4-21) wherein L ^Z4 is a Ci _-3 alkylene group.

(B4-23) A compound as described in paragraph (B4-22) wherein L ^Z4 is independently -CH ₂ -, -CH ₂ CH ₂ -, or -CH ₂ CH ₂ CH ₂ -.

(B4-24) A compound as described in paragraph (B4-22) wherein L ^Z4 is independently -CH ₂ - or -CH ₂ CH -.

(B4-25) A compound as described in paragraph (B4-22) wherein L is independently -CH ₂ -.

(B4-26) A compound as described in any one of paragraphs (B3-21) to (B3-25) wherein R ^Z4 is selected from -F, -CI, -CF ₃ , -S e, -OH, -OMe, and -OCF ₃ .

(B4-27) A compound as described in paragraph (B3-26) wherein R ^Z4 is selected from -SMe, -OMe and -CF _3. (B4-28) A compound as described in any one of paragraphs (B4-3) to (B4-11), wherein - ^Y4 , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, or -tBu.

(B4-30) A compound as described in any one of paragraphs (B4-3) to (B4-11), wherein -R ^Y4 , if present, is independently -Me, -Et, -nPr, or -iPr.

(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.

(B4-32) A compound as described in any one of paragraphs (B4-3) to (B4-11), wherein -R ^Y4 , if present, is independently -Me.

(B4-33) A compound as described in paragraph (B4-3), wherein -B ⁴ is independently

-CHz-O-Me.

(B4-34) A compound as described in paragraph (B4-3), wherein -B ⁴ is independently

-CH ₂ -0-CH ₂ -OMe.

(B4-35) A compound as described in paragraph (B4-3), wherein -B ⁴ is independently

-CH ₂ -0-CH ₂ -SMe.

(B4-36) A compound as described in paragraph (B4-3), wherein -B ⁴ is independently

-CH ₂ -0-CH ₂ -CF ₃ .

B ⁵ - 3-Aryl-Alkyl Compounds

(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 .

(B5-2) A compound as described in paragraph (B5-1), wherein -B ⁵ is independently

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.

(B5-3) A compound as described in paragraph (B5-1), wherein -B ⁵ is independently -L ^Y5 -Ar ^Y5 , wherein:

-L ^Y5 - is independently saturated aliphatic Ci. ₄ alkylene, or saturated aliphatic

C ₃ . _s cyc!oa!ky!ene; and

-Ar ^Y5 is independently C _5-6 heteroaryl or -Ph,

wherein each of said C ₅ . ₆ heteroaryl and -Ph is optionally substituted, for example, with one or more groups selected from:

-F, -CI, -Br, -I,

-R ^Y5A , -CF ₃ ,

-OH, -OR ^Y5A , -OCF ₃ ,

-SR ^Y5A ,

-NH ₂ , -NHR ^Y5A , -NR ^Y5A ₂ , pyrrolidino, piperidino, morpholino, piperizino,

(/V-d^alky -piperizino,

-C(=0)OH, -C(=0)OR ^Y5A ,

-C(=0)R ^Y5A ,

-OC(=0)R ^Y5A ,

-C(=0)NH ₂ , -C(=0)NHR ^Y5A , -C(=0)NR ^Y5A ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(N-Ci. ₄ alkyl)-piperizino, -NHC(=0)R ^Y5A , -NR ^YSA C(=0)R ^Y5A ,

-OC(=0)NH ₂ , -OC(=0)NHR ^Y5A , -OC(=0)NR ^Y5A ₂ , -OC(=0)-pyrrolidino,

-OC(=0)-piperidino, -OC(=0)-morpholino, -OC(=0)-piperizino, (/V-C ₄ alkyl)-piperizino,

-NHC(=0)OH, -NHC(=0)OR ^Y5A , -NR ^Y5A C(=0)OR ^Y5A ,

-NHC(=0)NH ₂ , -NHC(=0)NHR ^Y5A , -NHC(=0)NR ^Y5A ₂ , -NHC(=0)-pyrrolidino,

-NHC(=0)-piperidino, -NHC(=0)-morpholino, -NHC(=0)-piperizino,

-NHC( -piperizino _l

wherein each -R ^Y5A 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 ^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.

(B5-6) A compound as described in any one of paragraphs (B5-3) to (B5-4), wherein -L ^Y5 - is independently saturated aliphatic C^alkylene.

(B5-7) A compound as described in any one of paragraphs (B5-3) to (B5-6), wherein -L ^YS - 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 )-.

(B5-8) A compound as described in any one of paragraphs (B5-3) to (B5-6), wherein -L ^YS - is independently -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 )-.

(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 )-.

(B5-11) A compound as described in any one of paragraphs (B5-3) to (B5-6), wherein -L ^YS - is independently -CH(CH ₃ )-.

(B5-12) A compound as described in any one of paragraphs (B5-3) to (B5-6), wherein -L ^Y5 - is independently -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 )-.

(B5-14) A compound as described in any one of paragraphs (B5-3) to (B5-6), wherein -L ^Y5 - is independently -CH ₂ CH ₂ -.

(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. The term 'C ₃ . ₆ cycloalkylene', as used herein, 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.

(B5-16) A compound as described in paragraph (B5-15), wherein -L ^Y5 - is independently cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene.

(B5-17) A compound as described in paragraph (B5-15), wherein -L ^Y5 - is independently a group selected from:

(B5-18) A compound as described in any one of paragraphs (B5-15) to (B5-17), wherein -L - is optionally substituted, for example by one or more substituents selected from:

-F, -CI, -Br, -I,

- , -CF ₃ ,

-OH, -OR, -OCF ₃ ,

-NH ₂ , -NHR, -NR ₂ ,

-C(=0)OH, -C(=0)OR,

-C(=0)R,

-OC(=0)R,

-C(=0)NH ₂ , -C(=0)NHR, -C(=0)NR ₂ ,

-NHC(=0)R, -NRC(=0)R,

-S(=0) ₂ R, -S(=0) ₂ NR ₂ , and

-CN;

wherein 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

(B5-19) 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,

wherein each of said furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, and -Ph is optionally substituted,

(B5-20) 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.

(B5-21) A compound as described in any one of paragraphs (B5-3) to (B5-18), wherein -Ar ^YS is independently C ₅ . ₅ 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 ^Y6A , -CF ₃ ,

-OH, -OR ^Y5A , -0CF ₃ ,

-NH ₂ , -NHR ^YSA , -NR ^Y5A ₂ , pyrrolidino piperidino, morpholino, piperizino,

(A/-C _1-4 alkyl)-piperizino,

-C(=0)OH, -C(=0)OR ^Y5A ,

-C(=0)R ^Y5A , -OC(=0)R ^Y6A ,

-C(=0)NH ₂ , -C(=0)NHR ^Y5A , -C(=0)NR ^Y5A ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino,

-C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(/V-C _1-4 alkyl)-piperizino,

-NHC(=0)R ^Y5A , -NR ^Y5A C(=0)R ^Y5A , and

-CN.

(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,

wherein 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,

-C(=0)-pyrrolidino, -C(=0)-piperidino,

-C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(/V-Ci.4alkyl)-piperizino,

-NHC(=0)R ^Y5A , -NR ^Y5A C(=0)R ^Y5A , and -CN.

(B5-23) 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, -O ^Y5A , -OCF ₃ ,

-NH ₂ , -NHR ^Y5A , -NR ^Y5A ₂ , pyrrolidino piperidino, morpholino, piperizino,

(/V-Ci- ₄ alkyl)-piperizino,

-C(=0)OH, -C(=0)OR ^Y5A ,

-C(=0)R ^Y5A ,

-OC(=0)R ^Y5A ,

-C(=0)NH ₂ , -C(=0)NHR ^Y5A , -C(=0)NR ^Y5A ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino,

-C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-( \/-Ci.4alkyl)-piperizino,

-NHC(=0)R ^Y5A , -NR ^Y5A C(=0)R ^Y5A , and -CN.

(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 .

(B5-26) 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, and -OR ^Y5A (B5-27) A compound as described in any one of paragraphs (B5-3) to (B5-18), wherein -Ar ^YS is independently -Ph, wherein said -Ph is optionally substituted with one or more groups selected from: -Br and -OMe.

(B5-28) A compound as described in any one of paragraphs (B5-3) to (B5-18), wherein -Ar ^Y5 is independently unsubstituted -Ph.

(B5-29) A compound as described in paragraph (B5-3), wherein -B ⁵ is -CH ₂ -Ph, wherein said -Ph is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, and -OMe.

(B5-30) A compound as described in paragraph (B5-3), wherein -B ⁵ is -CH ₂ -Ph.

(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.

(B5-32) A compound as described in paragraph (B5-3), wherein -B ⁵ is -CH(CH ₃ )-Ph.

(B5-33) A compound as described in paragraph (B5-32) wherein -B ⁵ is selected from:

A compound as described in paragraph (B5-32) wherein -B ⁵ is:

B - 8-Acyl-Alkyl, 8-Acid-Alkyl. and 8-Ester-Alkyl Compounds

(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 .

(B6-2) A compound as described in paragraph (86-1), wherein -B ⁶ is independently

acyl-Ci. ₆ alkyl, carboxy-Ci. ₆ alkyl, oxyacyl-Ci. ₆ alkyl, or acyloxy-Ci _-6 alkyl.

(B6-3) A compound as described in paragraph (B6-1), wherein -B ⁶ is independently:

-L ^Y6 -C(=0)R ^Y6 , -L ^Y6 -C(=0)OH, -L ^Y6 -C(=0)OR ^Y6 , or -L ^Y6 -0-C(=0)R ^Y6 ,

wherein:

-L ^Y6 - is independently saturated aliphatic and

-R ^Y6 is independently saturated aliphatic C _1-4 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 C ₃ - ₆ cycloalkyl, C _5-6 heteroaryl, and -Ph is optionally substituted, for example, with one or more groups selected from:

-F, -CI, -Br, -I,

-R ^Y6A , -CF ₃ ,

-OH, -OR ^Y6A , -OCF ₃ ,

-SR ^Y6A , -NH ₂ , -NHR ^Y6A , -NR ^Y6A ₂ , pyrrolidino, piperidino, morpholino, piperizino,

(/V-C^alky -piperizino,

-C(=0)OH, -C(=0)OR ^Y6A ,

-C(=0)R ^Y6A ,

-OC(=0)R ^Y6A ,

-C(=0)NH ₂₎ -C(=0)NHR ^Y6A , -C(=0)NR ^Y6A _2l -C(=0)-pyrrolidino, -C(=0)-piperidino,

-C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(A/-Ci. ₄ alkyl)-piperizino,

-NHC(=0)R ^Y6A , -NR ^Y6A C(=0)R ^Y6A ,

-OC(=0)NH ₂ , -OC(=0)NHR ^Y6A , -OC(=0)NR ^Y6A ₂ , -OC(=0)-pyrrolidino,

-OC(=0)-piperidino, -OC(=0)-morpholino, -OC(=0)-piperizino, (/V-Ci _-4 alkyl)-piperizino,

-NHC(=0)OH, -NHC(=0)OR ^Y6A , -NR ^Y6A C(=0)OR ^Y6A ,

-NHC(=0)NH _2l -NHC(=0)NHR ^Y6A , -NHC(=0)NR ^Y6A ₂ , -NHC(=0)-pyrrolidino,

-NHC(=0)-piperidino, -NHC(=0)-morpholino, -NHC(=0)-piperizino,

-NHC(=0)-(/V-C ₁ . ₄ alkyl)-piperizino,

-N0 ₂ , and -CN,

wherein 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.

(B6-4) A compound as described in paragraph (B6-3), wherein -B ⁶ is independently

-L ^Y6 -C(=0)R ^Y6 .

(B6-5) A compound as described in paragraph (B6-3), wherein -B ⁶ is independently

-L ^Y6 -C(=0)OH, -L ^Y6 -C(=0)OR ^Y6 , or -L ^Y6 -0-C(=0)R ^Y6 .

(B6-6) A compound as described in paragraph (B6-3), wherein -B ⁶ is independently

-L ^Y6 -C(=0)OH or -L ^Y6 -C(=0)OR ^YS .

(B6-7) A compound as described in paragraph (B6-3), wherein -B ⁶ is independently

-L ^Y6 -C(=0)OH.

(B6-8) A compound as described in paragraph (B6-3), wherein -B ⁶ is independently

-L ^Y6 -C(=0)OR ^Y6 .

(B6-9) A compound as described in paragraph (B6-3), wherein -B ⁶ is independently

-L ^Y6 -0-C(=0)R ^Y6 .

(B6-10) A compound as described in any one of paragraphs (B6-3) to (B6-9), wherein -L ^Ye - is independently saturated aliphatic Ci. ₃ alkylene.

(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 -.

(B6-13) A compound as described in any one of paragraphs (B6-3) to (B6-9), wherein -l_ ^Y6 - is independently -CH ₂ - or -CH ₂ CH ₂ -. (B6-14) A compound as described in any one of paragraphs (B6-3) to (B6-9), wherein -L ^Y6 - is independently -CH ₂ CH ₂ -.

(B6-15) A compound as described in any one of paragraphs (B6-3) to (B6-9), wherein -L ^Y6 - is independently -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.

(B6-17) 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, -Ph, or -CH ₂ -Ph, wherein said -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:

-F, -CI, -Br, -I,

-R ^Y6A , -CF ₃ ,

-OH, -OR ^Y6A , -OCF ₃ ,

-NH ₂ , -NHR ^Y6A , -NR ^Y6A 2, pyrrolidino piperidino, morpholino, piperizino,

(N-C^alky -piperizino,

-C(=0)OH, -C(=0)OR ^Y6A ,

-C(=0)R ^Y6A ,

-OC(=0)R ^Y6A ,

-C(=0)NH ₂ , -C(=0)NHR ^Y6A , -C(=0)NR ^YSA ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino, -C(=0)-piperizino, -C^OH/V-C^alky -piperizino,

-NHC(=0)R ^Y6A , -NR ^Y6A C(=0)R ^Y6A , and

-CN.

(B6-19) A compound as described in any one of paragraphs (B6-3) to (B6-15), wherein -R ^Y6 , 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 with one or more groups selected from:

-F, -CI, -Br, -I,

-R ^Y6A , -CF ₃ ,

-NH ₂ , -NHR ^Y6A , -NR ^Y6A 2, pyrrolidino piperidino, morpholino, piperizino,

(A/-Ci. ₄ alkyl)-piperizino,

-C(=0)OH, -C(=0)OR ^Y6A ,

-C(=0)R ^Y6A ,

-OC(=0)R ^Y6A ,

-C(=0)NH ₂ , -C(=0)NHR ^Y6A , -C(=0)NR ^6A ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(/N/-C ₁ . ₄ alkyl)-piperizino,

-NHC(=0)R ^Y6A , -NR ^Y6A C(=0)R ^Y6A , and

-CN.

(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:

-F, -CI, -Br, -I, 2, pyrrolidino piperidino, morpholino, piperizino, (/V-C _1- alkyl)-piperi2ino,

-C(=0)OH, -C(=0)OR ^Y6A , -C(=0)R ^Y6A , -OC(=0)R ^Y6A ,

-C(=0)NH ₂ , -C(=0)NHR ^Y6A , -C(=0)NR ^Y6A ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(/V-C ₁ . ₄ alkyl)-piperizino,

-NHC(=0)R ^Y6A , -NR ^Y6A C(=0)R ^Y6A , and -CN.

(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 . ₆ heteroaryl, 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 .

(B6-22) 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.

(B6-25) 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, saturated C ₃ - ₆ cycloalkyl, -Ph, or -CHrPh.

(B6-26) 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, -Ph, or -CH ₂ -Ph.

(B6-27) A compound as described in any one of paragraphs (B6-3) to (B6-15), wherein -R ^Y6 , if present, is independently saturated aliphatic C _h alky!.

(B6-28) A compound as described in any one of paragraphs (B6-3) to (B6-15), wherein -R ^YS , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, or -tBu.

(B6-29) A compound as described in paragraph (B6-3), wherein -B ⁶ is independently

-CH ₂ -C(=0)-0-Et.

B ⁷ - 3-Amido-Alkyl Compounds

(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.

(B7-3) A compound as described in paragraph (B7-1 ), wherein -B ⁷ is independently:

-L ^Y7 -C(=0)NH ₂ , -L^-C^OJNHR ⁷ , -L ^Y7 -C(=0)NR ^Y7 ₂ , -L ^Y7 -C(=0)-pyrrolidino,

-L ^Y7 -C(=0)-piperidino, -L^-C^OJ-morpholino, -L ^Y7 -C(=0)-piperizino, or

-L ^Y7 -C(=0)-(A-C ₁ . ₄ alkyl)-piperizino,

wherein:

-L ^Y7 - is independently saturated aliphatic C _1-4 alkylene, and

-R ^Y7 is independently saturated aliphatic Ci. ₄ alkyl, saturated C ₃ . ₆ cycioalkyl,

C ₅ . ₆ heteroaryl, -CH ₂ -C _5- 6heteroaryl, -Ph, or -CH ₂ -Ph,

wherein 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:

-F, -CI, -Br, -I,

-R ^m , -CF ₃ ,

-OH, -OR™, -OCF ₃ ,

-SR™,

-NH ₂ , -NHR , -NR ^Y7A ₂ , pyrrolidine piperidino, morpholino, piperizino,

(/V-Ci- ₄ alkyl)-piperizino,

-C(=0)OH, -C(=0)OR ^Y7A ,

-C^OJR™,

-OC(=0)R ^y7A ,

o,

wherein each -R is independently saturated aliphatic d^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 Ci _-4 alkyl.

(B7-4) A compound as described in paragraph (B7-3), wherein -B ⁷ is independently

-L ^Y7 -C(=0)NH ₂ , -L ^Y7 -C(=0)NHR ^Y7 , or -L ^Y7 -C(=0)NR ^Y7 ₂ .

(B7-5) A compound as described in paragraph (B7-3), wherein -B ⁷ is independently

-L ^Y7 -C(=0)NH ₂ .

(B7-6) A compound as described in paragraph (B7-3), wherein -B ⁷ is independently

-L ^Y7 -C(=0)-pyrrolidino, -L ^Y7 -C(=0)-piperidino, -L ^Y7 -C(=0)-morpholino, -L ^Y7 -C(=0)-piperizino, or -L ^Y7 -C(=0)-(/\/-C ₁ . ₄ alkyl)-piperizino.

(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 -.

(B7-1 1 ) A compound as described in any one of paragraphs (B7-3) to (B7-6), wherein - ⁷ - is independently -CH ₂ CH ₂ -.

(B7-12) A compound as described in any one of paragraphs (B7-3) to (B7-6), wherein -L - is independently -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.

(B7-14) A compound as described in any one of paragraphs (B7-3) to (B7-12), wherein -Ρ ⁷ , if present, is independently saturated aliphatic C _1-4 alkyl, -Ph, or -CH ₂ -Ph, wherein said -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:

-F, -CI, -Br, -I,

-R™ -CF 3,

-OH, -OR ^Y7A , -OCF ₃ ,

piperizino,

-C(=0)-piperidino,

-CN.

(B7-16) A compound as described in any one of paragraphs (B7-3) to (B7-12), wherein -R ⁷ , 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 ^Y7A , -CF ₃ ,

-OH, -OR™, -OCF ₃ ,

-NH ₂ , -NHR™, -NR ^Y7A ₂ , pyrrolidino piperidino, morpholino, piperizino,

(/V-Ci- ₄ alkyl)-piperizino,

-C(=0)OH, -C(=0)OR ^Y7A ,

-C(=0)R ^Y7A , -OC(=0)R ^Y7A ,

-C(=0)NH ₂ , -C(=0)NHR ^Y7A , -C^OJNR ⁷ ^, -C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(A/-Ci _-4 alkyl)-piperizino,

-NHC(=0)R ^Y7A , -NR ^Y7A C(=0)R ^Y7A , and -CN.

(B7-17) A compound as described in any one of paragraphs (B7-3) to (B7-12), wherein -R ⁷ , 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,

-R™, -CF ₃ ,

-OH, -OR™, -OCF _3l

-NH ₂ , -NHR ^Y7A , -NR pyrrolidino piperidino, morpholino, piperizino,

(/V-Ci- ₄ alkyl)-piperizino,

-C(=0)OH, -C(=0)OR ^Y7A ,

-C(=0)R ^Y7A ,

-OC(=0)R ^Y7A ,

-C(=0)NH ₂ , -C(=0)NHR ^Y7A , -C(=0)NR ^Y7A ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(/V-Ci. ₄ alkyl)-piperizino,

-NHC(=0)R ^Y7A , -NR ^Y7A C(=0)R ^Y7A , and

-CN.

(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 . ₆ heteroaryl, and -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, -R™, -CF ₃ , -OH, -OR™, 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, -R™, -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.

(B7-22) A compound as described in any one of paragraphs (B7-3) to (B7-12), wherein -R ^Y7 , if present, is independently saturated aliphatic C _1-4 alkyl.

(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.

(B7-24) A compound as described in any one of paragraphs (B7-3) to (B7-12), wherein -R^, if present, is independently -Me, -Et, -nPr, or -iPr.

(B7-25) A compound as described in any one of paragraphs (B7-3) to (B7-12), wherein -R^, if present, is independently -Me or -Et. (B7-26) A compound as described in any one of paragraphs (B7-3) to (B7-12), wherein -R^ ⁷ , if present, is independently -Me.

(B7-27) A compound as described in paragraph (B7-3), wherein -B ⁷ , if present, is

independently:

-CH ₂ -C(=0)NH ₂ , -CH ₂ -C(=0)NHMe, -CH ₂ -C(=0)NMe ₂ ,

-CH ₂ CH ₂ -C(=0)NH ₂ , -CH ₂ CH ₂ -C(=0)NHMe, -CH ₂ CH ₂ -C(=0)NMe _2>

-CH ₂ -C(=0)-piperidino, or -CH ₂ CH ₂ -C(=0)-piperidino.

B ⁸ - 3-Cyclic and 3-Cyclic-Alkyl Compounds

(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 .

(B8-2) A compound as described in paragraph (B8-1 ), wherein -B ⁸ is independently

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.

(B8-3) A compound as described in paragraph (B8-1 ), wherein -B ⁸ is independently:

-R ^YB or -L ^Y8 -R ^Y8 ,

wherein:

-L ^Ya - is independently saturated aliphatic Ci. alkylene, and

-R ^Y8 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 , -OCF ₃ ,

-NH ₂ , -NHR ^Y8A , -NR ^Y8A 2, pyrrolidino piperidino, morpholino, piperizino,

(A/-C ₁ . alkyl)-piperizino,

-C(=0)OH, -C(=0)OR ^Y8A ,

-C(=0)R ^Y8A ,

-OC(=0)R ^Y8A ,

-C(=0)NH ₂ , -C(=0)NHR ^Y8A , -C(=0)NR ^Y8A ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino, -C(=0)-piperizino, -C(=OHW-Ci. alkyl)-piperizino,

-NHC(=0)R ^V8A , -NR ^Y8A C(=0)R ^Y8A , and

-CN;

wherein each -R ^Y8A is independently saturated aliphatic d. alkyl, saturated

C ₃ . ₆ cycloalkyl, -Ph, or -CH ₂ -Ph, wherein each of said C ₃ . ₆ cycioalkyl and -Ph is optionally substituted with one or more substituents selected from -F, -CI, -Br, -I, -R ^Y8B , -CF ₃ , -OH, -OR ^Y8B , and -OCF ₃ , wherein each -R ^Y8B is independently saturated aliphatic C _1-4 alkyl.

(B8-4) A compound as described in paragraph (B8-3), wherein -B ⁸ is independently -R ^Y8 .

(B8-5) A compound as described in paragraph (B8-3), wherein -B ⁸ is independently -L ^Y8 -R ^Y8 .

(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 -.

(B8-10) 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 -.

(B8-11) A compound as described in any one of paragraphs (B8-3) to (B8-5), wherein -L ^Y8 -, if present, is independently -CH ₂ -.

(B8-12) A compound as described in any one of paragraphs (B8-3) to (B8-11), wherein -R ^Y8 is independently saturated C ₃ . ₆ cycloalkyl, and is optionally substituted.

(B8-13) A compound as described in any one of paragraphs (B8-3) to (B8-11), wherein -R ^Y8 is independently saturated C ₃ . ₆ heterocyclyl, and is optionally substituted.

(B8-14) A compound as described in any one of paragraphs (B8-3) to (B8-11), wherein -R ^Y8 is independently saturated pyrrolidinyl, piperidinyl, piperizinyl, or morpholinyl, and is optionally substituted.

(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 .

(B8-17) A compound as described in any one of paragraphs (B8-3) to (B8-11), wherein and -R is independently saturated C _3-6 heterocyc!y!, wherein said C ₃ . ₆ heterocyc!y! 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 .

(B8-19) A compound as described in any one of paragraphs (B8-3) to (B8-11), wherein and -R is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

(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.

5 ⁹ - 8-Trifluoromethyl-Alkyl Compounds

(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 .

(B9-2) A compound as described in paragraph (B9-1), wherein -B ⁹ is independently

trifluoromethyl or trifluoromethyl-C _1-6 alkyl.

(B9-3) A compound as described in paragraph (B9-2), wherein -B ⁹ is independently

trifluoromethyl-Ci.4alkyl.

(B9-4) A compound as described in paragraph (B9-2), wherein -B ⁹ is independently selected from:

-CF ₃

-CH ₂ CH ₂ CF ₃ , -CH(CF ₃ )CH _3l

-CH(CF ₃ )CH ₂ CH ₃ , -CH ₂ CH(CF ₃ )CH ₃ , or -CH ₂ CH ₂ CH ₂ CF ₃ .

(B9-5) A compound as described in paragraph (B9-2), wherein -B ⁹ is independently selected from:

-CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , or -CH ₂ CH ₂ CH ₂ CF ₃ .

(B9-6) A compound as described in paragraph (B9-2), wherein -B ⁹ is independently selected from:

-CF ₃ and -CH ₂ CF ₃ .

(B9-7) A compound as described in paragraph (B9-2), wherein -B ⁹ is independently -CH ₂ CF ₃ . B ¹⁰ - 8-Nitro-Alkyl Compounds

(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.

(B10-3) A compound as described in paragraph (B 0-1 ), wherein -B ¹⁰ is independently

-L ^Y10 -NO ₂ , wherein -L ^Y1 °- is independently saturated aliphatic C _1-4 alkylene.

(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 )-.

(B10-5) A compound as described in paragraph (B 0-3), wherein -L ^Y1Q - is independently -CH ₂ -, -CH2CH ₂ - or -CH ₂ CH ₂ CH ₂ -.

(B10-6) A compound as described in paragraph (B10-3), wherein -L ^Y °- is independently -CH ₂ -. (B10-7) A compound as described in paragraph (B10-3), wherein -B ¹⁰ is independently

-CH ₂ -N0 ₂ .

B11. 8-Cvano-Alkyl Compounds

(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 1-2) A compound as described in paragraph (B1 1-1), wherein -B ¹¹ is independently cyano-Ci _-6 alkyl.

(B1 1-3) A compound as described in paragraph (B11-1), wherein -B ¹¹ is independently

-L ^Y11 -CN, wherein -L ^Y11 - is independently saturated aliphatic d^alkylene.

(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 )-.

(B1 1-5) A compound as described in paragraph (B11-3), wherein -L ^Y11 - is independently -CH ₂ -, -CH ₂ CH ₂ - or -CH ₂ CH ₂ CH;;-.

(B -6) A compound as described in paragraph (B 1-3), wherein -L ^Y11 - is independently -CH ₂ - or -CH ₂ CH ₂ -.

(B1 1 -7) A compound as described in paragraph (B1 1-3), wherein -B ¹¹ is independently -CH ₂ - CN.

B12. 8-Phosphate-Alkyl Compounds

(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.

(B12-3) A compound as described in paragraph (B12-1 ), wherein -B ¹² is independently:

-L ^Y1 -P(=0)(OH) _2l -L ^Y12 -P(=0)(OH)(OR ^Y12 ), or -L ^Y12 -P(=0)(OR ^Y12 ) ₂ ,

wherein:

-L ^{Y 2} - is independently saturated aliphatic C^alkylene, and

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,

wherein each of said C ₃ .6cycloalkyl, C^eheteroaryl, and -Ph is optionally substituted, for example, with one or more groups selected from:

-F, -CI, -Br, -I,

Y12A

-R -CF

-OH, -OR ^Y12A , -OCF ₃ ,

-NH ₂ , -NHR ^{Y 2A} , -NR ^{Y1 2A} 2, pyrrolidino piperidino, morpholino, piperizino,

(/V-d^alky -piperizino,

-C(=0)OH, -C(=0)OR ^Y12A ,

-C(=0)R ^Y12A ,

-OC(=0)R ^Y12A , -C(=0)NH ₂ , -C(=0)NHR ^Y12A , -C(=0)NR ^{Y 2A} _2l -C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(/V-Ci. alkyl)-piperizino,

-NHC(=0)R ^Y12A , -NR ^{Y 2A} C(=0)R ^Y12A , and

-CN;

wherein each -R ^Y12A 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 ^Y12B , -CF ₃ , -OH, -OR ^Y12B , and -OCF ₃ , wherein each -R ^Y12B is independently saturated aliphatic d. ₄ alkyl.

(B12-4) A compound as described in paragraph (B12-3), wherein -B ¹² is independently

-L ^{Y 2} -P(=0)(OH) ₂ .

(B12-5) A compound as described in paragraph (B12-3), wherein -B ¹² is independently

-L ^Y12 -P(=0)(OH)(OR ^Y12 ).

(B12-6) A compound as described in paragraph (B12-3), wherein -B ² is independently

-L ^Y12 -P(=0)(OR ^Y12 ) ₂ .

(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 -|_ ^Y12 - is independently -CH ₂ - or -CH ₂ CH ₂ -.

(B12-9) A compound as described in any one of paragraphs (B12-3) to (B12-6), wherein -L ^Y12 - is independently -CH ₂ -.

(B12-10) A compound as described in any one of paragraphs (B12-3) to (B12-6), wherein -L ^{Y 2} - is independently -CH ₂ CH ₂ -.

(B12-11 ) A compound as described in any one of paragraphs (B12-3) to (B12-10), wherein each -R ^{Y 2} , 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.

(B12-12) A compound as described in any one of paragraphs (B12-3) to (B12-10), wherein each -R ^Y12 , if present, is independently saturated aliphatic C _n-4 alkyl, -Ph, or -CH ₂ -Ph, wherein said -Ph is optionally substituted.

(B12-13) A compound as described in any one of paragraphs (B12-3) to (B12-10), wherein each -R ^Y12 , if present, is independently saturated aliphatic C^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 .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 .

(B12-14) A compound as described in any one of paragraphs (B12-3) to (B12-10), wherein 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 .

(B12-15) A compound as described in any one of paragraphs (B12-3) to (B12-10), wherein 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 .

(B12-16) A compound as described in any one of paragraphs (B12-3) to (B12-10), wherein each -R ^{Y 2} , if present, is independently saturated aliphatic C alkyl, -Ph, or -CH ₂ -Ph.

(B12-17) A compound as described in any one of paragraphs (B12-3) to (B12-10), wherein each -R ^{Y 2} , if present, is independently saturated aliphatic C _1- alkyl.

(B12-18) A compound as described in any one of paragraphs (B12-3) to (B12-10), wherein each -R ^Y12 , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, or -tBu.

(B12-19) A compound as described in any one of paragraphs (B12-3) to (B12-10), wherein each -R ^Y12 , if present, is independently -Me, -Et, -nPr, or -iPr.

(B12-20) A compound as described in any one of paragraphs (B12-3) to (B12-10), wherein each -R ^Y1Z , if present, is independently -Me or -Et.

(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.

(B12-22) A compound as described in paragraph (B12-3), wherein each -B ¹² is

-CH ₂ -P(=0)(OEt) ₂ .

B13. 8-Carbamate-Alkyl Compounds

(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 .

(B13-2) A compound as described in paragraph (B13-1), wherein -B ¹³ is independently carbamate-Ci _-6 alkyl.

(B13-3) A compound as described in paragraph (B13-1), wherein -B ¹³ is independently:

-L ^Y13 -NH-C(=0)OH, -L ^Y13 -NH-C(=0)-R ^Y13 , -L ^Y13 -NR ^Y13 -C(=0)OH, or

-L ^Y13 -NR ^Y13 -C(=0)-R ^Y13 ,

wherein:

-i_ ^Y13 - is independently saturated aliphatic C^a!ky!ene, and

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,

wherein 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:

-F, -CI, -Br, -I,

-R ^Y13A , -CF ₃ ,

-OH, -OR ^Y13A , -OCF ₃ ,

-NH ₂ , -NHR ^Y13A , -NR ^Y13A ₂ , pyrrolidino piperidino, morpholino, piperizino,

(A/'d^alky -piperizino,

-C(=0)OH, -C(=0)OR ^Y13A ,

-C(=0)R ^Ym ,

-0C(=0)R ^Y13A ,

-C(=0)NH ₂ , -C(=0)NHR ^{Y 3A} , -C(=0)NR ^Y13A ₂ , -C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(/\/-C ₁ .4alkyl)-piperi2ino, -NHC(=0)R ^{Y 3A} , -NR ^Y13A C(=0)R ^Y13A , and

-CN;

wherein each -R ^{Y 3A} 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 ^Y13B , -CF ₃ , -OH, -OR ^Y13B , and -OCF ₃ , wherein each -R ^Y13B is independently saturated aliphatic C alkyl.

(B13-4) A compound as described in paragraph (B13-3), wherein -B ¹³ is independently

-L ^Y13 -NH-C(=0)OH, or -L ^Y13 -NH-C(=0)-R ^Y13 .

(B13-5) A compound as described in paragraph (B13-3), wherein -B ¹³ is independently

-L ^Y13 -NH-C(=0)OH.

(B13-6) A compound as described in paragraph (B13-3), wherein -B ¹³ is independently

-L ^Y13 -NH-C(=0)-R ^Y13 .

(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 )-.

(B13-8) A compound as described in any one of paragraphs (B13-3) to (B13-6), wherein -L ^Y13 - is independently -CH ₂ - or -CH ₂ CH ₂ -.

(B13-9) A compound as described in any one of paragraphs (B13-3) to (B13-6), wherein -L ^V13 - is independently -CH ₂ -.

(B13-10) A compound as described in any one of paragraphs (B13-3) to (B13-6), wherein -L ^{Y 3} - is independently -CH ₂ CH ₂ -.

(B13-11) A compound as described in any one of paragraphs (B13-3) to (B13-10), wherein each -R ^Y13 , if present, 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.

(B13-12) A compound as described in any one of paragraphs (B13-3) to (B13-10), wherein each -R ^Y13 , if present, is independently fluorenyl or -CH ₂ -fluorenyl, wherein said fluorenyl is optionally substituted.

(B13-13) A compound as described in any one of paragraphs (B13-3) to (B13-10), wherein each -R ^Y13 , if present, is independently saturated aliphatic CMalkyl, -Ph, or -CH ₂ -Ph, wherein said -Ph is optionally substituted.

(B13-14) A compound as described in any one of paragraphs (B13-3) to (B13-10), wherein each -R ^Y13 , if present, 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 . ₆ heteroaryl, 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 .

(B13-15) A compound as described in any one of paragraphs (B13-3) to (B13-10), wherein each -R ^Y13 , if present, 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. 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 ^Y12A , -CF ₃ , -OH, -OR ^Y12A , and -OCF ₃ .

(B13-17) 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 _-4 alkyl, -Ph, or -CH ₂ -Ph.

(B13-18) A compound as described in any one of paragraphs (B13-3) to (B13-10), wherein each -R ^Y13 , if present, is independently saturated aliphatic

(B13-19) A compound as described in any one of paragraphs (B13-3) to (B13-10), wherein -R ^Y13 is fluorenyl or -CH ₂ -fluorenyl.

B14. 8-Oxime-Alkyl Compounds

(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 .

(B14-2) A compound as described in paragraph (B14-1), wherein -B ¹⁴ is independently oxime-C _1-6 alkyl.

(B14-3) A compound as described in paragraph (814-1), wherein -B ⁴ is independently:

-L ^Y14 -CH(=N-0-H), -L ^Y1 -CH(=N-0-R ^Y14 ), -L ^Y14 -CR ^Y14 (=N-0-H), or

-L ^Y14 -CR ^Y14 (=N-0-R ^Y14 ),

wherein:

-L ^Y14 - is independently saturated aliphatic C _1-4 alkylene, and

each -R ^Y14 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 C ₃ . ₆ cycloalkyl, C _s . ₆ heteroaryl, and -Ph is optionally substituted, for example, with one or more groups selected from:

-F, -CI, -Br, -I,

-R ^Y14A , -CF ₃ ,

-OH, -OR ^Y14A , -OCF ₃ ,

piperidino, morpholino, piperizino,

-C(=0)-pyrrolidino, -C(=0)-piperidino, -C(=0)-morpholino, -C(=0)-piperizino, -C(=0)-(/V-Ci. alkyl)-piperizino,

-NHC(=0)R ^{Y1 A} , -NR ^Y14A C(=0)R ^{Y A} , and

-CN;

wherein 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.

(B14-4) A compound as described in paragraph (B14-3), wherein -B ¹⁴ is independently

-L ^Y,4 -CH(=N-0-R ^Y14 ) or -L ^Y5 -CR ^Y5 (=N-0-R ^Y5 ). (B14-5) A compound as described in paragraph (B14-3), wherein -B ¹⁴ is independently

-L ^Y14 -CR ^Y1 (=N-0-R ^Y14 ).

(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 -.

(B14-8) A compound as described in any one of paragraphs (B14-3) to (B14-5), wherein -L ^Y14 - is independently -CH ₂ -.

(B14-9) A compound as described in any one of paragraphs (B14-3) to (B14-5), wherein -L ^Y14 - is independently -CH ₂ CH ₂ -.

(B14-10) A compound as described in any one of paragraphs (B14-3) to (B14-9), wherein each -R ^Y14 , 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.

(B14-11) A compound as described in any one of paragraphs (B14-3) to (B14-9), wherein each -R ^Y14 , if present, is independently saturated aliphatic C _1-4 alkyl, -Ph, or -CH ₂ -Ph, wherein said -Ph is optionally substituted.

(B14-12) A compound as described in any one of paragraphs (B14-3) to (B14-9), wherein each -R ^Y14 , if present, is independently saturated aliphatic C _1-4 a1kyl, 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 . 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 .

(B14-13) A compound as described in any one of paragraphs (B14-3) to (B14-9), wherein 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 .

(B14-14) A compound as described in any one of paragraphs (B14-3) to (B14-9), wherein 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 .

(B14-15) A compound as described in any one of paragraphs (B14-3) to (B14-9), wherein each -R ^{Y 4} , if present, is independently saturated aliphatic C _1-4 alkyl, -Ph, or -CH ₂ -Ph.

(B1 -16) A compound as described in any one of paragraphs (B14-3) to (B14-9), wherein each -R ^Y14 , if present, is independently saturated aliphatic C alkyl.

(B14-17) A compound as described in any one of paragraphs (B14-3) to (B14-9), wherein each -R ^Y14 , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, or -tBu.

(B14-18) A compound as described in any one of paragraphs (B14-3) to (B14-9), wherein each -R ^Y14 , if present, is independently -Me, -Et, -nPr, or -iPr. (B14-19) A compound as described in any one of paragraphs (B14-3) to (B14-9), wherein each -R ^{V 4} , if present, is independently -Me or -Et.

(B14-20) A compound as described in paragraph (B14-3), wherein -B ¹⁴ is independently -CH ₂ -C(Et)(=N-0-Me).

Certain Preferred Embodiments

(C1) A compound of formula (I) as defined herein, wherein:

-X is independently X ¹ , for example as set out in any one of (X1-1) to (X1-31);

-B is independently:

-B ² , for example, as set out in any one of (B2-1) to (B2-6);

-B ⁵ , for example, as set out in any one of (B5-1) to (B5-34); or

-B ⁹ , for example, as set out in any one of (B9-1) to (B9-7);

and -Y is independently H.

(C2) A compound of formula (I) as defined herein, wherein:

-X is independently X ² , for example as set out in any one of (X2-1) to (X2-76);

-B is independently:

-B ¹ , for example, as set out in any one of (B1-1) to (B1-12);

-B ² , for example, as set out in any one of (B2-1) to (B2-6);

-B ³ , for example, as set out in any one of (B3-1) to (B3-32);

-B ⁴ , for example, as set out in any one of (B4-1) to (B4-36);

-B ⁵ , for example, as set out in any one of (B5-1) to (B5-34); or

-B ⁹ , for example, as set out in any one of (B9-1) to (B9-7);

and -Y is independently H.

(C3) A compound of formula (I) as defined herein, wherein:

-X is independently X ³ , for example as set out in any one of (X3-1) to (X3-9);

-B is independently:

-B\ for example, as set out in any one of (B1-1) to (B1-12);

-B ² , for example, as set out in any one of (B2-1) to (B2-6);

-B ³ , for example, as set out in any one of (B3-1) to (B3-32); or

-B ⁹ , for example, as set out in any one of (B9-1) to (B9-7);

and -Y is independently H.

(C-4) A compound of formula (!) as defined herein, wherein:

-X is independently X ¹ , for example as set out in any one of (X1-1) to (X1-31);

-B is independently B ² for example as set out in any one of (B2-1) to (B2-6)

and -Y is independently H.

(C5) A compound of formula (I) as defined herein, wherein:

-X is independently X ¹ , for example as set out in any one of (X1-1) to (X1-31);

-B is independently B ⁵ , for example as set out in any one of (B5-1) to (B5-34);

and -Y is independently H.

(C6) A compound of formula (I) as defined herein, wherein:

-X is independently X ¹ , for example as set out in any one of (X1-1) to (X1-31);

-B is independently B ⁹ , for example as set out in any one of (B9-1) to (B9-7);

and -Y is independently H. (C7) A compound of formula (I) as defined herein, wherein:

-X is independently X ² , for example as set out in any one of (X2-1) to (X2-76);

-B is independently B ¹ , for example as set out in any one of (B1-1) to (B1-12);

and -Y is independently H.

(C8) A compound of formula (I) as defined herein, wherein:

-X is independently X ² , for example as set out in any one of (X2-1) to (X2-76);

-B is independently B ^z , for example as set out in any one of (B2-1) to (B2-6);

and -Y is independently H.

(C9) A compound of formula (I) as defined herein, wherein:

-X is independently X ² , for example as set out in any one of (X2-1) to (X2-76); -B is independently B ³ , for example as set out in any one of (B3-1) to (B3-32);

and -Y is independently H.

(C10) A compound of formula (I) as defined herein, wherein:

-X is independently X ² , for example as set out in any one of (X2-1) to (X2-76);

-B is independently B ⁴ , for example as set out in any one of (B4-1) to (B4-36);

and -Y is independently H.

(C11) A compound of formula (I) as defined herein, wherein:

-X is independently X ² , for example as set out in any one of (X2-1) to (X2-67);

-B is independently B ⁵ , for example as set out in any one of (B5-1) to (B5-34);

and -Y is independently H.

(C12) A compound of formula (I) as defined herein, wherein:

-X is independently X ² , for example as set out in any one of (X2-1) to (X2-76);

-B is independently B ⁹ , for example as set out in any one of (B9-1) to (B9-7);

and -Y is independently H.

(C13) A compound of formula (I) as defined herein, wherein:

-X is independently X ³ , for example as set out in any one of (X3-1) to (X3-9);

-B is independently B\ for example as set out in any one of (B1-1) to (B1-12);

and -Y is independently H.

(C14) A compound of formula (I) as defined herein, wherein:

-X is independently X ³ , for example, as set out in any one of (X3-1) to (X3-9);

-B is independently B ² , for example as set out in any one of (B2-1) to (B2-6);

and -Y is independently H.

(C15) A compound of formula (I) as defined herein, wherein:

-X is independently X ³ , for example as set out in any one of (X3-1) to (X3-9);

-B is independently B ³ , for example as set out in any one of (B3-1) to (B3-32);

and -Y is independently H.

(C16) A compound of formula (I) as defined herein, wherein:

-X is independently X ³ , for example as set out in any one of (X3-1) to (X3-9);

-B is independently B ⁹ , for example as set out in any one of (B9-1) to (B9-7);

and -Y is independently H.

(C-17) A compound of formula (I) as defined herein, selected from the following compounds and pharmaceutically acceptable salts, hydrates, and solvates thereof: 2012/085501

PCT/GB2011/001739 01739

Molecular Weight

In one embodiment, the compound has a molecular weight of from 200 to 1200.

In one embodiment, the bottom of range is from 210, 220, 225, 250, 275, 300, or 350.

In one embodiment, the top of range is 1100, i OOO, 900, 800, 700, or 600.

In one embodiment, the range is 220 to 600.

Combinations

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments pertaining to the chemical groups represented by the variables (e.g., -X ¹ , -X ² , -X ³ , Y, -B ¹ , -B ² , -B ³ , -B ⁴ , -B ⁵ , -B ⁶ , -B ⁷ , -B ⁸ , -B ⁹ , -B ⁰ , -B ¹¹ , B ¹² , -B ¹³ , -B ¹⁴ etc) are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterised, and tested for biological activity). In addition, all sub-combinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein.

Substantially Purified Forms

One aspect of the present invention pertains to compounds as described herein, in substantially purified form and/or in a form substantially free from contaminants.

In one embodiment, the compound is in a substantially purified form with a purity of least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.

Unless specified, the substantially purified form refers to the compound in any stereoisomeric or enantiomeric form. For example, in one embodiment, the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds. In one embodiment, the substantially purified form refers to one stereoisomer, e.g., optically pure stereoisomer. In one embodiment, the substantially purified form refers to a mixture of enantiomers. In one embodiment, the substantially purified form refers to an equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.

In one embodiment, the compound is in a form substantially free from contaminants wherein the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1% by weight.

Unless specified, the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.

In one embodiment, the compound is in a substantially purified form with an optical purity of at least 60% (i.e., 60% of the compound, on a molar basis, is the desired enantiomer, and 40% is the undesired enantiomer), e.g., at least 70%, e.g., at least 80%, e.g., at least 90%, e.g., at least 95%, e.g., at least 97%, e.g., at least 98%, e.g., at least 99%,

Isomers

Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and

combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").

Note that, except as discussed below for tautomeric forms, specifically excluded from the term "isomers," as used herein, are structural (or constitutional) isomers (i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space). For example, a reference to a methoxy group, -OCH ₃ , is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH ₂ OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C _1-7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.

keto enol enolate

Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including ¹ H, ² H (D), and ³ H (T); C may be in any isotopic form, including ¹² C, ¹³ C, and ⁴ C; O may be in any isotopic form, including ¹⁶ 0 and ¹⁸ 0; and the like.

Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof. Methods for the preparation

(e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.

Salts

It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci„ Vol. 66, pp. 1-19.

For example, if the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO ^" ), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na ⁺ and K ⁺ , alkaline earth cations such as Ca ²⁺ and g ²⁺ , and other cations such as Α ³ . Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH ₄ ⁺ ) and substituted ammonium ions (e.g., NH ₃ R ⁺ , NH ₂ R2 ⁺ , NHR ₃ ⁺ , NR ₄ ⁺ ). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH ₃ ) ₄ ⁺ .

If the compound is cationic, or has a functional group which may be cationic (e.g., -NH ₂ may be -NH ₃ ⁺ ), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous. Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic,

camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric,

glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

Unless otherwise specified, a reference to a particular compound also includes salt forms thereof.

Hydrates and Solvates

It may be convenient or desirable to prepare, purify, and/or handle a corresponding hydrate or solvate of the compound (e.g., pharmaceutically acceptable hydrates or solvates of the compound). The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri- hydrate, etc.

Unless otherwise specified, a reference to a particular compound also includes hydrate and solvate forms thereof.

Chemically Protected Forms

It may be convenient or desirable to prepare, purify, and/or handle the compound in a chemically protected form. The term "chemically protected form" is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like). In practice, well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006).

A wide variety of such "protecting," "blocking," or "masking" methods are widely used and well known in organic synthesis. For example, a compound which has two nonequivalent reactive functional groups, both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups "protected," and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group may be "deprotected" to return it to its original functionality. For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=0)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=0)CH ₃ , -OAc).

For example, an aldehyde or ketone group may be protected as an acetal (R-CH(OR) ₂ ) or ketal (R ₂ C(OR) ₂ ), respectively, in which the carbonyl group (>C=0) is converted to a diether

(>C(OR) ₂ ), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.

For example, an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a benzyloxy amide (-NHCO-OCH ₂ C ₆ H ₅ , -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH ₃ ) ₃ , -NH-Boc); a 2-biphenyl- 2-propoxy amide (-NHCO-OC(CH ₃ ) ₂ C ₆ H4C ₆ H5, -NH-Bpoc), as a 9-fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH- Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-Alloc), as a 2(- phenylsulfonyl)ethyloxy amide (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>Ν-0·).

For example, a carboxylic acid group may be protected as an ester for example, as: an Ci.7alkyl ester (e.g., a methyl ester; a t-butyl ester); a d. ₇ haloalkyl ester (e.g., a C trihaloalkyl ester); a triCi. ₇ alkylsilyl-C _-7 alkyl ester; or a C ₅ . ₂ oaryl-Ci. ₇ alk l ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.

For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH ₂ NHC(=0)CH ₃ ).

For example, a carbonyl group may be protected as an oxime (-C(=NOH)-) or a substituted oxime (-C(=NOR)-), for example, where R is saturated aliphatic C - alkyl.

Prodrugs

It may be convenient or desirable to prepare, purify, and/or handle the compound in the form of a prodrug. The term "prodrug," as used herein, pertains to a compound which, when metabolised (e.g., in vivo), yields the desired active compound. Typically, the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.

For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=0)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (-C(=0)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.

Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative. Chemical Synthesis

Several methods for the chemical synthesis of the compounds of the present invention are described herein. These and/or other well known methods may be modified and/or adapted in known ways in order to facilitate the synthesis of additional compounds within the scope of the present invention.

See, for example, Wang, Y., et al., 1998, "Antitumour imidazotetrazines. Part 36. Conversion of 5-amino-imidazole-4-carboxamide to imidazo[5,1-c/][1 ,2,3,5]tetrazin-4(3H)-ones and

imidazo[1 ,5-a][1 ,3,5]triazin-4(3H)-ones related in structure to the antitumour agents

temozolomide and mitozolomide," J. Chem. Soc, Perkin Trans 1, Vol. 10, pp. 1669-1675;

Stevens, M.F.G., et al., 1984, "Antitumour imidazotetrazines. Part 1. Synthesis and chemistry of e-carbamoyl-S-iZ-chloroeth imidazotl .S- /l-I ^.S.S-tetrazin^iSH^one, a novel broad spectrum antitumour agent", J. Med. Chem.. Vol. 27, pp. 196-201.

In one approach, a suitable isocyanate is reacted with a suitable 5-diazo-4-sulfonyl-imidazole to give the corresponding 3-substituted imidazotetrazine, for example as illustrated in the following scheme.

Scheme 1

Suitable isocyanates may be obtained from commercial sources, or prepared using known methods, or by adapting known methods in known ways. For example, methods for preparing certain isocyanates are described in WO 96/27588 and in co-pending application

PCT/GB2010/001233.

Classical routes to isocyanates include treatment of a primary amine with phosgene, or a phosgene equivalent, and the Curtius rearrangement of an acyl azide (see, e.g., Ozaki, S., 1972, Chem. Rev., Vol. 72, pp. 457-496; Saunders, J.H., et al., 1948, Chem. Rev.. Vol. 43, pp. 203-218). Acy! azides are commonly prepared by the treatment of an acid chloride with sodium azide or, more conveniently, are prepared directly from the carboxylic acid using

diphenylphosphoryl azide (dppa) (see, e.g., Shioiri, T., et al., 1972, J. Am. Chem. Soc, Vol. 94, pp. 6203-6205) and are not normally isolated. Other methods are also known in the art.

Suitable 4-diazo-5-sulfonyl-imidazole compounds may be prepared from the corresponding 5- amino-4-sulfonyl-imidazole compounds as shown in the scheme below: Scheme 2a

As will be understood by those skilled in the art, the same 4-diazo-5-sulfonyl-imidazole compounds could equally be prepared from the corresponding 4-amino-5-sulfonyl-imidazole tautomers, i.e.:

Scheme 2b

As used herein, the two possible tautomeric forms of these imidazole compounds may together be referred to as 5(4)-amino-4(5)-sulfonyl-imidazole compounds. Analogous nomenclature is used for other imidazole intermediates discussed herein, which may also exist in two tautomeric imidazole forms.

Under certain reaction conditions these tautomeric forms will interconvert. Furthermore it may not always be possible to know which tautomeric form of the intermediate is produced in a preceding synthetic step. However, this does not affect the identity of the final product of the synthesis, i.e. the imidazotetrazine, as would be evident to those in the art.

Methods for the conversion of an amine to the corresponding diazo compound are known in the art, for example the amine may be treated with sodium nitrite in a procedure such as that set out in J. Med. Chem.. 1987, Vol. 30, p.357.

Certain suitable 5(4)-amino-4(5)-su!fony!-imid3∑ole compounds may be obtained by reduction, for example by catalytic hydrogenation, of the corresponding nitro compounds, as shown in the following scheme.

Scheme 3

In some embodiments, certain of said 5(4)-nitro-4(5)-sulfonyl-imidazole compounds can be prepared, for example, from 5(4)-nitro-1 H-imidazole-4(5)-sulfonyl chloride or 2-methyl-5(4)-nitro- 1 H-imidazole-4(5)-sulfonyl chloride, for example by coupling with an appropriate amine.

Scheme 4

5(4)-Nitro-1 H-imidazole-4(5)-sulfonyl chloride or 2-methyl-5(4)-nitro-imidazole-4(5)-sulfonyl chloride can themselves be prepared from readily available starting materials by a modification of the procedures described in Can. J. Chem.. 1961 , Vol. 39, p.501 and J. Am. Chem. Soc, 1957, vol. 79, p. 2188.

An alternative approach to the compounds of the present invention has also been developed, which proceeds via an intermediate of general formula (II):

wherein X and Y are as previously defined.

The intermediate of general formula (II) has a N-H group at the 3-position. Similar intermediates and their synthesis are described in co-pending application PCT/GB2011/000266, which is hereby incorporated by reference. As described therein, 3-NH intermediates such as these had not previously been successfully synthesised.

In the methods of the present invention, compounds of formula (II) may be prepared from compounds of formula (III):

wherein

X and Y are as previously defined;

J ¹ and J ² are each independently H or d. ₃ alkyl; and

P ¹ and P ² are each independently H or an amine protecting group or P ¹ and P ² together form an amine protecting group. A wide variety of amine protecting groups are widely used and well known in organic synthesis. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006).

In some embodiments, the amine protecting group is an acid-cleavable protecting group.

In some embodiments, P ¹ and P ² are each independently -H or an amine protecting group In some embodiments, one of P ¹ and P ² is -H and the other is an amine protecting group.

In some embodiments, one of P ¹ and P ² is -H and the other is an amine protecting group selected from terf-butoxycarbonyl (Boc), acetyl (Ac), tetrahydropyran (THP), trimethyl silyl (TMS), triisopropyl silyl (TIPS), tetra-butyl dimethyl silyl (TBDMS), benzyl (Bn),

para-methoxybenzyl (PMB), triphenyl methyl (trityl).

In some embodiments, P ¹ and P ² are each independently -H.

In some embodiments, P ¹ and P ² together form an amine protecting group.

In some embodiments, P ¹ and P ² together form a cyclic imide, for example a phthalimide group:

In some embodiments, J ¹ and J ² are each independently selected from -H, -Me, -Et, -nPr, and -iPr.

In some embodiments, J ¹ and J ² are each independently selected from -H, -Me and -Et.

In some embodiments, J ¹ and J ² are each independently selected from -H and -Me.

In some embodiments, one of J ¹ and J ² is -H and the other is independently C _L3 alkyl.

In some embodiments, one of J ¹ and J ² is -H and the other is independently selected from -Me,

-Et, -nPr, and -iPr.

In some embodiments, one of J ¹ and J ² is H and the other is independently selected from Me and -Et.

In some embodiments, one of J ¹ and J ² is H and the other is independently -Me.

In some embodiments, J ¹ and J ² are each independently -H.

In some embodiments, J ¹ and J ² are each independently -Me.

The step of preparing the compound of formula (II) from the corresponding compound of formula (III) is referred to herein as the deprotection step. It has been found that the protected nitrogen eliminates spontaneously upon removal of P ¹ and P ² to give the free 3-NH.

The conditions needed for the deprotection step will depend on the nature of the amine protecting group(s) P ¹ and/or P ² . Methods for the removal of amine protecting groups are known in the art. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006).

In some embodiments, the deprotection step comprises treatment of the compound of formula (III) with a suitable acid. In some embodiments the acid may be aqueous hydrochloric acid, for example aqueous hydrochloric acid at a concentration of from 0.5N to 5N, preferably about 3N. Compounds of formula (III) may be prepared by methods analogous to known methods for the synthesis of temozolomide and analogues, wherein a suitable isocyanate is reacted with a diazoimidazole to give the corresponding 3-substituted imidazotetrazine (for example, the various methods as illustrated above).

Accordingly, compounds of formula (III) can be prepared by reaction of an isocyanate of general formula (IV):

wherein J ¹ , J ² , P ¹ and P ² are as defined above. with a diazoimidazole compound of general formula (V):

wherein X and Y are as defined herein. These compounds may be obtained from the

corresponding amines, as shown above in Scheme 2.

Suitable isocyanates may be obtained from commercial sources, or prepared using known methods, or by adapting known methods in known ways. For example, the methods for producing isocyanates described above.

In some embodiments, the isocyanate of formula (IV) is tert-butyl isocyanatomethylcarbamate. terf-Butyl isocyanatomethylcarbamate may be prepared from /V-Boc-glycine and ethyl chloroformate, as shown in the scheme below:

This method is adapted from that described in J.Chem.Soc, Perkin Trans. 1, 2000, 4328-4331.

Other compounds of formula (IV) may be prepared, in an analogous manner, from an appropriate protected amino acid, of general formula (VI):

Compounds of formula (VI) may be obtained from commercial sources, or prepared using Known methods, or by adapting known methods in known ways.

In some embodiments, reaction of compound (IV) with compound (V) is performed under an inert atmosphere, such as an argon or nitrogen atmosphere. In some embodiments, the reaction is performed in the dark. The reaction is preferably performed in the presence of a suitable organic solvent. In some embodiments, the solvent is selected from DMSO, toluene, ethyl acetate, or mixtures thereof.

Accordingly, as described above, compounds of formula (II) may be prepared by a method comprising the following steps:

- optionally, preparing an isocyanate of formula (IV) from an amino acid of formula (VI);

- optionally, preparing a diazoimidazole of formula (V) from the corresponding amine;

- reaction of an isocyanate of formula (IV) with a diazoimidazole of formula (V), to form a compound of formula (III);

- deprotection of a compound of formula (III) to form a compound of formula (II).

Reaction of the 3-NH group of a compound of formula (II) with a suitable electrophile may be performed, as described herein, to arrive at compounds of formula (I).

For example, the 3-NH group may be reacted with a suitable electrophile to produce various groups, for example /V-alkyl and substituted /V-alkyl groups, at the 3-position. For convenience this is referred to hereafter as the 'electrophile addition step'. In some embodiments, it may be referred to as the alkylation step.

In some embodiments, the electrophile addition step is performed in a reaction medium comprising an organic solvent. In some embodiments, the solvent is DMF (dimethylformamide). In some embodiments the electrophile addition step is performed at room temperature or below. In some embodiments, the temperature is 10°C or less, 5°C or less, or 0°C or less.

Suitable alkylating agents for use in the electrophile addition (alkylation) step are known in the art and include, but are not limited to, aikyl halides, epoxides, a!ky! alcohols, activated a!ky! alcohols (for example, an alkyl alcohol in the presence of triphenylphosphine), alkyl alkoxides. Aldehydes may also be reacted with the 3-NH group, to produce hydroxy-substituted /V-alkyl groups at the 3-position.

In some embodiments, the electrophile is an alkylating agent.

In some embodiments, the alkylating agent used in the alkylation step may be a compound of formula B-X ^LG , where B is as defined herein for the compounds of formula (I), and X ^LG is a leaving group.

Suitable leaving groups are known in the art and include, but are not limited to, halide (-F, -CI, - Br, -I) , alkoxide (-OR), hydroxide (-OH), water (- ⁺ OH ₂ ), alcohol (- ⁺ OHR), sulfonates such as tosylate (-OTs; -OS0 ₂ (p-MePh)) or mesylate (-OMs, -OS0 ₂ e), and triflate (-OTf, -OS0 ₂ (CF ₃ )). Various leaving groups are discussed, for example, in 'March's Advanced Organic Chemistry, Wiley, 6 ^th Edition, pages 496-501 and 555-571 and in 'Organic Chemistry', Clayden et a I, Oxford University Press, 1 ^st Edition, pages 407-445.

In some embodiments, X ^LG is halide.

In some embodiments, X ^LG is selected from -F, -CI, -Br, and -I.

In some embodiments, the alkylating agent is an alkyl halide.

In some embodiments, the alkylating agent is a C 6 alkyl halide.

In some embodiments, the alkylating agent is a C1.6 alkyl iodide.

In some embodiments, the alkylating agent is methyl iodide.

In some embodiments, the alkylating agent is a C1-6 alkynyl halide.

In some embodiments, the alkylating agent is propargyl bromide.

In some embodiments, the alkylating agent is an aldehyde.

In some embodiments, the alkylating agent is formaldehyde.

In some embodiments, in the electrophile addition step, the compound of formula (II) is treated with a base, preferably prior to addition of the electrophile. In some embodiments, the base is selected from sodium hydride, potassium hydride, calcium hydride, potassium carbonate, lithium diisopropyl amine, diisopropylethyl amine, and DBU (1 ,8-diazabicyclo(5.4.0)undec-7- ene).ln some preferred embodiments, the base is sodium hydride.

In some cases, a compound with a less labile leaving group, such as a hydroxide or alkoxide, may be activated to form a better leaving group. For example this could be by protonation, by reaction with e.g. PBr ₃ , or via a reaction such as a Mitsunobu reaction, which uses a

combination of a phosphine, for example triphenylphosphine (PPh ₃ ), and an azodicarboxylate, for example DEAD or DIAD, to activate a hydroxide group to nucleophilic attack.

This is illustrated in the scheme below:

In some embodiments, the alkylation step comprises a Mitsunobu reaction.

In some embodiments, the alkylation step comprises a Mitsunobu reaction between a compound of formula (II) and an alcohol.

In some embodiments, the alkylation step comprises a Mitsunobu reaction between a compound of formula (II) and an alcohol of general formula B-OH.

In some embodiments, the alkylation step comprises a Mitsunobu reaction between a compound of formula (II) and an alcohol of general formula B-OH, in the presence of triphenylphosphine and an azodicarboxylate.

In some embodiments, the azodicarboxylate is selected from diethylazodicarboxylate (DEAD). In some embodiments, the azodicarboxylate is selected from diisopropylazodicarboxylate (DIAD).

In some embodiments, the triphenylphosphine is polymer-supported.

In some embodiments, the alcohol is a Ce alkyl alcohol and is optionally substituted.

In some embodiments, the alcohol is benzyl alcohol.

In some embodiments, the alcohol is glycidol.

Compounds of formula (I) produced by any of the above methods may, in some embodiments, be further modified to produce compounds of the invention having different X, Y and/or B substituents, as would be evident to those skilled in the art.

For example, further synthetic modifications to the group introduced at the 3-position may be made to create further analogues, using synthetic techniques and transformations which are known in the art and which can readily be devised by the skilled person. In one such example, a 3-hydroxymethyl compound as shown below may be used to prepare a range of other 3- subsituted compounds, by reaction with a suitable halide (e.g., R-X ^Hal , where X ^Hal is, for example, -I), for example, in the presence of a suitable base. A wide variety of halides is known and/or can be relatively easily prepared. An example of this method is illustrated in the following scheme.

Examples of compounds which could be made using this method include, but are not limited to, compounds where R is selected from groups such as benzyl, p-methoxy benz l, methyl, ethyl, propyl, propargyl, or methoxymethyl (MOM).

Compositions

One aspect of the present invention pertains to a composition (e.g., a pharmaceutical composition) comprising a compound of the invention, as described herein, and a

pharmaceutically acceptable carrier, diluent, or excipient.

Another aspect of the present invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising admixing a compound of the invention, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.

Uses

The compounds of the invention described herein are useful, for example, in the treatment of proliferative disorders, such as, for example, cancer, etc.

Use in Methods of Inhibiting Cell Proliferation, Etc.

The compounds of the invention described herein, e.g., (a) regulate (e.g., inhibit) cell proliferation; (b) inhibit cell cycle progression; (c) promote apoptosis; or (d) a combination of one or more of these.

One aspect of the present invention pertains to a method 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.

In one embodiment, the method is a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of the invention, as described herein.

In one embodiment, the method is performed in vitro.

In one embodiment, the method is performed in vivo.

In one embodiment, the compound of the invention is provided in the form of a pharmaceutically acceptable composition.

Any type of cell may be treated, including but not limited to, cancer cells derived from tumours or the lung, gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin. Cancer stem cells may also be treated with the compounds of the invention.

One of ordinary skill in the art is readily able to determine whether or not a candidate compound regulates (e.g., inhibits) cell proliferation, etc. For example, assays which may conveniently be used to assess the activity offered by a particular compound are described herein.

For example, a sample of cells (e.g., from a tumour) may be grown in vitro and a compound brought into contact with said cells, and the effect of the compound on those cells observed. As an example of "effect," the morphological status of the cells (e.g., alive or dead, etc.) may be determined. Where the compound is found to exert an influence on the cells, this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a patient carrying cells of the same cellular type.

Use in Methods of Therapy

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.

Use in the Manufacture of Medicaments

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.

In one embodiment, the medicament comprises the compound.

Methods of Treatment

Another aspect of the present invention pertains to a method of treatment comprising administering to a patient 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.

Conditions Treated - Proliferative Disorders and Cancer

In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of

medicaments, of methods of treatment), the treatment is treatment of a proliferative disorder.

The term "proliferative condition," as used herein, pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth.

In one embodiment, the treatment is treatment of: a proliferative condition characterised by benign, pre-malignant, or malignant cellular proliferation, including but not limited to, neoplasms, hyperplasias, and tumours (e.g., histocytoma, glioma, astrocyoma, osteoma), cancers (see below), psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), pulmonary fibrosis, atherosclerosis, smooth muscle cell proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.

In one embodiment, the treatment is treatment of: cancer.

In one embodiment, the treatment is treatment of: lung cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, stomach cancer, bowel cancer, colon cancer, rectal cancer, colorectal cancer, thyroid cancer, breast cancer, ovarian cancer, endometrial cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, renal cell carcinoma, bladder cancer, pancreatic cancer, brain cancer, glioma, sarcoma, osteosarcoma, bone cancer, nasopharyngeal cancer, squamous carcinoma of the head or neck, skin cancer, squamous cancer, Kaposi's sarcoma, melanoma, malignant melanoma, lymphoma, or leukemia.

In one embodiment, the treatment is treatment of:

a carcinoma, for example a carcinoma of the bladder, breast, colon (e.g., colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermal, liver, lung (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas),

oesophagus, gall bladder, ovary, pancreas (e.g., exocrine pancreatic carcinoma), stomach, cervix, thyroid, prostate, skin (e.g., squamous cell carcinoma);

a hematopoietic tumour of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma;

a hematopoietic tumour of myeloid lineage, for example acute and chronic myelogenous leukemias, myelodysplastic syndrome, or promyelocytic leukemia;

a tumour of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma; a tumour of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma;

melanoma; seminoma; teratocarcinoma; osteosarcoma; xenoderoma pigmentoum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.

In one embodiment, the treatment is treatment of solid tumour cancer.

In one embodiment, the treatment is treatment of haematological cancer.

In one embodiment, 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.

In one embodiment, the treatment is treatment of glioma.

In one embodiment, the cancer is characterised by, or further characterised by, cancer stem cells.

In one embodiment, the treatment comprises treatment of cancer stem cells.

In one embodiment, the cancer is MGMT- cancer.

In one embodiment, the cancer is MGMT+ cancer.

In one embodiment, the cancer is MMR proficient cancer.

In one embodiment, the cancer is MMR deficient cancer.

In one embodiment, the cancer is temozolomide resistant or temozolomide refractory.

In one embodiment, the cancer is inherently temozolomide resistant or inherently temozolomide refractory.

In one embodiment, the cancer is temozolomide resistant or temozolomide refractory following exposure to (e.g., treatment with) temozolomide.

The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of cell cycle progression, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death). The compounds of the present invention may be used in the treatment of the cancers described herein, independent of the mechanisms discussed herein.

Treatment

The term "treatment," as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviation of symptoms of the condition, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e., prophylaxis) is also included. For example, use with patients who have not yet developed the condition, but who are at risk of developing the condition, is encompassed by the term "treatment."

For example, treatment includes the prophylaxis of cancer, reducing the incidence of cancer, alleviating the symptoms of cancer, etc.

The term "therapeutically-effective amount," as used herein, pertains to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.

Combination Therapies

The term "treatment" includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously. For example, the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents, for example, cytotoxic agents, anticancer agents, molecularly- targeted agents, etc. Examples of treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy; photodynamic therapy; gene therapy; and controlled diets.

For example, it may be beneficial to combine treatment with a compound of the invention as described herein with one or more other (e.g., 1, 2, 3, 4) agents or therapies that regulates cell growth or survival or differentiation via a different mechanism, thus treating several

characteristic features of cancer development.

One aspect of the present invention pertains to a compound of the invention as described herein, in combination with one or more additional therapeutic agents, as described below.

In one embodiment, the compound of the invention may be in combination with one or more inhibitors of DNA repair processes, for example with a PARP inhibitor.

The particular combination would be at the discretion of the physician who would select dosages using his common general knowledge and dosing regimens known to a skilled practitioner.

The agents (i.e., the compound of the invention, described herein, plus one or more other agents) may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes. For example, when administered sequentially, the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1 , 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).

The agents (i.e., the compound of the invention described here, plus one or more other agents) may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.

Other Uses

The compounds of the invention described herein may also be used as cell culture additives to inhibit cell proliferation, etc.

The compounds of the invention described herein may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.

The compounds of the invention described herein may also be used as a standard, for example, in an assay, in order to identify other compounds, other anti-proliferative agents, other anti-cancer agents, etc.

Kits

One aspect of the invention pertains to a kit comprising (a) a compound of the invention as described herein, or a composition comprising a compound of the invention as described herein, e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.

The written instructions may also include a list of indications for which the active ingredient is a suitable treatment.

Routes of Administration

The compound of the invention or pharmaceutical composition comprising the compound of the invention may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).

Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal;

sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. The Subject/Patient

The subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a monotreme (e.g. a platypus), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.

Furthermore, the subject/patient may be any of its forms of development, for example, a foetus.

In one preferred embodiment, the subject/patient is a human.

Formulations

While it is possible for the compound of the invention to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one compound of the invention, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents. The formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.

Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one compound of the invention, as described herein, together with one or more other

pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.

The term "pharmaceutically acceptable," as used herein, pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences. 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5th edition, 2005.

The formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.

The formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof. Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.

Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir.

The compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients. The compound may be presented in a liposome or other microparticulate which is designed to target the compound, for example, to blood components or one or more organs.

Formulations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in- water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.

Formulations suitable for buccal administration include mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Losenges typically comprise the compound in a flavored basis, usually sucrose and acacia or tragacanth. Pastilles typically comprise the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically comprise the compound in a suitable liquid carrier.

Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills.

Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in- water, water-in-oil), mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.

Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in- water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.

Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.

Tablets may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate);

preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid);

flavours, flavour enhancing agents, and sweeteners. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the compound therein using, for example,

hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.

Ointments are typically prepared from the compound and a paraffinic or a water-miscible ointment base.

Creams are typically prepared from the compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxy! groups such as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.

Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax, and the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low. Thus the cream should preferably be a non-greasy, non-staining and washabie product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for intranasal administration, where the carrier is a liquid, include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the compound.

Formulations suitable for intranasal administration, where the carrier is a solid, include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.

Formulations suitable for pulmonary administration (e.g., by inhalation or insufflation therapy) include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.

Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.

Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the compound, such carriers as are known in the art to be appropriate.

Formulations suitable for parenteral administration (e.g., by injection), include aqueous or nonaqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate). Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection. Typically, the concentration of the compound in the liquid is from about 1 ng/ml to about 10 pg/ml, for example from about 10 ng/ml to about 1 g/ml. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

Dosage

It will be appreciated by one of skill in the art that appropriate dosages of the compounds of the invention , and compositions comprising the compounds of the invention , can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound of the invention, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects. Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.

In general, a suitable dose of the compound of the invention is in the range of about 10 g to about 250 mg (more typically about 100 ig to about 25 mg) per kilogram body weight of the subject per day. Where the compound is a salt, an ester, an amide, a prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.

EXAMPLES

The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.

Synthetic Examples

4(5)-Bromo-2-methyl-5(4)~nitro-1H-imidazole:

4-Bromo-2-methyl-1 H-imidazole (5 g, 31.1 mmol) was added in portions to a stirred solution of nitric acid (40 mL) and sulphuric acid (40 mL) at 5 °C. The reaction mixture was allowed to warm to room temperature and was then stirred at 90 °C for 1 hour. The reaction mixture was cooled to room temperature and then poured into ice. The resulting precipitate was filtered, washed successively with water and diethyl ether and air-dried to give 2.7 g of the title compound as a white solid. (42% yield)

5(4)-nitro-1 H-imidazole-4(5)-thiol, ammonia salt, 4(5)-(methylthio)-5(4)-nitro-1 H-imidazole, 4(5)-(methylsulfonyl)-5(4)-nitro-1 H-imidazole were prepared following the procedure reported in J.Am.Chem.Soc., 1957, 79, 2188.

2-methyl-5(4)-nitro-1 H-imidazole-4(5)-thiol, ammonia salt, 2-methyl-4(5)-(methylthio)-5(4)-nitro- 1 H-imidazole, 2-methyl-4(5)-(methylsulfonyl)-5(4)-nitro-1 H-imidazole were prepared from 4(5)- bromo-2-methyl-5(4)-nitro-1 H-imidazole following the procedure reported in JAm.Criem.Soc., 1957, 79, 2188.

Note 1 : For the synthesis of 5(4)-nitro- H-imidazole-4(5)-thiol, ammonia salt, it was found desirable to bubble H ₂ S (g) for 45 minutes instead of 5 minutes.

Note 2: It is not necessarily possible to know which tautomer has been made, especially under strong acidic or basic conditions. See earlier discussion. 5(4)-Nitro- 1 H-imidazole-4(5)-sulfonyl chloride:

(modification of the procedure reported in Can.J.Chem., 1961 , 39, 501)

Chlorine (g) (generated by the addition of concentrated HCI to solid KMnO„), was bubbled through a suspension of 5(4)-nitro-1H-imidazole-4(5)-thio!ate (4 g, 24.7 mmol) in 1 M HCI (100 mL) at 0 °C for 10 minutes. The mixture was stirred at 0 °C for 10-15 minutes, during which, most of the product went into solution. The suspension was filtered and the precipitate was washed successively with water and diethyl ether and then dried under suction. The precipitate, which formed during the concentration of the filtrate under suction after 30 minutes, was filtered, washed with diethyl ether and hexane and air-dried, to give 2.06 g of the title compound as a white solid. After concentration of the filtrate during the drying process, a second crop of the title compound was obtained, to give 1.37 g of the title compound as a white solid (66% combined yield). δ _Η (d ₆ -DMSO): 7.54 (1 H, s), 7.60 (1 H, broad singlet).

LCMS analysis of the product mixed with morpholine showed formation of 4-(5(4)-nitro-1 H- imidazol-4-ylsulfonyl)morpholine (m/z (ES+): 263 (MH ⁺ )), which confirmed the structure of the product.

2-Methyl-5(4)-nitro-1H-imidazole'4(5)-sulfonyl chloride:

Chlorine (g) (generated by the addition of concentrated HCI to solid KMn0 ₄ ), was bubbled through a suspension of 5-nitro-1 H-imidazole-4-thiolate (2.4 g, 13.6 mmol) in 1 M HCI (100 mL) at 0 °C for 15 minutes. The resulting yellow suspension was stirred at 0 °C for 30 minutes and was filtered. The solid was washed with diethyl ether, and the filtrate was concentrated under suction for 15 minutes. The aqueous layer was extracted with a diethyl ether: ethyl acetate mixture and the combined organic extracts were dried over MgS0 ₄ , and concentrated under vacuum to give 2.2 g of the title compound as a cream coloured solid. (72% yield) δ _Η (d ₆ -D SO): 13.9 (1H, s (br)), 2.25 (3H, s).

LCMS analysis of the product mixed with morpholine showed formation of 4-(5-nitro-1 H- imidazol-4(5)-ylsulfonyl)morpholine (m/z (ES+): 277 (MH ⁺ )), which confirmed the structure of the product. General procedure 1: Syntheses of 5(4)-amino-2-alkyl-1 H-imidazole-4(5)~sulfonamides:

Procedure 1A:

5(4)-Amino^-(4-methoxybenzyl)-1H-imidazole~4(5)-sulfonamide:

5(4)-Nitro-1H-imida2ole-4(5)-sulfonyl chloride (1.4 g, 6.63 mmol) was added in portions to a two-phase solution of 4-methoxybenzylamine (8.8 ml_, 67.3 mmol, 10 equ.) in water (35 mL) at 0 °C and the mixture was stirred at 0 C for 30 minutes. Concentrated HCI (~10mL) was added and the resulting suspension was filtered. The precipitate was washed successively with water and diethyl ether to give 1.55g of 5(4)-nitro-N-(4-methoxybenzyl)-1 H-imidazole-4(5)-sulfonamide hydrochloride as a white solid (67% yield).

A solution of 5(4)-nitro-N-(4-methoxybenzyl)-1 H-imidazole-4(5)-sulfonamide hydrochloride (550 mg, 1.58 mmol) and Ni (Raney) (50% wt in water, 110 μΙ_, 10% by wt.) in 1 M NaOH (1.58mL, 1.58mmol, 1 equ.) : MeOH (11 mL) was stirred under an hydrogen atmosphere overnight, after which, LCMS analysis of the reaction mixture showed completion of the reaction. The reaction mixture was filtered through Celite ® and the filtrate was concentrated to dryness under vacuum. The product was dissolved in DCM.MeOH, absorbed on silica and purified by flash chromatography (DCM:MeOH 97.5:2.5) to give 190 mg of the title compound as a red hygroscopic solid (43% yield). δ _Η (d ₆ -D SO): 11.5 (1 H, s (br)), 7.53 (1H, s (br)), 7.16-7.18 (2H, d, J=8.4; 1H, s (overlapped)), 6.83-6.85 (2H, d, J=8.4), 5.30 (2H, s (br)), 3.87-3.88 (2H, d, J=4.4), 3.72 (3H, s). m/z (ES+): 305.0 (M+Na ⁺ ), 283.1 (MH ⁺ ).

5(4)-Amino-N-methyl-1H-imidazole-4(5)-sulfonamide:

The title compound was obtained in 35% overall yield following procedure 1A using an aqueous solution of methylamine instead of 4-methoxybenzylamine.

δ _Η (d ₆ -DMSO): 11.50 (1 H, s), 7.15 (1 H, s), 6.87 (1H, d, J = 5.0), 5.28 (2H, s), 2.67 (3H, s).

Notel: 2 equivalents of 2M NaOH were used during the reduction of 5(4)-nitro-N-Methyl-1H- imidazole-4(5)-sulfonamide hydrochloride.

Note2: A gradient elution of DCM:MeOH 20:1 to 10:1 was used during the purification in this case. 4(5)-(Morpholinosulfonyl)-1H-imidazol-5(4)-amine:

The title compound was obtained in 42% yield as an orange crystalline solid following procedure 1A using morpholine instead of 4-methoxybenzylamine.

δ _Η (d ₆ -DMSO): 11.6 (1 H, s (br)), 7.19 (1 H, s), 5.45 (2H, s (br)), 3.59-3.64 (4H, m), 2.92-2.94 (4H, m).

Notel : DC :MeOH 90:10 was used as eluent during the purification in this case.

Note2: The title compound could also be synthesized in similar yields following procedure 1B.

5(4)'Amino-N, 2-dimethyl-1H-imidazole-4(5)-sulfonamide:

The title compound was obtained from methylamine and 2-methyl-5(4)-nitro-1H-imidazole-4(5)- sulfonyl chloride in 66% yield as a red/brown oil following procedure 1A.

Notel : In this case, the aqueous methylamine/ 2-methyl-5(4)-nitro-1 H-imidazole-4(5)-sulfonyl chloride reaction mixture was concentrated to dryness under vacuum to give crude N,2- dimethyl-5(4)-nitro-1 H-imidazole-4(5)-sulfonamide, which was used without further purification in the hydrogenation step.

Note2: A gradient elution of DCM:MeOH 10:1 - 10:2 was used during the purification in this case. The product was obtained as a mixture of tautomers as shown by NMR analysis. δ _Η (ds-D SO): 11.8 (0.3H, s (br)), 1.4 (0.7H, s (br)), 6.78 (1 H, s (br)), 5.18 (2H, s (br)), 4.12 (3H, d (br), J=3.7), 2.13 (3H, s).

Procedure 1B:

5(4)-Amino-N,N-dimethyl-1H-imidazole-4(5)-sulfonamide:

5(4)-Nitro-1 H-imidazole-4(5)-sulfonyl chloride (2.0 g, 9.45 mmol) was added in portions to an aqueous solution of dimethylamine (40% wt in water, 6 ml_, 47.3 mmol, 5 equ.) at 0 °C and the mixture was stirred at 0 °C for 40 minutes. Concentrated HCI was added to the yellow solution and the resulting suspension was filtered. The precipitate was washed successively with water and diethyl ether to give 2.14 g of 5-nitro-N,N-dimethyl-1 H-imidazole-4-sulfonamide

hydrochloride as a white solid. The product was suspended in MeCN.MeOH and triethylamine (1.3 mL, 9.33 mmol, 1.1 equ.) was added. The resulting yellow solution was stirred for 5-10 min. and was then absorbed on silica. The product was purified by flash chromatography

(DCM.MeOH 90:10) to give 1.78 g of 5(4)-nitro-N,N-dimethyl-1 H-imida2ole-4(5)-sulfonamide as a yellow solid.

A solution of 5(4)-nitro-N,N-dimethyl-1 H-imidazole-4(5)-sulfonamide (1.78 g, 8.08 mmol) and Ni (Raney) (50% wt in water, 360 μΙ_, 10% by wt.) in 1 NaOH (8mL, 8mmol, 1 equ.) : MeOH (40 mL) was stirred under an hydrogen atmosphere overnight. The reaction mixture was filtered through Celite ® and the filtrate was concentrated to dryness under vacuum. The product was dissolved in MeCN:MeOH, absorbed on silica and purified by flash chromatography

(DCM:MeOH 90: 10) to give 700mg of the title compound as a purple/red solid. (39% yield over two steps).

The product was obtained as mixture of tautomers as shown by NMR analysis. δ _Η (d ₆ -DMSO): 12.4 (0.1 H, s (br)), 11.6 (0.9H, s (br)), 7.16 (1 H, s), 5.37 (2H, s (br)), 2.60 (6H, s).

Procedure 1C: N-ethyl- 1 H-imidazole-4( 5)-sulfonamide:

5-nitro-1 H-imidazole-4-sulfonyl chloride (1g, 4.73 mmol) was added in portions to an aqueous solution of ethylamine (70% wt., 10mL) at 0 °C and the mixture was stirred at 0 °C for 30 minutes, then at room temperature for 3 days. The reaction mixture was concentrated to dryness under vacuum and the resulting yellow solid was suspended in water. Concentrated HCI (~2mL) was added at 0 °C and the resulting suspension was filtered. The precipitate was washed successively with acetonitrile and diethyl ether to give 800 mg of 5-nitro-A/-ethyl-1H- imidazole-4-sulfonamide hydrochloride as a white solid. (66% yield). δ _Η (d ₆ -DMSO): 14.3 ( H, s (br)), 8.21 -8.24 (1 H, t, J=5.7), 7.99 (1 H, s), 2.96-3.03 (2H, dq, J=7.2, J=5.7), 0.95-0.99 (3H, t,

J=7.2).

A solution of 5-nitro-N-ethyl-1 H-imidazole-4-sulfonamide hydrochloride (800 mg, 3.12 mmol) and Ni (Raney) (50% wt in water, 500 μΐ, 30% by wt.) in 1M NaOH (3.12 mL, 3.12 rnmc!, 1 equ.) : MeOH (16 mL) was stirred under an hydrogen atmosphere for 3 days, after which, LCMS analysis of the reaction mixture showed completion of the reaction. The reaction mixture was filtered through Celite ® and the filtrate was concentrated to dryness under vacuum. The product was dissolved in DCM:MeOH, absorbed on silica and purified by flash chromatography (gradient elution neat DCM - Acetone: DCM 1 : 1 - 3: 1) to give 205mg of the title compound as a light brown solid. (35% yield).

The product was used without further characterization in general procedure 3B 5(4)-amino-N-isopropyl-1H-imidazole-4(5)-sulfonamide:

The title compound was obtained in 16% overall yield following procedure 1C using

isopropylamine instead of ethylamine,

Note: δ _Η (d ₆ -DMSO) for 5-nitro-A/-isopropyl- H-imidazole-4-sulfonamide hydrochloride: 14.3 (1H, s (br)), 8.25-8.27 (1H, d, J=8.0), 7.98 (1H, s), 3.39-3.51 ( H, d-spt, J=8.0, 6.5), 1.00 (6H, d, J=6.5). -cyclopropyl- 1 H-imidazole~4(5)-sulfonamide:

The title compound was obtained in 16% overall yield following procedure 1C using

cyclopropylamine instead of ethylamine.

Note: δ _Η (d ₆ -DM$0) for 5-nitro-A/-cyclopropyl-1H-imidazole-4-sulfonamide hydrochloride: 14.4 (1 H, s (br)), 8.60-8.61 (1H, d, J=2.4), 8.02 (1 H, s), 2.32-2.38 (1H, m), 0.46-0.54 (3H, m), 0.39- 0.45 (3H, m).

General procedure 2: Synthesis of 5(4)-amino-1H-imidazole-4(5)-sulfones:

sulfonyl)-1H-imidazol-5(4)-amine:

4(5)-(Methylsulfonyl)-5(4)-nitro-1 H-imidazole (0.500 g, 2.62 mmol) was stirred in MeOH (25 ml) with 1M NaOH (2.62 ml, 2.62 mmol, 1 equ.) until fully dissolved. Pd/C (0. 5 g) was added and the solution was stirred under an hydrogen atmosphere for 4 days, after which, LCMS analysis of the reaction mixture showed completion of the reaction. The reaction mixture was filtered through Celite ® and the filtrate was concentrated under vacuum and adsorbed on silica. The product was purified by flash chromatography (gradient elution, DCM:MeOH 100% - 10:1) to give 86 mg of 4(5)-(methylsulfonyl)-1H-imidazol-5(4)-amine as a dark green (20 % yield). δ _Η (d ₆ -DMSO): 11.6 (1 H, s (br)), 7.18 (1H, s), 5.49 (2H, s (br)), 2.98 (3H, s). )-(methylsulfonyl)- 1 H-imidazol-5(4)-amine: The title compound was obtained from 2-methyl-4(5)-(methylsulfonyI)-5(4)-nitro-1 H-imidazole in 28% yield as a dark purple oil following general procedure 2. δ _Η (d ₆ -DMSO): 12.0 (0.25H, s (br)), 11.4 (0.75H, s (br)), 5.39 (1.5H, s (br)), 5.16 (0..5H, s (br)), 2.95 (3H, s), 2.12 (3H, s).

General procedure 3: Synthesis of 4-diazo-1H-imidazole-5-sulfo compounds Procedure 3A: (J.Med. Chem., 1987. 30. 357)

A solution of the appropriate 5(4)-amino-1 H-imidazole-4(5)-sulfo compound in 2 HCI was added dropwise at 0°C to an aqueous solution of sodium nitrite in the dark and the mixture was stirred for 30 min. at 0°C, then 20 min. at room temperature. The precipitate was filtered, washed successively with water and a small amount of diethyl ether and dried under suction. The product was dried in a dessicator overnight to give the required 4-diazo-1H-imidazole-5- sulfo compound as a yellow/orange solid.

If a precipitate did not form during the reaction, the reaction mixture was extracted three times with ethyl acetate and the combined organic extracts were dried over MgS0 ₄ and concentrated under vacuum to give the pure 5-diazo-1H-imidazole-4-sulfo compounds.

4-Diazo-N-(4-methoxybenzyl)-4H-imidazole-5-sulfonamide:

The title compound was prepared following procedure 3A in 86% yield δ _Η (d ₆ -DMSO): 8.72-8.75 (1 H, t, J=6.0), 7.70 ( H, s), 7.15-7.18 (2H, d, J=8.8), 6.84-6.88 (2H, d, J=8.8), 4.12-4.13 (2H, d, J=6.0), 3.72 (3H, s).

IR (vmax, cm ¹ ): 3047.6 (w (br)), 2837.4 (w (br)), 2193 (m), 2177.7 (m), 1608.7 (m), 1512.2 (S), 1425.4 (m (br)), 1336.8 (s (br)), 1253.8 (s), 1217.1 (s), 1157.3 (s), 1 138.0 (s), 1084.0 (m), 1068.6 (m), 1031.9 (m), 841.0 (s).

4-Diazo-N-methyl-4H-irnidazole-5-sulfonamide.

The title compound was prepared following procedure 3A in 74% yield δ _Η (d ₆ -DMSO): 8.09 (1 H, q, J = 4.8), 7.74 (1 H, s), 2.61 (3H, d, J = 4.8). 4-Diazo-N,N-dimethyl-4H-imidazole-5-sulfonamide.

The title compound was prepared following procedure 3A in 82% yield. δ _Η (de-D SO): 7.78 (1H, s), 2.82 (6H, s). 4-(4-Diazo-4H-imidazol-5-ylsulfonyl)morpholine.

The title compound was prepared following procedure 3A in 74% yield δ _Η (d ₆ -DMSO): 7.81 (1 H, s), 3.64-3.67 (4H, m), 3.15-3.16 (4H, m). Procedure 3B:

4-Diazo-N,2-dimethyl-4H-imidazole-5-sulfonamide, 4-diazo-5-(methylsulfonyl)-4H-imidazole, 4- diazo-2-methyl-5-(methylsulfonyl)-4H-imidazole 4-diazo-N-ethyl-4H-imidazole-5-sulfonamide, 4- diazo-N-isopropyl-4H-imidazole-5-sulfonamide and N-cyclopropyl-4-diazo-4H-imidazole-5- sulfonamide were obtained following procedure 3A and were used crude in the next step without further characterization.

4-Diazo-N,2-dimethyl-4H-imidazole-5-sulfonamide

4~Diazo-5-(methylsulfonyl)~4H-imidazole.

4-Diazo-2- ethyl-5~(methylsulfonyl)-4H-imidazole.

4-diazo-N-ethyl-4H-imidazole-5-sulfonamide:

4-diazo-N-isopropyl-4H-imidazole-5-sulfonamide:

N-cyclopropyl-4-diazo-4H-imidazole-5-sulfonamide:

Genera! procedure 4: Syntheses of 3-substitued-4-oxo-3,4-dihydroimidazo[5, 1- dlf1,2, 3, 5]tetrazine-8-sulfo compounds.

Procedure 4 A:

A solution (or suspension) of the appropriate 4-diazo-4H-imidazole-5-sulfo compound and the appropriate isocyanate (8 equ.) in dry ethyl acetate (2 mL/100 mg) was stirred under nitrogen in the dark overnight. A diethyl ether:hexane (~10:1) mixture was added and the resulting suspension was filtered. The product was washed with a small amount of diethyl ether and dried under suction to give the pure 4-oxo-3,4-dihydroimida2o[5,1-d][1 ,2,3,5]tetrazine-8-sulfo compound in 26-100% yield.

Notel : Pure products were isolated by filtering the reaction mixture or after purification by flash chromatography in yields ranging from 21-46% when methyl isocyanate (20equ.) was used.

Note2: When specified, e.g. in the case of /N/-methyl-3-substituted-4-oxo-3,4-dihydroimidazo[5,1- dJ[1,2,3,5]tetrazine-8-sulfonamides, pure 3-substituted-4-oxo-3,4-dihydroimidazo[5,1- d][1 ,2,3,5]tetrazine-8-sulfo compounds were obtained by a) concentration of the reaction mixture to a small volume and trituration of the residue with methanol or b) purification by flash chromatography using the appropriate gradient of solvents.

Procedure 4B:

The appropriate isocyanate (1.2-3 equ.) was added dropwise to a solution of the appropriate 4- diazo-4H-imidazole-5-sulfo compound in dry DMSO (1 mL/100 mg) in the dark and the mixture was stirred under nitrogen overnight. The reaction was monitored by LCMS and a further 2 to 3 equivalents of isocyanate were added if required. The reaction mixture was poured into ice and the precipitate was washed successively with water and small amount of diethyl ether. The product was dissolved in MeCN:MeOH, absorbed on silica and purified by flash chromatography (DCM:MeCN 90:10 or 80:10) to give the pure 4-oxo-3,4-dihydroimidazo[5,1- d][1 ,2,3,5]tetrazine-8-sulfo compound in 6-63% yield.

Procedure 4C:

A solution of the appropriate 4-diazo-4H-imidazole-5-sulfonamide (or 5-sulfone) synthesized from procedure 3B and the appropriate isocyanate (1.2 equ.) in dry ethyl acetate (2 mL/100 mg) was stirred under nitrogen in the dark overnight. The reaction mixture was monitored by LCMS analysis and 1.2 equivalents of the appropriate isocyanate were added if necessary. The mixture was stirred for a further 24 hours and was then absorbed on silica. The product was purified by flash chromatography (gradient elution DCM:MeCN 100% - 0:1) to give the pure 8- sulfo-imidazo-4-one or the pure 4-oxo-3,4-dihydroimidazo[5,1-d][1 ,2,3,5]tetrazine-8-sulfo compound in 4-21% yield over 2 steps.

Syntheses of isocvanates:

1. (Methylthio)methylisocyanate

(Methylthio)methylisocyanate was prepared following the procedure described in WO 96/27588 and was used crude.

2. lsocyanato(methoxy)methane

lsocyanato(methoxy)methane was prepared from chloromethyl methyl ether and silver cyanate according to the method of Jones and Powers. (Jones L.W., Powers D.H., J.Am.Chem.Soc, 1924, 46, 2518).

3. Trifluoroethyl isocyanate and methyl isocyanate:

Trifluoroethyl isocyanate and methyl isocyanate were prepared following the procedure described in J. Chem.Soc, Perkin Trans.1 , 1998, 1669.

Note: Methyl amine was used instead of [ ² H ₃ ]-methylamine hydrochloride.

4. Propargyl isocyanate:

Triphosgene (17.16 g, 57.8 mmol, 0.33 equ.) was added to a two phase solution of propargyl amine (12 mL, 1 5 mmol) in saturated NaHC0 ₃ /DCM (300 mL/300 ml.) at 0 °C and the mixture was vigorously stirred at 0°C for 20 minutes and was then transferred to a separating funnel. The layers were separated and the aqueous layer was extracted several times with DCM. The combined organic layers were dried over MgS0 ₄ and the solution of isocyanate was

concentrated by distillation under atmospheric pressure until the volume of the solution reached 30-40 mL. The solution was then transferred to a smaller flask and a distillation column was fitted. The mixture was concentrated and the temperature of the oil bath was increased. The fraction boiling between 60 and >800°C was collected to give 4.31g of propargyl isocyanate as a colourless liquid. NMR analysis of the product showed that it contained 25% wt. DCM.

δ _Η (d ₆ -DMSO): 4.02 (2H, d, J = 2.5), 2.43 (1 H, t, J = 2.5).

Alternatively, propargyl isocyanate could be obtained by cracking 1 , 1-Diphenyl-3-(prop-2- ynyl)urea:

(i) To a solution of diphenylcarbamoyl chloride ( 05.48 g; 468 mmol) in tetrahydrofuran (1.5 L) in a 5 L 3-necked flask fitted with an overhead stirrer was added DIPEA (81.6 mL; 468 mmol), followed by propargylamine (26.316 g; 477.6 mmol). The solution was refluxed for 2.5 h, then allowed to cool, and stand at room temperature overnight, during which time crystals of diisopropylethylamine hydrochloride formed. The reaction mixture was concentrated, and water (~ 1 L) added to the residue. The dark brown solid was filtered, and washed with ethyl acetate, then with toluene to give a pale brown powder. The filtrate was separated, and the aqueous layer extracted (*3) with ethyl acetate. The combined organic extracts were concentrated under vacuum, and the product was filtered from the remaining toluene and washed with toluene. The combined pale brown solids were dried overnight at 40 °C under vacuum to give 103.51 g of 1 ,1 -Diphenyl-3-(prop-2-ynyl)urea (88 % yield).

δ _Η (d ₆ -DMSO): 7.41-7.36 (4H, m), 7.33-7.23 (6H, m), 4.73 (1 H, bs), 4.09 (2H, dd, J = 5.4, 2.5), 2.21 (2H, t, J = 2.5).

(ii) 1 ,1-Diphenyl-3-(prop-2-ynyl)urea (10 g; 40 mmol) was heated in a 50 mL flask fitted with microdistillation apparatus using a heating mantle, until it cracked. The propargyl isocyanate formed was distilled (b.p. 95 °C) as a colourless liquid.

5. (lsocyanatomethyl)(2, 2, 2-trifluoroethyl)sulfane:

A solution of 2,2,2-trifluoroethanethiol (10 g, 86.1 mmol, 1.2 equ.) in DMF (36 mL) under nitrogen was cooled to 0 °C in an ice bath, and sodium hydride (60% in mineral oil, 3.01 g, 75.4 mmol, 1.05 equ.) was added in several portions over a 12 minutes period. After stirring 15 minutes vigorously, methyl bromoacetate (6.79 mL, 7 .8 mmol) was added to the reaction mixture dropwise over 4 minutes. The reaction mixture was allowed to warm slowly to room temperature and was stirred overnight. Cold water was added and the product was extracted several times with diethyl ether. The combined organic extracts were washed with water (3 x 50mL), dried over MgS0 ₄ , filtered and concentrated at atmospheric pressure. The resulting crude oil was purified by distillation under reduced pressure and the fractions boiling between 80°C and 120 ^e C were collected to give 12.3 g of methyl 2-(2,2,2-trifluoroethylthio)acetate as a very pale yellow oil (91 % yield). δ _Η (d ₆ -D SO). 3.77 (3H, s), 3.38 (2H, s), 3.23-3.31 (2H, q, J=9.8).

A solution of methyl 2-(2,2,2-trifluoroethylthio)acetate (8.8g, 46.8mmol) and hydrazine hydrate (2.73mL, 56.1 mmol, 1.2 equ.) in EtOH (60 mL) was refluxed for 2 hours. The mixture was cooled to room temperature and concentrated under vacuum to give 2-(2,2,2- trifluoroethylthio)acetohydrazide. The hydrazide was then diluted with CHCI ₃ (95 mL) and HCI (1 M, 95 mL) and then vigorously stirred at 0 °C. An aqueous solution (10mL) of sodium nitrite (3.87 g, 56.1 mmol, 1.2 equ.) was added dropwise to the reaction mixture. After 10 minutes, the organic layer was separated, and the aqueous layer extracted with cold CHCI ₃ (3 x 50mL). The combined organics were dried at 0°C over MgS0 ₄ , filtered and then a condenser was fitted to the flask. The solution was heated slowly to 50°C, at which temperature, nitrogen gas evolution was observed. This temperature was maintained for 30 minutes and the reaction mixture was then heated slowly to reflux over a 30 minutes period. The mixture was refluxed for a further 30 minutes and was then concentrated by distillation under reduce pressure to give 6.0 g of the title compound as a pale yellow oil. The product was obtained as a 1.0.2 mixture with chloroform, as determined by N R analysis (64% yield).

δ _Η (de-DMSO): 4.62 (2H, s), 3.70-3.79 (2H, q, J=10.8).

6. (lsocyanatomethyl)(methoxymethyl)sulfane:

Sodium hydride (60% in mineral oil, 182 mg, 4.56 mmol, 1 equ.) was added in portions to a solution of ethyl mercaptoacetate (500μί, 4.56 mmol) in DMF (20mL) at 0 °C and the mixture was stirred for 2 minutes before the dropwise addition of chloromethyl methyl ether (364 μί, 4.79 mmol, 1.05 equ.) at 0 °C. The reaction mixture was stirred for 3 days and was then diluted with cold water. The product was extracted with ethyl acetate and the combined organic extracts were washed with water (3x20mL), dried over gS0 ₄ and concentrated under vacuum. The product was purified by short flash chromatography (Hexane:EtOAc 80:20) to give 625mg of ethyl 2-(methoxymethylthio)acetate as a pale yellow oil (83% yield).

δ _Η (CDCIs): 4.73 (2H, s), 4.18-4.23 (2H, q, J=8.0), 3.38 (3H, s), 3.31 (2H, s), 1.28-1.32 (3H, t,

J=8.0)

Note: Alternatively, the product could be obtained by the dropwise addition of chloromethyl methyl ether (2.29 mL, 30 mmol, 1.1 equ.) to a solution of ethyl mercaptoacetate (3 mL, 27.4 mmol) and N,N-diisopropylethylamine (5.22 mL, 30 mmol, 1.1 equ.) in DCM (150 mL) at 0 °C. The mixture was stirred overnight and 1 M HCI was added. The product was extracted with DCM and the combined organic extracts were washed with water, dried over MgS0 ₄ and concentrated under vacuum. The product was purified by short flash chromatography

(Hexane:EtOAc 80:20) to give 3.61 g of ethyl 2-(methoxymethylthio)acetate as a pale yellow oil (83% yield).

A solution of ethyl 2-(methoxymethylthio)acetate (300 mg, 1.83 mmol) and hydrazine hydrate ( 06 μί, 2.19 mmol, 1.2 equ.) in ethanol (2 mL) was refluxed for 2 hours. The mixture was allowed to cool to room temperature and was then concentrated under vacuum to give 2- (methoxymethylthio)acetohydrazide. An aqueous solution (1 mL) of NaN0 ₂ (151 mg, 2.19 mmol, 1.2 equ.) was added dropwise at 0°C to a two phase solution of the crude hydrazide in 1 M HCI:CHCI ₃ (3 mL:3 mL) and the resulting mixture was vigorously stirred for 10 minutes. The organic layer was separated and the aqueous layer was extracted with CHCI ₃ . The combined organic extracts were dried over MgS0 ₄ at 0 °C. The solution of 2-(methoxymethylthio)acetyl azide in CHCI ₃ was heated slowly until nitrogen (g) evolution was observed, which occurred at 45 °C. The temperature was maintained at 48 °C for 45 minutes and was then increased slowly to reflux. The mixture was refluxed for 45 minutes and was then allowed to cool to room temperature. The mixture was concentrated under vacuum to 185mg of the title compound as a yellow oil. (76% yield).

δ _Η (DMSO-cf ₆ ): 4.86 (2H, s), 4.53 (2H, s), 3.29 (3H, s).

I (vmax, cm ^"1 ): 2272.2 (m), 2237.5 (s), 1276.9 (m (br)), 1182.4 (m), 1080.2 (s), 904.6 (m), 850.6 (s).

7. 1-isocyanatobut-2-yne:

But-2-yn-1 -amine was prepared by modification of a procedure reported in J. Chem. Soc. Perkin Trans. //, 1987, 1077.

Bromo-2-butyne (5 g, 37.6 mmol) was added dropwise to a suspension of potassium

phthalimide (8.89 g, 48.9 mmol, 1.3 equ.) in DMSO and the mixture was stirred for 3 days. The reaction mixture was diluted with water and the product was extracted with chloroform. The combined organic extracts were washed successively with 0.5% NaOH and water, dried over MgS0 , then concentrated under vacuum.

Hydrazine hydrate (3 mL, 51.4 mmol, 1.4 equ.) was added to a suspension of the resulting off- white solid in EtOH (150 mL) and the mixture was stirred overnight. 1mL (17.3 mmol, 0.47 equ.) of hydrazine hydrate was added and the reaction mixture was stirred for 4 hours, after which LCMS analysis showed completion of the reaction. The resulting suspension was diluted with water and the pH of the aqueous layer was adjusted to 3.5 by addition of concentrated HCI. The resulting suspension was filtered and the filtrate was concentrated to dryness under vacuum. Water was added to the resulting solid and the solution was basified with 10 NaOH (20mL). The product was extracted with DCM and the combined organic extracts were dried over MgS0 ₄ . The solution was concentrated by distillation at atmospheric pressure and But-2-yn-1- amine was purified by distillation, (b.p.: 114°C) (863 mg, 33% yield).

δ _Η (CDCI ₃ ): 3.37-3.39 (2H, q, J=2.5), 1.80-1.82 (3H, t, J=2.5), 1.33 (2H, s (br)). Triphosgene (1.23 g, 4.13 mmol, 0.33 equ.) was added in portions to a two-phase solution of but-2-yn-1 -amine (863 mg, 12.5 mmol) in 1 :1 DCM:sat. NaHC0 ₃ (40 mL) at 0°C and the mixture was stirred at 0 ^C C for 20 min., then transferred into a separating funnel. The layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were dried over MgS0 ₄ and the resulting solution was concentrated by distillation at atmospheric pressure. The title compound was purified by distillation (b.p. 80°C)

δ _Η (d ₆ -DMSO): 4.16-4.88 (2H, q, J=2.4), 1.82-1 .84 (3H, t, J=2.4).

8. 1, 1, 1-trifluoro-2-(isocyanatomethoxy)ethane:

Sodium hydride (60% in mineral oil, 5.04 g, 126 mmol, 1.2 equ.) was added in portions to a solution of trifluoroethanol (9.06 mL, 126 mmol, 1.2.equ.) in DMF (20mL) at 0°C and the mixture was stirred for 15 minutes before the dropwise addition of methyl bromoacetate (10 ml_,105 mmol) at 0°C. The reaction mixture was stirred overnight and was diluted with cold water. The product was extracted with Et ₂ 0 and the combined organic extracts were washed twice with water, dried over MgS0 ₄ and concentrated under vacuum. The product was purified by distillation under reduced pressure to give 8.3 g of methyl 2-(2,2,2-trifluoroethoxy)acetate as a colourless oil. (46% yield).

5 _H (CDCI ₃ ): 4.32 (2H, s), 4.12-4.19 (2H, q, J=9.3), 3.67 (3H, s).

A solution of methyl 2-(2,2,2-trifluoroethoxy)acetate (3.68g, 21..4 mmol) and hydrazine hydrate (1.46 mL, 30.0 mmol, 1.4 equ.) in ethanol (22 mL) was refluxed for 2.5 hours. The mixture was allowed to cool to room temperature and was then concentrated under vacuum to give 2-(2,2,2- trifluoroethoxy)acetohydrazide. An aqueous solution (10 mL) of NaN0 ₂ (2.07 g, 30.0 mmol, 1.4 equ.) was added dropwise at 0°C to a two phase solution of the crude hydrazide in 1 :1 1 M HCI:CHCI ₃ (55 mL) and the resulting mixture was vigorously stirred for 10 minutes. The organic layer was separated and the aqueous layer was extracted with CHCI ₃ . The combined organic extracts were dried over MgS0 ₄ at 0°C. The solution of 2-(methoxymethylthio)acetyl azide in CHCI ₃ was heated slowly until nitrogen (g) evolution was observed, which occurred at 30°C. The temperature was maintained at 45°C for 50 minutes and was then increased slowly to reflux. The mixture was refluxed for 30 minutes and was then allowed to cool to room temperature. The mixture was concentrated under vacuum to give 1 .29 g of the title compound as a yellow oil. (39% yield).

δ _Η (d ₆ -DMSO): 5.02 (2H, s), 4.19-4.26 (2H, q, J=9.3).

General procedure 5: Deorotection of N-(4-methoxybenzyl)-3-substituted-4-oxo-3,4- dihvdroimidazof5, 1-dlf1,2,3,5ltetrazine-8-suifonamides

N-(4-methoxybenzyl)-3-substituted-4-oxo-3,4-dihydroimidaz o[5,1 -d][1 ,2,3,5]tetrazine-8- sulfonamides were deprotected following the procedure reported in J.Med.Chem., 1987, 30, 357.

General procedure 6; Oxidation of 3-(methylthiomethyl)-4-oxo-3A-dihydroimidazof5, 1- d][1 , 2, 3, 51tetrazine-8-sulfonamides

Ozone was bubbled through a solution of the appropriate 3-(methylthiomethyl)-4-oxo-3,4- dihydroimidazo[5,1 -d][1 ,2,3,5]tetrazine-8-sulfo compound in DCMiMeOH at -78 °C for 12 minutes, after which TLC analysis of the reaction mixture showed completion of the reaction. Nitrogen was bubbled through the resulting white suspension for 10 minutes and the mixture was concentrated to a small volume under vacuum. Diethyl ether, followed by a small amount of hexane were added and the precipitate was filtered, washed with diethyl ether and dried under suction to give the required 3-(methylsulfinylmethyl)-4-oxo-3,4-dihydroimidazo[5,1-d] [1 ,2,3,5]tetrazine-8-sulfo compound in 60 to 87% yield.

Note: the reaction was carried out at room temperature if the 3-(methylthiomethyl)-4-oxo-3,4- dihydroimidazo[5,1-d][1 ,2,3,5]tetrazine-8-sulfo compound was not soluble in DCM. eOH at -78 °C.

N-(4-Methoxybenzyl)-3-(methoxymethyl)-4-oxo-3, 4-dihydroimidazo[5, 1 -d][1, 2, 3, 5]tetrazine-8- sulfonamide (1).

Prepared following procedure 4A in 94% yield.

δ _Η (DMSO-de): 8.95 (1H, s), 8.70-8.73 (1H, t (br), J=5.4), 7.14-7.16 (2H, d, J=8.7), 6.80-6.82 (2H, d, J=8.7), 5.63 (2H, s), 4.10-4.12 (2H, d, J=5.4), 3.71 (3H, s), 3.44 (3H, s). m/z (ES+): 403 (M+Na+ ).

Note: the product could also be prepared following procedure 4B in 21% yield.

N-(4-Met oxybenzyl)-3-(methylthiomethyl)-4-oxo-3, 4-dihydroimidazo[5, 1-d][ 1, 2, 3, 5]tetrazine-8- sulfonamide (2).

Prepared following procedure 4A in 80% yield.

δ _Η (DMSO-de): 8.92 (1H, s), 8.70-8.73 (1 H, t (br), J=5.8), 7.13-7.16 (2H, d, J=8.7), 6.79-6.81 (2H, d, J=8.7), 5.45 (2H, s), 4.10-4.11 (2H, d, J=5.8), 3.71 (3H, s), 2.28 (3H, s) m/z (ES+): 419 (!vHNa+ ).

Note: the product could also be prepared following procedure 4B in 18% yield. N-(4-Met oxybenzyl)-4-oxo-3-(prop-2-ynyl)-3, 4-dihydroimidazo[5, 1-d][1, 2, 3, 5]tetrazine-8- sulfonamide (3).

Prepared following procedure 4B in 63% yield.

δ _Η (DMSO-de): 8.92 (1 H, s), 8.67-8.69 (1 H, t, J=6.0), 7.13-7.16 (2H, d, J=8.8), 6.79-6.81 (2H, d, J=8.8), 5.16-5.17 (2H, d, J=2.4), 4.09-4.10 (2H, d, J=6.0), 3.71 (3H, s), 3.57-3.58 (1 H, t, J=2.4). m/z (ES+): 397 (M+Na+ ).

4-Oxo-3-(prop-2-ynyl)-3, 4-dihydroimidazo[5, 1-d][1, 2, 3, 5]tetrazine-8-sulfonamide (4).

Prepared following the general procedure 5 from N-(4-methoxybenzyl)-4-oxo-3-(prop-2-ynyl)- 3,4-dihydroimidazo[5,1-d][1 ,2,3,5]tetrazine-8-sulfonamide in 64% yield.

<5 _H (DMSO-d ₆ ): 8.94 (1 H, s), 7.95 (2H, s), 5.14-5.15 (2H, d, J=2.5), 3.54-3.56 (1 H, t, J=2.5).

3-fMefr)y/fr)/ornefrjy/j-4-oxo-3, 4-dihydroimidazo[5, 1-d][ 1, 2, 3, 5]tetrazine-8-sulfonamide (5).

Prepared following the general procedure 5 from N-(4-methoxybenzyl)-3-(methylthiomethyl)-4- oxo-3,4-dihydroimidazo[5,1-d][1 ,2,3,5]tetrazine-8-sulfonamide in 34% yield.

<5 _H (DMSO-ci ₆ ): 8.93 (1 H, s), 7.95 (2H, s), 5.44 (2H, s), 2.26 (3H, s).

3-(Methylsulfinylmethyl)-4-oxo-3, 4-dihydroimidazo[5, 1 -d][ 1,2,3, 5]tetrazine-8-sulfonamide (6).

Prepared following general procedure 6 from 3-(methylthiomethyl)-4-oxo-3,4- dihydroimidazo[5,1 -d][1 ,2,3,5]tetrazine-8-sulfonamide in 61% yield.

<5 _H (DMSO-cfe): 8.99 (1 H, s), 8.00 (2H, s), 5.60-5.63 (1 H, d, J=13.2), 5.46-5.49 (1H, d, J=13.2), 2.77 (3H, s). N-Methyl-3-(methylthiomethyl)-4-oxo-3, 4-dihydroimidazo[5, 1-d][1, 2, 3, 5]tetrazine-8-sulfonamide (7).

Prepared following procedure 4A in 27% yield. The product was purified by flash

chromatography (gradient elution DCM.MeOH 98% -95%) in this case.

δ _Η (D SO-cf ₆ ): 8.95 (1 H, s), 8.03 (1 H, q, J=4.8), 5.44 (2H, s), 2.59 (3H, d, J= 4.8), 2.26 (3H, s). m/z (ES+): 313 ( +Na+).

3-(Methoxymethyl)-N-methyl-4-oxo-3, 4-dihydroimidazo[5, 1-d][ 1, 2, 3, 5Jtetrazine-8-sulfonamide (8).

Prepared following procedure 4A in 26% yield. The product was purified by flash

chromatography (gradient elution DCM:MeOH 98% -95%) in this case.

δ _Η (DMSO-de): 8.98 (1 H, s), 8.05 (1 H, q, J=4..8), 5.62 (2H, s), 3.42 (3H, s), 2.59 (3H, d, J=4.8). m/z (ES ⁺ ): 297 (M+Na) ⁺

3-(Methoxymethyl)-4-oxo-3, 4-dihydroimidazo[5, 1-d][1, 2, 3, 5]tetrazine-8-sulfonamide (9).

Prepared following the general procedure 5 from N-(4-methoxybenzyl)-3-(methoxymethyl)-4- oxo-S^-dihydroimidazofS.I -djil ^.S.Sjtetrazine-S-sulfonamide in 43% yield.

<5 _H (DMSO-de): 8.94 (1 H, s), 7.95 (2H, s), 5.62 (2H, s), 3.42 (3H, s).

N,N-Dimethyl-3-(methylthiomethyl)-4-oxo-3,4-dihydroim^

sulfonamide (13).

Prepared following procedure 4A in 76% yield.

δ _Η (D SO-c ₆ ): 9.00 (1 H, s), 5.46 (2H, s), 2.80 (6H, s), 2.27 (3H, s). m/z (ES+): 327 (M+Na+ ), 305 (MH+).

N, N-Dimethyl-3-(methylsulfinylmethyl)-4-oxo-3, 4-dihydroimidazo[5, 1-d][1, 2, 3, 5]tetrazine-8- sulfonami e ( 14).

Prepared following the general procedure 6 from N,N-dimethyl-3-(methylthiomethyl)-4-oxo-3,4- dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-sulfonamide in 87% yield.

<5 _H (DMSO-cfe): 9.06 (1 H, s), 5.62-5.65 (1 H, d, J=13.2), 5.50-5.53 (1H, d, J=13.2), 2.81 (6H, s), 2.79 (3H, s).

N-(4-Methoxybenzyl)~3-methyl-4-oxo-3, 4-dihydroimidazo[5, 1 -d][1, 2, 3, 5]tetrazine-8-sulfonamide (10).

Prepared following procedure 4A in 26% yield. The product was purified by flash

chromatography (DCM:MeCN 80:20) in this case.

δ» (DMSO-cfe): 8.69 (1H, s), 8.64-8.67 ( H, t, J=6.4), 7.12-7.15 (2H, d, J=8.7), 6.80-6.82 (2H, d, J=8.7), 4.09-4.10 (2H, d, J=6.4), 3.89 (3H, s), 3.71 (3H, s).

N-(4-Methoxybenzy/)-4-oxo-3-(2, 2, 2-trifluoroet yl)-3, 4-di ydroimidazo[5, 1-d][1, 2, 3, 5)tetrazine-8- sulfonamide (11).

Prepared following procedure 4A in 26% yield.

δ» (DMSO-de): 8.99 (1 H, s), 8.73-8.76 (1 H, t, J=6.2), 7.14-7.16 (2H, d, J=8.7), 6.79-6.82 (2H, d, J=8.7), 5.25-5.32 (2H, q, J=9.2), 4.10-4.12 (2H, d, J=6.2), 3.71 (3H, s).

m/z (ES ⁺ ): 441 (M+Na ⁺ ).

N, N-Dimethyl-4-oxo-3-(2, 2, 2-trifluoroethyl)-3, 4-dihydroimidazo[5, 1-d][1, 2, 3, 5]tetrazine-8- sulfonamide (12).

Prepared following procedure 4A in 82% yield.

<5 _H (DMSO-cfe): 9.06 (1 H, s), 5.27-5.34 (2H, q, J=8.8), 2.81 (6H, s).

m/z (ES ⁺ ): 349 (M+Na ⁺ ), 327. (MhT).

3-(Methylthiomethyl)-8-(morpholinosulfonyl)imidazo[5, 1-d][ 1, 2, 3, 5]tetrazin-4(3H)-one (16). Prepared following procedure 4A in 79% yield.

«5Ή (DMSO-cfe): 9.01 (1 H, s), 5.47 (2H, s), 3.65-3.67 (4H, m), 3.11 -3.13 (4H, m), 2.27 (3H, s). m/z (ES ⁺ ): 369 (M+Na ⁺ ), 347 <MH ⁺ ).

3-((Methoxymethylthio)methyl)-8-(morpholino$ulfonyl)imida zo[5, 1 ~d][1, 2, 3, 5]tetrazin-4(3H)-one (17).

Prepared following procedure 4A in 89% yield.

όΉ (DMSO-cfe): 9.03 (1 H, s), 5.51 (2H, s), 5.82 (2H, s), 3.64-3.67 (4H, m), 3.29 (3H, s), 3.10-3.12 (4H, m). 3-(Methylsulfinylmethyl)-8-(morpholinosulfonyl)imidazo[5, 1-dJ[1, 2, 3, 5]tetrazin-4(3H)-one (19).

Prepared following general procedure 6 from 3-((methoxymethylthio)methyl)-6- (morpholinosulfonyl)imidazo[5,1 -d][1 ,2,3,5]tetra2in-4(3H)-one in 87% yield.

<5 _H (DMSO-£/ ₆ ): 9.06 (1 H, s), 5.62-5.65 (2H, d, J=13.2), 5.49-5.53 (2H, d, J=13.2), 3.65-3.67 (4H, m), 3.11-3.13 (4H, m), 2.79 (3H, s).

N-Methyl-4-oxo-3-(prop-2-ynyl)-3, 4-dihydroimidazo[5, 1 -d][ 1,2,3, 5]tetrazine-8-sulfonamide (15). Prepared following procedure 4A in 44% yield.

<5 _H (DMSO-d ₆ ): 8.96 (1 H, s), 8.02 (1 H, q, J=4.8), 5.15 (2H, d, J=2.5), 3.55 (1 H, t, J=2.5 Hz), 2.57 (3H, d, J=4.8).

m/z (ES ⁺ ): 291 (M+Na ⁺ ).

3-((Methoxymethylt io)met yl)-N, N-dimethyl-4-oxo~3, 4-dihydroimidazo[5, 1 -d][1, 2, 3, 5]tetrazine- 8-sulfonamide (18).

Prepared following procedure 4A in 73% yield.

δ _Η (DMSO-c/e): 9.01 (1H, s), 5.51 (2H, s), 4.82 (2H, s), 3.28 (3H, s), 2.79 (6H, s). 8-(Morp olinosulfonyl)-3-(2, 2, 2-trifluoroethyl)imidazo[5, 1-d][ 1,2,3, 5]tetrazin-4(3H)-one (20). Prepared following procedure 4 A in 00% yield.

δ~ _Η (DMSO-d ₆ ): 9.07 (1 H, s), 5.27-5.34 (2H, q, J=8.8), 3.64-3.67 (4H, m), 3.10-3.12 (4H, m). m/z (ES ⁺ ): 391 (M+Na ⁺ ).

3-((Methoxymethylthio)methyl)-N-methyl-4-oxo-3, 4-dihydroimidazo[5, 1-d][1, 2, 3, 5]tetrazine-8- sulfonamide (21).

Prepared following procedure 4A in 32% yield. In this case, the reaction mixture was concentrated to a small volume and the residue was triturated with methanol to give the pure title compound.

<5 _H (D SO-d ₆ ); 8.98 (1 H, s), 8.06 (1 H, q, J=4.8), 5.48 (2H, s), 4.80 (2H, s), 3.26 (3H, s), 2.57 (3H, d, J=4.8).

m/z (ES ⁺ ): 343 (M+Na ⁺ ), 321 ( H ⁺ ).

8-(Morpholinosulfonyl)-3^rop-2-ynyl)imidazo[5, 1-d][1,2,3,^ (22). Prepared following procedure 4A in 86% yield.

O ^~ H (DMSO- / ₆ ): 9.01 (1 H, s), 5.17-5.18 (2H, d, J=2.5), 3.63-3.65 (4H, m), 3.56-3.57 (1 H, t, J=2.5), 3.08-3.10 (4H, m).

m/z (ES ⁺ ): 347 (M+Na ⁺ ).

N,N-Dimethyl-4-oxo-3-(prop-2-ynyl)-3,4-dihydroimidazo[5, 1-d][

(23).

Prepared following procedure 4A in 83% yield.

δ ^" _Η (DMSO-C ₆ ): 8.99 (1 H, s), 5.17 (2H, d, J=2.5), 3.55-3.57 (1 H, t, J=2.5), 2.78 (6H, s).

m/z (ES ⁺ ): 305 (M+Na ⁺ ).

N-Methyl-4-oxo-3-(2, 2, 2-trifluoroethyl)-3, 4-dihydroimidazo[5, 1-d][1, 2, 3, 5]tetrazine-8-sulfonamide (24).

Prepared following procedure 4A in 26% yield.

<5H (D SO-d ₆ ): 9.01 (1 H, s), 8.08 (1 H, q, J=4.9), 5.27 (2H, q, J=8.9), 2.59 (3H, d, J=4.9).

m/z (ES ⁺ ): 335 ( +Na ⁺ ), 313 (MH ⁺ ).

N-Methyl-3-(methylsulfinylmethyl)~4-oxo-3, 4-dihydroimidazo[5, 1-d][ 1, 2, 3, 5}tetrazine-8- sulfonamide (25).

Prepared following the general procedure 6 from N-methyl-3-(methylthiomethyl)-4-oxo-3,4- dihydroimidazo[5,1-d][1 ,2,3,5]tetrazine-8-sulfonamide in 47% yield.

o ^~ _H (DMSO-d ₆ ): 9.01 (1 H, s), 8.08 (1 H, q, J=4.8), 5.61 (1 H, d, J=13.2), 5.47 (1H, d, J=13.2), 2.77 (3H, s), 2.60 (3H, d, J=4.8).

8-(Methylsulfonyl)-3-(prop-2-ynyl)imidazo[5, 1-d][1,2, 3, 5]tetrazin-4(3H)-one (31). Prepared following procedure 4C in 21 % yield over two steps.

δ _Η (DMSO-de): 9.04 (1 H, s), 5.19 (2H, d, J=2.5), 3.57 (1 H, t, J= 2.5), 3.37 (3H, s). e-(Methylsulfonyl)-3~(2, 2, 2-trifluoroethyl)imidazo[5, 1-d][1, 2, 3, 5]tetrazin-4(3H)-one (30). Prepared following procedure 4C in 8% yield over two steps.

δ _Η (DMSO-d ₆ ): 9.10 (1 H, s), 5.36 (2H, q, J=8.9), 3.39 (3H, s).

N, 6-Dimethyl-4-oxo-3-(2, 2, 2-trifluoroethyl)-3, 4-dihydroimidazo[5, 1-d][1, 2, 3, 5]tetrazine~8- sulfonamide (33).

Prepared following procedure 4C in 10% yield over two steps.

6Ή (DMSO-de): 8.03 (1 H, q, J= 4.8), 5.22 (2H, q, J=8.9), 2.81 (3H, s), 2.59 (3H, d, J=4.8).

N, 6-Djmethyl-3-(methylthiomethyl)-4-oxc 3 -dihydroimidazo

sulfonamide (34).

Prepared following procedure 4C in 13% yield over two steps.

6 (DMSO-d ₆ ): 7.97 (1 H, q, J= 4.9), 5.37 (2H, s), 2.81 (3H, s), (3H, d, J=4.9).

3-Met yl-8-(morp olinosulfonyl)imidazo[5, 1-dJ[1, 2, 3, 5]tetrazin-4(3H)~one (27).

Prepared following procedure 4A in 35% yield. The product was isolated pure by filtering the reaction mixture in this case.

<5H (DMSO-d ₆ ): 8.98 (1H, s), 3.90 (3H, s), 3.63-3.65 (m, 4H), 3.08-3.10 (m, 4H).

m/z (ES ⁺ ): 323 (M+Na ⁺ ), 301 (MH ⁺ ). N,6-Dimethyl-3-(methylsulfinylmethyl)-4-oxo-3,4-dihydrom^

sulfonamide (32).

Prepared following the general procedure 5 from N,6-dimethyl-3-(methylthiomethyl)-4-oxo-3,4' dihydroimidazo[5,1 -d][1 ,2,3,5]tetrazine-8-sulfonamide in 50% yield.

<5 _H (DMSO-de): 8.03 (1 H, s), 5.52-5.55 (1 H, d, J=13.2), 5.39-5.42 (1 H, s, J=13.2), 2.81 (3H, s), 2.77 (3H, s), 2.59 (3H, s).

N-Methyl-4-oxo-3-((2, 2, 2~trifluoroethylthio)methyl)-3, 4-dihydroimidazo[5, 1-d][1, 2, 3, 5]tetrazine-8- sulfonamide (28).

Prepared following procedure 4A in 81 % yield.

In this case, hexane was added to the reaction mixture and the resulting suspension was filtered. The solid was collected and purified by flash chromatography (DCM:MeOH 40:1 ). The pure title compound was then obtained by precipitation in a DCM:Et ₂ 0 mixture.

0 ^* H (DMSO-de): 8.98 (1H, s), 8.03 (1 H (br)), 5.59 (2H, s), 3.69 (2H, q, J=11), 2.60 (3H, s).

m/z (ES ⁺ ): 381 (M+Na ⁺ ), 359 ( H ⁺ ).

6-Methyl-8-(methylsulfonyl)-3-(prop-2-ynyl)imidazo[5, 1-d][1,2, 3, 5]tetrazin-4(3H)-one (29). Prepared following procedure 4C in 4% yield over two steps.

<5 _H (DMSO-de): 5.12 (2H, d, J=2.5), 3.55-3.56 (1 H, t, J=2.5), 3.35 (3H, s), 2.82 (3H, s).

m/z (ES ⁺ ): 268 (MH ⁺ ).

N, N, 3-trimethyl-4-oxo-3, 4-dihydroimidazo[5, 1 -d][ 1,2,3, 5]tetrazine-8-sulfonamide (26).

Prepared following procedure 4A in 46% yield. The product was isolated pure by filtering the reaction mixture in this case.

δ _Η (DMSO-cf ₆ ): 8.97 (1 H, s), 3.90 (3H, s), 2.78 (6H, s).

m/z (ES ⁺ ): 281 ( +Na ⁺ ), 259 (MH ⁺ ).

3-(but-2-ynyl)-N-methyl-4-oxo-3,4-dihydroimidazo (35)

Prepared following procedure 4A in 43% yield (note: 10equ. of 1 -isocyanatobut-2-yne were used in this case). The product was purified by flash chromatography (DCM.MeCN 20:1 then re- purified with gradient elution DC :MeCN 30:1 - 20:1) in this case.

δ _Η (de-DMSO): 8.93 (1H, s), 8.01 (1 H, s), 5.08-5.10 (2H, q, J=2.4), 3.32 (3H, s), 1.83-1.84 (3H, t, J=2.4)

3-(but-2-ynyl)-N, 6-dimethyl-4-oxo-3, 4-dihydroimidazo[5, 1-d][1,2, 3, 5]tetrazine-8-sulfonamide (36)

Prepared following procedure 4A in 35% yield, (note: 4equ. of 1 -isocyanatobut-2-yne were used in this case, the reaction mixture was stirred for 5 days). In this case, the product was purified by flash chromatography (gradient elution DCM:MeCN 40:1 -20:1 then re-purified with gradient

80:1 - 60: 1 - 40:1 - 20:1).

δ _Η (d ₆ -D SO): 7.94 (1 H, s (br)), 5.01-5.03 (2H, q, J=2.4), 2.79 (3H, s), 2.56 (3H, s), 1.82-1.84 (3H, t, J=2.4).

N, 6-dimethyl-4-oxo~3-(prop-2-ynyl)~3, 4-dihydroimidazo[5, 1 -d][ 1,2,3, 5]tetrazine-8-sulfonamide (37)

Prepared following procedure 4A in 46% yield (note: 3.8equ. of propargyl isocyanate were used in this case). The product was purified by flash chromatography (gradient elution DCM:MeCN urified with gradient elution DCM.MeCN 80:1 - 60: 1 - 40: 1) in this case.

δ _Η (d ₆ -DMSO): 7.94-7.97 (1 H, q, J=4.9), 5.07-5.08 (2H, d, J=2.5), 3.51-3.53 (1 H, t, J=2.5), 2.80 (3H, s), 2.55-2.57 (3H, 2, J=4.9). 3-(but-2-ynyJ)-8-(methylsulfonyl)imidazo[5, 1-d][1, 2, 3, 5]tetrazin-4(3H)-one (38):

Prepared following procedure 4A in 31% yield (note: 4equ. of -isocyanatobut-2-yne were used in this case, the reaction mixture was stirred for 4 days).The product was purified by flash chromatography (gradient elution DCM. eCN 40:1 -20:1) in this case.

δ _Η (d ₆ -DMSO): 9.01 (1 H, s), 5.12-5.14 (2H, t, J=2.4), 3.36 (3H, s), 1.83-1.84 (3H, d, J=2.4).

N-ethyl-4-oxo-3-(prop-2-ynyl)-3,4-dihydroimidazo[5, 1~d][1, 2,3,5 (39):

Prepared following procedure 4A in 70% yield. In this case, the reaction mixture was absorbed on silica and the product was purified by flash chromatography (gradient elution DCM:MeCN 40:1 -20:1).

δ _Η (d ₆ -DMSO): 8.94 (1H, s), 8.14 (1H, s (br)), 5.14-5.15 (2H, d, J=2.5), 3.54-3.55 (1 H, t, J=2.5), 2.96-3.01 (2H, q, J=7.2), 1.01-1.05 (3H, t, J=7.2).

N-isopropyl-4-oxo-3-(prop-2-ynyl)-3, 4-dihydroimidazo[5, 1-d][1, 2, 3, 5]tetrazine-8-sulfonamide

(40) :

Prepared following procedure 4A in 69% yield. In this case, the reaction mixture was absorbed on silica and the product was purified by flash chromatography (gradient elution DCM.MeCN

δ _Η (d ₆ -DMSO): 8.93 (1H, s), 8.15 (1H, s (br)), 5.14 (2H, d, J=2.5), 3.54-3.55 (1 H, t, J=2.5), 3.48- 3.50 (1 H, m), 1.03-1.05 (6H, d, J=6.6)

N-cyclopropyl-4-oxo-3-(prop-2-ynyl)-3, 4-dihydroimidazo[5, 1 -dj[ 1,2,3, 5Jtetrazine-8sulfonamide

(41) :

Prepared following procedure 4A in 44% yield. The product was purified by flash

chromatography (gradient elution DCM:MeCN 40:1 -20:1) in this case.

δ _Η (d ₆ -DMSO): 8.96 (1H, s), 8.52 (1H, s (br)), 5.15-5.17 (2H, d, J=2.5), 3.54-3.55 (1 H, t, J=2.5), 2,35-2.40 (1H, m), 0.47-0.50 (4H, m).

8-(morpholinosulfonyl)-3-(prop-2-ynyl)imidazo[5, 1-d][1,^ (42):

Prepared following procedure 4A in 15% yield. In this case, the product was purified by flash chromatography (gradient elution DCM: eCN 40:1 -20:1 then re-purified by flash

chromatography gradient elution DCM:THF 60:1 - 50:1 followed by trituration in Et ₂ 0).

δ _Η (d _s -DMSO): 9.01 (1H, s), 5.18-5.19 (2H, d, J=2.5), 3.64-3.67 (4H, m), 3.56-3.58 (1H, t, J=2.5), 3.09-3.12 (4H, m),

(R)-8-(morpholinosulfonyl)-3-(1^henylethyl)imidazo[5, 1-d][1,2,3, 5]tetrazin-4(3H)-one (43):

Prepared following procedure 4A in 25% yield. In this case, the reaction mixture was absorbed on silica and the product was purified by flash chromatography (gradient elution DCM. eCN 40:1 -20:1).

O δ _Η (CDCI ₃ ): 8.41 (1H, s), 7.51-7.54 (2H, m), 7.32-7.40 (3H, m), 6.16-6.21 (1H, q, J=7.2), 3.76- 3.78 (4H, m), 3.34-3.36 (4H, m), 2.04-2.05 (3H, d, J=7.2).

(R)-N-methyl-4-oxo-3-(1^henylethyi)-3 -di ydroimidazo[5, 1-d][1 _^

(44):

Prepared following procedure 4A in 34% yield, (note: the reaction mixture was stirred for 4 days). In this case, the reaction mixture was absorbed on silica and the product was purified by flash chromatography (gradient elution DCM:MeCN 100:1 - 40:1 -20:1).

δ _Η (d ₆ -DMSO): 8.89 (1H, s), 7.96-7.99 (1H, q, J=4.8), 7.47-7.50 (2H, m), 7.30-7.40 (3H, m), 6.09-6.14 (1 H, q, J=7.0), 2.57-2.58 (3H, d, J=4.8), 1.88-1.90 (3H, d, J=7.0)

N-methyl-4-oxo-3-((2, 2, 2-trifluoroethoxy)methyl)-3, 4-dihydroimidazo[5, 1-d][1, 2, 3, 5}tetrazine-8- sulfonamide (45):

Prepared following procedure 4A in 15% yield (note: the reaction mixture was stirred for 2 purified by flash chromatography (gradient elution DCM:MeCN 100:1 ^■

δ _Η (de-D SO): 9.02 (1H, s), 8.07-8. 1 (1H, q, J=4.8), 5.84 (2H, s), 4.28-4.35 (2H, q, J=9.2), 2.59-2.61 (3H, d, J=4.9).

3-(But-2-ynyl)-6-methyl-8-(methylsulfonyl)imidazo[5, 1-d][1, 2, 3, 5]tetrazin-4(3H)-one (46)

Prepared following procedure 4A in 9% yield (4.5 equ. of 1-isocyanatobut-2-yne were used in this case). In this case, the product was purified by flash chromatography (gradient elution DC :MeCN 5

δ _Η (d ₆ -DMSO): 5.04-5.06 (2H, q, J=2.4), 3.37 (3H, s), 2.81 (3H, s), 1.83-1.84 (3H, d, J=2.4).

General Procedure 7: Alternative synthesis via 4-oxo-3,4-dihydroimidazo[5, 1-d]

f 2,3, 51tetrazine-8-su!fo intermediates

5-Nitro-1 H-imidazole-4-sulfonyl chloride was prepared as already described above (modification of the procedure reported in Can.J.Chem., 1961 , 39, 501 ). This was converted to 5-amino- N,N- dimethyl-1 H-imidazole-4-sulfonamide by Procedure 1 B as set out above, of by the alternative procedure set out below:

5-Amino-N, N-dimethyl-1H-imidazole-4-sulfonamide (alternative synthesis):

5-nitro-1 H-imidazole-4-sulfonyl chloride (1.0 g, 4.73 mmol) was added in portions to a 26%wt. aqueous solution of dimethylamine (26mL,15.1 mmol, 3.2 equ.) at 0°C and the mixture was stirred at 0 °C for 1 h. Concentrated HCI (~2mL) was added and the resulting suspension was filtered. The precipitate was washed successively with water, acetonitrile and diethyl ether to give 1.0g of 5-nitro-N,N-dimethyl-1 H-imidazole-4-sulfonamide hydrochloride as a white solid. (82% yield).

A solution of 5-5-nitro-/V,A/-dimethyl-1 H-imidazole-4-sulfonamide hydrochloride (1.0 g, 4.55 mmol) and Ni (Raney) (50% wt in water, 600 μΐ, 30% by wt.) in 1 M NaOH (6.82 mL, 6.82 mmol, 1.5 equ.) : MeOH (20 mL) was stirred under an hydrogen atmosphere overnight, after which, LCMS analysis of the reaction mixture showed completion of the reaction. The reaction mixture was filtered through Ceiite ® and the filtrate was concentrated to dryness under vacuum. The product was dissolved in DCM:MeOH, absorbed on silica and purified by flash chromatography (DCM then DCM.acetone 1 :1) to give 150mg of the title compound as a red hygroscopic solid. (19% yield).

4-diazo-N,N-dimethyl-4H-imidazole-5-sulfonamide: A solution of 5-amino-N,N-dimethyl-1 H-irnida2ole-4-sulfonamide (150 mg, 0.789) in 2M HCI (734μί) was added dropwise at 0°C to an aqueous solution of sodium nitrite (86 mg, 1.25 mmol, 1 .6 equ. in 1.5 mL water) in the dark and the resulting precipitate was filtered, washed with water followed by hexane. The product was dried under suction to give 65 mg (41% yield) of the title compound as a pale brown solid.

δ _Η (de-DMSO): 7.78 (1 H, s), 2.82 (6H, s).

Ted-butyl (8-(N, N-dimethylsulfamoyl)-4-oxoimidazo[5, 1-d][1, 2, 3, 5]tetrazin-3(4H)-yl)

methylcarbamate:

A solution of tert-butyl isocyanatomethylcarbamate in toluene (23% wt., 3.49 g, 2.59 mmol, 8 equ.) was added to a suspension of 4-diazo-N,N-dimethyl-4H-imidazole-5-sulfonamide (65 mg, 0.323 mmol) in dry ethyl acetate (1 mL) and the resulting suspension was stirred under nitrogen in the dark overnight. A diethyl ether.hexane (-12:1) mixture was added and the resulting suspension was filtered. LCMS and NMR analyses showed that the precipitate was tert-butyl carbonylbis(azanediyl) bis(methylene)dicarbamate, product formed by decomposition of the isocyanate. The filtrate was concentrated under vacuum and the resulting solid was triturated with acetonitrile. The precipitate, which corresponded to the by-product formed by

decomposition of the isocyanate (LCMS analysis), was filtered. The filtrate was absorbed on silica and the product was purified by flash chromatography (gradient elution DCM:MeCN 20:1 to 10:1 ) to give 16 mg ( 3% yield) of the title compound as a white solid.

δ _Η (DMSO-ds): 8.97 (1 H, s), 8.10 (1 H, s (br)), 5.52-5.50 (2H, d, J=6.5), 2.78 (6H, s), 1.39 (9H, s) m/z (ES ⁺ ): 769 (2M+Na ⁺ ).

N, N-di ethyl-4-oxo~3, -dihydroimidazo[5, 1-d][1, 2, 3, 5]tetrazine-8-sulfonamide:

A solution of tert-butyl (8-(N,N-dimethylsulfamoyl)-4-oxoimidazo[5,1 -d][1 ,2,3,5]tetrazin-3(4H)- yl)methylcarbamate in 3N HCI was stirred at room temperature for h., after which LCMS analysis showed completion of the reaction. The reaction mixture was concentrated to dryness under vacuum and the resulting solid was triturated with Et ₂ 0. The precipitate was filtered and dried in a vacuum oven overnight to give mg (quantitative) of the title compound as a white solid.

δ _Η (DMSO-de): 15.25 (1 H, s (br)), 8.91 (1 H, s), 2.77 (6H, s); m/z (ES+): 267 (M+Na+).

Note: NMR analysis showed that the product contained 23% wt. ammonium chloride. The product was used without further purification in the next step. N, N, 3-trimethyl-4-oxo-3, 4-dihydroimidazo[5, 1-d][1, 2, 3, 5]tetrazine-8-sulfonamide (26):

Sodium hydride (60% in mineral oil, 5 mg, 0.123 mmol, 3 equ.) was added to a solution of Λ/,Λ/- dimethyl-4-oxo-3,4-dihydroimidazo[5, 1-d][1 ,2,3,5]tetrazine-8-sulfonamide (77% wt„ 10 mg, 0.041 mmol) in dry DMF (200 pL) at 0°C and the mixture was stirred for 30min. at 0°C before the addition of methyl iodide (25pL, 0.41 mmol, 10 equ.). The mixture was stirred at room temperature for 1 h. and was then kept at -18°C overnight. The reaction mixture was concentrated to dryness under vacuum and the resulting solid was absorbed on silica. The product was purified by flash chromatography (gradient elution neat DCM then DCM:MeCN 40: 1 , 20:1 , 10:1 ) to give 0.9 mg (9% yield) of the title compound as a white solid.

δ _Η (DMSO-d ₆ ): 8.46 ( H, s), 4.06 (3H, s), 2.99 (6H, s);

m/z (ES ⁺ ): 259 (MH ⁺ ), 281 ( +Na ⁺ ), 539 (2M+Na ⁺ ).

The product was spiked with a sample of V,A/,3-trimethyl-4-oxo-3,4-dihydroimidazo[5,1- d][1 ,2,3,5]tetrazine-8-sulfonamide synthesized from the reaction of 4-diazo-N,N-dimethyl-4H- imidazole-5-sulfonamide with methyl isocyanate, which showed that the NMR spectra were identical.

Biological Methods

General Cell Culture Methods

The cell culture techniques were carried out in a Class II microbiological safety cabinet which was swabbed with 70% IMS in distilled water before each use. Glioma cells were routinely cultured in Costar tissue culture flasks in RPMI 1640 liquid medium (containing 0.3 g/L

L-glutamine and 2 g/L sodium bicarbonate) supplemented with 10% heat inactivated FBS (55- 59°C) for 1 hour to denature complement proteins which would otherwise evoke a cellular immune response resulting in cell lysis, 1 % non-essential amino acids, 50 pg/mL gentamicin and 400 pg/mL G418 (vector selection reagent).

Ce!!s were grown at 37°C in a humidified incubator in an atmosphere comprising 95% air / 5% C0 ₂ . Cells were sub-cultured when growth exceeded approximately 80% confluence, normally twice weekly. The medium was aspirated from the flask and approximately 0.8 mL trypsin- EDTA 1 x solution added. The cells were re-incubated at 37°C until they had visibly detached from the flask. The cells were re-suspended in 5 mL medium and 0.5 - mL was transferred to a new flask (25 cm ² ) with 7 mL culture medium. The cells were further incubated at 37°C. To minimize phenotypic drift, cells were disposed of once they had been subcultured 30 times. New batches of cells were thawed rapidly in 37°C water bath once taken from liquid nitrogen storage and re-suspended in 10 mL of culture medium in a 25 cm ² flask. Cells were passaged twice to allow normal growth to resume prior to use in experiments.

For cryopreservation, viable cells at 60-80% confluence were detached by minimum amount of trypsin/EDTA and re-suspended in sterile filtered freezing medium (95% FBS, 5% DMSO), transferred to sterile cryogenic vials, and frozen overnight at -20°C followed by -80°C for 1-2 days and stored in liquid nitrogen for long term storage. Drug Solutions

Most test compounds, including temozolomide, were prepared as 100 mM stock solutions in DMSO and used immediately after dissolution.

MTT Assay for 7-Day Toxicity Assay

This assay was first described in Mosmann, T., 1983, "Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays", Journal of

Immunological Methods, Vol. 65, Nos. 1-2, pp. 55-63.

Glioma cell lines, SNB19 and U373, stably transfected with MGMT (i.e. SNB19M and U373M) or its respective vector control (i.e. SNB19V and U373V) were used at 60-80% confluence, during the logarithmic phase of growth.

Following harvesting with trypsin/EDTA, cells in suspension were gently syringed through a 23 gauge needle to obtain a near-single cell suspension. Cells were then seeded into 96-well plates at the desired density in 180 μί culture medium if only one test compound was to be added, or in 160 μί. if two test compounds were to be added in combination. Cells were allowed to attach overnight by incubation at 37°C in 95% air/5% C0 ₂ . For the 7 day assay, the cell seeding density for SNB19V, SNB19M U373V, and U373M was 650 cells/well.

The two peripheral lanes of each plate were used as blank wells (cell free) and filled with 200 pL of medium in order to minimise medium evaporation from the plate. A separate time zero (T ₀ ) plate was set up alongside other plates. Serial dilutions in tissue culture medium of a 100 mM stock of test compound were prepared immediately before each assay to ten times the final concentrations required. 20 μΙ_ was added to each well (200 μΙ_ total media per well) to achieve final concentrations of 0.5 μΜ, 1 μΜ, 5 μΜ, 10 μΜ, 50 μΜ, 100 μΜ, 500 μΜ, and 1000 μΜ. A minimum of four wells received the same test compound concentration. To control wells, including those in the T ₀ plate, 20 μΙ_ of medium was added. Previous assays had been carried out to verify that cell viability was not affected by the amount of DMSO added into the test compound-treated wells. A separate plate treated in the same way, but free of test compound, was used as a measure of cell viability at the time of drug addition (T ₀ ).

After incubation at 37°C, 95% air/5% C0 ₂ for 7 days (or immediately for the day 0 plate), cell viability was quantified using the MTT assay. 50 μί of sterile filtered MTT (3-(4,5- dimethylthiazoi-2-yl)-2,5-diphenyltetrazolium bromide) (2 mg/mL in phosphate buffered saline) were added to each well (final concentration 0.4 mg/mL) and the plates were re-incubated for 4 hours to allow metabolic conversion of MTT by dehydrogenases in viable cells to insoluble formazan crystals. The medium and any unconverted MTT was aspirated, 150 μΙ. of DMSO was added to each well, and the plates were shaken on a plate shaker (Grant-Bio plate shaker PMS 1000) to ensure complete formazan solubilization. Absorbance was then read at 550 nm on an Labtech LT-4000 plate reader and with a Manta (Dazdaq Solutions Ltd.) data analysis software , where the absorbance readings (corrected for background absorbance) were recorded.

The absorbance at 550 nm is directly proportional to viable cell number. A linear relationship exists between cell number and the amount of formazan so the mean absorbance determined for all wells of the same concentration can be used as a quantitative measure of viable cells compared to the controls. A graph of absorbance against drug concentration was plotted and the test compound concentration causing 50% inhibition (Gl _so ) of control cell growth

(absorbance increase from T ₀ ) was calculated by interpolation.

Biological Data

As shown in the following table (representing more than 80 replicates), the parent compound, Temozolomide (TMZ), is demonstrably more active in the glioma lines which are MGMT- (SNB 19V) than those which express MGMT (MGMT+ lines SNB 19M).

As shown in table 2, almost all compounds of the invention tested have a SNB19V Gl ₅₀ of less than 65 μΜ, and many have a SNB19V Gl ₅₀ of less than 45 μΜ.

For example, each of the following compounds has a SNB19V Gl ₅₀ of less than 45 μΜ:

Compound Nos 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 17, 18, 21 , 22, 23, 25, 26, 27, 28, 29, 31 , 32, 43, 44, 45.

Additionally, whereas TMZ has a SNB19M G\ ₅₀ of 526.3 μΜ, most compounds of the invention which were tested have a SNB19M Gl ₅₀ of less than 100 μΜ, and many have a SNB19M Gl ₅₀ of less than 50μΜ.

For example, each of the following compounds has a SNB19M Gl ₅₀ of less than 50 μΜ:

Compound Nos 1 , 2, 3, 4, 5, 6, 7, 8, 9, 14, 15, 17, 18, 19, 21 , 22, 23, 25, 28, 29, 31 , 32, 43, 44, 45.

SNB 19V Gl ₅₀ and SNB19M Gl ₅₀ values for exemplary compounds of the present invention are shown in the table below:

SNB19V SNB19

Compound No.

GIso (μ ) GIso (μΜ)

1 36* 41.7*

2 29.6* 50*

3 25.8* 28.4*

4 20.8* 22.2*

S 44.8* 48.5*

6 17.3* 19.6*

7 25.4* 22.4*

8 38.0* 38.9*

9 34.4* 41.3*

10 32.1 222

11 255 229

12 84.3 97.7

13 78.8 87.8

14 12.9* 19.0*

15 21.0* 21.4*

16 59.6* 60.3* SNB19V SNB19M

Compound No.

GIso (μΜ) GIso (μ )

17 38.6* 43.8*

18 46.3* 46.3*

19 10.7* 12.8*

20 88.3 76.9

21 20.8* 28.4*

22 24.1* 24.3*

23 29.5* 24.1*

24 219.3 214*

25 21.1* 22.2*

26 28.5* 219*

27 34.3* 332*

28 16.6* 17.3*

29 25.3* 26.8*

30 364* 339*

31 30.4* 25.7*

32 23.6* 25.7*

33 155* 96.8*

34 76.5* 66.2*

43 24.8* 33.2*

44 23.4* 32.4

45 34.7* 33.9

* mean values from multiple screening

All of these compounds have a SNB19M activity that is better than that of TMZ (526.3 μΜ). The majority of these compounds additionally have a SNB 9V activity that is similar to or better than that of TMZ (45.6 μΜ).

These results were echoed in similar studies in the U373 cell line.

Data for a few particular compounds are summarised in the following table:

Table 2

Gl ₅₀ Values ^*

U373V U373M

GIso (MM) Gl ₅₀ (μ )

TMZ 72.9 394.8

42 31.6 29.2

46 30.7 28.8

* mean values from multiple screening

As shown by the data discussed above, and unlike TMZ, these compounds have good activity against tumour cell lines regardless of the MGMT and MMR (Mis-Match Repair) status of the cell line. Several of the compounds of the invention have also been tested and found to be active in other cell lines. In addition, compounds of the invention possess improved PK and solubility properties compared to TMZ and other analogues.

The foregoing described the principles, preferred embodiments, and modes of operation of the present invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be regarded as illustrative rather than restrictive, and it should be appreciated that variations may be made in those embodiments by workers skilled in the art without departing from the scope of the present invention.