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WO2007135350A1 - Benzotriazepinone derivatives - Google Patents

Benzotriazepinone derivatives Download PDF

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Publication number
WO2007135350A1
WO2007135350A1 PCT/GB2006/004512 GB2006004512W WO2007135350A1 WO 2007135350 A1 WO2007135350 A1 WO 2007135350A1 GB 2006004512 W GB2006004512 W GB 2006004512W WO 2007135350 A1 WO2007135350 A1 WO 2007135350A1
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Prior art keywords
alkyl
aryl
aralkyl
alkaryl
groups
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PCT/GB2006/004512
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French (fr)
Inventor
Iain Mair Mcdonald
John Spencer
Ildiko Maria Buck
David John Dunstone
Ian Duncan Linney
Patrizia Tisselli
Robert Anthony David Hull
Carol Austin
Elaine Anne Harper
David Sykes
Eric Griffin
Mark Shaxted
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James Black Foundation Ltd
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James Black Foundation Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
    • C07D255/04—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A61P5/20—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of PTH

Definitions

  • the present invention is concerned with benzotriazepinone derivatives, their intermediates, uses thereof and processes for their production.
  • the present invention relates to parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrp) receptor ligands, (PTH-I or PTH/PTHrp receptor ligands).
  • PTH parathyroid hormone
  • PTHrp parathyroid hormone related protein
  • the invention also relates to methods of preparing such ligands and to compounds which are useful as intermediates in such methods.
  • PTH is an 84 amino acid peptide circulating hormone produced by the parathyroid glands.
  • the primary function of PTH is to maintain a constant concentration of calcium in the extracellular fluid. It does so by acting directly or indirectly on various peripheral target tissues to mobilise calcium entry into the blood. Ia turn, PTH synthesis and release are controlled principally by the level of serum calcium. When the concentration of calcium is low, PTH secretion increases but is decreased when the calcium concentration is high. PTH enhances the distal tubular reabsorption of calcium in the kidney (Marcus, R. in The Pharmacological Basis of Therapeutics, 9 th Ed. (1996), ppl525-1529, Hardman, J. G.; Goodman Gilman, A. and Limbard, L. E. Ed.
  • osteoblasts Once located at the bone surface these cells are transformed into multinucleated osteoblasts that cause bone lysis by secretion of acid and enzymes thereby generating resorption pits in the bone. Bone remodeling is completed by ingress of preosteoblasts into theses cavities which on progression into osteoblasts deposit bone matrix constituents such as collagen and osteocalcin, amongst other proteins.
  • PTHrp Parathyroid hormone related peptide
  • PTHrp shares some of the actions of PTH (Clemens, T. L. et al, Br. J. Pharmacol, (2001), 134, 1113-1116).
  • PTHrp is found in three forms of 173, 141 and 139 amino acids and shares significant N-terminal amino acid sequence homology with PTH, particularly within the first 13 residues.
  • PTHrp is not normally present in the circulation but is thought to act as a paracrine or autocrine factor.
  • PTHrp regulates chondrocyte growth, differentiation in the growth plates of developing long bones, and branching morphogenesis of the mammary gland.
  • tumour cell types including those responsible for prostate, breast, lung, ovarian, bladder and squamous carcinomas and in Leydig tumour cells and other cancers of the kidney.
  • PTH-I receptors PTH-I or PTH/PTHrp receptors, hereinafter termed PTH-I receptors, are located predominantly in the kidney and on bone osteoblasts and are responsible for the effects of PTH on calcium homeostasis (Gardella, T. J. and Juppner, H. Trends in Endocrinology and Metabolism, (2001), 12(5), 210-217).
  • PTHrp is a selective stimulant of PTH-I receptors.
  • PTH-2 receptors are predominantly located in the brain suggesting a distinct physiological role to PTH-I receptors.
  • TIP39 tuberoinfundibular peptide
  • ligands Compounds which interact with PTH-I receptors are important because of their potential pharmaceutical use as antagonists, partial inverse agonists, inverse agonists, agonists or partial agonists of the endogenous peptides PTH or PTHrp. Such compounds are described herein as ligands. Thus, the term ligand, as used herein, can mean that the compound is an antagonist, partial inverse agonist, inverse agonist, agonist or partial agonist.
  • Disruption of calcium homeostasis may produce clinical impairment of bone such as osteoporosis, as well as other clinical disorders including, anaemia, renal impairment, ulcers, myopathy and neuropathy.
  • Hypercalcemia is a condition characterised by elevation of serum calcium and is often associated with primary hyperparathyroidism in which an excess of PTH production occurs.
  • PTHrp-producing squamous, renal, breast, ovarian or bladder carcinomas Both forms of hypercalcemia may be expected to benefit from a PTH-I receptor antagonist.
  • Cell lines originating from tumours in kidney, breast, prostate, lung and from osteosarcomas have been shown to be capable of growing in response to either PTH or PTHrp.
  • a PTH-I antagonist may have a role in the treatment or prevention of primary tumours, most especially osteosarcoma, clear cell renal carcinoma, and prostate, breast, gastric, ovarian, and bladder cancers, tissue from each of which has been shown to contain both PTH-I receptors and to secrete PTHrp.
  • cancers of the lung, prostate and breast have a propensity for metastasis to bone, a process underpinned by PTH and PTHrp (Guise, T. A. et al, J. Clin. Invest, (1996), 98(7), 1544-1549).
  • PTH-I receptors are present on bone osteoblasts and control the activation of osteoclasts. Osteoclasts act on bone, providing sites for bone metastases to form and resulting in number of factors to b,e released, including PTHrp, which act to stimulate growth of both the primary tumour and of the bone metastases. These actions release more PTHrp leading to a vicious cycle of tumour growth.
  • PTH-I antagonists may be expected to help treat or prevent bone metastases resulting from these primary cancers.
  • these compounds might be expected to alleviate the clinical sequelae, such as fracture, severe bone pain, spinal cord compression and hypercalcaemia often associated with bone metastases.
  • PTHrp is also considered to contribute to cachexia, the condition of malnutrition, muscle wasting and net protein loss often associated with cancer patients.
  • PTH-I receptor antagonists may be expected to help prevent this condition, hi addition elevated PTH and/or
  • PTHrp levels have been associated with lack of hair eruption in transgenic mice, in congestive heart failure and in a number of inflammatory and auotoknmune diseases such as rheumatoid arthritis. These findings suggest a possible role may exist for PTH-I receptor antagonists in helping to treat or prevent these and other conditions either associated with elevated levels of
  • PTH or PTHrp or with over-activation of PTH-I receptors.
  • PTH has an anabolic action on osteoblasts therefore indicating a potential benefit for a PTH-I receptor ligand (such as an agonist or partial agonist) in helping to prevent or treat osteoporosis.
  • a PTH-I receptor ligand such as an agonist or partial agonist
  • Other conditions where such compounds may be considered to have a potential role are, for example, in the treatment of diabetes, in wound healing and other conditions either associated with lowered levels of PTH or PTHrp, or with under-activation of PTH-I receptors.
  • PTH-I receptor antagonists have been described based on the bovine sequence of PTH (([NIe 8 ' 18 , D-Trp 12 , Tyr 34 ]bPTH(7-34)NH 2 , (BIM-44002)), (Rosen, H. N. et al, Calcif. Tissue Int.
  • WO-A-03/041714 discloses a number of benzotriazepinone derivatives for use in the treatment of gastrin related disorders.
  • EP-A-0645378 describes a class of bicyclic compounds which are said to inhibit squalene synthetase.
  • R 1 , R 4 and R 5 are independently selected from H, COOH, COO(C 1-6 alkyl), COO(C 6-20 aryl), COO(C 7-20 aralkyl), COO(C 7-20 alkaryl), SH 5 S(C 1-6 alkyl), S(C 6-20 aryl), S(C 7-20 alkaryl), S(C 7-20 aralkyl), SO 2 H, SO 3 H 5 SO 2 (C 1-6 alkyl), SO 2 (C 6-20 aryl), SO 2 (C 7-20 alkaryl), SO 2 (C 7-20 aralkyl), SO(Ci -6 alkyl), SO(C 6-20 aryl), SO(C 7-20 alkaiyl), SO(C 7-20 aralkyl), P(OH)(O) 2 , halo, OH, 0
  • R la and R 5a are independently selected from H, COOH, COOCH 3 , COOCH 2 CH 3 , halo, OH, OCH 3 , OCH 2 CH 3 , OCF 3 , CF 3 , CH 3 , OCCl 3 , CCl 3 , OCF 2 CF 31 CF 2 CF 31 NH 2 , NH(CH 3 ), N(CH 3 ) 2 , NHC(O)(CH 3 ), NO 2 , CN, OC(O)CH 3 and C(O)H; or R 1 is joined to R 5 , R 5a or R la to form a 5, 6, 7, 8, 9 or 10-membered saturated, unsaturated or aromatic, heterocyclic or carbocyclic ring which is optionally substituted with one or more of the groups, preferably, 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (b) and (c) above; or R 5 is joined to R 1 , R 5a or R la to form a 5, 6, 7, 8, 9 or
  • R 3 is selected from H, COOH, COO(Cj -20 alkyl), COO(C 6-20 aryl), COO(C 7-20 aralkyl), COO(C 7-20 alkaryl), SO 3 H, SO 2 (C 1-6 alkyl), SO 2 (C 6-20 aryl), SO 2 (C 7-20 alkaryl), SO 2 (C 7-20 aralkyl), CN, SO 2 NH 2 , SO 2 NH(C 1-6 alkyl), SO 2 N(Cj -6 alkyl) 2 , SO 2 NH(C 6-20 aryl), SO 2 N(C 6-20 aryl) 2 , SO 2 NH(C 7-20 aralkyl), SO 2 NH(C 7-20 alkaryl), SO 2 N(Cj -6 alkyl)(C 6-20 aryl), SO 2 N(Cj -6 alkyl)(C 7-20 aralkyl), SO 2 N(Cj -6 alkyl)(C 7-20 alkaryl), SO 2 N(
  • R 2 is a group
  • Z, Z 1 and Z 2 are selected from the group consisting of C and N, wherein Z and Z 1 are not the same; n is an integer of 0, 1, 2, 3, 4 or 5; m is an integer of 0, 1, 2, 3, 4 or 5; n 1 is an integer of 0 or 1; m 1 is an integer of 0 or 1 ; m 2 is an integer of 0, 1, 2, 3, 4 or 5; wherein the groups -(CH 2 ) m - and -(CH 2 ) m 2 - are optionally independently substituted by 1 or more -OH groups on the CH 2 backbone, preferably 1 -OH group; wherein the -(O) 1n 1 - and -(O) n 1 - groups are not directly linked to one another;
  • R 7 and R 8 are independently selected from the group consisting of H, COOH, COO(Ci -6 alkyl), COO(C 6-20 aryl), COO(C 7-20 aralkyl), COO(C 7-20 alkaryl), SH, S(C 1-6 alkyl), SO 2 H, SO 3 H, SO 2 (C 1-6 alkyl), SO 2 (C 6-20 aryl), SO 2 (C 7-20 alkaryl), SO 2 (C 7-20 aralkyl), SO(C 1-6 alkyl), SO(C 6-20 aryl), SO(C 7-20 alkaryl), SO(C 7-20 aralkyl), P(OH)(O) 2 , halo, OH, 0(C 1-6 alkyl), NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , NHC(O)(C 1-6 alkyl), NO 2 , CN, SO 2 NH 2 , SO 2 NH(C 1-6 alkyl),
  • R 9 is selected from the group consisting of H and Ci -6 alkyl, C 3-20 cycloalkyl, C 4-20 (cycloalkyl)alkyl, C 6-20 aryl, C 7-20 aralkyl, C 7-20 alkaryl, C 1-20 heteroaryl and C 2-20 heterocyclyl;
  • R 10 is selected from the group consisting of, H, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkoxyalkyl, C 7-30 alkoxyaryl, C 2-20 alkynyl, C 3-30 cycloalkyl, C 4-30 (cycloalkyl)alkyl, C 5-30 cycloalkenyl, C 7-30 cycloalkynyl, C 7-30 aralkyl, C 7-30 alkaryl, C 6-30 aryl, C 1-30 heteroaryl, C 2-30 heterocyclyl, C 2-30 heteroaralkyl, C 3-30 heterocyclylalkyl, Cg -30 heterocyclylalkaryl, C 4-30 heterocyclylalkoxyalkyl,
  • R 9 and R 10 may be joined to form a 3, 4, 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring; any of the groups defined as R 10 (except H) being optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from C 1-I0 alkyl, C 1-20 haloalkyl, C 1-20 perhaloalkyl, C 1-20 hydroxyalkyl, C 3-10 cycloalkyl, halo, OH, OC 1-6 alkyl, NH 2 , OC(C 1-6 alkyl), OC(C 6-20 aryl), OC(C 7-20 aralkyl), OC(C 7-20 alkaryl), OCO(C 1-6 alkyl), OCO(C 6-20 aryl), OCO
  • each R 14 is joined to one another to form a 5, 6, 7, 8, 9 or
  • R 15 is selected from the group consisting of H, CN, Ci -20 alkyl, C 2-20 alkenyl, C 2-20 alkoxyalkyl,
  • the groups -(CH 2 ) m - and -(CH 2 ) m 2 - are substituted by 1 -OH groups on the CH 2 backbone.
  • each compound of formula (I) only one of the groups -(CH 2 ) m - and -(CH 2 ) m 2 - is substituted .
  • neither of the -(CH 2 ) m - and -(CH 2 ) m 2 - groups are substituted by -OH groups.
  • the groups -(O) n , 1 - and -(O) n 1 - groups are not directly bonded to one another, i.e., there is no O-O bond.
  • n 1 is O
  • m 2 is O
  • n, n 1 , m, m 1 and m 2 are all O.
  • Z is N and Z 1 is C.
  • Z 2 is C.
  • Z is N, Z 1 is C and Z 2 is N. In another embodiment, Z is N, Z 1 is C and Z 2 is C.
  • R 2 is selected from the group consisting of the structures (i), (ii) and (iii) shown below: wherein, n, n 1 , m, m 1 , m 2 , R 6 , R 7 and R 8 have the same meaning as above; and the groups -(CH 2 ) m - and -(CH 2 ) m 2 - are optionally independently substituted by 1 or more -OH groups on the CH 2 backbone, preferably 1 -OH group.
  • R 2 comprises the structure (ii).
  • R 2 is selected from the group consisting of the structures (ia), (iia) and (iiia) shown below: wherein R 7 and R 8 are independently selected from the group consisting of H, C 1-6 alkyl, halo, haloC 1-6 alkyl, perhaloC 1-6 alkyl, OH, NH 2 , NO 2 , CN, COOH, C(O)H, C(O)O(C 1-6 alkyl) and C(O)(Ci -6 alkyl), R 6 is as defined above, wherein n is O or 1, m 1 is O or 1, m is 1, 2 or 3, and the group -(CH 2 ) m - is optionally substituted by 1 or more -OH groups on the CH 2 backbone, preferably 1 -OH group.
  • R 7 and R 8 are independently selected from the group consisting of H, C 1-6 alkyl, halo, haloC 1-6 alkyl, perhaloC 1-6 alkyl, OH,
  • R 7 and/or R 8 are preferably located in the ortho or meta position relative to the -(CH 2 ) n - group, most preferably the meta position.
  • n is O
  • R 7 and/or R 8 are preferably located in the ortho or meta position relative to the N 1 atom, most preferably the meta position.
  • R 7 and R 8 are both H.
  • n is O.
  • m is O.
  • R 2 is represented by the structure (iia).
  • R 2 is a group having the structure (ib) or (iib) shown below:
  • R 7 and R 8 are independently selected from the group consisting of H, Ci -6 alkyl, halo, haloC 1-6 alkyl, perhaloC 1-6 alkyl, OH, NH 2 , NO 2 , CN, COOH, C(O)H, C(O)O(C 1-6 alkyl) and C(O)(Ci -6 alkyl), R 6 is as defined above and n is O or 1.
  • R 7 and/or R 8 are preferably located in the ortho or meta position relative to the -(CH 2 ) n - group, most preferably the meta position.
  • n is O
  • R 7 and/or R 8 are preferably located in the ortho or meta position relative to the N 1 atom, most preferably the meta position.
  • R 7 and R 8 are both H.
  • n is O.
  • R 2 comprises the structure (iib).
  • R 2 is a group having the structure (ic) or (iic) shown below: wherein R 7 and R 8 are independently selected from the group consisting of H, Ci -6 alkyl, halo, OH, NH 2 and CN.
  • R 7 and/or R 8 are preferably located in the ortho or meta position relative to the N 1 atom, most preferably the meta position.
  • -NR 9 R 10 is located in the meta or para position relative to the N 1 atom (the N 1 atom being shown in the representative structure of compound of formula (I) above).
  • R 7 is H and R 8 is H, Cl, Br, or F, preferably H or Br.
  • R 7 and R 8 are both H.
  • R 2 comprises the structure (iic).
  • R 2 is a group having the structure (id) or (iid) shown below:
  • R 2 comprises the structure (iid).
  • n, m, m 1 , n 1 and m 2 are all 0, and -R 6 is located in the meta or para position relative to the notional (CH 2 ) n group, most preferably the para position.
  • R 2 is selected from the group consisting of ((I H-imidazol-2-yl)methylamino)-pyridinyl, ((I H-imidazol-2-yl)ethylamino)-pyridinyl,
  • the pyridyl moiety of the R 2 group is substituted with the named substituents in the para position relative to the point of attachment of the R 2 group to the rest of the compound of formula (I).
  • the pyridinyl moiety is a pyridin-2-yl moiety.
  • R 6 comprises a guanidinyl moiety.
  • R 9 is selected from H, methyl, ethyl, propyl, phenyl, phenylethyl, benzyl, tolyl and xylyl, more preferably H or methyl, most preferably H.
  • R 10 is selected from the group consisting of Ci -I5 heteroaryl, C 2- i 5 heterocyclyl, C 2-I5 heteroaralkyl, C 3-I5 heterocyclylalkyl, Ci -I5 alkyl, C 6-20 aryl, C 7-20 aralkyl, C 3-I5 cycloalkyl and C 4-I5 cycloalkylalkyl, any of which are optionally substituted on the backbone with one or more groups, preferably 1 , 2, 3 or 4 groups, independently selected from NH 2 , NH(Ci -4 alkyl), N(Ci -4 alkyl) 2 , NH(C 6-16 aryl), N(C 6-16 aryl) 2 , NH(C 7-J6 aralkyl), N(C 7-I6 aralkyl) 2 , NH(C 7-I6 alkaryl), N(C 7-J6 alkaryl) 2 , N(Q -4 alkyl)(C
  • R 10 is selected from the group consisting Of C 6-20 aryl, C 7-20 aralkyl, C 3-15 cycloalkyl, C 4-I5 cycloalkylalkyl, C 1-I5 heteroaryl, C 2-15 heterocyclyl, C 2-15 heteroaralkyl, C 3-15 heterocyclylalkyl and C 1-I0 alkyl, any of which are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from NH 2 , NH(Ci -4 alkyl) OrN(Ci -4 3 UCyI) 2 .
  • R 10 is selected from the group consisting of Ci -10 heteroaryl, C 2-I0 heterocyclyl, C 3-I0 heteroaralkyl, C 4-I5 cycloalkylalkyl, C 3-I0 heterocyclylalkyl and Ci -6 alkyl, any of which are optionally substituted on the backbone with one or more groups, preferably 1, 2 or 3 groups, independently selected from NH 2 , NH(Ci -4 alkyl) or N(Cj -4 alkyl) 2 .
  • R 10 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclooctylethyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl, cyclooctylpropyl, furanyl, furanyl(C 1-3 alkyl), pyridyl, pyridyl(Ci -3 alkyl), phthalimido, phthalimido(C 1-3 alkyl),
  • imidazolemethyl dihydroimidazolyl, dihydroimidazolyl(Ci. 3 alkyl), dihydroimidazolylmethyl, tetrahydropyrimidinyl, tetrahydropyrimidinyl(Ci. 3 alkyl), benzimidazolyl, benzimidazoly ⁇ Q ⁇ alkyl), tetrahydroisoquinolinyl, tetrahydroisoquinolyl(Ci. 3 alkyl), pyrazolidinyl, pyrazolidinyl(C 1-3 alkyl), tetrahydrofuranyl, tetrahyrdofuranyl(Ci.
  • R 10 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclooctylethyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl, cyclooctylpropyl, furanyl, pyridyl, pyridyl(Ci -3 alkyl), phthalimido, phthalimido(C 1-3 alkyl), pyrrolyl, pyrrolyl(Ci
  • imidazolidinyl imidazolidinyl(Ci -3 alkyl), imidazolinyl, imidazolinyl(Ci. 3 alkyl), imidazolemethyl, dihydroimidazolyl, dihydroimidazolyl(Ci -3 alkyl), dihydroimidazolyhnethyl, tetrahydropyrimidinyl, tetrahydropyrimidinyl(Ci.
  • R 10 is selected from the group consisting of cyclopentylmethyl, piperidylmethyl, methylaminoethyl, aminocyclopentyhnethyl, methylaminocyclopentylmethyl, methylaminoethyl, tetrahydro-pyranylaminoethyl, tetrahydro- pyranylaminopropyl, propylaminoethyl, propylaminopropyl, dimethylaminoethyl, furanylmethylaminoethyl, piperidinylmethyl and l-meth.yl-piperidin-4-ylmeth.yl, any of which may be substituted with 1 or more groups independently selected from C 1-6 alkyl, halo, haloCi -6 alkyl, hydroxyC 1-6 alkyl, perhaloC 1-6 alkyl, OH, NH 2 , NO 2 , CN, COOH, C(O)
  • R 9 and R 10 are joined to form a 3, 4, 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, preferably a 5 or 6-membered, saturated, unsaturated or aromatic heterocyclic ring is formed.
  • Preferred ring systems are selected from the group consisting of 5 or 6-membered heterocyclyl and heteroaryl rings containing 1 or 2 nitrogen atoms. Such rings may additionally comprise 1 or more oxygen and/or sulphur atoms.
  • Preferred ring systems are selected from the group consisting of pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.
  • R 10 is not H.
  • each R 14 is independently selected from the group consisting of H, C 1-10 alkyl, C 2-10 alkenyl, C 2-I0 alkoxyalkyl, C 7-20 alkoxyaryl, C 2-10 alkynyl, C 3-20 cycloalkyl, C 4-20
  • (cycloalkyl)alkyl Cs -20 cycloalkenyl, C 7-20 cycloalkynyl, C 7-20 aralkyl, C 7-2O alkaryl, C 6-20 aryl, C 1-20 heteroaryl, C 2-2O heterocyclyl, C 2-20 heteroaralkyl, C 3-20 heterocyclylalkyl, Cj -10 aminoalkyl,
  • R 15 is selected from the group consisting of H, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkoxyalkyl, C 7-2O alkoxyaryl, C 2- io alkynyl, C 3-2O cycloalkyl, C 4-20 (cycloalkyl)alkyl, Cs -20 cycloalkenyl, C 7-20 cycloalkynyl, C 7-20 aralkyl, C 7-20 alkaryl, C 6-20 aryl, C 1-20 heteroaryl and C 2-20 heterocyclyl, C 2-20 heteroaralkyl, C 3-20 heterocyclylalkyl, C 1-10 aminoalkyl, C 6-I0 aminoaryl, guanidinyl C 1-6 alkyl, C 2-12 alkylguanidinylalkyl, ureayl C 1-6 alkyl and C 2-12 alkylureaylalkyl, any of which (except H) are optionally substituted on
  • R 15 and one of R 14 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R 14 not joined to R 15 is H or C 1-6 alkyl.
  • each R 14 is independently selected from the group consisting of H and Ci -4 alkyl, or R 15 and one of R 14 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R 14 not joined to R 15 is selected from the group consisting of H and C 1-4 alkyl.
  • R 15 and one of R 14 are joined to form a group selected from imidazole, dihydroimidazole, tetrahydropyrimidinyl, benzimidazole and triazole.
  • each R 14 is independently selected from the group consisting of H and methyl.
  • R 15 and one of R 14 are joined to form a group selected from imidazole, dihydroimidazole and tetrahydropyrimidinyl.
  • R 6 is a group
  • R 3 is independently selected from the group consisting of H, COOH, COO(Ci -6 alkyl), COO(C 6-20 aryl), COO(C 7-20 alkaryl), COO(C 7-20 aralkyl), C(O)H, C(O)(Ci -6 alkyl), C(O)NH 2 , C(O)NH(Ci -6 alkyl), C(O)N(Ci -6 alkyl) 2 , C(O)NH(C 6-15 aryl), C(O)N(C 6-I5 aryl) 2 , C(O)NH(C 7-I5 aralkyl), C(O)N(C 7-J5 aralkyl) 2 , C(O)NH(C 7-I5 alkaryl), C(O)N(C 7-15 alkaryl) 2 and hydrocarbyl or heterocarbyl groups selected from C 1-20 alkyl, C 2-20 alkenyl, C 1-20 alkoxy, C 2- 20
  • R 3 is not H.
  • R 3 is -(CR 16 R 1 V-X-R 18 ; wherein: m 3 is 0, 1, 2, 3 or 4;
  • R 16 and R 17 are independently selected from the group consisting of H, Ci -20 alkyl, C 2-20 alkenyl, C 2-20 alkoxyalkyl, C 7-30 alkoxyaryl, C 2-20 alkynyl, C 3-30 cycloalkyl, C 4-30 (cycloalkyl)alkyl, C 5-30 cycloalkenyl, C 7-30 cycloalkynyl, C 7-30 aralkyl, C 7-30 alkaryl, C 6-30 aryl, C 1-30 heteroaryl, C 2-30 heterocyclyl, C 2-30 heteroaralkyl, C 3-30 heterocyclylalkyl, C 1-10 aminoalkyl and C 6-20 aminoaryl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from COOH, COO(C 1-6 alkyl), SH, S(Ci -6 alkyl), SO 2 H, SO 2 (C 1-6 alkyl), SO 2
  • R 18 is selected from the group consisting of H, Ci -20 alkyl, C 2-20 alkenyl, C 2-20 alkoxyalkyl, C 7-30 alkoxyaryl, Ci 2-30 aryloxyaryl, C 2-20 alkynyl, C 3-30 cycloalkyl, C 4-30 (cycloalkyl)alkyl, C 5-30 cycloalkenyl, C 7-30 cycloalkynyl, C 7-30 aralkyl, C 7-30 alkaryl, C 6-30 aryl, C 1-30 heteroaryl, C 2-30 heterocyclyl, C 2-30 heteroaralkyl, C 3-30 heterocyclylalkyl, Ci -I0 aminoalkyl, C 6-20 aminoaryl, guanidine Ci -I0 alkyl, C 2-20 alkylguanidinylalkyl, urea Ci -I0 alkyl and C 2-20 alkylureaylalkyl, any of which (except H) are optionally substituted on
  • X is a bond, C(O)NH, C(O)N(Cj -6 alkyl), C(O)N(C 6-20 aryl), NH, N(Cj -6 alkyl) or O.
  • R 16 and R 17 are independently selected from the group consisting of H, C 1-J0 alkyl, C 2-20 alkoxyalkyl, C 7-20 alkoxyaryl, Cj 2-20 aryloxyaryl, C 3-20 cycloalkyl, C 4-20 (cycloalkyl)alkyl, C 7-20 aralkyl, C 7-20 alkaryl, C 6-20 aryl, C 1-20 heteroaryl, C 2-20 heterocyclyl, C 2-20 heteroaralkyl and C 3-20 heterocyclylalkyl.
  • R 16 and R 17 are joined to form a 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14-membered, saturated, unsaturated or aromatic ring.
  • the ring may be a heterocyclic or heteroaromatic ring.
  • the ring formed by R 16 and R 17 is a cycloalkyl, heterocyclyl or heteroaromatic group.
  • the ring is a C 6-10 cycloalkyl, C 4-10 heterocyclyl or C 1-10 heteroaryl group.
  • m 3 is O
  • X is a bond and R 18 is a Cs -12 cycloalkyl group.
  • X is a bond, C(O)NH or C(O)N(C 1-6 alkyl).
  • X is a bond
  • R 16 and R 17 are both H
  • m 3 is O or 1
  • X is C(O)NH
  • R 16 and R 17 are both H
  • m 3 is O or 1
  • X is a bond
  • R 18 is selected from the group consisting of methyl, ethyl, propyl, butyl, phenyl, benzyl, biphenyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, quinolinyl, naphthyl, tetramethylcyclohexyl, benzocycloheptyl, benzodioxepinyl, bicyclooctyl, tetrahydropyranyl, dihydropyranyl, tetramethyltetrahydropyranyl, cyclohexylmethyl, phenylethylbenzyl, phenoxybenzyl, phenylethynylbenzyl, cyclohexylbenzyl, pyranyl, tetrahydropyranyl, tolyl, ethylbenz
  • X is a bond
  • m 3 is O
  • R 18 is C 2-2O heterocyclyl
  • R 3 comprises a benzyl group, optionally substituted with 1, 2 or 3 groups, independently selected from COO(C 1-6 alkyl), COO(C 6-20 aryl), COO(C 7-20 aralkyl), COO(C 7-20 alkaryl), halo, trihalomethyl, OH, NH 2 , 0(Ci -6 alkyl), 0(C 6-20 aryl), 0(C 7-20 aralkyl), 0(C 7-20 alkaryl), Ci -6 alkyl, C 6-I2 aryl, C 7-I2 aralkyl, C 7-I2 alkaryl, C 8-I2 aralkynyl, C 6-I2 aryloxy, C 1-I2 heteroaryl, C 5-12 cycloalkyl and C(O)(Ci -6 alkyl) on the backbone.
  • 1, 2 or 3 groups independently selected from COO(C 1-6 alkyl), COO(C 6-20 aryl), COO(C
  • R 3 comprises a methyl, ethyl, propyl, butyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, quinolinyl, tetrahydropyranyl, naphthyl, benzocycloheptyl, or benzodioxepinyl group, optionally substituted with 1, 2, 3 or 4 groups independently selected from COO(Ci -6 alkyl), halo, trihalomethyl, OH, NH 2 , 0(C 1-6 alkyl), C 1-6 alkyl, C 6 - I2 aryl, C 7-12 aralkyl, C 7-12 alkaryl, C 6-I2 aryloxy, C 1-12 heteroaryl, C 5-I2 cycloalkyl and C(O)(Ci -6 alkyl) on the backbone.
  • R 3 is preferably a tetrahydropyranyl group or a propyl group.
  • R 19 is not H.
  • R 19 is selected from the group consisting of dihydroimidazolyl and imidazolyl, particularly lH-imidazol-2-yl and 4,5-dihydro-lH-imidazol-2-yl, which are linked to the rest of the compound of formula (I) by a carbon atom of one of these groups.
  • Such preferred groups may be optionally substituted with 1, 2 or 3 groups selected from halo, CH 3 , OH, OCH 3 , OCH 2 CH 3 and NH 2 .
  • R 19 is not substituted in the backbone.
  • R 19 is not substituted on the backbone.
  • R 1 , R 4 and R 5 are independently selected from the group consisting of H, COOH, COO(C 1-6 alkyl), CN, SH, S(C 1-6 alkyl), S(C 6-20 aryl), S(C 7-20 alkaryl), S(C 7-20 aralkyl), SO 2 H, SO 3 H, SO 2 (C 1-6 alkyl), SO 2 (C 6-20 aryl), SO 2 (C 7-20 alkaryl), SO 2 (C 7-20 aralkyl), SO(Cj -6 alkyl), SO(C 6-20 aryl), SO(C 7-20 alkaryl), SO(C 7-20 aralkyl), P(OH)(O) 2 , halo, OH, 0(Ci -6 alkyl), NH 2 , NH(Ci -6 alkyl), N(Ci -6 alkyl) 2 , NHC(O)(C 1-6 alkyl), NO 2 , CN, SO 2 NH 2 , C(C 1-6
  • R 1 is joined to R 5 , R 5a or R la to form a ring, or when R 5 is joined to R 5a or R la to form a ring, preferably it is a 5, 6 or 7-membered ring which is optionally substituted with 1, 2 or 3 of the groups independently selected from the groups defined in (b) and (c) above.
  • none of R 1 , R la , R 5 or R 5a are joined to one another to form a ring.
  • R 5a , R 5 , R 1 and R la are in the 6, 7, 8 and 9 positions respectively of the compound of formula (I).
  • R 5a , R 5 , R 1 and R la are linked with one another to form a ring, adjacently positioned groups are linked, rather than remotely positioned groups.
  • R 5a and R 5 are preferably joined to one another when they are in the 6 and 7 position respectively.
  • R 1 and R 5 are independently selected from the group consisting of H, COOH, SH 3 SO 2 H, P(OH)(O) 2 , F, Cl, Br, I, OH, NH 2 , NO 2 , CN, SO 2 NH 2 , C(O)H, and hydrocarbyl or heterocarbyl groups selected from Ci -6 alkyl, Ci -6 alkoxy, C 2-6 alkoxyalkyl, C 7-20 alkoxyaryl, C 3-20 cycloalkyl, C 4-20 (cycloalkyl)alkyl, C 7-20 aralkyl, C 7-20 alkaryl, C 6-20 aryl, C 1-20 heteroaryl and C 2-20 heterocyclyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups, preferably 1, 2, 3 or 4 groups, independently selected from the groups defined in (a), (b) and (c):
  • R 1 and R 5 are independently selected from the group consisting of C 1-4 alkyl, C 5-8 cycloalkyl, C 1-4 alkoxy, C 1-4 alkylcarbonylamino, Ci -4 alkylaminocarbonyl, C 3-10 cycloalkylcarbonylamino, C 3-10 cycloaUcylaminocarbonyl, C 2- I 0 heterocyclylcarbonylamino, C 2-10 heterocyclylaminocarbonyl, C 6- io arylcarbonylamino, C 6- I 0 arylaminocarbonyl, C 1-1O heteroarylcarbonylamino, C 1-I0 heteroarylaminocarbonyl, C 1-6 alkylamino, di (C 1-4 alkyl)amino, C 7-1O aralkyl, C 7-1O alkaryl, C 6-1 O aryl, C 1-10 heteroaryl and C 2- io heterocyclyl, any of which are optionally substituted with one
  • R 1 and R 5 are independently selected from the group consisting of H, F, Cl, Br, Ci -4 alkyl, C(O)Ci -6 alkyl, C 5-8 cycloalkyl, C 1-4 alkoxy, dimethylamino, tolyl, xylyl, pyridyl, pyridinyl, furanyl, hydroxyphenyl, phenylamino, acetamido, oxopyrrolidinyl, dibenzylamido, piperidinylcarbonyl, benzylamido, benzylamino, OH, NH 2 and N(CH 3 ) 2 .
  • R 5 is H and R 1 is selected from the group consisting of H, F, Cl, Br, methoxy, methyl, tolyl, xylyl, pyridinyl, pyridiyl, furanyl, hydroxyphenyl, phenylamino, acetamido, oxopyrrolidinyl, dibenzylamido, piperidinylcarbonyl, benzylamido, benzylamino, OH, NH 2 andN(CH 3 ) 2 .
  • R 5 and R 1 are both H.
  • R 5 is H and R 1 is selected from methyl, Cl and methoxy.
  • R 1 and R 5 are located in the 8 and 7 positions respectively of the compound of formula (I).
  • R 1 is a methyl group located in the 8-position of the compound of formula (I) as indicated herein.
  • R 4 is selected from the group consisting of H, hydrocarbyl or heterocarbyl groups selected from Ci -I0 alkyl, C 2-1O alkoxyalkyl, C 12-20 aryloxyaryl, C 7-20 aryloxyalkyl, C 1-I o alkoxy, C 7-2O alkoxyaryl, C 4-20 alkoxycycloalkyl, C 3-2O cycloalkyl, C 4-20 (cycloalkyl)alkyl, C 7-2O aralkyl, C 7-2O alkaryl, C 6-2O aryl, Ci -2O heteroaryl, C 2-2O heteroaralkyl and C 2-20 heterocyclyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups, preferably 1, 2 or 3 groups, independently selected from the groups defined in (a), (b) and (c):
  • R 4 is selected from the group consisting of Ci -6 alkyl, C 2-6 alkoxyalkyl, C 12-20 aryloxyaryl, C 7-12 aryloxyalkyl, Ci -I0 alkoxy, C 7-12 alkoxyaryl, C 5-I2 alkoxycycloalkyl, C 3-I2 cycloalkyl, C 4-I2 (cycloalkyl)alkyl, C 7-12 aralkyl, C 7-I2 alkaryl, C 6-I2 aryl, Ci -I2 heteroaryl, C 2-12 heteroaralkyl and C 2-I2 heterocyclyl, any of which is optionally substituted with one or more of the groups, preferably 1, 2 or 3 groups, independently selected from the groups defined in (a), (b) and (c): (a) S, C(O)NH, NHC(O), C(O)NMe, NMeC(O), C(O)O, NHC(O)NH, NHC(O)O,
  • R 4 is selected from the group consisting of Ci -6 alkyl, C 3-I2 cycloalkyl, C 6-12 aryl, Q- I2 heteroaryl, C 2-12 heterocyclyl, C 2-6 alkoxyalkyl, Cs -I2 alkoxycycloalkyl, C 2-I0 alkylthioalkyl, C 4-12 alkylthiocycloalkyl, C 2-I0 alkylsulfonylalkyl, C 6-12 alkylsulfonylcycloalkyl and C 6-12 alkylarninocycloalkyl.
  • R 4 is selected from the group consisting of methyl, cyclohexyl, phenyl, isopropyl, fluorophenyl, cyclohexylmethyl, adamantyl, pyranyl, tetrahydropyranyl, piperidinyhnethyl, cyclohexylsulfanylmethyl, cyclohexanesulfonylmethyl, phenoxymethyl, cyclohexylphenoxymethyl, methoxyphenoxymethyl, naphthalenyloxymethyl, ethanoylphenoxymethoxy, aminoacetylaminophenoxymethyl, cyanophenoxymethyl, acetylaminophenoxymethyl, cyclohexylidenemethyl and aminoacetylphenoxymethyl.
  • R 4 is a cyclohexyl group.
  • R 4 is not H.
  • R la and R 5a are independently selected from H, CH 3 , F, Cl, Br and OH. Most preferably, both R la and R 5a are H.
  • R la and R 5a are located in the 9 and 6 positions respectively of the compound of formula (I).
  • the substitution may be in any of the positions designated 6, 7, 8 or 9 in formula (I).
  • the nitrogen atom is unsubstituted.
  • the benzo moiety of the benzotriazepinone ring system is unsubstituted in the benzo ring.
  • Certain compounds of the invention exist in various regioisomeric, enantiomeric, tautomeric and diastereomeric forms. It will be understood that the invention comprehends the different regioisomers, enantiomers, tautomers and diastereomers in isolation from each other as well as mixtures.
  • 1,3,4-benzotriazepinones are prepared by treatment of a suitable 2-amino phenyl ketone (III), with a suitable bifunctional carbonyl reagent, such as phosgene, trichloromethyl chloroformate or bis(trichloromethyl) carbonate and a suitable hydrazine, NH 2 NHP (wherein P represents either a protecting group, R 3 or a suitable precursor R 3 ' thereof).
  • a suitable 2-amino phenyl ketone (III) with a suitable bifunctional carbonyl reagent, such as phosgene, trichloromethyl chloroformate or bis(trichloromethyl) carbonate and a suitable hydrazine, NH 2 NHP (wherein P represents either a protecting group, R 3 or a suitable precursor R 3 ' thereof).
  • thiophosgene may be used in place of a suitable bifunctional carbonyl reagent to afford a l,3,4-benzotriazpin-2-thione (IV), followed by basic peroxide-mediated oxidation to obtain the 1,3,4-benzotriazepinone (V) (Reaction Scheme 2).
  • Reaction Scheme 2 Reaction Scheme 2
  • 1,3,4-benzotriazepinones (V) may also be obtained by initial activation of a suitable 2-amino phenyl ketone (III) with a suitable bifunctional carbonyl reagent, such as /> ⁇ ra-nitrobenzyl chloroformate, bis(trichloromethyl) carbonate or l,l'-carbonyldiimidazole, followed by treatment with a suitable urethane-protected hydrazine, P 1 NHNHR 3 (wherein P 1 represents a urethane protecting group and R 3 represents R 3 or a suitable precursor thereof) to form a substituted semicarbazide derivative (VI) as an intermediate (Reaction Scheme 3). Removal of the urethane protecting group P', results in concomitant ring closure to form the 1,3,4-benzotriazepinones (V).
  • a suitable 2-amino phenyl ketone (III) with a suitable bifunctional carbonyl reagent, such as />
  • the 1,3,4-benzotriazepine (V) may also be obtained by starting from a suitable 2-iodo aniline (VII) (Reaction scheme 4). Sonogashira reaction (Tykwinski, R. R. Angew. Int. Ed. (2003), 42, 1566) affords the corresponding acetylide derivative (VIII) which, on reaction with a suitable bifunctional carbonyl reagent and a suitable urethane-protected hydrazine, PTSfHNHR 3 ', affords the semicarbazide intermediate (EX).
  • Mercuric oxide-mediated oxidation yields the required ketone precursor (VI), suitable for conversion to the 1,3,4-benzotriazepine (V) according to the method outlined in reaction scheme 3.
  • N-I substituted benzodiazepines (X) are obtained from (V) by base catalysed alkylation using sodium hydride and a suitable alkyl halide, R 2 Br or R 2 F, (wherein R 2' represents a suitable precursor of R 2 ) (Reaction scheme 5).
  • arylation may be achieved by copper-mediated arylation reaction with a suitable aryl iodide R 2 1.
  • R 2 groups which are suitable precursors of R 2 will depend on the particular nature of R 2 .
  • a suitable precursor of R 2 is:
  • a suitable precursor of R 2 is:
  • R 6 is a suitable precursor of R 6 .
  • R 6 groups which are suitable precursors of R 6 will depend on the particular nature of R 6 .
  • Suitable R 6 substituents include NO 2 , which can be reduced by tin (II) chloride or catalytic hydrogenation to the corresponding aniline.
  • the aniline substituent can be further modified to the required R 6 group by, amongst others, acylation with amino acid derivatives, reductive amination with an appropriate aldehyde, or guanylation with a suitable guanylating agent.
  • Other suitable R 6 substituents include esters that can be converted to amide derivatives via the corresponding carboxylic acid.
  • R 6 represents a dihydroimidazolyl group
  • suitable R 6 ' substituents include CHO, which can be converted to a dihydroimidazolyl group by the method of Huh (D.H. Huh, J. S. Jeong, H.B. Lee et al. Tetrahedron, 2002, 58, 9925).
  • Other suitable R 6' substituents include CN, from which a dihydroimidazolyl group can be obtained by formation of the corresponding imidate, using methanolic-HCl, followed by treatment with a 1,2-ethylenediamine (G. Marciniak, D. Decolin, et al., J. Med. Chem., 1988, 31, 2289).
  • R 6 represents an imidazolyl group
  • suitable R 6 substituents include alkyl halides or activated alcohols, from which the desired imidazolyl group can be obtained by displacement of the halide or activated alcohol with a suitable imidazolecarbanion.
  • R 3 substituents which are suitable precursors of R 3 will depend on the particular nature of R 3 .
  • P represents R 3
  • these can obtained directly by treatment of (III) using the appropriate substituted hydrazine, or indirectly when P represents a protecting group, such as
  • the present invention also provides a method of making compounds according to formula (I).
  • Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I), substantially as described hereinbefore, with a pharmaceutically acceptable diluent or carrier.
  • Yet another aspect of the present invention is a method of making a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) substantially as described hereinbefore, comprising mixing said compound with a pharmaceutically acceptable diluent or carrier.
  • the present invention provides a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore, for use in therapy.
  • Some diseases that may be treated according to the present invention include, cardiovascular diseases, disorders of the peripheral and central nervous system, inflammation, urological diseases, developmental disorders, cancer, metabolic diseases, endocrinological diseases and disorders of the gastroenterology system in a mammal.
  • the present invention provides a method for the treatment of a disease mediated by PTH-I receptors, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drag thereof, substantially as described hereinbefore.
  • the present invention provides a method for the prophylaxis or treatment of cancer, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore.
  • the present invention provides a method for the prophylaxis or treatment of osteoporosis, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore.
  • the present invention provides a method for the prophylaxis or treatment of an inflammatory disease, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore.
  • the present invention provides a method for the prophylaxis or treatment of an autoimmune disease, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drag thereof, substantially as described hereinbefore.
  • the present invention provides a method for the prophylaxis or treatment of metastases, particularly bone metastases, by administration to a subject of- a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore.
  • the present invention provides a method for the treatment of lack of hair eruption, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore.
  • Specific diseases that may be treated or prevented according to the present invention include osteoporosis, anaemia, renal impairment, ulcers, myopathy, neuropathy, hypercalcemia, hyperparathyroidism, parathyroid gland adenoma, parathyroid gland hyperplasia, parathyroid gland carcinoma, squamous carcinoma, renal carcinoma, breast carcinoma, prostate carcinoma, lung carcinomas, osteosarcomas, clear cell renal carcinoma, prostate cancer, lung cancer, breast cancer, gastric cancer, ovarian cancer, bladder cancer, bone fracture, severe bone pain, spinal cord compression, cachexia, malnutrition, muscle wasting, net protein loss, arthritis, rheumatoid arthritis, diabetes, congestive heart failure and wound healing.
  • the present invention also provides the use of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore, in the manufacture of a medicament for the prophylaxis or treatment of any of the diseases described hereinbefore.
  • the compounds of the present invention may also be present in the form of pharmaceutical acceptable salts.
  • the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts.”
  • FDA approved pharmaceutical acceptable salt forms International J. Pharm. 1986, 33,201-217; J. Pharm. Sci., 1977, Jan, 66 (1), pi
  • salts of the acidic or basic compounds of the invention can of course be made by conventional procedures, such as by reacting the free base or acid with at least a stoichiometric amount of the desired salt-forming acid or base.
  • Pharmaceutically acceptable salts of the acidic compounds of the invention include salts with inorganic cations such as sodium, potassium, calcium, magnesium, zinc, and ammonium, and salts with organic bases. Suitable organic bases include N-methyl-D-glucamine, arginine, benzathine, diolamine, olamine, procaine and tromethamine. Pharmaceutically acceptable salts of the basic compounds of the invention include salts derived from organic or inorganic acids.
  • Suitable anions include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, pamoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, tosylate and triethiodide.
  • Hydrochloride salts of compound (I) are particularly preferred.
  • the invention also comprehends derivative compounds ("pro-drugs") which are degraded in vivo to yield the species of formula (T).
  • Pro-drugs are usually (but not always) of lower potency at the target receptor than the species to which they are degraded.
  • Pro-drugs are particularly useful when the desired species has chemical or physical properties which make its administration difficult or inefficient. For example, the desired species may be only poorly soluble, it may be poorly transported across the mucosal epithelium, or it may have an undesirably short plasma half-life. Further discussion of pro-drags may be found in Stella, V. J. et al, "Prodrugs", Drug Delivery Systems, 1985, pp. 112-176, Drugs, 1985, 29, pp. 455-473 and "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • Pro-drag forms of the pharmacologically-active compounds of the invention will generally be compounds according to formula (T) having an acid group which is esterified or amidated. Included in such esterified acid groups are groups of the form -COOR a , wherein R a is Ci -6 alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, or one of the following:
  • Amidated acid groups include groups of the formula -CONR b R°, wherein R b is H, C 1-5 alkyl, phenyl, substituted phenyl, benzyl, or substituted benzyl, and R c is -OH or one of the groups just recited for R b .
  • compositions of formula (T) having an amino group may be derivatised with a ketone or an aldehyde such as formaldehyde to form a Mannich base. This will hydrolyse with first order kinetics in aqueous solution.
  • administering shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject.
  • ester derivatives in which one or more free hydroxy groups are esterified in the form of a pharmaceutically acceptable ester are particularly pro-drug esters that may be convertible by solvolysis under physiological conditions to the compounds of the present invention having tree hydroxy groups.
  • the compounds of the invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration, and inhalation.
  • the compounds of the invention will generally be provided in the form of tablets or capsules or as an aqueous solution or suspension.
  • Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives.
  • suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate and lactose.
  • Corn starch and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatine.
  • the lubricating agent if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
  • Capsules for oral use include hard gelatine capsules in which the active ingredient is mixed with a solid diluent and soft gelatine capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin.
  • Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
  • Effective doses of the compounds of the present invention may be ascertained be conventional methods.
  • the specific dosage level required for any particular patient will depend on a number of factors, including severity of the condition being treated, the route of administration and the weight of the patient. In general, however, it is anticipated that the daily dose (whether administered as a single dose or as divided doses) will be in the range 0.001 to 5000 mg per day, more usually from 1 to 1000 mg per day, and most usually from 10 to 200 mg per day. Expressed as dosage per unit body weight, a typical dose will be expected to be between 0.01 ⁇ g/kg and 50 mg/kg, especially between 10 ⁇ g/kg and 10 mg/kg, between 100 ⁇ g/kg and 2 mg/kg. Where reference is made to dialkyl groups [e.g. N(C 1-6 alkyl) 2 ], it is understood that the two alkyl groups may be the same or different.
  • Formulaic representation of apparent orientation of a group within the backbone is not necessarily intended to represent actual orientation.
  • a divalent amide group represented as C(O)NH is also intended to cover NHC(O).
  • linking bonds may be on any suitable ring atom, subject to the normal rules of valency.
  • pyrrolyl substituted on the backbone contemplates all possible isomeric forms.
  • pyrrolyl substituted on the backbone includes all of the following permutations:
  • halogen or "halo” is used herein to refer to any of fluorine, chlorine, bromine and iodine. Most usually, however, halogen substituents in the compounds of the invention are chlorine, bromine and fluorine substituents. Groups such as 1IaIo(C 1-6 alkyl) includes mono-, di- or tri-halo substituted Ci -6 alkyl groups. Moreover, the halo substitution may be at any position in the alkyl chain. "Perhalo” means completely halogenated, e.g., trihalomethyl and pentachloroethyl.
  • the terms “comprising” and “comprises” means “including” as well as “consisting” e.g. a composition "comprising" X may consist exclusively of X or may include something additional e.g. X + Y.
  • May means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form or individual enantiomers may be prepared by standard techniques known to those skilled in the art, for example, by enantiospecific synthesis or resolution, formation of diastereomeric pairs by salt formation with an optically active acid, followed by fractional crystallization and regeneration of the free base.
  • solvate means a compound of as defined herein, or a pharmaceutically acceptable salt of a compound of structure (I), wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a hydrate.
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • the groups R 1 , R 3 , R 4 , R 5 , R 7 , R 8 , R 10 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 are unsubstituted, in or on the backbone.
  • the group R 1 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 3 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 3 or 4, more preferably by 1 substituent, as defined herein.
  • the group R 4 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 5 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 7 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 8 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 10 is substituted, in or on the backbone, by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 14 is substituted, in or on the backbone, by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 15 is substituted, in or on the backbone, by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 16 is substituted, in or on the backbone, by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 17 is substituted, in or on the backbone, by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 18 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 19 is substituted, in or on the backbone, by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • backbone preferably means the carbon backbone of the group being referred to.
  • backbone includes the possibility for substitution on a heteroatom, such as nitrogen, which is located in the carbon backbone.
  • the term "in the backbone" when referring to a substitution means that the backbone is interrupted by one or more of the groups indicated. Where more than one substitution occurs, they may be adjacent to one another or remote, i.e., separated by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more carbon atoms.
  • both “ethylaminocarbonyl” and “methylaminocarbonylbutyl” fall under the scope of the definition "C 1-6 alkyl group substituted with an NHC(O) group".
  • the NHC(O) group links the ethyl group to the rest of the molecule
  • the NHC(O) group interrupts the carbon chain
  • the butyl moiety links the methylaminocarbonyl moiety to the rest of the molecule.
  • the term "on the backbone" when referring to a substitution means that one or more hydrogen atoms on the backbone is replaced by one or more of the groups indicated. Where more than one substitution occurs, they may be on the same, adjacent or remote carbon atoms, i.e., located on carbon atoms that are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more carbon atoms apart.
  • a group comprises two or more moieties defined by a single carbon atom number, for example, C 2-20 alkoxyalkyl
  • the carbon atom number indicates the total number of carbon atoms in the group.
  • heteroatom includes N, O, S, P, Si and halogen (including F, Cl, Br and I).
  • hydrocarbyl group refers to a monovalent hydrocarbon radical, having the number of carbon atoms as indicated, which contains a carbon backbone comprising one or more hydrogen atoms.
  • hydrocarbyl group is intended to cover alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, cycloalkynyl, aralkyl, alkaryl, aryl, all of which are further defined herein. This list is non-exhaustive, and the skilled person will readily understand other groups and combinations of the above-mentioned groups fall under the scope of the term “hydrocarbyl group”.
  • heterocarbyl group refers to a monovalent hydrocarbon radical, having the number of carbon atoms as indicated, which contains a carbon backbone comprising one or more heteroatoms in or on the carbon backbone, and optionally containing one or more hydrogen atoms.
  • heterocarbyl group is intended to cover alkoxyalkyl, alkoxyaryl, heteroaryl, heterocyclyl, heteroaralkyl, heterocyclylalkyl, aryloxyalkyl, alkoxy, cycloalkyloxy, aryloxy, alkylamino, cycloalkylamino, arylamino, alkylaminoalkyl, aralkylamino, alkarylamino, aminoalkyl, aminoaryl, aminoaralkyl, aminoalkaryl, guanidinyl, guanidinylalkyl, alkylguanidinyl, alkylguanidinylalkyl, ureayl, ureaylalkyl, alkylureayl and alkylureaylalkyl, all of which are further defined herein. This list is non-exhaustive, and the skilled person will readily understand other groups and combinations of the above-mentioned groups fall under the scope
  • alkyl refers to a straight or branched saturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated.
  • suitable alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, dodecyl and eicosyl.
  • alkenyl refers to a straight or branched unsaturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated, and the distinguishing feature of a carbon-carbon double bond.
  • alkenyl groups include ethenyl, propenyl, butenyl, penentyl, hexenyl, octenyl, nonenyl, dodecenyl and eicosenyl, wherein the double bond may be located any where in the carbon backbone.
  • alkynyl refers to a straight or branched unsaturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated, and the distinguishing feature of a carbon-carbon triple bond.
  • suitable alkynyl groups include ethynyl, propynyl, butynyl, penynyl, hexynyl, octynyl, nonynyl, dodycenyl and eicosynyl, wherein the triple bond may be located any where in the carbon backbone.
  • the te ⁇ n "cycloalkyl” refers to a cyclic saturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated.
  • suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl, trimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, spiroundecyl, bicyclooctyl and adamantyl.
  • (cycloalkyl)alkyl refers to an alkyl group with a cycloalkyl substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated.
  • suitable (cycloalkyl)alkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentyhnethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, methylcyclohexylmethyl, dimethylcyclohexylmethyl, trimethylcyclohexyhnethyl, cycloheptyhnethyl, cycloheptylethyl, cycloheptylpropyl, cycloheptylbutyl, methylcyclohexylmethyl, di
  • cycloalkenyl and “cycloalkynyl” refer to cyclic unsaturated monovalent hydrocarbon radicals.
  • a “cycloalkenyl” is characterized by a carbon-carbon double bond and a “cycloalkynyl” is characterized by a carbon-carbon triple bond.
  • Such groups have the number of carbon atoms as indicated.
  • suitable cycloalkenyl groups include cyclohexene and cyclohexadiene.
  • Alkoxy refers to the group "alkyl-O-", where alkyl is as defined above.
  • suitable alkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
  • Aryloxy refers to the group "aryl-O", where aryl is as defined herein.
  • suitable aryloxy groups include phenoxy, tolyloxy and xylyloxy.
  • alkoxyalkyl refers to an alkyl group having an alkoxy substituent. Binding is through the alkyl group.
  • the alkyl group and/or the alkoxy group has the number of carbon atoms as indicated.
  • the alkyl moiety may be straight or branched.
  • the alk and alkyl moieties of such a group may be substituted as defined above, with regard to the definition of alkyl.
  • suitable alkoxyalkyl groups include methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxypropyl and ethoxypropyl.
  • alkoxyaryl refers to an aryl group having an alkoxy substituent. Binding is through the aryl group.
  • the aryl group and/or the alkoxy group have the number of carbon atoms as indicated.
  • the alkoxy and aryl moieties of such a group may be substituted as defined herein, with regard to the definitions of alkoxy and aryl.
  • the alkyl moiety may be straight or branched.
  • suitable alkoxyaryl groups include methoxyphenyl, ethoxyphenyl, dimethoxyphenyl and trimethoxyphenyl.
  • aryl refers to monovalent unsaturated aromatic carbocyclic radical having one, two, three, four, five or six rings, preferably one, two or three rings, which may be fused or bicyclic.
  • aryl refers to an aromatic monocyclic ring containing 6 carbon atoms, which may be substituted on the ring with 1, 2, 3, 4 or 5 substituents as defined herein; an aromatic bicyclic or fused ring system containing 7, 8, 9 or 10 carbon atoms, which may be substituted on the ring with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents as defined herein; or an aromatic tricyclic ring system containing 10, 11, 12, 13 or 14 carbon atoms, which may be substituted on the ring with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 substituents as defined herein.
  • suitable aryl groups include phenyl, biphenyl, binaphthyl, indanyl, phenanthryl, fluoryl, flourenyl, stilbyl, benzphenanthryl, acenaphthyl, azulenyl, phenylnaphthyl, benzfluoryl, tetrahydronaphthyl, perylenyl, picenyl, chrysyl, pyrenyl, tolyl, chlorophenyl, dichlorophenyl, trichlorophenyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, fluorophenyl, difluorophenyl, trifluorophenyl, nitrophenyl, dinitrophenyl, trinitrophenyl, aminophenyl, diaminophenyl, triaminophenyl, cyanophenyl,
  • heteroaryl refers to a monovalent unsaturated aromatic heterocyclic radical having one, two, three, four, five or six rings, preferably one, two or three rings, which may be fused or bicyclic.
  • heteroaryl refers to an aromatic monocyclic ring system containing five members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms, an aromatic monocyclic ring having six members of which one, two or three members are a N atom, an aromatic bicyclic or fused ring having nine members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms or an aromatic bicyclic ring having ten members of which one, two or three members are a N atom.
  • suitable heteroaryl groups include furanyl, pyranyl, pyridyl, phthalimido, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, pyronyl, pyrazinyl, tetrazolyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxadinyl,
  • heterocyclyl refers to a saturated or partially unsaturated ring having three members of which at least one member is a N, O or S atom and which optionally contains one additional O atom or additional N atom; a saturated or partially unsaturated ring having four members of which at least one member is a N, O or S atom and which optionally contains one additional O atom or one or two additional N atoms; a saturated or partially unsaturated ring having five members of which at least one member is a N, O or S atom and which optionally contains one additional O atom or one, two or three additional N atoms; a saturated or partially unsaturated ring having six members of which one, two or three members are an N, O or S atom and which optionally contains one additional O atom or one, two or three additional N atoms; a saturated or partially unsaturated ring having seven members of which one, two or three members are an N, O or S atom and which optionally contains one additional O atom or one, two or three additional N atom
  • heterocycles comprising peroxide groups are excluded from the definition of hetercyclyl.
  • suitable heterocyclyl groups include pyrrolinyl, pyrrolidinyl, dioxolanyl, tetrahydrofuranyl, morpholinyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrothiopyranyl and piperazinyl.
  • heterocyclylalkyl refers to an alkyl group with a heterocyclyl substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated.
  • the heterocyclyl and alkyl moieties of such a group may be substituted as defined herein, with regard to the definitions of heterocyclyl and alkyl.
  • the alkyl moiety may be straight or branched.
  • suitable heterocyclylalkyl groups include methyl, ethyl, propyl, butyl, pentyl and hexyl substituted with one or more of the heterocyclyl groups indicated immediately above.
  • alkaryl refers to an aryl group with an alkyl substituent. Binding is through the aryl group. Such groups have the number of carbon atoms as indicated.
  • the alkyl and aryl moieties of such a group may be substituted as defined herein, with regard to the definitions of alkyl and aryl.
  • the alkyl moiety may be straight or branched.
  • alkaryl include tolyl, xylyl, butylphenyl, mesityl, ethyltolyl, methylindanyl, methylnaphthyl, methyltetrahydronaphthyl, ethylnaphthyl, dimethylnaphthyl, propylnaphthyl, butylnaphthyl, methylfluoryl and methylchrysyl.
  • aralkyl refers to an alkyl group with an aryl substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated.
  • the aryl and alkyl moieties of such a group may be substituted as defined herein, with regard to the definitions of aryl and alkyl.
  • the alkyl moiety may be straight or branched.
  • aralkyl include benzyl, methylbenzyl, ethylbenzyl, dimethylbenzyl, diethylbenzyl, methylethylbenzyl, methoxybenzyl, chlorobenzyl, dichlorobenzyl, trichlorobenzyl, phenethyl, phenylpropyl, diphenylpropyl, phenylbutyl, biphenylmethyl, fluorobenzyl, difluorobenzyl, trifluorobenzyl, phenyltolylmethyl, trifluoromethylbenzyl, bis(trifluoromethyl)benzyl, propylbenzyl, tolyhnethyl, fluorophenethyl, fluorenyhnethyl, methoxyphenethyl, dimethoxybenzyl, dichlorophenethyl, phenylethylbenzyl, isopropylbenzyl, diphenyl
  • heteroarylkyl refers to an alkyl group with a heteroaryl substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated.
  • the heteroaryl and alkyl moieties of such a group may be substituted as defined herein, with regard to the definitions of heteroaryl and alkyl.
  • the alkyl moiety may be straight or branched.
  • suitable heteroaralkyl groups include methyl, ethyl, propyl, butyl, pentyl and hexyl substituted with one or more of the specific heteroaryl groups indicated above.
  • alkylamino refers to an amine group with an alkyl substituent. Binding is through the amine group. Such groups have the number of carbon atoms as indicated.
  • the alkyl moiety of such a group may be substituted as defined herein, with regard to the definition of alkyl.
  • the alkyl moiety may be straight or branched.
  • suitable alkylamino groups include methylamino, ethylamino, propylamino, butylamino, pentylamino and hexylamino.
  • cycloalkylamino refers to an amine group with a cycloalkyl substituent. Binding is through the amine group. Such groups have the number of carbon atoms as indicated.
  • the cycloalkyl moiety of such a group may be substituted as defined herein, with regard to the definition of cycloalkyl.
  • the alkyl moiety may be straight or branched.
  • suitable cycloalkylamino groups include cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino, cyclononylamino and cyclododecylamino.
  • aminoalkyl refers to an alkyl group with an amine substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated. The alkyl moiety of such a group maybe substituted as defined herein, with regard to the definition of alkyl.
  • suitable aminoalkyl groups include aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl and aminohexyl.
  • arylamino refers to an amine group with an aryl substituent. Binding is through the amine group. Such groups have the number of carbon atoms as indicated. The aryl moiety of such a group may be substituted as defined herein, with regard to the definition of aryl.
  • suitable arylamino groups include phenylamino, biphenylamino, methylphenylamino, methoxyphenylamino, tolylamino and chlorophenylamino.
  • alkarylamino refers to an amine group with an alkaryl substituent. Binding is through the amine group. Such groups have the number of carbon atoms as indicated. The alkaryl moiety of such a group may be substituted as defined herein, with regard to the definition of alkaryl. The alkyl moiety may be straight or branched.
  • aminooaralkyl refers to an aralkyl group with an amine substituent. Binding is through the aralkyl group. Such groups have the number of carbon atoms as indicated. The aralkyl moiety of such a group may be substituted as defined herein, with regard to the definition of aralkyl. The alkyl moiety may be straight or branched.
  • aminoalkaryl refers to an alkaryl group with an amine substituent. Binding is through the alkaryl group. Such groups have the number of carbon atoms as indicated.
  • the alkaryl moiety of such a group may be substituted as defined herein, with regard to the definition of alkaryl.
  • the alkyl moiety may be straight or branched.
  • guanidinyl refers to a guanidine group that has had one or more hydrogen atoms removed to form a radical.
  • ureayl refers to a urea group that has had one or more hydrogen atoms removed to form a radical.
  • substituents which are referred to as being on the carbon backbone of a group with a compound definition for example, "alkaryl”
  • the substituent may be on either or both of the component moieties, e.g., on the alkyl and/or aryl moieties.
  • substituents which are referred to as being in the carbon backbone of a group with a compound definition for example, “heteroaralkyl”
  • the substituent may interrupt either or both of the component moieties, e.g., in the alkyl and/or aryl moieties.
  • cyclic systems e.g., cycloalkyl, aryl, heteroaryl, etc.
  • Such systems comprise fused, non-fused and spiro conformations, such as bicyclooctyl, adamantyl, biphenyl and benzofuran.
  • Step a Subcloning and engineering of IMAGE clones encoding the human PTHlR into a mammalian expression vector
  • NCBI database http://www.ncbi.nlm.nih.gov
  • the NCBI database contained 4 mRNA sequences for the human PTHl receptor, having the accession numbers L04308 (Schipani et al. Endocrinology 132, 2157-2165 (1993)), U17418 (Adams et al. Biochemistry, 34, 10553-10559 (1995)), X68596 (Schneider et al. Eur. J. Pharmacol. 246, 149-155 (1993)) and NM_000316 (Hoey et al. Br J Cancer 2003, 88, 567-573). Alignment of these sequences revealed that all four sequences had 100% amino acid identity.
  • the consensus sequence was taken as the wild type (WT) sequence.
  • IMAGE clones Integrated Molecular Analysis of Genomes and their Expression
  • HGMP Human Genome Mapping Project, Cambridge, U.K.
  • Plasmid DNA was prepared using EndoFreeTM plasmid Maxi-prep columns (Qiagen). The DNA was then sequenced using primers 1-5 (see Table 1).
  • the Maxi-prep plasmid DNAs for clones 5183607 and 5186838 were amplified by PCR (polymerase chain reaction) from the start codon to the stop codon using primers 6 and 7, containing Eco Rl (Promega) and Xba I (Promega) restriction sites, respectively.
  • the PCR was performed in 2OmM Tris-HCl (pH 8.8), 1OmM KCl, 1OmM (NHO 2 SO 4 , 2mM MgCl 2 , 0.2mM dNTP containing 0.1 ⁇ M of each primer and Ing of the template DNA.
  • a hot start PCR was used: the reactions were denatured for 2min at 95 0 C, cooled to 75 0 C, then IU of Taq Polymerase (hivitrogen) was added and the reactions were cycled 30 times at 95 0 C for lmin, 55 0 C for 30sec and 72 0 C for 3min. After a final extension at 72 0 C for 5min, the samples were cooled to 4 0 C and analysed by electrophoresis.
  • PCR products from IMAGE clones 5183607 and 5186838 were purified separately using the MinEluteTM PCR purification kit.
  • 5 ⁇ g of the 1.8kb PCR product generated from IMAGE clone 5183607 (N138S mutation) was restriction-digested with Eco Rl and Kpn I in buffer E (Promega, 6mM Tris-HCl, 6mM MgCl 2 , 10OmM NaCl, pH 7.5, ImM DTT) containing O.l ⁇ g/ ⁇ l BSA at 37 0 C for Ih 40min.
  • Both PCR fragments i.e. 60ng of the 337bp fragment and 280ng of the 1.4kb fragment
  • PCR fragments were ligated together in a single ligation reaction in the presence of lOOng of Eco Rl I Xba I digested and shrimp alkaline phosphatase (Promega) treated mammalian expression vector using the QuickStickTM DNA Ligation kit (Bioline). After 15 min at room temperature, 2.5 ⁇ l of the ligation mix was transformed into lOO ⁇ l XLl -Blue competent cells (Stratagene).
  • DNA from eleven of the resulting transformed colonies was prepared using plasmid Mini prep columns (Qiagen) according to the manufacturer's instructions. Of the ten clones that were positive (as determined by restriction digestion of the miniprep DNA), DNA was prepared from one positive clone using the plasmid Maxi-prep columns. The resulting DNA was then fully sequenced by MWG-Biotech AG (Ebersberg, Germany) on both strands using primers 2 and 8-12 (see Table 1). Sequence analysis revealed 100% amino acid identity within the coding region compared to sequence L04308 (WT human PTHlR).
  • HEK293 cells from the European Collection of Cultures were cultured in Minimal Essential Media (with Earle's Salts) (hivitrogen), containing 2mM Glutamaxl (Invitrogen), 10% heat-inactivated foetal bovine serum (Invitrogen), Ix non-essential amino acids (hivitrogen).
  • Cells (2.1 x 10 6 ) were seeded into 100mm x 20mm dishes (Corning) and transfected the following day using the TransfastTM reagent (Promega), using either 13, 26 or 31 ⁇ g of the plasmid DNA containing the engineered hPTHlR per dish, at a ratio of 1:1 (TransfastTM reagentDNA).
  • the cells were trypsinised (Culture of Animal Cells, a Manual of Basic Techniques; 4th ed.; Freshney, R. Wiley Press) and seeded in duplicate 35mm x 10mm dishes at low densities (10,000, 2,500 or 500 cells/dish) in media containing 800 ⁇ g/ml G-418. The remainder of the cells were kept for whole cell radioligand binding analyses.
  • the plated cells were selected for 20 days, with media changes every 3-4 days, using 10% conditioned media from untransfected HEK293 cells, until individual colonies appeared visible to the naked eye. Cloning rings were used to isolate individual, well-separated colonies and trypsinisation was used to transfer the cells in each colony to a suitable vessel for expansion.
  • the cells were expanded and analysed by RT-PCR and radioligand binding analysis.
  • Media containing 400 ⁇ g/ml G-418, was used for routine culture of the HEK293/hPTHlR cell lines.
  • Cells were trypsinised and used straight away for whole cell radioligand binding assays or frozen as a pellet on dry ice then stored at -8O 0 C for membrane-based radioligand binding assays.
  • Step c Clonal selection Stable clones, with the greatest expression of the human PTHj receptor, were selected by establishing the specific binding of [ 125 I]-[NIe 8 ' 18 , Tyr 34 ]-hPTH(l-34) at a range of cell concentrations (2.5 x 10 4 - 7.5 x 10 5 cell ml "1 ) using assay conditions previously described (ORLOFF, J.G., WU, T.L., HEATH, H. W., BRADY, T.G., BRINES, M.L. & STEWART, A.F. J. Biol. Chem., (1989), 264, 6097-6103).
  • clone 9B3 was selected because it gave the highest amount of specific binding (74% and 4911cpm) at an added cell concentration of 1 x 10 5 cell niTW [ 125 I]-[NIe 8 ' 18 , Tyr 34 ]-hPTH(l-34) concentration of 2OpM. hi addition, there was a linear relationship between cell concentration and specific binding.
  • Step e Incubation conditions
  • membranes were prepared as described in step d and used at a concentration of 3 x 10 4 cells ml "1 .
  • Non-specific binding was defined with PTH( J-34) (50 ⁇ l; lO ⁇ M).
  • competition 200pM
  • saturation 2pM-300nM
  • Step g Competition studies A number of reference compounds and compounds of the invention were tested for their ability to compete for human PTH 1 receptors labelled with [ 125 I]-[NIe 8 ' 18 , Tyr 34 ]-hPTH(l-34). Compounds were diluted and added to 96 well plates together with radioligand and membranes using a Beckman Biomek. The ability of compounds to inhibit specific binding was determined in at least two experiments, in triplicate and over a range of concentrations at half-log unit intervals. Compound affinity values (pICso; mid-point curve location) and mid-point slope parameter (nu) were derived through fitting competition data to the Hill equation (Graph-Pad Prism).
  • Dissociation constants were determined using the Cheng & Prusoff equation (1973) to correct for the receptor occupancy of the ligand. In practice pIC 5 o values are equivalent to pKj values due to the low occupancy of the radioligand.
  • the PK 1 values for reference compounds are shown in the table below.
  • Step a Cell culture and harvesting
  • Human SaOS2 cells obtained from the ATCC were seeded into Tl 75 cm 2 dishes and grown in McCoys 5 A medium containing 2mM glutamax and 10% foetal bovine serum (FBS) (1.7 million cells). Cells were maintained at 37 0 C in 5% C ⁇ 2 /humidified air the media being changed every 3-4days. On the 13 th day of culture the media was changed to OptiMEM medium. The following day the cell culture medium was removed and the monolayer briefly washed in 1OmL Hank's buffered salt solution (HBSS). Hanks based cell dissociation medium (1OmL) was added and left for 5min at 37 0 C and cell detachment was aided by gently tapping the culture flask.
  • HBSS Hank's buffered salt solution
  • Step b Preparation of drug solutions hHPTH(l-34), hPTHrP(l-34), [Nle 30 ]-hTIP(7-39) and hTIP(l-39) were dissolved in 20% ultra high purity (UHP) water and 80% ethanol to provide a stock concentration of ImM.
  • CFM cell freezing medium
  • Step d Opimisation of cell concentration for PTH induced accumulation of cAMP
  • hHPTH(l-34) was diluted in RPMI containing 25mM HEPES (20pM-20 ⁇ M) and aliquoted in triplicate (5 ⁇ l) into 384-well OptiPlates prior to the addition of SaOS-2 whole cells (5 ⁇ l, 3x10 5 , 6XlO 5 HiL '1 ).
  • the assay was terminated by addition of detection buffer after 120min at 21 ⁇ 3°C.
  • TopSEAL-A film was affixed to each plate and the plate was placed on a plate shaker for 90min. Following a 16h incubation the plates were counted on an EnVision (PerkinElmer) counter. A cell concentration of 6x10 5 cells mL "1 was chosen for the experiments.
  • Step e Establishing optimal assay stimulation times Basal and hPTH(l-34)-stimulated cAMP accumulation was determined by incubating whole cells at 21+3 0 C (5 ⁇ l, 6xlO 5 cells mL "1 ) for increasing time intervals with RPMI containing 25mM HEPES (5 ⁇ l) and hPTH(l-34) (5 ⁇ l, 20pM-20mM) respectively.
  • the assay was terminated by addition of detection buffer, Alexa Fluor ® 647-anti cAMP antibody, 2.5mM IBMX and 0.2-0.5% BSA was added to the cells to stop degradation or further productin of cAMP.
  • TopSEAL-A film was affixed to each plate and the plate was placed on a plate shaker for 90min.
  • cAMP formation in response to PTH-R ligands was measured in whole cells seeded in 384-well Optiplates plates using FRET-based LANCE technology (PerkinElmer). Briefly, cells, 3xlO 3 per well were incubated in stimulation buffer consisting of RPMI containing 25mM HEPES (pH7.4), bacitracin O.SmgmL "1 , IBMX 2.5mM and rolipram ImM and actiated by 120 min exposure to the PTH-R ligands.
  • stimulation buffer consisting of RPMI containing 25mM HEPES (pH7.4), bacitracin O.SmgmL "1 , IBMX 2.5mM and rolipram ImM and actiated by 120 min exposure to the PTH-R ligands.
  • Antagonist potency was determined by pre- incubating the cells with antagonist for 30min before addition to 384-well Optiplates plates containing PTH-R agonists. Finally, detection mix containing the Alexa Fluor ® 647-anti cAMP antibody, 2.5mM IBMX and 0.2-0.5% BSA was added to the cells to stop degradation or further production of cAMP.
  • Step f Assay characterisation with PTH-R ligands
  • Ligands (hPTH(l-34), hTIP(l-39), hPTHrP(l-34) and [Nle 30 ]-hTIP(7-39)) were serially diluted into RPMI containing 25mM HEPES and aliquoted (5 ⁇ l) in triplicate into Optiplates (2XlO "11 ⁇ XIO -5 M) prior to the addition of whole cells resuspended in RPMI containing 25mM HEPES, 5mM IBMX and 2mM rolipram (5 ⁇ l; 5x10 6 cells/ mL).
  • a cAMP standard curve, defined in triplicate was included in each assay.
  • PTHi receptor peptide antagonists namely hPTHrP(7-34) and [Nle 30 ]-hTIP(7-39) to inhibit hPTH(l- 34)- and hPTHrP(l-34)-stimulated cAMP production.
  • Antagonists were preincubated with cells for a standard 30min.
  • a cAMP standard curve defined in triplicate was included in each assay.All data was analysed using GraphPad Prism software to determine P[A] 5O , upper asymptote ( ⁇ ) and mid-point slope parameter (n ⁇ - equivalent to the Hill slope). The values below are estimated by logistic fitting of the mean data (triplicates) obtained from n experiments where p[A] 5 o is the midpoint location of the agonist concentration-effect curve and n H is the midpoint slope parameter of the curve.
  • Affinity estimates (pA 2 and pK ⁇ values) were mathematically derived from either single (JpA 2 ) or multiple concentrations (pK ⁇ ) of antagonist.
  • DCM dichloromethane
  • DCE 1,2-dichloroethane
  • EtOAc ethyl acetate
  • THF tetrahydrofuran
  • DMF N,N-dimethylformamide
  • the reaction mixture was allowed to warm to ambient temperature and was washed with H 2 O
  • step f 120mg, 0.12mmol was dissolved in 4N HCl in dioxan (1OmL) and stirred at ambient temperature for Ih. The solvent was removed at reduced pressure and the residue was diluted with DCM (2OmL) and reconcentrated. Et 2 O was added and the solvent was evaporated to afford the title compound as the HCl salt (75mg, 34%).
  • HCl salt of the title compound was obtained using steps f and g of example 1 except that methyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester was used in step f in place of ⁇ -N-tert- butoxycarbonylamino cyclopentanecarboxaldehyde.
  • Example 4 ⁇ -Chloro- ⁇ -cyclohexyl-l- ⁇ - ⁇ -methylamino-ethylaminoJ-pyridin ⁇ -ylJ-S- (tetrahydro-pyran-4-y I)-IH-1 , 3, 4-benzot ⁇ azepin-2(3H)-one
  • Step a l-(5-Amino-pyridin-2-yl)-8-chloro-5-cycloheocyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4- benzotriazepin-2(3H)-one was obtained using steps a, and steps c-e of example 1 except that 3- chloro aniline was used in step a in place of m-toluidine.
  • the HCl salt of the title compound was obtained using steps f and g of example 1 except that 1 -(5-amino-pyridin-2-yl)-8-chloro-5-cyclohexyl-3-(tetrahydro-pyran-4-yl)- 1 H- 1 ,3 ,4- benzotriazepin-2(3H)-one and methyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester were used in step f in place of l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)- lH-l,3,4-benzotriazepin-2(3H)-one and 1-N-fert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively.
  • Example 5 5-Cyclohexyl-8-methoxyA-(5-(2-methylamino-ethylamino)-pyridin-2-yl)-S- (tetrahydro-pyran-4-yl)-lH-l, 3, 4-benzotriazepin-2(3H)-one
  • Step a 5-Cyclohexyl-8-methoxy-l-(5-nitro--py ⁇ din-2-yl)-3-(tetrahydro-pyran-4-yl)-lH-l, 3, 4- benzotriazepin-2(3H)-one was obtained using steps a, c and d of example 1 except that 3- methoxy aniline was used in step a in place of m-toluidine.
  • step a The product from step a (1.39g, 2.91mmol) was dissolved in MeOH-THF (1:1 / 12mL) with 10% Pd/C (150mg) and stirred under a hydrogen atmosphere for 16h. After filtration through a pad of Celite, the solvents were removed at reduced pressure. The residue was purified by chromatography (EtOAc-hexane (1:2)) to afford the product (1.23g, 94%).
  • Step c l-(5-(2-(N-tert-Butoxycarbonyl)methylamino-ethylamino)-pyridin-2-yl)-5-cyclohexyl-8- methoxy-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin ⁇ 2(3H)-one was obtained using step f of example 1 except that l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8-methoxy-3- (tetrahydro-pyran-4-yl)- 1 H- 1 ,3 ,4-benzotriazepin-2(3H)-one and methyl-(2-oxo-ethyl)- carbamic acid tert-butyl ester were used in place of l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8- methyl-3-(tetrahydro-pyran
  • the HCl salt of the title compound was obtained using step g of example 1 except that l-(5-(2- (N-tert-butoxycarbonyl)memylamino-ethylamino)-pyridin-2-yl)-5-cyclohexyl-8-methoxy-3- (tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one was used in place of 1-(5-((1-N- te ⁇ butoxycarbonylammo-cyclopen1yhiiethyl)-arnmo)-pyridin-2-yl)-5-cyclohexyl-8-methyl-3- (tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one.
  • Step a l-(5-(2-Amino-ethylamino)-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4- yl)-lH-l,3,4-benzotriazepin-2(3H)-one was obtained using step f of example 1 except that tert- butyl N-(2-oxoethyl)carbamate was used in step f in place of 1-TV-ter ⁇ -butoxycarbonylamino cyclopentanecarboxaldehyde.
  • step f of example 1 The title compound was obtained using step f of example 1 except that l-(5-(2-amino- ethylamino)-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4- benzotriazepin-2(3H)-one and tetrahydro-4H-pyran-4 ⁇ one were used in place of l-(5-amino- pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l ⁇ -l,3,4-benzotriazepin- 2(3H)-one and 1-N-fert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively.
  • step f of example 1 The title compound was obtained using step f of example 1 except that l-(5-(2-amino- ethylamino)-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4- benzotriazepin-2(3H)-one (Example 6, step a) and acetone were used in place of l-(5-amino- pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin- 2(3H)-one and 1-N-fert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively.
  • Example 8 8-Chloro-5-cyclohexyl-l-(5-(2-dimethylamino-ethylamino)-pyridin-2-yl)-3- (tetrahydro-pyran-4-yl)-lH-l , 3, 4-benzotriazepin-2(3H)-one
  • Example 9 S-Cyclohexyl-S-methoxy-l ⁇ S-fmethyl ⁇ -methylarnino-ethyiyaminoypyridin ⁇ -yl)- 3-(tetrahydro-pyran-4-yl)-lH-l , 3, 4-benzotriazepin-2(3H)-one
  • the HCl salt of the title compound was obtained using steps f and g of example 1 except that l-(5-(2-(N-te ⁇ butoxycarbonyl)methylammo-ethylamino)-pyridin-2-yl)-5-cyclohexyl-8- methoxy-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one (example 5, step c) and formaldehyde were used in step f in place of l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8
  • Step a N'-Isopropyl-hydrazinecarboxylic acid tert-butyl ester was obtained using step b of example 1 except that acetone was used in place of tetrahydro-4H-pyran-4-one.
  • 1 H NMR (CDCl 3 ) 6.12 (IH, br s), 3.85 (IH, br s), 3.12 (IH, m), 1.46 (9H, s), 1.02 (6H, d).
  • Step b 5-Cycloheocyl-3'isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3Hyone was obtained using step c of example 1 except that N'-isopropyl-hydrazinecarboxylic acid tert-butyl ester was used in place of N'-(tetrahydro-pyran-4-yl)-hydrazinecarboxylic acid tert-butyl ester.
  • Step c l-(5-Amino-pyHdin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin- 2(3H)-one was obtained using steps d and e of example 1 except that 5-cyclohexyl-3- isopropyl-8-methyl-l,2-dihydro-lH-l,3,4-benzotriazepin-2(3H)-one was used in step d in place of 5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one.
  • step f of example 1 The title compound was obtained using step f of example 1 except that l-(5-amino-pyridin-2- yl)-5-cyclohexyl-3-isopropyl-8-methyllH-l,3,4-benzotriazepin-2(3H)-one and 1-methyl- piperidine-4-carbaldehyde were used in place of l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8- methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one and 1-N-tert- butoxycarbonylamino cyclopentanecarboxaldehyde respectively.
  • Example 12 5-Cyclohexyl-3-isopropyl-8-methyl-l-(5-(2-methylamino-ethylamino)-pyndin-2- yl)-lH-l, 3, 4-benzotriazepin-2(3H)-one
  • the HCl salt of the title compound was obtained using steps f and g of example 1 except that l-(5-amino-pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3H)- one (example 11, step c) and methyl-(2-oxo-ethyl)-carbamic acid tert-bvtiyl ester were used in step f in place of l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)- lH
  • Step b 6-(5-Cyclohexyl-2, 3-dihydro-8-methyl-2-oxo-3-(tetrahydro-pyran-4-yl)-lH-l, 3, 4- benzotriazepin-l-yl)-nicotinic acid methyl ester was obtained using step d of example 1 except that 6-fluoro-nicotinic acid methyl ester was used in place of 2-fluoro-5-nitro-pyridine.
  • Step d 6-(5-Cyclohexyl-l, 2-dihydro-8-methyl-2-oxo-3-(tetrahydro-pyran-4-yl)-lH-l, 3, 4- benzotriazepin-l-yl)-pyridine-3-carbaldehyde DMSO (113 ⁇ L, 1.5mniol) in DCM (5mL) was added dropwise to a solution of oxalyl chloride (108mg, 0.86mmol) in DCM (5mL) at -78°C.
  • Example 14 l-(5-((J-Amino-cyclopentylmethyl)-amino)-py ⁇ din-2-yl)-5-cyclohexyl-8-methyl- 3-isopropyl-lH-l, 3, 4-benzot ⁇ azepin-2(3H)-one
  • Step a l-fS-ffl-N-tert-Butoxycarbonylamino-cyclopentylmethylJ-aminoJ-pyridin ⁇ -yfy-S- cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3H)-one was obtained using the method of example 1 step f, except that l-(5-amino-pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8- methyl-lH-l,3,4-benzotriazepin-2(3H)-one (example 11, step c) was used in
  • Step a l-(5-((l-(N-tert-Butoxycarbonyl-N-methylamino)cyclopentylmethyl)amino)pyridin-2- yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotTiazepin-2(3H)-one was obtained using the method of example 1 step f, except that l-(5-amino-pyridin-2-yl)-5-cyclohexyl-3- isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3H)-one (example 11, step c) and l-(N-tert- butoxycarbonyl-N-methylamino) cyclopentanecarboxaldehyde were used in place of l-(5- amino-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran
  • the title compound was obtained using the method of example 14 step b, except that l-(5-((l- (N-tert-butoxycarbonyl-N-methylamino)cyclopentylmethyl)amino)pyridin-2-yl)-5-cyclohexyl- 3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3H)-one was used in place of l-(5-((l-N-tert- butoxycarbonylamino-cyclopentyknethyl)-amino)-pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8- methyl-lH-l,3,4-benzotriazepin-2(3H)-one.
  • Step a 5-Cyclohexyl-8-methyl-l-(5-(3-(phthalimido)propylamino)pyridin-2-yl)-3-(tetrahydro- 2H-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one was obtained using the method of example 1 step f, except that 3-(l,3-dioxoisoindolin-2-yl)propanal (J. Joossens et al, J. Med. Chem. 2004, 47, 2411) was used in place of 1-N-tert-butoxycarbonylamino cyclopentanecarboxaldehyde.
  • Step b l-(5-(3- ⁇ An ⁇ inopropylamino)pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-2H' pyran-4-yl)-lH-l , 3, 4-benzotriazepin-2(3H)-one
  • the title compound was obtained by the method of example 1 step f, except that l-(5-(3- ammopropylamino)pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-2H-pyran-4-yl)-lH- l,3,4-benzotriazepin-2(3H)-one and tetrahydropyran-4-one were used in place of l-(5-amino- pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-
  • the title compound was obtained by the method of example 1 step f, except that l-(5-(3- aminopropylamino)pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-2H-pyran-4-yl)- IH- l,3,4-benzotriazepin-2(3H)-one (example 16, step b) and acetone were used in place of l-(5- amino-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4- benzotriazepin-2(3H)-one and 1-iV-tert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively.
  • Step a 5-Cyclohexyl-3-isopropyl-8-methyl-l-(5-(3-(phthalimido)ethylamino)pyridin-2-yl)-lH- l,3,4-benzotriazepin-2(3H)-one was obtained by the method of example 1 step f, except that 1- (5-amino-pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3H)- one (example 11, step c) and 2-(l,3-dioxoisoindolin-2-yl)acetaldehyde (R. Thayumanavan, F.
  • Step b l-(5-(2-Amifioethylamino)pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l, 3, 4- benzotriazepin-2(3H)-one was obtained by the method of example 16 step b, except that 5- cyclohexyl-3-isopropyl-8-methyl-l-(5-(3-(phthalimido)ethylamino)pyridin-2-yl)-lH-l,3,4- benzotriazepin-2(3H)-one was used in place of 5-cyclohexyl-8-methyl-l-(5-(3- (phthalimido)propylamino)pyridin-2-yl)-3 -(tetrahydro-2H-pyran-4-yl)- 1 H- 1 ,3 ,4- benzotriazepin-2(3H)-one.
  • Step c The title compound was obtained by the method of example 1 step f, except that l-(5-(2- amdnoethylainino)pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin- 2(3H)-one and 3-furaldehyde were used in place of l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8- methyl-3 -(tetrahydro-pyran-4-yl)- 1 H- 1 ,3 ,4-benzotriazepin-2(3H)-one and 1 -N-tert- butoxycarbonylamino cyclopentanecarboxaldehyde respectively.
  • Step a 5-Cyclohexyl-8-methyl-l-(5-(3-(phthalimido)ethylammo)pyridin-2-yl)-3-(tetrahydro- 2H-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one was obtained using the method of example 1 step f, except that 2-(l,3-dioxoisoindolin-2-yl)acetaldehyde was used in place of ⁇ -N-tert- butoxycarbonylamino cyclopentanecarboxaldehyde.
  • Step b l-fS ⁇ -AminoethylaminoJpyridin ⁇ -ylJS-cyclohexyl-S-methyl-S-ftetrahydro ⁇ H-pyran-
  • Step c l-(5-(2-(4-tert-Butyloxycarbonyl-piperazin-l-yl)ethylamino)pyridin-2-yl)-5-cyclohexyl- 8-methyl ⁇ 3-(tetrahydro-2H-pyran-4-yl)-lH-l,3,4-benzot ⁇ azepin-2(3H)-one was obtained using the method of example 1 step f, except that l-(5-(2-aminoethylamino)pyridin-2-yl)-5- cyclohexyl-8-methyl-3-(tetrahydro-2H-pyi-an-4-yl)-lH-l ,3,4-benzotriazepin-2(3H)-one and N- (tert-butyloxycarbonyl)-4-piperidone were used in place of l-(5-amino-pyridin-2-yl)-5- cyclohexyl-8-methyl
  • the title compound was obtained using the method of example 14 step b, except that l-(5-(2- (4-tert-butyloxycarbonyl-piperazin-l-yl)emylamino)pyridin-2-yl)-5-cyclohexyl-8-methyl-3- (tetrahydro-2H-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one was used in place of l-(5-((l- N-tert-butoxycarbonylamino-cyclopentylmethyl)-amino)-pyridin-2-yl)-5-cyclohexyl-3- isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3H)-one.
  • the title compound was obtained using the method of example 1 step f, except that l-(5-(2- aminoethylamino)pyridin-2-yl)-5-cyclohexyl-3-isopro ⁇ yl-8-methyl-lH-l,3,4-benzotriazephi- 2(3H)-one (example 18 step b) and acetone were used in place of l-(5-amino-pyridin-2-yl)-5- cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one and 1-7V- ter ⁇ -butoxycarbonylamino cyclopentanecarboxaldehyde respectively.
  • Example 23 8-Chloro-5-cyclohexyl-3-isopropyl-l-(5-(2-(tetrahydro-2H-pyran-4- ylamino)ethylammo)pyridin-2-yl)-lH-l,3,4-benzotriazepin-2(3H)-one
  • Step a (2 ⁇ Amino-4-chlorophenyl)(cyclohexyl)methanone was obtained using the method of example 1 step a, except that 3-chloroaniline was used in place of r ⁇ -toluidine.
  • Step b 8-Chloro-5-cyclohexyl-3-isopropyl-lH-l,3,4-benzotriazepin-2(3H)-one was obtained using the method of example 1 step c, except that (2-amino-4- chlorophenyl)(cyclohexyl)methanone and N'-isopropyl-hydrazinecarboxylic acid tert-butyl ester were used in place of (2-amino-4-methyl-phenyl)-cyclohexyl-methanone and N'- (tetrahydro-pyran-4-yl)-hydrazinecarboxylic acid tert-butyl ester respectively.
  • Step c 8 ⁇ Chloro-5-cyclohexyl-3-isopropyl-l-(5-nitropyridin-2-yl)-lH-l, 3, 4-benzotriazepin- 2(3H)-one was obtained using the method of example 1 step d, except that 8-chloro-5- cyclohexyl-3-isopropyl-lH-l,3,4-benzotriazepin-2(3H)-one was used in place of 5-cyclohexyl- 8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one.
  • Step d l-(5-Aminopyridin ⁇ 2-yl)-8-chloro-5-cyclohexyl-3-isopropyl-lH-l, 3, 4-benzotriazepin- 2(3H)-one was obtained using the method of example 1 step e, except that 8-chloro-5- cyclohexyl-3-isopropyl-l-(5-nitropyridin-2-yl)-lH-l,3,4-benzotriazepin-2(3H)-one was used in place of 5-cyclohexyl-8-methyl-l-(5-nitro-pyridin-2-yl)-3-(tetrahydro-pyran-4-yl)-lH-l,3,4- benzotriazepin-2(3H)-one.
  • Step e 8-Chloro-5-cyclohexyl-3-isopropyl-l-(5-(3-(phthalimido)ethylamino)pyridin-2-yl)-lH- l,3,4-benzotriazepin-2(3H)-one was obtained using the method of example 1 step f, except that l-(5-aminopyridin-2-yl)-8-chloro-5-cyclohexyl-3-isopropyl-lH-l,3,4-benzotriazepin-2(3H)- one and 2-(l,3-dioxoisoindolin-2-yl)acetaldehyde were used in place of l-(5-amino-pyridin-2- yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one and 1-iV
  • Step f l ⁇ S ⁇ -Aminoethylaminojpyridin ⁇ -yiyS-chloroS-cyclohexylS-isopropyl-lH-l.
  • SA- benzotriazepin-2(3H)-one was obtained using the method of example 16 step b, except that 8- cMoro-5-cyclohexyl-3-isopropyl-l-(5-(3-(phthalimido)ethylamino)pyridin-2-yl)-lH-l,3,4- benzotriazepin-2(3H)-one was used in place of 5-cyclohexyl-8-methyl-l-(5-(3- (phthalimido)propylamino)pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-lH-l,3,4- benzotriazepin-2(3H)-one.
  • the title compound was obtained using the method of example 1 step f, except that l-(5-(2- aminoethylamino)pyridin-2-yl)-8-chloro-5-cyclohexyl-3-isopropyl-lH-l,3,4-benzotriazepin- 2(3H)-one and tetrahydropyran-4-one were used in place of l-(5-amino-pyridm-2-yl)-5- cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)- IH-1 ,3 ,4-benzotriazepin-2(3H)-one and 1 -N- tert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively.
  • HCl salt of the title compound was obtained using steps f and g of the method of example 1, except that except that l-(5-aminopyrimidin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH- l,3,4-benzotriazepin-2(3H)-one and methyl-(2-oxo-ethyl)-carbamic acid tert-bntyl ester were used in place of l-(5-arnino-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)- lH-l,3,4-benzotriazepin-2(3H)-one and 1-iV-fert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively in step f.

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Abstract

The present invention is concerned with benzotriazepinone derivatives, their intermediates, uses thereof and processes for their production. In particular, the present invention relates to parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrp) receptor ligands, (PTH-1 or PTH/PTHrp receptor ligands). The invention also relates to methods of preparing such ligands and to compounds which are useful as intermediates in such methods.

Description

BENZOTRIAZEPINONE DERIVATIVES Field of the Invention
The present invention is concerned with benzotriazepinone derivatives, their intermediates, uses thereof and processes for their production. In particular, the present invention relates to parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrp) receptor ligands, (PTH-I or PTH/PTHrp receptor ligands). The invention also relates to methods of preparing such ligands and to compounds which are useful as intermediates in such methods.
Background of the Invention
PTH is an 84 amino acid peptide circulating hormone produced by the parathyroid glands. The primary function of PTH is to maintain a constant concentration of calcium in the extracellular fluid. It does so by acting directly or indirectly on various peripheral target tissues to mobilise calcium entry into the blood. Ia turn, PTH synthesis and release are controlled principally by the level of serum calcium. When the concentration of calcium is low, PTH secretion increases but is decreased when the calcium concentration is high. PTH enhances the distal tubular reabsorption of calcium in the kidney (Marcus, R. in The Pharmacological Basis of Therapeutics, 9th Ed. (1996), ppl525-1529, Hardman, J. G.; Goodman Gilman, A. and Limbard, L. E. Ed. (McGraw-Hill)). At the same time, it inhibits the reabsorption of phosphate and stimulates the conversion of vitamin D to 1,25-dihydroxyvitamin D or calcitriol. Calcitriol is secreted into the circulation and interacts with specific receptors in the intestine that contribute to a rise in the plasma calcium concentration by improving the efficiency of gut calcium absorption. PTH also increases the delivery of calcium to the extracellular fluid by increasing overall bone resorption during bone remodelling, hi bone remodeling osteoclast precursor cells are recruited to sites on the bone surface in response to physical or biochemical signals (such as the release of soluble cytokines by osteoblasts, or the expression of membrane-bound signalling proteins on the osteoblast cell surface). Once located at the bone surface these cells are transformed into multinucleated osteoblasts that cause bone lysis by secretion of acid and enzymes thereby generating resorption pits in the bone. Bone remodeling is completed by ingress of preosteoblasts into theses cavities which on progression into osteoblasts deposit bone matrix constituents such as collagen and osteocalcin, amongst other proteins.
Parathyroid hormone related peptide (PTHrp) shares some of the actions of PTH (Clemens, T. L. et al, Br. J. Pharmacol, (2001), 134, 1113-1116). PTHrp is found in three forms of 173, 141 and 139 amino acids and shares significant N-terminal amino acid sequence homology with PTH, particularly within the first 13 residues. Unlike PTH, PTHrp is not normally present in the circulation but is thought to act as a paracrine or autocrine factor. PTHrp regulates chondrocyte growth, differentiation in the growth plates of developing long bones, and branching morphogenesis of the mammary gland. It is also produced by the lactating breast, atria, brain, bone osteoblasts, uterus, bladder, stomach and by a number of tumour cell types including those responsible for prostate, breast, lung, ovarian, bladder and squamous carcinomas and in Leydig tumour cells and other cancers of the kidney.
PTH interacts with two distinct G-protein coupled receptors (Gensure, R. C. et ah, Biochem. Biophys. Res Comm., (2005), 328, 666-678). PTH-I or PTH/PTHrp receptors, hereinafter termed PTH-I receptors, are located predominantly in the kidney and on bone osteoblasts and are responsible for the effects of PTH on calcium homeostasis (Gardella, T. J. and Juppner, H. Trends in Endocrinology and Metabolism, (2001), 12(5), 210-217). They are also found on cancer cells, most particularly in prostate, breast, gastric, ovarian, bladder and Leydig tumours, where they are responsible for the involvement of PTH and/or PTHrp on the primary tumours as well as in the initiation of and progression to bone metastases, hi contrast to PTH, PTHrp is a selective stimulant of PTH-I receptors. PTH-2 receptors are predominantly located in the brain suggesting a distinct physiological role to PTH-I receptors. The N-terminal 39 residues of tuberoinfundibular peptide (TIP39) is a selective stimulant of PTH-2 receptors (Usdin, T. B. et ah, Trends in Endocrinology and Metabolism, (2003), 14(1), 14-19).
Compounds which interact with PTH-I receptors are important because of their potential pharmaceutical use as antagonists, partial inverse agonists, inverse agonists, agonists or partial agonists of the endogenous peptides PTH or PTHrp. Such compounds are described herein as ligands. Thus, the term ligand, as used herein, can mean that the compound is an antagonist, partial inverse agonist, inverse agonist, agonist or partial agonist.
Disruption of calcium homeostasis, resulting from conditions that produce an alteration in the level of PTH, may produce clinical impairment of bone such as osteoporosis, as well as other clinical disorders including, anaemia, renal impairment, ulcers, myopathy and neuropathy.
Hypercalcemia is a condition characterised by elevation of serum calcium and is often associated with primary hyperparathyroidism in which an excess of PTH production occurs.
This is often the result of parathyroid gland adenoma, hyperplasia or carcinoma. On the other hand, humoral hypercalcaemia of malignancy (HHM) results in most instances from
PTHrp-producing squamous, renal, breast, ovarian or bladder carcinomas. Both forms of hypercalcemia may be expected to benefit from a PTH-I receptor antagonist. Cell lines originating from tumours in kidney, breast, prostate, lung and from osteosarcomas have been shown to be capable of growing in response to either PTH or PTHrp. Thus a PTH-I antagonist may have a role in the treatment or prevention of primary tumours, most especially osteosarcoma, clear cell renal carcinoma, and prostate, breast, gastric, ovarian, and bladder cancers, tissue from each of which has been shown to contain both PTH-I receptors and to secrete PTHrp. Furthermore, cancers of the lung, prostate and breast have a propensity for metastasis to bone, a process underpinned by PTH and PTHrp (Guise, T. A. et al, J. Clin. Invest, (1996), 98(7), 1544-1549). PTH-I receptors are present on bone osteoblasts and control the activation of osteoclasts. Osteoclasts act on bone, providing sites for bone metastases to form and resulting in number of factors to b,e released, including PTHrp, which act to stimulate growth of both the primary tumour and of the bone metastases. These actions release more PTHrp leading to a vicious cycle of tumour growth. Thus, in addition to their actions on the primary tumour, PTH-I antagonists may be expected to help treat or prevent bone metastases resulting from these primary cancers. As such, these compounds might be expected to alleviate the clinical sequelae, such as fracture, severe bone pain, spinal cord compression and hypercalcaemia often associated with bone metastases.
PTHrp is also considered to contribute to cachexia, the condition of malnutrition, muscle wasting and net protein loss often associated with cancer patients. As such, PTH-I receptor antagonists may be expected to help prevent this condition, hi addition elevated PTH and/or
PTHrp levels have been associated with lack of hair eruption in transgenic mice, in congestive heart failure and in a number of inflammatory and auotoknmune diseases such as rheumatoid arthritis. These findings suggest a possible role may exist for PTH-I receptor antagonists in helping to treat or prevent these and other conditions either associated with elevated levels of
PTH or PTHrp, or with over-activation of PTH-I receptors.
PTH has an anabolic action on osteoblasts therefore indicating a potential benefit for a PTH-I receptor ligand (such as an agonist or partial agonist) in helping to prevent or treat osteoporosis. Other conditions where such compounds may be considered to have a potential role are, for example, in the treatment of diabetes, in wound healing and other conditions either associated with lowered levels of PTH or PTHrp, or with under-activation of PTH-I receptors.
Various peptide-based ligands for PTH-I receptors have been obtained by modification of the hormones for PTH receptors. Synthetic PTH(I -34) retains the full activity displayed by larger fragments of PTH. Truncation of this fragment from the C-terminal end has in general resulted in less potent agonists. The potency of these ligands, containing the native amnio acid sequence, has also been enhanced by incorporating amino acid substitutions {inter alia Aib for Ala at positions 1 and 3) at the N-terminus. For example, compounds of this type of 21 and 19 (Gensure, R. C. et al, MoI. Endocrinology, (2003), 17(12), 2647-2658) and of 14 amino acid residues in length (Shimuzu, N. et al, J. Biol. Chem., (2001), 276(52), 49003-49012) display agonism in cell based assays. In contrast, based on the behaviour of compounds obtained by truncation of PTH(I -34) from the N-terminal, including amongst others, PTH(7-34) (Nutt, R. F. et al, Endocrinology, (1990), 127(1), 491-493) and PTH/PTHrp(14-34) (Caulfield, M. P. et al, Endocrinology, (1990), 127(1), 83-87 and Abou-Samra, A. B. et al, Endocrinology, (1989), 125(4), 2215-2217), changes of this type have generally afforded partial agonists or antagonists. PTH-I receptor antagonists have been described based on the bovine sequence of PTH (([NIe8'18, D-Trp12, Tyr34]bPTH(7-34)NH2, (BIM-44002)), (Rosen, H. N. et al, Calcif. Tissue Int. (1997), 61, 455-459)) and on the bovine and mouse sequences of TIP, bTEP(7-39) (Hoare, S. R. J. et al, J. Biol Chem., (2000), 275(35), 27274-27283) and mTIP(7-39) (Hoare, S. R. J. and Usdin, T. B. Peptides, (2002), 23(5), 989-998) respectively. Octapeptides containing £>-amino acids are reported to be PTH-I receptor antagonists based on their effects on PTH(l-34) stimulated cAMP in rat osteosarcoma cells (US 2004/ 0235749).
WO-A-03/041714 discloses a number of benzotriazepinone derivatives for use in the treatment of gastrin related disorders.
US Patent No. 5,091,381 describes benzotriazepines which are said to bind to peripheral benzodiazepine receptors.
EP-A-0645378 describes a class of bicyclic compounds which are said to inhibit squalene synthetase.
Summary of the Invention
In a first aspect of the present invention, there is provided a compound of formula (I):
Figure imgf000005_0001
(I) or a salt, solvate or pro-drug thereof; wherein: one of the carbon atoms labelled 6, 7, 8 or 9 may be replaced by a nitrogen atom; R1, R4 and R5 are independently selected from H, COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH5 S(C1-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H5 SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(Ci-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaiyl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(C1-6 alkyl), 0(C6-20 aryl), 0(C7-20 alkaiyl), 0(C7-20 aralkyl), NH2, NH(C1-5 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), NH(C7-20 alkaiyl), NH(C7-20 aralkyl), N(C1-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-20 alkaiyl), N(Ci-6 alkyl)(C7-20 aralkyl), N(C6-20 aryl)2, N(C6-20 aryl)(C7-20 alkaiyl), N(C6-20 aryl)(C7-20 aralkyl), NHC(O)(C1-6 alkyl), NHC(O)(C6-20 aryl), NHC(O)(C7-20 alkaiyl), NHC(O)(C7-20 aralkyl), N(C1-6 alkyl)C(O)(C6-20 aryl), N(C1-6 alkyl)C(O)(C7-20 alkaiyl), N(C1-6 alkyl)C(O)(C7-20 aralkyl), C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)2, C(O)NH(C6-20 aryl), C(O)N(C6-20 aryl)2, C(O)NH(C7-20 aralkyl), C(O)N(C7-20 aralkyl)2, C(O)NH(C7-20 alkaiyl), C(O)N(C7-20 alkaryl)2, C(O)N(C1-6 alkyl)(C6-20 aryl), C(O)N(C1-6 alkyl)(C7-20 alkaiyl), C(O)N(C1-6 alkyl)(C7-20 aralkyl), C(O)N(C6-20 aryl)(C7-20 alkaiyl), C(O)N(C6-20 aryl)(C7-20 aralkyl), NO2, CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(C1-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, SO2N(C1-6 alkyl)(C6-20 aryl), SO2N(C1-6 alkyl)(C7-20 alkaiyl), SO2N(C1-6 alkyl)(C7-20 aralkyl), SO2N(C6-20 aryl)(C7-20 alkaiyl), SO2N(C6-20 aryl)(C7-20 aralkyl), C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaiyl), C(O)(C7-20 aralkyl), OC(O)(C1-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 aralkyl), OC(O)(C7-20 alkaiyl) and C1-30 hydrocarbyl or C1-30 heterocarbyl groups, wherein any of the C1-30 hydrocarbyl or C1-30 heterocarbyl groups are optionally substituted with one or more of the groups, preferably 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (a), (b) and (c):
(a) -CH=CH-, -OC-, S, N, -N=, Si(C1-6 alkyl)2, Si(OH)2, Si(OC1-6 alkyl)2, C(O)NH, C(O)N(C1-6 alkyl), C(O)O, N(C1-6 alkyl)C(O)N(C1-6 alkyl), NHC(O)N(C1-6 alkyl), N(C1-6 alkyl)C(O)O, NHC(O)NH, NHC(O)O, NH, N(C1-6 alkyl), N(C6-20 aryl), N(C7-20 alkaiyl), N(C7-20 aralkyl), O, CO, SO2, NHSO2, NHSO2NH, N(C1-6 alkyl)SO2NH, N(C1-6 alkyl)SO2N(C1-6 alkyl), N(C6-20 aryl)SO2NH, SO, C(O)N(C6-20 aryl), N(C1-6 alkyl)SO2, N(C6-20 aryl)SO2, C(O)NHNHC(O), =N-N- and C(O)NHNH in the backbone; (b) COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaiyl), SH, S(C1-6 alkyl), S(C6-20 aryl), S(C7-20 alkaiyl), S(C7-20 aralkyl), SO2H, SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaiyl), SO2(C7-20 aralkyl), SO(Ci-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaiyl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(Cj-6 alkyl), 0(C6-20 aryl), 0(C7-20 alkaiyl), 0(C7-20 aralkyl), =0, NH2, =NH, NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), NH(C7-20 aralkyl), NH(C7-20 alkaiyl), N(C1-6 alkyl)(C6-20 aryl), N(Ci-6 alkyl)(C7-20 aralkyl), N(Cj-6 alkyl)(C7-20 alkaiyl), =N(Ci-6 alkyl), =N(C6-20 aryl), =N(C7-20 aralkyl), =N(C7.20 alkaiyl), NHC(O)(C1-6 alkyl), NHC(O)(C6-20 aryl), NHC(O)(C7-20 aralkyl), NHC(O)(C7-20 alkaryl), N(C1-6 alkyl)C(O)(C6-20 aryl), N(C1-6 alkyl)C(O)(C7-20 aralkyl), N(C1-6 alkyl)C(O)(C7-20 alkaryl), NO2, CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(C1-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, SO2NH(C7-20 aralkyl), SO2NH(C7-20 alkaryl), SO2N(C1-6 alkyl)(C6-20 aryl), SO2N(C1-6 alkyl)(C7-20 aralkyl), SO2N(C1-6 alkyl)(C7-20 alkaryl), NHSO2(Ci-6 alkyl), NHSO2(C6-20 aryl), NHSO2(C7-20 aralkyl), NHSO2(C7-20 alkaryl), N(C1-6 alkyl)SO2(C1-6 alkyl), N(C1-6 alkyl)SO2(C6-20 aryl), N(C1-6 alkyl)SO2(C7-20 aralkyl), N(C1-6 alkyl)SO2(C7-20 alkaryl), C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl), .C(O)(C7-20 aralkyl), OC(O)(C1-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 aralkyl), OC(O)(C7-20 alkaryl), C(O)NH(C1-6 alkyl), C(O)NH(C6-20 aryl), C(O)NH(C7-20 aralkyl), C(O)NH(C7-20 alkaryl), C(O)N(C1-6 alkyl)2, C(O)N(C1-6 alkyl)(C6-20 aryl), C(O)N(Cj-6 alkyl)(C7-20 aralkyl) and C(O)N(C1-6 alkyl)(C7-20 alkaryl) on the backbone; and,
(c) groups independently selected from the group consisting of CJ-I0 alkyl, C2-J0 alkoxyalkyl, C7-20 alkoxyaryl, Ci2-20 aryloxyaryl, C7-20 aryloxyalkyl, Ci-J0 alkoxy, C6-20 aryloxy, C2-J0 alkenyl, C2-J0 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl and C6-20 aryl on the backbone;
Rla and R5a are independently selected from H, COOH, COOCH3, COOCH2CH3, halo, OH, OCH3, OCH2CH3, OCF3, CF3, CH3, OCCl3, CCl3, OCF2CF31 CF2CF31 NH2, NH(CH3), N(CH3)2, NHC(O)(CH3), NO2, CN, OC(O)CH3 and C(O)H; or R1 is joined to R5, R5a or Rla to form a 5, 6, 7, 8, 9 or 10-membered saturated, unsaturated or aromatic, heterocyclic or carbocyclic ring which is optionally substituted with one or more of the groups, preferably, 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (b) and (c) above; or R5 is joined to R1, R5a or Rla to form a 5, 6, 7, 8, 9 or 10-membered saturated, unsaturated or aromatic, heterocyclic or carbocyclic ring which is optionally substituted with one or more of the groups, preferably, 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (b) and (c) above;
R3 is selected from H, COOH, COO(Cj-20 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(Cj-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, SO2NH(C7-20 aralkyl), SO2NH(C7-20 alkaryl), SO2N(Cj-6 alkyl)(C6-20 aryl), SO2N(Cj-6 alkyl)(C7-20 aralkyl), SO2N(Cj-6 alkyl)(C7-20 alkaryl), SO2N(C6-20 aryl)2, SO2N(C6-20 aryl)(C7-20 aralkyl), SO2N(C6-20 aryl)(C7-20 alkaryl), C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl), C(O)(C7-20 aralkyl), C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)2, C(O)NH(C6-20 aryl), C(O)N(C6-20 aryl)2, C(O)NH(C7-20 aralkyl), C(O)N(C7-20 aralkyl)2, C(O)NH(C7-20 alkaryl), C(O)N(C7-20 alkaryl)2, C(O)N(Ci-6 alkyl)(C6-20 aryl), C(O)N(C1-6 alkyl)(C7-20 aralkyl), C(O)N(C1-6 alkyl)(C7-20 alkaryl), C(O)N(C6-20 aryl)(C7-20 aralkyl), C(O)N(C6-20 aryl)(C7-20 alkaryl) and C1-30 hydrocarbyl or Cj-30 heterocarbyl groups, wherein any of the C1-30 hydrocarbyl or C1-30 heterocarbyl groups are optionally substituted with one or more of the groups, preferably 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (d), (e) and (f):
(d) -CH=CH-, -C≡C-, S, N, -N=, Si(C1-6 alkyl)2, Si(OH)2, Si(OC1-6 alkyl)2, C(O)NH, C(O)N(C1-6 alkyl), C(O)O, N(C1-6 3UCyI)C(O)N(C1 -6 alkyl), NHC(O)N(C1-6 alkyl), N(C1-6 alkyl)C(O)O, NHC(O)NH, NHC(O)O, NH, N(C1-6 alkyl), N(C6-20 aryl), N(C7-20 alkaryl), N(C7-20 aralkyl), O, CO, SO2, NHSO2, NHSO2NH, N(C1-6 alkyl)SO2NH, N(C1-6 alkyl)SO2N(C1-6 alkyl), N(C6-20 aryl)SO2NH, SO, C(O)N(C6-20 aryl), N(C1-6 alkyl)SO2, N(C6-20 aryl)SO2, C(O)NHNHC(O), =N-N- and C(O)NHNH in the backbone; (e) COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH, S(C1-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(C1-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(C1-6 alkyl), 0(C6-20 aryl), 0(C7-20 alkaryl), 0(C7-20 aralkyl), =0, NH2, =NH, NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), NH(C7-20 aralkyl), NH(C7-20 alkaryl), N(C1-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-20 aralkyl), N(C1-6 alkyl)(C7-20 alkaryl), =N(C1-6 alkyl), =N(C6-20 aryl), =N(C7-20 aralkyl), =N(C7-20 alkaryl), NHC(O)(C1-6 alkyl), NHC(O)(C6-20 aryl), NHC(O)(C7-20 aralkyl), NHC(O)(C7-20 alkaryl), N(C1-6 alkyl)C(O)(C6-20 aryl), N(C1-6 alkyl)C(O)(C7-20 aralkyl), N(C1-6 alkyl)C(O)(C7-20 alkaryl), NO2, CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(C1-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, SO2NH(C7-20 aralkyl), SO2NH(C7-20 alkaryl), SO2N(C1-6 alkyl)(C6-20 aryl), SO2N(C1-6 alkyl)(C7.20 aralkyl), SO2N(C1-6 alkyl)(C7-20 alkaryl), NHSO2(C1-6 alkyl), NHSO2(C6-20 aryl), NHSO2(C7-20 aralkyl), NHSO2(C7-20 alkaryl), N(C1-6 alkyl)SO2(C1-6 alkyl), N(C1-6 alkyl)SO2(C6-20 aryl), N(C1-6 alkyl)SO2(C7-20 aralkyl), N(C1-6 alkyl)SO2(C7-20 alkaryl), C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl), C(O)(C7-20 aralkyl), OC(O)(C1-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 aralkyl), OC(O)(C7-20 alkaryl), C(O)NH(C1-6 alkyl), C(O)NH(C6-20 aryl), C(O)NH(C7-20 aralkyl), C(O)NH(C7-20 alkaryl), C(O)N(C1-6 alkyl)2, C(O)N(C1-6 alkyl)(C6-20 aryl), C(O)N(C1-6 alkyl)(C7-20 aralkyl) and C(O)N(C1-6 alkyl)(C7-20 alkaryl) on the backbone; and, (f) groups independently selected from the group consisting of C1-10 alkyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, C12-20 aryloxyaryl, C7-20 aryloxyalkyl, C1-10 alkoxy, C6-20 aryloxy, C2-10 alkenyl, C2-10 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl and C6-20 aryl on the backbone;
R2 is a group
Figure imgf000009_0001
wherein:
Z, Z1 and Z2 are selected from the group consisting of C and N, wherein Z and Z1 are not the same; n is an integer of 0, 1, 2, 3, 4 or 5; m is an integer of 0, 1, 2, 3, 4 or 5; n1 is an integer of 0 or 1; m1 is an integer of 0 or 1 ; m2 is an integer of 0, 1, 2, 3, 4 or 5; wherein the groups -(CH2)m- and -(CH2)m 2- are optionally independently substituted by 1 or more -OH groups on the CH2 backbone, preferably 1 -OH group; wherein the -(O)1n 1- and -(O)n 1- groups are not directly linked to one another;
R7 and R8 are independently selected from the group consisting of H, COOH, COO(Ci-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH, S(C1-6 alkyl), SO2H, SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(C1-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(C1-6 alkyl), NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NHC(O)(C1-6 alkyl), NO2, CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(C1-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl) and C(O)(C7-20 aralkyl), and hydrocarbyl or heterocarbyl groups selected from Ci-20 alkyl, C2-20 alkenyl, Ci-20 alkoxy, C2-20 alkoxyalkyl, C6-30 aryloxy, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-3O alkaryl, C6-30 aryl, Ci-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl and C3-30 heterocyclylalkyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups, preferably 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (g), (h) and (i):
(g) -CH=CH-, -C≡C-, S, N, -N=, Si(Ci-6 alkyl)2, Si(OH)2, Si(OCi-6 alkyl)2, C(O)NH, C(O)N(Ci-6 alkyl), C(O)O, N(Ci-6 alkyl)C(O)N(C1-6 alkyl), NHC(O)N(Ci-6 alkyl), N(Ci-6 alkyl)C(O)O, NHC(O)NH, NHC(O)O, NH, N(Ci-6 alkyl), N(C6-20 aryl), N(C7-20 alkaryl), N(C7-20 aralkyl), O, CO, SO2, NHSO2 and C(O)NHNH in the backbone;
(h) COOH, COO(Ci-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH,
S(C1-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H, SO2(Ci-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(C)-6 alkyl), SO(C6-20 aryl),
SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, O(C,-6 alkyl), 0(C6-20 aryl),
0(C7-20 alkaryl), 0(C7-20 aralkyl), =0, NH2, =NH, NH(C1-6 alkyl), N(C1-6 alkyl)2, =N(C1-6 alkyl), NHC(O)(C1-6 alkyl), NO2, CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(Ci-6 alkyl)2,
SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl) and C(O)(C7-20 aralkyl) on the backbone; and,
(i) groups independently selected from the group consisting of C1-10 alkyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, C12-20 aryloxyaryl, C7-20 aryloxyalkyl, C1-I0 alkoxy, C6-20 aryloxy, C2-10 alkenyl, C2-10 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl and C6-20 aryl on the backbone; when n is 1 or more, -(O)m 1-(CH2)m-(O)n 1-(CH2)m 2-R6 is located in the ortho, meta or para position relative to the -(CH2)n- group; when n is O, -(O)m 1-(CH2)m-(O)n 1-(CH2)m 2-R6 is located in the meta or para position relative to the N1 atom (the N1 atom being shown in the representative structure of compound of formula (I) above);
R6 is selected from the group consisting of NR9R10, CONR9R10, NR9COR10, R19, NR9C(=NR15)N(R14)2 and N=C(NR15R9)N(R14)2; wherein:
R9 is selected from the group consisting of H and Ci-6 alkyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C6-20 aryl, C7-20 aralkyl, C7-20 alkaryl, C1-20 heteroaryl and C2-20 heterocyclyl;
R10 is selected from the group consisting of, H, C1-20 alkyl, C2-20 alkenyl, C2-20 alkoxyalkyl, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, C1-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, Cg-30 heterocyclylalkaryl, C4-30 heterocyclylalkoxyalkyl,
C4-30 heterocyclylalkylaminoalkyl, C4-30 heterocyclylaminoalkyl, C8-30 heteroarylalkaryl, C3-30 heteroarylalkoxyalkyl, C3-30 heteroarylalkylarninoalkyl, C7-30 aryloxyalkyl, C7-30 arylarninoalkyl, C7-30 alkylaminoaryl, Ci-20 aminoalkyl, C7-20 aminoaralkyl, C7-20 aminoalkaryl,
C2-20 alkylguanidinylalkyl and ureayl Ci-I0 alkyl; or, in the groups NR9R10 and CONR9R10, R9 and R10 may be joined to form a 3, 4, 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring; any of the groups defined as R10 (except H) being optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from C1-I0 alkyl, C1-20 haloalkyl, C1-20 perhaloalkyl, C1-20 hydroxyalkyl, C3-10 cycloalkyl, halo, OH, OC1-6 alkyl, NH2, OC(C1-6 alkyl), OC(C6-20 aryl), OC(C7-20 aralkyl), OC(C7-20 alkaryl), OCO(C1-6 alkyl), OCO(C6-20 aryl), OCO(C7-20 aralkyl), OCO(C7-20 alkaryl), COOH, COO(Ci-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), N(C6-20 aryl)2, NH(C7-20 aralkyl), N(C7-20 aralkyl)2, NH(C7-20 alkaryl), N(C7-20 alkaryl)2, N(Ci-6 alkyl)(C6-20 aryl), N(Cj-6 alkyl)(C7-20 alkaryl), N(Ci-6 alkyl)(C7-20 aralkyl), N(C6-20 aryl)(C6-20 aryl), N(C6-20 aryl)(C7-20 alkaryl), N(C6-20 aryl)(C7-20 aralkyl), NO2, CN, C(O)H, C(O)(Cj-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 aralkyl) and C(O)(C7-20 alkaryl); any of the groups defined as R10 (except H) being optionally substituted in the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from -CH=CH-, -C=C-, S, N, -N=, Si(C1-6 alkyl)2, Si(OH)2, Si(OC1-6 alkyl)2, C(O)NH, C(O)N(Ci-6 alkyl), C(O)O, N(Ci-6 alkyl)C(O)N(Ci-6 alkyl), NHC(O)N(Ci-6 alkyl), N(Ci-6 alkyl)C(O)O, NHC(O)NH, NHC(O)O, NH, N(C1-6 alkyl), N(C6-20 aryl), N(C7-20 alkaryl), N(C7-20 aralkyl), O, CO, SO2, NHSO2, NHSO2NH, N(Ci-6 alkyl)SO2NH, N(Ci-6 alkyl)SO2N(Ci-6 alkyl), N(C6-20 aryl)SO2NH, SO, C(O)N(C6-20 aryl), N(Cj-6 alkyl)SO2, N(C6-20 aryl)SO2, C(O)NHNHC(O), =N-N- and C(O)NHNH; each R14 is independently selected from the group consisting of H, Ci-20 alkyl, C2-20 alkenyl, C2- 20 alkoxyalkyl, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, Cs-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, Ci-30 heteroaryl and C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, Ci-I0 aminoalkyl, C6-20 aminoaryl, guanidinyl C1-I0 alkyl, C2-20 alkylguanidinylalkyl, ureayl C1-I0 alkyl and C2-20 alkylureaylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, OH, OC1-6 alkyl, NH2,
COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl),
OC(O)(C1-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 aralkyl), OC(O)(C7-20 alkaryl), NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), N(C6-20 aryl)2, NH(C7-20 aralkyl), N(C7-20 aralkyl)2,
NH(C7-20 alkaryl), N(C7-20 alkaryl)2, N(Cj-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-20 aralkyl), N(C1-6 alkyl)(C7-20 alkaryl), N(C6-20 aryl)(C7-20 aralkyl), N(C6-20 aryl)(C7-20 alkaryl), NO2, CN,
C(O)H and C(O)(C1-6 alkyl), or each R14 is joined to one another to form a 5, 6, 7, 8, 9 or
10-membered, saturated, unsaturated or aromatic heterocyclic ring;
R15 is selected from the group consisting of H, CN, Ci-20 alkyl, C2-20 alkenyl, C2-20 alkoxyalkyl,
C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, C1-30 heteroaryl and C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-3O heterocyclylalkyl, Ci-10 aminoalkyl, C6-2O aminoaryl, guanidinyl C1-1O alkyl, C2-20 alkylguanidinylalkyl, ureayl Ci-Io alkyl and C2-2O alkylureaylalkyl, any of which (except H) are optionally on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, OH, OCj-6 alkyl, NH2, COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), N(C6-20 aryl)2, NH(C7-20 aralkyl), N(C7-20 aralkyl)2, NH(C7-20 alkaryl), N(C7-20 alkaryl)2, NO2, CN, C(O)H and C(O)(C1-6 alkyl); or R15 and one of R14 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R14 not joined to R15 is H or C1-6 alkyl; and, R19 is selected from the group consisting of H, -C(=NH)NH2, -C(=NH)NHC1-20 alkyl, -C(=NH)N(C1-20 alkyl)2, -C(=NH)NHC3-30 cycloalkyl, -C(=NH)N(C3-30 cycloalkyl)2, -C(=NH)NHC6-30 aryl, -C(=NH)N(C6-30 aryl)2, -C(=NH)NHC6-30 alkaryl, -C(=NH)N(C6-30 alkaryl)2, -C(=NH)NHC6-30 aralkyl, -C(=NH)N(C6-30 aralkyl)2, -C(=NH)NHC2-30 heterocyclyl, -C(=NH)N(C2-30 heterocyclyl)2, -C(=NH)NHCi-30 heteroaryl, -C(=NH)N(Cj-30 heteroaryl)2, -C(=NC1-20 alkyl)NH2, -C(=NC1-20 alkyl)NHC1-20 alkyl, -C(=NC1-20 alkyl)N(C1-20 alkyl)2, -C(=NC1-20 alkyl)NHC3-30 cycloalkyl, -C(=NC1-20 alkyl)N(C3-30 cycloalkyl)2, -C(=NC1-20 alkyl)NHC6-30 aryl, -C(=NC1-20 alkyl)N(C6-30 aryl)2, -C(=NC1-20 alkyl)NHC6-30 alkaryl, -C(=NC1-20 alkyl)N(C6-30 alkaryl)2, -C(=NC1-20 alkyl)NHC6-30 aralkyl, -C(=NC1-20 alkyl)N(C6-30 aralkyl)2, -C(=NCi-20 alkyl)NHC2-30 heterocyclyl, -C(=NC1-20 alkyl)N(C2-30 heterocyclyl)2, -C(=NC1-20 alkyl)NHC1-30 heteroaryl, -C(=NC1-20 alkyl)N(Cj-30 heteroaryl)2, C1-20 alkyl, C2-20 alkenyl, C2-20 alkoxyalkyl, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, C1-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, Cg-30 heterocyclylalkaryl, C4-30 heterocyclylalkoxyalkyl, C4-30 heterocyclylalkylaminoalkyl, C8-30 heteroarylalkaryl, C3-30 heteroarylalkoxyalkyl, C3-30 heteroarylaUsylaminoaUcyl, C7-3O aryloxyalkyl, C7-30 arylaminoalkyl, C7-30 alkylaminoaryl, Ci-1O aminoalkyl, C7-2O aminoaralkyl, C7-2O aminoalkaryl, C2-20 alkylguanidinylalkyl and ureayl C1-I0 alkyl; any of the groups defined as R19 (except H) being optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from C1-10 alkyl, C1-2O haloalkyl, Ci-2O perhaloalkyl, Cj-2O hydroxyalkyl, C3-I0 cycloalkyl, halo, OH, OC1-6 alkyl, NH2, OC(C1-6 alkyl), OC(C6-20 aryl), OC(C7-20 aralkyl), OC(C7-20 alkaryl), OCO(C1-6 alkyl), OCO(C6-20 aryl), OCO(C7-20 aralkyl), OCO(C7-20 alkaryl), COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), NH(Ci-6 alkyl), N(Ci-6 alkyl)2, NH(C6-20 aryl), N(C6-20 aryl)2, NH(C7-20 aralkyl), N(C7-20 aralkyl)2, NH(C7-20 alkaryl), N(C7-20 alkaryl)2, N(Ci-6 alkyl)(C6-20 aryl), N(Ci-6 alkyl)(C7-20 alkaryl), N(Ci-6 alkyl)(C7-20 aralkyl), N(C6-20 aryl)(C6-20 sayϊ), N(C6-20 aryl)(C7-20 alkaryl), N(C6-20 aryl)(C7-20 aralkyl), NO2, CN, C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 aralkyl) and C(O)(C7-20 alkaryl); any of the groups defined as R19 (except H) being optionally substituted in the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from -CH=CH-, -C≡C-, S, N, -N=, Si(C1-6 alkyl)2, Si(OH)2, Si(OCx-6 alkyl)2, C(O)NH, C(O)N(C1-6 alkyl),
C(O)O, N(Ci-6 alkyl)C(O)N(C1-6 alkyl), NHC(O)N(C1-6 alkyl), N(Ci-6 alkyl)C(O)O,
NHC(O)NH, NHC(O)O, NH, N(C1-6 alkyl), N(C6-20 aryl), N(C7-20 alkaryl), N(C7-20 aralkyl), O,
CO, SO2, NHSO2, NHSO2NH, N(C1-6 alkyl)SO2NH, N(C1-6 alkyl)SO2N(Ci-6 alkyl), N(C6-20 aryl)SO2NH, SO, C(O)N(C6-20 aryl), N(C1-6 alkyl)SO2, N(C6-20 aryl)SO2, C(O)NHNHC(O), =N-N- and C(O)NHNH.
Preferably, the groups -(CH2)m- and -(CH2)m 2- are substituted by 1 -OH groups on the CH2 backbone. Preferably, in each compound of formula (I), only one of the groups -(CH2)m- and -(CH2)m 2- is substituted . hi a preferred embodiment, neither of the -(CH2)m- and -(CH2)m 2- groups are substituted by -OH groups. Preferably, when m is O, either or both of m1 and n1 is O.
The groups -(O)n,1- and -(O)n 1- groups are not directly bonded to one another, i.e., there is no O-O bond.
Preferably, when n1 is O, m2 is O. Preferably, n, n1, m, m1 and m2 are all O. Preferably, Z is N and Z1 is C. Preferably, Z2 is C.
In a preferred embodiment, Z is N, Z1 is C and Z2 is N. In another embodiment, Z is N, Z1 is C and Z2 is C.
Preferably, R2 is selected from the group consisting of the structures (i), (ii) and (iii) shown below:
Figure imgf000014_0001
wherein, n, n1, m, m1, m2, R6, R7 and R8 have the same meaning as above; and the groups -(CH2)m- and -(CH2)m 2- are optionally independently substituted by 1 or more -OH groups on the CH2 backbone, preferably 1 -OH group.
With regard to the structures (i), (ii) and (iii), when n is 1 or more, -(O)m 1-(CH2)m-(O)n 1- (CH2)m 2-R6 is located in the ortho, meta or para position relative to the -(CH2)n- group; when n is 0, -(O)m l-(CH2)m-(O)n -(CH2)J-R6 is located in the meta or para position relative to the N1 atom (the N1 atom being shown in the representative structure of compound of formula (T) above).
Preferably, R2 comprises the structure (ii).
Preferably, R2 is selected from the group consisting of the structures (ia), (iia) and (iiia) shown below:
Figure imgf000015_0001
wherein R7 and R8 are independently selected from the group consisting of H, C1-6 alkyl, halo, haloC1-6 alkyl, perhaloC1-6 alkyl, OH, NH2, NO2, CN, COOH, C(O)H, C(O)O(C1-6 alkyl) and C(O)(Ci-6 alkyl), R6 is as defined above, wherein n is O or 1, m1 is O or 1, m is 1, 2 or 3, and the group -(CH2)m- is optionally substituted by 1 or more -OH groups on the CH2 backbone, preferably 1 -OH group.
With regard to the structures (ia), (iia) and (iiia), where n is 1 or more, R7 and/or R8 are preferably located in the ortho or meta position relative to the -(CH2)n- group, most preferably the meta position. Where n is O, R7 and/or R8 are preferably located in the ortho or meta position relative to the N1 atom, most preferably the meta position.
With regard to the structures (ia), (iia) and (iiia), when n is 1 or more, -(O)m 1-(CH2)m-R6 is located in the ortho, meta or para position relative to the -(CH2)n- group; when n is O, -(O)n,1- (CH2)m-R6 is located in the meta or para position relative to the N1 atom (the N1 atom being shown in the representative structure of compound of formula (I) above). With regard to the structures (ia), (iia) and (iiia), preferably, R7 is H and R8 is H, Cl, Br, or F, preferably H or Br.
With regard to the structures (ia), (iia) and (iiia), preferably, R7 and R8 are both H. With regard to the structures (ia), (iia) and (iiia), preferably, n is O. With regard to the structures (ia), (iia) and (iiia), preferably, m is O. With regard to the structures (ia), (iia) and (iiia), preferably, m1 is O. In a particularly preferred embodiment, R2 is represented by the structure (iia). Preferably, R2 is a group having the structure (ib) or (iib) shown below:
Figure imgf000016_0001
wherein R7 and R8 are independently selected from the group consisting of H, Ci-6 alkyl, halo, haloC1-6 alkyl, perhaloC1-6 alkyl, OH, NH2, NO2, CN, COOH, C(O)H, C(O)O(C1-6 alkyl) and C(O)(Ci-6 alkyl), R6 is as defined above and n is O or 1.
With regard to the structures (ib) and (iib), where n is 1, R7 and/or R8 are preferably located in the ortho or meta position relative to the -(CH2)n- group, most preferably the meta position. Where n is O, R7 and/or R8 are preferably located in the ortho or meta position relative to the N1 atom, most preferably the meta position.
With regard to the structures (ib) and (iib), when n is 1, -R6 is located in the ortho, meta or para position relative to the -(CH2)n- group; when n is O, -R6 is located in the meta or para position relative to the N1 atom (the N1 atom being shown in the representative structure of compound of formula (I) above), most preferably the para position. With regard to the structures (ib) and (iib), preferably, R7 is H and R8 is H, Cl, Br, or F, more preferably H or Br.
With regard to the structures (ib) and (iib), preferably, R7 and R8 are both H. With regard to the structures (ib) and (iib), preferably, n is O. Preferably, R2 comprises the structure (iib). Preferably, R2 is a group having the structure (ic) or (iic) shown below:
Figure imgf000017_0001
wherein R7 and R8 are independently selected from the group consisting of H, Ci-6 alkyl, halo, OH, NH2 and CN.
With regard to the structures (ic) and (iic), R7 and/or R8 are preferably located in the ortho or meta position relative to the N1 atom, most preferably the meta position.
With regard to the structures (ic) and (iic), -NR9R10 is located in the meta or para position relative to the N1 atom (the N1 atom being shown in the representative structure of compound of formula (I) above).
With regard to the structures (ic) and (iic), preferably, R7 is H and R8 is H, Cl, Br, or F, preferably H or Br.
With regard to the structures (ic) and (iic), preferably, R7 and R8 are both H.
Preferably, R2 comprises the structure (iic).
Preferably, R2 is a group having the structure (id) or (iid) shown below:
Figure imgf000017_0002
Figure imgf000017_0003
Preferably, R2 comprises the structure (iid). With regard to R2, in a particularly preferred embodiment, n, m, m1, n1 and m2 are all 0, and -R6 is located in the meta or para position relative to the notional (CH2)n group, most preferably the para position.
In a preferred embodiment, R2 is selected from the group consisting of ((I H-imidazol-2-yl)methylamino)-pyridinyl, ((I H-imidazol-2-yl)ethylamino)-pyridinyl,
((lH-imidazol-2-yl)propylamino)-pyridinyl, (4,5-dihydro-lH-imidazol-2-ylamino)-pyridinyl, (4,5-dihydro-lH-imidazol-2-yhnethyl)-pyridinyl, ((aminocyclopentyl)methylamino)-pyridinyl, ((methylaminocyclopentyl)methylamino)-pyridinyl, ((piperidinyl)methylamino)-pyridinyl, (methylamino)ethylamino-pyridinyl, ((tetrahydro-pyranylamino)ethylamino)-pyridinyl, ((propylamino)ethylamino)-pyridinyl, ((dimethylamino)ethylamino)-pyridinyl, ((piperidin-4- yl)methylamino)-pyridinyl and ((l-methyl-piperidin-4-yl)methylamino)-pyridinyl. In the above groups, preferably the pyridyl moiety of the R2 group is substituted with the named substituents in the para position relative to the point of attachment of the R2 group to the rest of the compound of formula (I). Preferably, the pyridinyl moiety is a pyridin-2-yl moiety. Preferably, R6 comprises a guanidinyl moiety.
Preferably, R9 is selected from H, methyl, ethyl, propyl, phenyl, phenylethyl, benzyl, tolyl and xylyl, more preferably H or methyl, most preferably H.
Preferably, R10 is selected from the group consisting of Ci-I5 heteroaryl, C2-i5 heterocyclyl, C2-I5 heteroaralkyl, C3-I5 heterocyclylalkyl, Ci-I5 alkyl, C6-20 aryl, C7-20 aralkyl, C3-I5 cycloalkyl and C4-I5 cycloalkylalkyl, any of which are optionally substituted on the backbone with one or more groups, preferably 1 , 2, 3 or 4 groups, independently selected from NH2, NH(Ci-4 alkyl), N(Ci-4 alkyl)2, NH(C6-16 aryl), N(C6-16 aryl)2, NH(C7-J6 aralkyl), N(C7-I6 aralkyl)2, NH(C7-I6 alkaryl), N(C7-J6 alkaryl)2, N(Q-4 alkyl)(C6-i6 aryl), N(C1-4 alkyl)(C7-I6 alkaryl), N(Ci-4 alkyl)(C7-i6 aralkyl), N(C6-I6 aryl)(C7-i6 alkaryl), N(C6-16 aryl)(C7-i6 aralkyl), NH(C2-I5 heterocyclyl), NH(C3-15 heterocyclylalkyl), N(C1-4 alkyl)(C2-i5 heterocyclyl), N(Ci-4 alkyl)(C3-i5 heterocyclylalkyl), S(Ci-6 alkyl), NO2, CN, OH, SH, OCi-6 alkyl, C(O)H and C(O)(Ci-6 alkyl).
Preferably, R10 is selected from the group consisting Of C6-20 aryl, C7-20 aralkyl, C3-15 cycloalkyl, C4-I5 cycloalkylalkyl, C1-I5 heteroaryl, C2-15 heterocyclyl, C2-15 heteroaralkyl, C3-15 heterocyclylalkyl and C1-I0 alkyl, any of which are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from NH2, NH(Ci-4 alkyl) OrN(Ci-4 3UCyI)2.
Preferably, R10 is selected from the group consisting of Ci-10 heteroaryl, C2-I0 heterocyclyl, C3-I0 heteroaralkyl, C4-I5 cycloalkylalkyl, C3-I0 heterocyclylalkyl and Ci-6 alkyl, any of which are optionally substituted on the backbone with one or more groups, preferably 1, 2 or 3 groups, independently selected from NH2, NH(Ci-4 alkyl) or N(Cj-4 alkyl)2.
Preferably, R10 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclooctylethyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl, cyclooctylpropyl, furanyl, furanyl(C1-3 alkyl), pyridyl, pyridyl(Ci-3 alkyl), phthalimido, phthalimido(C1-3 alkyl), thienyl, thienyl(Ci-3 alkyl), pyrrolyl, pyrrolyl(Ci-3 alkyl), imidazolyl, imidazolyl(C1-6 alkyl), pyrazolyl, pyrazolyl(C].3 alkyl), thiazolyl, thiazolyl(Ci-3 alkyl), isothiazolyl, isothiazolyl(C1-3 alkyl), thiazolylmethyl, isothiazolylmethyl, oxazolyl, oxazolyl(C1-3 alkyl), pyrrolidinyl, pyrrolidinyl(Ci.3 alkyl), pyrrolinyl, pyrrolinyl(Ci-3 alkyl), imidazolidinyl, imidazolidinyl(C1-3 alkyl), iniidazolinyl, imidazolinyl(Ci.3 alkyl), imidazolemethyl, dihydroimidazolyl, dihydroimidazolyl(Ci.3 alkyl), dihydroimidazolylmethyl, tetrahydropyrimidinyl, tetrahydropyrimidinyl(Ci.3 alkyl), benzimidazolyl, benzimidazoly^Q^ alkyl), tetrahydroisoquinolinyl, tetrahydroisoquinolyl(Ci.3 alkyl), pyrazolidinyl, pyrazolidinyl(C1-3 alkyl), tetrahydrofuranyl, tetrahyrdofuranyl(Ci.3 alkyl), pyranyl, pyranyl(Ci-3 alkyl), pyridonyl, pyridonyl(C1-3 alkyl), pyronyl, pyronyl(C1-3 alkyl), pyrazinyl, pyrazinyl(Ci-3 alkyl), pyridazinyl, pyridazinyl(Ci..3 alkyl), piperidinyl, piperidiny^Cio alkyl), piperazinyl, piperazinyl(C1-3 alkyl), morpholinyl, morpholinyl(Ci-3 alkyl), thionaphthyl, thionaphthy^C^ alkyl), benzofuranyl, benzofuranyl(C1-3 alkyl), isobenzofuryl, isobenZofury^C^ alkyl), indolyl, indolyl(Cϊ-3 alkyl), oxyindolyl, oxyindonlyl(Ci-3 alkyl), isoindolyl, isoindolyl(C1-3 alkyl), indazolyl, indazolyl(Ci-3 alkyl), indolinyl, indolinyl(C1-3 alkyl), isoindolinyl, isoindolinyl(C1-3 alkyl), isoindazolyl, isoindazolyl(C1-3 alkyl), benzopyranyl, benopyranyl(C1-3 alkyl), coumarinyl, coumarinyl(C1-3 alkyl), isocoumarinyl, isocoumarinyl(Ci_3 alkyl), quinolyl, quinolyl(C1-3 alkyl), isoquinolyl, isoquinolyl(C1-3 alkyl), napthridinyl, naphthridinyl(Ci.3 alkyl), cinnolinyl, CnTnOInIyI(C1-3 alkyl), quinazolinyl, quinazolinyl(C1-3 alkyl), pyridopyridyl, pyridopyridyl(Ci-3 alkyl), benzoxazinyl, benzoxazinyl(C1-3 alkyl), quinoxadinyl, quinoxadinyl(Ci-3 alkyl), chromenyl, chromenyl(Ci-3 alkyl), chromanyl, chromanyl(C1-3 alkyl), isochromanyl, isochromanyl(Ci.3 alkyl), carbolinyl, carbolinyl(C1-3 alkyl), thiophenyl, thiophenyl(C1-3 alkyl), thiazolyl, thiazolinyl(Ci-3 alkyl), isoxazolyl, isooxazolyl(Ci-3 alkyl), isoxazolonyl, isoxazolonyl(C1-3 alkyl), isothiazolyl, isothiazolyl(C1-3 alkyl), triazolyl, triazolyl(C1-3 alkyl), oxadiazolyl, oxadiazolyl(C1-3 alkyl), thiadiazolyl, thiadiazolyl(C1-3 alkyl), pyridazyl, pyridazyl(C1-3 alkyl), any of which are optionally substituted on the backbone with one or more groups independently selected from =0, COOH, SH, SO2H5 P(OH)(O)2, halo, trihalomethyl, OH, NH2, =NH, NH(C1-6 alkyl), =N(C1-6 alkyl), NO2, CN, OCH3, SO2NH2 and C(O)H, Ci-6 alkyl, C2-6 alkoxyalkyl, C7-io alkoxyaryl, C3-I0 cycloalkyl, C4-J5 (cycloalkyl)alkyl, C7-12 aralkyl, C7-I2 alkaryl, Ci-I2 heteroaryl and C6-I2 aryl, most preferably optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, CH3, OH, OCH3, OCH2CH3 and NH2.
Preferably, R10 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclooctylethyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl, cyclooctylpropyl, furanyl, pyridyl, pyridyl(Ci-3 alkyl), phthalimido, phthalimido(C1-3 alkyl), pyrrolyl, pyrrolyl(Ci-3 alkyl), imidazolyl, imidazolyl(Ci-6 alkyl), pyrazolyl, pyrazolyl(C1-3 alkyl), thiazolyl, thiazolyl(Ci-3 alkyl), isothiazolyl, isothiazolyl(C1-3 alkyl), thiazolyhnethyl, isothiazolyhnethyl, oxazolyl, oxazolyl(C1-3 alkyl), pyrrolidinyl, pyrrolidinyl(Ci_3 alkyl), pyrrolinyl, pyrrolinyl(Ci.3 alkyl), imidazolidinyl, imidazolidinyl(Ci-3 alkyl), imidazolinyl, imidazolinyl(Ci.3 alkyl), imidazolemethyl, dihydroimidazolyl, dihydroimidazolyl(Ci-3 alkyl), dihydroimidazolyhnethyl, tetrahydropyrimidinyl, tetrahydropyrimidinyl(Ci.3 alkyl), benzimidazolyl, benzimidazolyl(Ci-3 alkyl), tetrahydroisoquinolinyl, tetrahydroisoquinolyl(Ci-3 alkyl), pyrazolidinyl, pyrazolidinyl(Ci-3 alkyl), pyridonyl, pyridonyl(Ci-3 alkyl), pyrazinyl, PyTaZUIyI(C1-3 alkyl), pyridazinyl, pyridazinyl(C1-3 alkyl), piperidinyl, piperidinyl(C1-3 alkyl), piperazinyl, piperaziny^C]^ alkyl), morpholinyl, morpholinyl(Ci-3 alkyl), indolyl, indolyl(Ci-3 alkyl), oxyindolyl, OXyUIdOnIyI(C1-3 alkyl), isoindolyl, isoindolyl(Ci-3 alkyl), indazolyl, indazolyl(Ci-3 alkyl), indolinyl, indoliny^C]^ alkyl), isoindolinyl, isoindolinyl(C1-3 alkyl), isoindazolyl, isoindazolyl(Ci-3 alkyl), quinolyl, quinolyl(Ci-3 alkyl), isoquinolyl, isoquinolyl(Ci.3 alkyl), quinazolinyl, quinazolinyl(C1-3 alkyl), pyridopyridyl, pyridopyridyl(Ci-3 alkyl), benzoxazinyl, benzoxazinyl(Ci-3 alkyl), quinoxadinyl, quinoxadinyl(Ci-3 alkyl), carbolinyl, carbolinyl(C1-3 alkyl), thiophenyl, thiophenyl(Ci.3 alkyl), thiazolyl, thiazolinyl(Ci-3 alkyl), isoxazolyl, isooxazolyl(Ci-3 alkyl), isoxazolonyl, isoxazolonyl(Ci-3 alkyl), isothiazolyl, isothiazolyl(Ci-3 alkyl), triazolyl, triazolyl(C1-3 alkyl), oxadiazolyl, oxadiazolyl(C1-3 alkyl), thiadiazolyl, thiadiazolyl(Ci-3 alkyl), pyridazyl, pyridazyl(Ci-3 alkyl), any of which are optionally substituted on the backbone with one or more groups independently selected from =0, COOH, SH, SO2H, P(OH)(O)2, halo, trihalomethyl, OH, NH2, =NH, NH(C1-6 alkyl), =N(Ci-6 alkyl), NO2, CN, OCH3, SO2NH2 and C(O)H, C1-6 alkyl, C2-6 alkoxyalkyl, C7-io alkoxyaryl, C3-10 cycloalkyl, C4-15 (cycloalkyl)alkyl, C7-I2 aralkyl, C7-I2 alkaryl, C1-12 heteroaryl and C6-I2 aryl, most preferably optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, CH3, OH, OCH3, OCH2CH3 and NH2. In a particularly preferred embodiment, R10 is selected from the group consisting of cyclopentylmethyl, piperidylmethyl, methylaminoethyl, aminocyclopentyhnethyl, methylaminocyclopentylmethyl, methylaminoethyl, tetrahydro-pyranylaminoethyl, tetrahydro- pyranylaminopropyl, propylaminoethyl, propylaminopropyl, dimethylaminoethyl, furanylmethylaminoethyl, piperidinylmethyl and l-meth.yl-piperidin-4-ylmeth.yl, any of which may be substituted with 1 or more groups independently selected from C1-6 alkyl, halo, haloCi-6 alkyl, hydroxyC1-6 alkyl, perhaloC1-6 alkyl, OH, NH2, NO2, CN, COOH, C(O)H, C(O)O(C1-6 alkyl), 0(C1-6 alkyl), OC(O)(C1-6 alkyl) and C(O)(C1-6 alkyl).
In the optional embodiment where R9 and R10 are joined to form a 3, 4, 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, preferably a 5 or 6-membered, saturated, unsaturated or aromatic heterocyclic ring is formed. Preferred ring systems are selected from the group consisting of 5 or 6-membered heterocyclyl and heteroaryl rings containing 1 or 2 nitrogen atoms. Such rings may additionally comprise 1 or more oxygen and/or sulphur atoms. Preferred ring systems are selected from the group consisting of pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.
Preferably, R10 is not H. Preferably, each R14 is independently selected from the group consisting of H, C1-10 alkyl, C2-10 alkenyl, C2-I0 alkoxyalkyl, C7-20 alkoxyaryl, C2-10 alkynyl, C3-20 cycloalkyl, C4-20
(cycloalkyl)alkyl, Cs-20 cycloalkenyl, C7-20 cycloalkynyl, C7-20 aralkyl, C7-2O alkaryl, C6-20 aryl, C1-20 heteroaryl, C2-2O heterocyclyl, C2-20 heteroaralkyl, C3-20 heterocyclylalkyl, Cj-10 aminoalkyl,
C6-1O aminoaryl, guanidinyl C1-6 alkyl, C2-12 alkylguanidinylalkyl, ureayl C1-6 alkyl and C2-12 alkylureaylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, OH, OCH3, OCH2CH3 and NH2, or each R14 is joined to one another to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring; and,
Preferably, R15 is selected from the group consisting of H, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkoxyalkyl, C7-2O alkoxyaryl, C2-io alkynyl, C3-2O cycloalkyl, C4-20 (cycloalkyl)alkyl, Cs-20 cycloalkenyl, C7-20 cycloalkynyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, C1-20 heteroaryl and C2-20 heterocyclyl, C2-20 heteroaralkyl, C3-20 heterocyclylalkyl, C1-10 aminoalkyl, C6-I0 aminoaryl, guanidinyl C1-6 alkyl, C2-12 alkylguanidinylalkyl, ureayl C1-6 alkyl and C2-12 alkylureaylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, OH, OCH3, OCH2CH3 and
NH2; or R15 and one of R14 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R14 not joined to R15 is H or C1-6 alkyl. Preferably, each R14 is independently selected from the group consisting of H and Ci-4 alkyl, or R15 and one of R14 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R14 not joined to R15 is selected from the group consisting of H and C1-4 alkyl. Preferably, R15 and one of R14 are joined to form a group selected from imidazole, dihydroimidazole, tetrahydropyrimidinyl, benzimidazole and triazole.
Preferably, each R14 is independently selected from the group consisting of H and methyl.
Preferably, R15 and one of R14 are joined to form a group selected from imidazole, dihydroimidazole and tetrahydropyrimidinyl. hi one embodiment, preferably, R6 is a group
Figure imgf000022_0001
where each R14 and R15 are H.
Preferably, R3 is independently selected from the group consisting of H, COOH, COO(Ci-6 alkyl), COO(C6-20 aryl), COO(C7-20 alkaryl), COO(C7-20 aralkyl), C(O)H, C(O)(Ci-6 alkyl), C(O)NH2, C(O)NH(Ci-6 alkyl), C(O)N(Ci-6 alkyl)2, C(O)NH(C6-15 aryl), C(O)N(C6-I5 aryl)2, C(O)NH(C7-I5 aralkyl), C(O)N(C7-J5 aralkyl)2, C(O)NH(C7-I5 alkaryl), C(O)N(C7-15 alkaryl)2 and hydrocarbyl or heterocarbyl groups selected from C1-20 alkyl, C2-20 alkenyl, C1-20 alkoxy, C2- 20 alkoxyalkyl, C6-30 aryloxy, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, C1-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl and C3-30 heterocyclylalkyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups, preferably 1, 2, 3 or 4 groups, independently selected from the groups defined in (d), (e) and (f):
(d) -CH=CH-, -C≡C-, S, N, -N=, Si(C1-6 alkyl)2, Si(OH)2, C(O)NH, C(O)N(Cj-6 alkyl), C(O)O, N(C1-6 alkyl)C(O)N(C1-6 alkyl), NHC(O)N(C1-6 alkyl), N(Cj-6 alkyl)C(O)O, NHC(O)NH, NHC(O)O, NH, N(Cj-6 alkyl), O, CO, SO2, NHSO2 and C(O)NHNH in the backbone;
(e) COOH, COO(Cj-6 alkyl), SH, S(C1-6 alkyl), SO2H, SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(C1-6 alkyl), OC(O)(C1-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 alkaryl), OC(O)(C7-20 aralkyl), =0, NH2, =NH, NH(C1-6 alkyl), N(C1-6 alkyl)2, =N(C1-6 alkyl), NHC(O)(C1-6 alkyl), C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)2, C(O)NH(C6-15 aryl), C(O)N(C6-15 aryl)2, C(O)NH(C7-I5 aralkyl), C(O)N(C7-I5 aralkyl)2, C(O)NH(C7-15 alkaryl), C(O)N(C7-15 alkaryl)2, NO2, CN, SO2NH2, C(O)H, C(O)(C1-6 alkyl) on the backbone; and, (f) groups independently selected from the group consisting of C1-I0 alkyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, Ci2-20 aryloxyaryl, C7-20 aryloxyalkyl, Ci-10 alkoxy, C6-20 aryloxy, C2-I0 alkenyl, C2-I0 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl and C6-20 aryl on the backbone.
Preferably, R3 is not H.
Preferably, R3 is -(CR16R1V-X-R18; wherein: m3 is 0, 1, 2, 3 or 4;
X is a bond, -CH=CH-, -C≡C-, S, N, Si(Ci-6 alkyl)2, Si(OH)2, Si(OCi-6 alkyl)2, C(O)NH, C(O)NC1-6 alkyl, C(O)NC6-20 aryl, C(O)NC7-20 aralkyl, C(O)NC7-20 alkaryl, C(O)O, N(C1-6 alkyl)C(O)N(C1-6 alkyl), NHC(O)N(Ci-6 alkyl), OC(O)N(C1-6 alkyl), NHC(O)NH, NHC(O)O, NH, N(Ci-6 alkyl), O, CO, SO2, SO2NH, NHSO2, and C(O)NHNH;
R16 and R17 are independently selected from the group consisting of H, Ci-20 alkyl, C2-20 alkenyl, C2-20 alkoxyalkyl, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, C1-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, C1-10 aminoalkyl and C6-20 aminoaryl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from COOH, COO(C1-6 alkyl), SH, S(Ci-6 alkyl), SO2H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), P(OH)(O)2, halo, haloCi-6 alkyl, perhaloC1-6 alkyl, OH, 0(Ci-6 alkyl), =0, NH2, =NH, NH(Cj-6 alkyl), N(Ci-6 alkyl)2, =N(Ci-6 alkyl), NHC(O)(C1-6 alkyl), NO2, CN, SO2NH2, C(O)H and C(O)(Ci-6 alkyl), Ci-10 alkyl, C2-I0 alkoxyalkyl, C7-20 alkoxyaryl, C2-I0 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C1-20 heteroaryl and C6-20 aryl; or R16 and R17 are joined to form a 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20-membered, saturated, unsaturated or aromatic, heterocyclic or carbocyclic ring; and,
R18 is selected from the group consisting of H, Ci-20 alkyl, C2-20 alkenyl, C2-20 alkoxyalkyl, C7-30 alkoxyaryl, Ci2-30 aryloxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, C1-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, Ci-I0 aminoalkyl, C6-20 aminoaryl, guanidine Ci-I0 alkyl, C2-20 alkylguanidinylalkyl, urea Ci-I0 alkyl and C2-20 alkylureaylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from COOH, COO(C1-6 alkyl), SH, S(C1-6 alkyl), SO2H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), P(OH)(O)2, halo, haloC1-6 alkyl, perhaloC1-6 alkyl, OH, 0(C1-6 alkyl), =0, NH2, =NH, NH(C1-6 alkyl), N(Ci-6 alkyl)2, =N(C1-6 alkyl), NHC(O)(C1-6 alkyl), C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(Ci-6 alkyl)2, C(O)NH(C6-I2 aryl), C(O)N(C6-I2 aryl)2, C(O)NH(C7-12 aralkyl), C(O)N(C7-12 aralkyl)2, C(O)NH(C7-I2 alkaryl), C(O)N(C7-I2 alkaryl)2, NO2, CN, SO2, SO2NH2, C(O)H and C(O)(C1-6 alkyl), Ci-I0 alkyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, C2-I0 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, Cj-20 heteroaryl and C6-20 aryl. Preferably, m3 is O, 1 or 2, more preferably O or 1.
Preferably, X is a bond, C(O)NH, C(O)N(Cj-6 alkyl), C(O)N(C6-20 aryl), NH, N(Cj-6 alkyl) or O.
Preferably, R16 and R17 are independently selected from the group consisting of H, C1-J0 alkyl, C2-20 alkoxyalkyl, C7-20 alkoxyaryl, Cj2-20 aryloxyaryl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, C1-20 heteroaryl, C2-20 heterocyclyl, C2-20 heteroaralkyl and C3-20 heterocyclylalkyl.
Preferably, R18 is selected from the group consisting of H, C1-I0 alkyl, C2-J0 alkoxyalkyl, C7-20 alkoxyaryl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, C1-20 heteroaryl, C2-20 heterocyclyl, C2-20 heteroaralkyl and C3-20 heterocyclylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2 or 3 groups, independently selected from =O, COOH, SH, SO2H, P(OH)(O)2, halo, trihalomethyl, OH, NH2, =NH, NH(Ci-6 alkyl), =N(Cj-6 alkyl), NO2, CN, OCH3, SO2NH2 and C(O)H, Cj-6 alkyl, C2-6 alkoxyalkyl, C7-10 alkoxyaryl, C3-10 cycloalkyl, C4-15 (cycloalkyl)alkyl, C7-12 aralkyl, C7-12 alkaryl, C1-12 heteroaryl and C6-J2 aryl. Preferably, R16 and R17 are joined to form a 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14-membered, saturated, unsaturated or aromatic ring. The ring may be a heterocyclic or heteroaromatic ring. Preferably, the ring formed by R16 and R17 is a cycloalkyl, heterocyclyl or heteroaromatic group. Preferably, the ring is a C6-10 cycloalkyl, C4-10 heterocyclyl or C1-10 heteroaryl group. hi a particularly preferred embodiment, m3 is O, X is a bond and R18 is a Cs-12 cycloalkyl group. In another preferred embodiment, X is a bond, C(O)NH or C(O)N(C1-6 alkyl).
In another preferred embodiment, X is a bond, R16 and R17 are both H, m3 is O or 1 and R18 is selected from the group consisting of C1-10 alkyl, C2-20 alkoxyalkyl, C7-20 alkoxyaryl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, C1-20 heteroaryl, C2-20 heterocyclyl, C2-20 heteroaralkyl and C4-20 heterocyclylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2 or 3 groups, independently selected from =O, COOH, SH, SO2H, P(OH)(O)2, halo, trihalomethyl, OH, NH2, =NH, NH(Ci-6 alkyl), =N(C1-6 alkyl), NO2, CN, OCH3, SO2NH2 and C(O)H. Preferably, X is C(O)NH, R16 and R17 are both H, m3 is O or 1 and R18 is selected from the group consisting of Ci-I0 alkyl, C2-20 alkoxyalkyl, C7-20 alkoxyaryl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, Ci-20 heteroaryl, C2-20 heterocyclyl, C2-20 heteroaralkyl and C3-20 heterocyclylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2 or 3 groups, independently selected from =O, COOH, halo, trihalomethyl, OH, NH2, NO2, CN, OCH3, Ci-6 alkyl, C2-6 alkoxyalkyl, C3-I0 cycloalkyl, C4-i5 (cycloalkyl)alkyl, C7-I2 aralkyl, C7-I2 alkaryl and C6-I2 aryl.
Preferably, X is a bond, m3 is O and R18 is selected from the group consisting of Ci-I0 alkyl, C2- 20 alkoxyalkyl, C7-20 alkoxyaryl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, Ci-20 heteroaryl, C2-20 heterocyclyl, C2-20 heteroaralkyl and C3-20 heterocyclylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2 or 3 groups, independently selected from =0, COOH, halo, trihalomethyl, OH, NH2, NO2, CN, OCH3, Ci-6 alkyl, C2-6 alkoxyalkyl, C3-I0 cycloalkyl, C4-I5 (cycloalkyl)alkyl, C7-I2 aralkyl, C7-J2 alkaryl and C6-I2 aryl.
Preferably, R18 is selected from the group consisting of methyl, ethyl, propyl, butyl, phenyl, benzyl, biphenyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, quinolinyl, naphthyl, tetramethylcyclohexyl, benzocycloheptyl, benzodioxepinyl, bicyclooctyl, tetrahydropyranyl, dihydropyranyl, tetramethyltetrahydropyranyl, cyclohexylmethyl, phenylethylbenzyl, phenoxybenzyl, phenylethynylbenzyl, cyclohexylbenzyl, pyranyl, tetrahydropyranyl, tolyl, ethylbenzyl, xylyl, isoprσpylbenzyl, cyclohexylmethyl, methoxyphenyl, diphenylmethyl, phenethyl, pyridylmethyl, butylphenyl, binaphthyl, adamantyl, propylbenzyl, mesitylyl, ethyltolyl, butylbenzyl, indanyl, diethylbenzyl, methylindanyl, dimethylethylbenzyl, phenylpentyl, tetramethylbenzyl, phenylhexyl, dipropylbenzyl, triethylbenzyl, tetrahydronaphthyl, cyclohexylbenzyl, methyhiaphthyl, naphthylmethyl, methyltetrahydronaphthyl, ethylnaphthyl, dimethyhiaphthyl, diphenylethyl, diphenylmethyl, propylnaphthyl, butyhiaphthyl, phenanthryl, fluoryl, stilbyl, methylfluoryl, benzphenanthryl, triphenyhnethyl, acenaphthyl, azulenyl, phenyhiaphthyl, methylchrysyl, benzfluoryl, pyrenyl, hexamethylbenzyl, perylenyl, picenyl, dihydroisoxazolyl, furanyl, pyridyl, phthalimido, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, carbolinyl, thiophenyl, thiazolyl, isoxazolyl, isoxazolonyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridazyl, tetrahydrobenzoannulenyl, phenylcyclohexyl, benzoylpiperidinyl, benzylpiperidinyl, cyclopropylmethyl and tetrahydrothiopyranyl, any of which are optionally substituted with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from =0, COOH, SH, SO2H, P(OH)(O)2, halo, trihalomethyl, OH, NH2, =NH, NH(C1-6 alkyl), =N(Ci-6 alkyl), NO2, CN, OCH3, SO2, SO2NH2 and C(O)H, Cj-6 alkyl, C2-6 alkoxyalkyl, C7-J0 alkoxyaryl, C3-io cycloalkyl, C4-I5 (cycloalkyl)alkyl, C7-I2 aralkyl, C7-I2 alkaryl, C1-12 heteroaryl and C6-I2 aryl.
Preferably, X is a bond, m3 is O and R18 is C2-2O heterocyclyl.
In a particularly preferred embodiment, R3 comprises a benzyl group, optionally substituted with 1, 2 or 3 groups, independently selected from COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), halo, trihalomethyl, OH, NH2, 0(Ci-6 alkyl), 0(C6-20 aryl), 0(C7-20 aralkyl), 0(C7-20 alkaryl), Ci-6 alkyl, C6-I2 aryl, C7-I2 aralkyl, C7-I2 alkaryl, C8-I2 aralkynyl, C6-I2 aryloxy, C1-I2 heteroaryl, C5-12 cycloalkyl and C(O)(Ci-6 alkyl) on the backbone.
In a particularly preferred embodiment, R3 comprises a methyl, ethyl, propyl, butyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, quinolinyl, tetrahydropyranyl, naphthyl, benzocycloheptyl, or benzodioxepinyl group, optionally substituted with 1, 2, 3 or 4 groups independently selected from COO(Ci-6 alkyl), halo, trihalomethyl, OH, NH2, 0(C1-6 alkyl), C1-6 alkyl, C6-I2 aryl, C7-12 aralkyl, C7-12 alkaryl, C6-I2 aryloxy, C1-12 heteroaryl, C5-I2 cycloalkyl and C(O)(Ci-6 alkyl) on the backbone.
R3 is preferably a tetrahydropyranyl group or a propyl group. Preferably, R19 is selected from the group consisting of -C(=NH)NH2, -C(=NH)NHCi-i0 alkyl, -C(=NH)N(Ci.io alkyl)2, -C(=NH)NHC3-i2 cycloalkyl, -C(=NH)N(C3-i2 cycloalkyl)2, -C(=NH)NHC6-12 aryl, -C(=NH)N(C6-i2 aryl)2, -C(=NH)NHC6-i5 alkaryl, -C(=NH)N(C6-15 alkaryl)2s -C(=NH)NHC6-15 aralkyl, -C(=NH)N(C6-i5 aralkyl)2, -C(=NH)NHC2-12 heterocyclyl, -C(=NH)N(C2-12 heterocyclyl)2, -C(=NH)NHCM2 heteroaryl, -C(=NH)N(C1-12 heteroaryl)2, -C(=NCi.io alkyl)NH2, -C(=NCW0 alkyl)NHC1-lo alkyl, -C(=NC1-10 alkyl)N(Ci.i0 alkyl)2, Ci-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, Cg-30 heterocyclylalkaryl, C4-30 heterocyclylalkoxyalkyl, C4-30 heterocyclylaUcylaminoaUcyl, C8-30 heteroarylalkaryl, C3-30 heteroarylalkoxyalkyl, C3-30 heteroarylalkylarninoalkyl, C7-30 aryloxyalkyl, C7-30 arylaminoalkyl, C7-30 alkylaminoaryl, Ci-10 aminoalkyl, C7-20 aminoaralkyl, C7-20 aminoalkaryl, C2-20 alkylguanidinylalkyl and ureayl Ci-I0 alkyl, and is linked to the rest of the compound of formula (I) by a carbon atom of one of these groups; any of the groups defined as R19 being optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from Ci-J0 alkyl, Ci-20 haloalkyl, Ci-20 perhaloalkyl, Ci-20 hydroxyalkyl, C3-I0 cycloalkyl, halo, OH, OCi-6 alkyl, NH2, OC(Ci-6 alkyl), OC(C6-20 aryl), OC(C7-20 aralkyl), OC(C7-20 alkaryl), OCO(C,-6 alkyl), OCO(C6-20 aryl), OCO(C7-20 aralkyl), OCO(C7-20 alkaryl), COOH, COO(Ci-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), N(C6-20 aryl)2, NH(C7-20 aralkyl), N(C7-20 aralkyl)2, NH(C7-20 alkaryl), N(C7-20 alkaryl)2, N(Ci-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-20 alkaryl), N(Ci-6 alkyl)(C7-20 aralkyl), N(C6-20 aryl)(C6-20 aryl), N(C6-20 aryl)(C7-20 alkaryl), N(C6-20 aryl)(C7-20 aralkyl), NO2, CN, C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 aralkyl) and C(O)(C7-20 alkaryl).
Preferably, R19 is not H.
Preferably R19 is selected from the group consisting of -C(=NH)NH2, -C(=NH)NHCi-6 alkyl, -C(=NH)N(C1-6 alkyl)2, -C(=NH)NHC3-12 cycloalkyl, -C(=NH)N(C3-i2 cycloalkyl)2,
-C(=NH)NHC6-io aryl, -C(=NH)N(C6-i0 aryl)2, -C(=NH)NHC6-i2 alkaryl, -C(=NH)N(C6-j2 alkaryl)2, -C(=NH)NHC6-i2 aralkyl, -C(=NH)N(C6-12 aralkyl)2, -C(=NH)NHC2-i0 heterocyclyl,
-C(=NH)N(C2-lo heterocyclyl)2, -C(=NH)NHC1-10 heteroaryl, -C(=NH)N(Ci-lo heteroaryl)2,
-C(=NC1-6 alkyl)NH2, -C(=NC1-6 alkyl)NHC1-6 alkyl, -C(=Nd-6 a]kyl)N(Ci-6 alkyl)2, Ci-15 heteroaryl and C2-15 heterocyclyl, and is linked to the rest of the compound of formula (I) by a carbon atom of one of these groups; any of the groups defined as R19 being optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, NH(C6-16 aryl), N(C6-I6 aryl)2,
NH(C7-16 aralkyl), N(C7-J6 aralkyl)2, NH(C7-16 alkaryl), N(C7-16 alkaryl)2, N(Ci-4 alkyl)(C6-16 aryl), N(Cj-4 alkyl)(C7-j6 alkaryl), N(Cj-4 alkyl)(C7-16 aralkyl), N(C6-16 aryl)(C7-j6 alkaryl),
N(C6-J6 aryl)(C7-16 aralkyl), S(Cj-6 alkyl), NO2, CN, OH, SH, OCj-6 alkyl, C(O)H and C(O)(C1-6 alkyl).
Preferably R19 is selected from the group consisting of -C(=NH)NH2, C1-15 heteroaryl and C2-15 heterocyclyl, and is linked to the rest of the compound of formula (I) by a carbon atom of one of these groups; any of the groups defined as R19 being optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from NH2, NH(Cj-4 alkyl) or N(C1-4 alkyl)2. Preferably R19 is selected from the group consisting of -C(=NH)NH2, Ci-I0 heteroaryl and C2-10 heterocyclyl, which are linked to the rest of the compound of formula (I) by a carbon atom of one of these groups.
Preferably R19 is selected from the group consisting of -C(=NH)NH2, C2-5 heteroaryl and C2-4 heterocyclyl, which are linked to the rest of the compound of formula (I) by a carbon atom of one of these groups.
Preferably R19 is selected from the group consisting of -Q=NH)NH2, furanyl, pyridyl, phthalimido, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, dihydroimidazolyl, tetrahydropyrimidinyl, benzimidazolyl, tetrahydroisoquinolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyridonyl, pyronyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, napthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxadinyl, chromenyl, chromanyl, isochromanyl, carbolinyl, thiophenyl, thiazolyl, isoxazolyl, isoxazolonyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and pyridazyl, and is linked to the rest of the compound of formula (I) by a carbon atom of one of these groups; any of the groups defined as R19 being optionally substituted on the backbone with one or more groups independently selected from =0, COOH, SH, SO2H, P(OH)(O)2, halo, trihalomethyl, OH, NH2, =NH, NH(C1-6 alkyl), ^N(C1-6 alkyl), NO2, CN, OCH3, SO2NH2 and C(O)H, Ci-6 alkyl, C2-6 alkoxyalkyl, C7-io alkoxyaryl, C3-I0 cycloalkyl, C4-15 (cycloalkyl)alkyl, C7-I2 aralkyl, C7-I2 alkaryl, Ci-I2 heteroaryl and C6-12 aryl, most preferably optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, CH3, OH, OCH3, OCH2CH3 and NH2. Preferably R19 is selected from the group consisting of -Q=NH)NH2, pyridyl, pyridyl, phthalimido, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, thiazolylmethyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, dihydroimidazolyl, tetrahydropyrimidinyl, benzimidazolyl, tetrahydroisoquinolinyl, pyrazolidinyl, pyridonyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, morpholinyl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, isoindazolyl, quinolyl, isoquinolyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxadinyl, carbolinyl, thiophenyl, thiazolyl, isoxazolyl, isoxazolonyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and pyridazyl, and is linked to the rest of the compound of formula (I) by a carbon atom of one of these groups; any of the groups defined as R19 being optionally substituted on the backbone with one or more groups independently selected from =0, COOH, SH, SO2H, P(OH)(O)2, halo, trihalomethyl, OH, NH2, =NH, NH(Ci-6 alkyl), =N(C1-6 alkyl), NO2, CN, OCH3, SO2NH2 and C(O)H, C1-6 alkyl, C2-6 alkoxyalkyl, C7-io alkoxyaryl, C3-I0 cycloalkyl, C4-i5 (cycloalkyl)alkyl, C7-I2 aralkyl, C7-12 alkaryl, Q-I2 heteroaryl and C6-I2 aryl, most preferably optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, CH3, OH, OCH3, OCH2CH3 and NH2.
Preferably, R19 is selected from the group consisting of dihydroimidazolyl and imidazolyl, particularly lH-imidazol-2-yl and 4,5-dihydro-lH-imidazol-2-yl, which are linked to the rest of the compound of formula (I) by a carbon atom of one of these groups. Such preferred groups may be optionally substituted with 1, 2 or 3 groups selected from halo, CH3, OH, OCH3, OCH2CH3 and NH2.
Preferably, R19 is not substituted in the backbone. Preferably, R19 is not substituted on the backbone.
Throughout the specification, in respect of the group R19, the clause, 'and is linked to the rest of the compound of formula (I) by a carbon atom of one of these groups' is intended to refer to the immediately preceding groups, not the subsequently defined substituents which may be attached to R19.
Preferably, R1, R4 and R5 are independently selected from the group consisting of H, COOH, COO(C1-6 alkyl), CN, SH, S(C1-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(Cj-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(Ci-6 alkyl), NH2, NH(Ci-6 alkyl), N(Ci-6 alkyl)2, NHC(O)(C1-6 alkyl), NO2, CN, SO2NH2, C(O)H and C(O)(C1-6 alkyl), and hydrocarbyl or heterocarbyl groups selected from Ci-20 alkyl, C2-20 alkenyl, Ci-20 alkoxy, C2-20 alkoxyalkyl, C6-30 aryloxy, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, C1-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl and C2-30 heterocyclylalkyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups independently selected from the groups defined in (a), (b) and (c):
(a) -CH=CH-, -C≡C-, S, -N=, Si(Ci-6 alkyl)2, Si(OH)2, C(O)NH, C(O)N(Ci-6 alkyl), C(O)O, N(Ci-6 alkyl)C(O)N(Ci-6 alkyl), NHC(O)N(Ci-6 alkyl), N(Ci-6 alkyl)C(O)O, NHC(O)NH, NHC(O)O, NH, N(Ci-6 alkyl), O, CO, SO2, NHSO2 and C(O)NHNH in the backbone;
(b) COOH, COO(Ci-6 alkyl), SH, S(Cj-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H, SO2(Ci-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(Ci-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(C1-6 alkyl), 0(C6-20 aryl), 0(C7-20 alkaryl), 0(C7-20 aralkyl), =0, NH2, =NH, NH(Ci-6 alkyl), N(C1-6 alkyl)2, =N(C1-6 alkyl), NHC(O)(C1-6 alkyl), NO2, CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(C1-6 alkyl)2, C(O)H and C(O)(Ci-6 alkyl) on the backbone; and,
(c) groups independently selected from the group consisting of C1-I0 alkyl, C2-I0 alkoxyalkyl, C7-20 alkoxyaryl, Ci2-20 aryloxyaryl, C7-20 aryloxyalkyl, Ci-I0 alkoxy, C6-20 aryloxy, C2-I0 alkenyl, C2-I0 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl and C6-20 aryl on the backbone.
When R1 is joined to R5, R5a or Rla to form a ring, or when R5 is joined to R5a or Rla to form a ring, preferably it is a 5, 6 or 7-membered ring which is optionally substituted with 1, 2 or 3 of the groups independently selected from the groups defined in (b) and (c) above.
Preferably, none of R1, Rla, R5 or R5a are joined to one another to form a ring.
Preferably, R5a, R5, R1 and Rla are in the 6, 7, 8 and 9 positions respectively of the compound of formula (I). Preferably, where any of R5a, R5, R1 and Rla are linked with one another to form a ring, adjacently positioned groups are linked, rather than remotely positioned groups. For example, R5a and R5 are preferably joined to one another when they are in the 6 and 7 position respectively.
Preferably, R1 and R5 are independently selected from the group consisting of H, COOH, SH3 SO2H, P(OH)(O)2, F, Cl, Br, I, OH, NH2, NO2, CN, SO2NH2, C(O)H, and hydrocarbyl or heterocarbyl groups selected from Ci-6 alkyl, Ci-6 alkoxy, C2-6 alkoxyalkyl, C7-20 alkoxyaryl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, C1-20 heteroaryl and C2-20 heterocyclyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups, preferably 1, 2, 3 or 4 groups, independently selected from the groups defined in (a), (b) and (c):
(a) C(O)NH, C(O)NMe, C(O)O, NHC(O)NH, NHC(O)O, NH, O, CO, SO2, NHSO2, and C(O)NHNH in the backbone;
(b) =0, COOH, SH, SO2H, SO3H, P(OH)(O)2, F, Cl, Br, I, OH, NH2, =NH, NH(C1-6 alkyl), =N(C1-6 alkyl), NO2, CN, SO2NH2, and C(O)H on the backbone; and,
(c) groups independently selected from the group consisting of C1-6 alkyl, C2-6 alkoxyalkyl, C7-10 alkoxyaryl, C3-10 cycloalkyl, C4-12 (cycloalkyl)alkyl, C7-12 aralkyl, C7-I2 alkaryl, CM2 heteroaryl and C6-I2 aryl on the backbone.
Preferably, R1 and R5 are independently selected from the group consisting of C1-4 alkyl, C5-8 cycloalkyl, C1-4 alkoxy, C1-4 alkylcarbonylamino, Ci-4 alkylaminocarbonyl, C3-10 cycloalkylcarbonylamino, C3-10 cycloaUcylaminocarbonyl, C2-I0 heterocyclylcarbonylamino, C2-10 heterocyclylaminocarbonyl, C6-io arylcarbonylamino, C6-I0 arylaminocarbonyl, C1-1O heteroarylcarbonylamino, C1-I0 heteroarylaminocarbonyl, C1-6 alkylamino, di (C1-4 alkyl)amino, C7-1O aralkyl, C7-1O alkaryl, C6-1O aryl, C1-10 heteroaryl and C2-io heterocyclyl, any of which are optionally substituted with one or more groups, preferably 1, 2 or 3 groups, independently selected from =0, COOH, F, Cl, Br, I, OH, NH2, NH(Ci-6 alkyl), NO2, CN and C(O)H;
H, F, Cl, Br, COOH, SH, SO2H5 P(OH)(O)2, OH, NH2, NO2, CN, SO3H, SO2NH2 and C(O)H.
Preferably, R1 and R5 are independently selected from the group consisting of H, F, Cl, Br, Ci-4 alkyl, C(O)Ci-6 alkyl, C5-8 cycloalkyl, C1-4 alkoxy, dimethylamino, tolyl, xylyl, pyridyl, pyridinyl, furanyl, hydroxyphenyl, phenylamino, acetamido, oxopyrrolidinyl, dibenzylamido, piperidinylcarbonyl, benzylamido, benzylamino, OH, NH2 and N(CH3)2.
Preferably, R5 is H and R1 is selected from the group consisting of H, F, Cl, Br, methoxy, methyl, tolyl, xylyl, pyridinyl, pyridiyl, furanyl, hydroxyphenyl, phenylamino, acetamido, oxopyrrolidinyl, dibenzylamido, piperidinylcarbonyl, benzylamido, benzylamino, OH, NH2 andN(CH3)2. In a particularly preferred embodiment, R5 and R1 are both H.
In a particularly preferred embodiment, R5 is H and R1 is selected from methyl, Cl and methoxy.
Preferably, R1 and R5 are located in the 8 and 7 positions respectively of the compound of formula (I). In an alternative particularly preferred embodiment, R1 is a methyl group located in the 8-position of the compound of formula (I) as indicated herein.
Preferably, R4 is selected from the group consisting of H, hydrocarbyl or heterocarbyl groups selected from Ci-I0 alkyl, C2-1O alkoxyalkyl, C12-20 aryloxyaryl, C7-20 aryloxyalkyl, C1-Io alkoxy, C7-2O alkoxyaryl, C4-20 alkoxycycloalkyl, C3-2O cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-2O aralkyl, C7-2O alkaryl, C6-2O aryl, Ci-2O heteroaryl, C2-2O heteroaralkyl and C2-20 heterocyclyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups, preferably 1, 2 or 3 groups, independently selected from the groups defined in (a), (b) and (c):
(a) S, C(O)NH, C(O)NMe, C(O)O, NHC(O)NH, NHC(O)O, NH, N, O, CO, SO2, SO2NH, NHSO2 and C(O)NHNH in the backbone;
(b) =0, COOH, SH, SO2H, P(OH)(O)2, F, Cl, Br, I, OH, NH2, =NH, NH(Ci-6 alkyl), =N(C1-6 alkyl), NO2, CN, SO3H, SO2NH2, C(O)(C1-6 alkyl) and C(O)H on the backbone; and, (c) groups independently selected from the group consisting of C1-6 alkyl, C2-6 alkoxyalkyl, C7-1O alkoxyaryl, C3-10 cycloalkyl, C4-I2 (cycloalkyl)alkyl, C7-I2 aralkyl, C7-12 alkaryl and C6-I2 aryl on the backbone.
Preferably, R4 is selected from the group consisting of Ci-6 alkyl, C2-6 alkoxyalkyl, C12-20 aryloxyaryl, C7-12 aryloxyalkyl, Ci-I0 alkoxy, C7-12 alkoxyaryl, C5-I2 alkoxycycloalkyl, C3-I2 cycloalkyl, C4-I2 (cycloalkyl)alkyl, C7-12 aralkyl, C7-I2 alkaryl, C6-I2 aryl, Ci-I2 heteroaryl, C2-12 heteroaralkyl and C2-I2 heterocyclyl, any of which is optionally substituted with one or more of the groups, preferably 1, 2 or 3 groups, independently selected from the groups defined in (a), (b) and (c): (a) S, C(O)NH, NHC(O), C(O)NMe, NMeC(O), C(O)O, NHC(O)NH, NHC(O)O, OC(O)NH, NH, O, CO, SO2, SO2NH, NHSO2, and C(O)NHNH in the backbone;
(b) COOH, SH, SO2H, P(OH)(O)2, F, Cl, Br, I, OH, NH2, =NH, NH(C1-6 alkyl), =N(Ci-6 alkyl), NO2, CN, SO3H, SO2NH2, C(O)(Cj-6 alkyl), C(O)(Ci-6 aminoalkyl), C(O)NH2, and C(O)H on the backbone; (c) groups independently selected from the group consisting of Ci-4 alkyl, Ci-4 alkoxy, C2-4 alkoxyalkyl, C7-io alkoxyaryl, Cs-I0 cycloalkyl, C4-10 (cycloalkyl)alkyl, C7-I0 aralkyl, C7-10 alkaryl, C1-12 heteroaryl and C6-I0 aryl on the backbone.
Preferably, R4 is selected from the group consisting of Ci-6 alkyl, C3-I2 cycloalkyl, C6-12 aryl, Q- I2 heteroaryl, C2-12 heterocyclyl, C2-6 alkoxyalkyl, Cs-I2 alkoxycycloalkyl, C2-I0 alkylthioalkyl, C4-12 alkylthiocycloalkyl, C2-I0 alkylsulfonylalkyl, C6-12 alkylsulfonylcycloalkyl and C6-12 alkylarninocycloalkyl.
Preferably, R4 is selected from the group consisting of methyl, cyclohexyl, phenyl, isopropyl, fluorophenyl, cyclohexylmethyl, adamantyl, pyranyl, tetrahydropyranyl, piperidinyhnethyl, cyclohexylsulfanylmethyl, cyclohexanesulfonylmethyl, phenoxymethyl, cyclohexylphenoxymethyl, methoxyphenoxymethyl, naphthalenyloxymethyl, ethanoylphenoxymethoxy, aminoacetylaminophenoxymethyl, cyanophenoxymethyl, acetylaminophenoxymethyl, cyclohexylidenemethyl and aminoacetylphenoxymethyl.
In a particularly preferred embodiment, R4 is a cyclohexyl group. Preferably, R4 is not H. Preferably, Rla and R5a are independently selected from H, CH3, F, Cl, Br and OH. Most preferably, both Rla and R5a are H. Preferably, Rla and R5a are located in the 9 and 6 positions respectively of the compound of formula (I).
Where the benzo moiety of the benzotriazepinone ring system is substituted in the benzo ring by a nitrogen atom, the substitution may be in any of the positions designated 6, 7, 8 or 9 in formula (I). Preferably, the nitrogen atom is unsubstituted. hi one embodiment, the benzo moiety of the benzotriazepinone ring system is unsubstituted in the benzo ring.
Certain compounds of the invention exist in various regioisomeric, enantiomeric, tautomeric and diastereomeric forms. It will be understood that the invention comprehends the different regioisomers, enantiomers, tautomers and diastereomers in isolation from each other as well as mixtures.
Compounds of the present invention are optionally prepared by the representative procedures shown in reaction schemes 1-7, or the general methods disclosed in WO-A-03/041714, or combinations thereof. 2-Amino phenyl ketones (III) are either obtained commercially, or prepared by Lewis acid-mediated reaction of an appropriate aniline (Y) with a suitable nitrile (R4CN) (Sugasawa, T. et ah, J. Am. Chem. Soc, (1978), 100, 4842). (Reaction Scheme 1). Alternatively, they may be obtained by reaction of an appropriate 2-amino-benzonitrile (II) with a Grignard reagent (R4MgCl) or alkyl lithium (R4Li). hi the following schemes, Rla and R5a are not shown in the interests of simplicity and clarity.
Reaction Scheme 1
Figure imgf000033_0001
1,3,4-benzotriazepinones (V) are prepared by treatment of a suitable 2-amino phenyl ketone (III), with a suitable bifunctional carbonyl reagent, such as phosgene, trichloromethyl chloroformate or bis(trichloromethyl) carbonate and a suitable hydrazine, NH2NHP (wherein P represents either a protecting group, R3 or a suitable precursor R3' thereof). Alternatively, thiophosgene may be used in place of a suitable bifunctional carbonyl reagent to afford a l,3,4-benzotriazpin-2-thione (IV), followed by basic peroxide-mediated oxidation to obtain the 1,3,4-benzotriazepinone (V) (Reaction Scheme 2). Reaction Scheme 2
1,3,4-benzotriazepinones (V) may also be obtained by initial activation of a suitable 2-amino phenyl ketone (III) with a suitable bifunctional carbonyl reagent, such as />αra-nitrobenzyl chloroformate, bis(trichloromethyl) carbonate or l,l'-carbonyldiimidazole, followed by treatment with a suitable urethane-protected hydrazine, P1NHNHR3 (wherein P1 represents a urethane protecting group and R3 represents R3 or a suitable precursor thereof) to form a substituted semicarbazide derivative (VI) as an intermediate (Reaction Scheme 3). Removal of the urethane protecting group P', results in concomitant ring closure to form the 1,3,4-benzotriazepinones (V).
Reaction Scheme 3
Figure imgf000034_0002
When R4 is a methyl substituent, the 1,3,4-benzotriazepine (V) may also be obtained by starting from a suitable 2-iodo aniline (VII) (Reaction scheme 4). Sonogashira reaction (Tykwinski, R. R. Angew. Int. Ed. (2003), 42, 1566) affords the corresponding acetylide derivative (VIII) which, on reaction with a suitable bifunctional carbonyl reagent and a suitable urethane-protected hydrazine, PTSfHNHR3', affords the semicarbazide intermediate (EX). Mercuric oxide-mediated oxidation yields the required ketone precursor (VI), suitable for conversion to the 1,3,4-benzotriazepine (V) according to the method outlined in reaction scheme 3.
Reaction Scheme 4
Figure imgf000035_0001
N-I substituted benzodiazepines (X) are obtained from (V) by base catalysed alkylation using sodium hydride and a suitable alkyl halide, R2Br or R2F, (wherein R2' represents a suitable precursor of R2) (Reaction scheme 5). Alternatively arylation may be achieved by copper-mediated arylation reaction with a suitable aryl iodide R21.
Reaction Scheme 5
Figure imgf000035_0002
(V) (X)
Certain compounds of the invention in which the R4 substituent is modified are obtained by brornination of (X), wherein R4 is a methyl substituent, using bromine in acetic acid. The corresponding bromide (XI) can then be displaced by a suitable nucleophile (Nu), affording 1,3,4-benzotriazepinones (XII) containing modification in the R4 substituent (Reaction scheme 6).
Reaction scheme 6
Figure imgf000036_0001
Modification of R2 and/or R3 groups affords the desired benzotriazepinones (XIII) (Reaction scheme 7).
Reaction scheme 7
Figure imgf000036_0002
(XIlI)
(X)
R2 groups which are suitable precursors of R2, will depend on the particular nature of R2. A suitable precursor of R2 is:
Figure imgf000036_0003
More preferably, a suitable precursor of R2 is:
Figure imgf000037_0001
In all of the immediately preceding structures, R6 is a suitable precursor of R6. R6 groups which are suitable precursors of R6, will depend on the particular nature of R6. Suitable R6 substituents include NO2, which can be reduced by tin (II) chloride or catalytic hydrogenation to the corresponding aniline. The aniline substituent can be further modified to the required R6 group by, amongst others, acylation with amino acid derivatives, reductive amination with an appropriate aldehyde, or guanylation with a suitable guanylating agent. Other suitable R6 substituents include esters that can be converted to amide derivatives via the corresponding carboxylic acid. When R6 represents a dihydroimidazolyl group suitable R6' substituents include CHO, which can be converted to a dihydroimidazolyl group by the method of Huh (D.H. Huh, J. S. Jeong, H.B. Lee et al. Tetrahedron, 2002, 58, 9925). Other suitable R6' substituents include CN, from which a dihydroimidazolyl group can be obtained by formation of the corresponding imidate, using methanolic-HCl, followed by treatment with a 1,2-ethylenediamine (G. Marciniak, D. Decolin, et al., J. Med. Chem., 1988, 31, 2289). When R6 represents an imidazolyl group, suitable R6 substituents include alkyl halides or activated alcohols, from which the desired imidazolyl group can be obtained by displacement of the halide or activated alcohol with a suitable imidazolecarbanion.
R3 substituents which are suitable precursors of R3 will depend on the particular nature of R3. When P represents R3 these can obtained directly by treatment of (III) using the appropriate substituted hydrazine, or indirectly when P represents a protecting group, such as
4-methoxybenzyl or tert-butyloxycarbonyl, by first removal of the protecting group with trifluoroacetic acid or hydrochloric acid, followed by base catalysed reaction using sodium hydride and R3'Br.
Hence, the present invention also provides a method of making compounds according to formula (I). Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I), substantially as described hereinbefore, with a pharmaceutically acceptable diluent or carrier.
Yet another aspect of the present invention is a method of making a pharmaceutical composition comprising a compound of formula (I) substantially as described hereinbefore, comprising mixing said compound with a pharmaceutically acceptable diluent or carrier.
The present invention provides a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore, for use in therapy.
Some diseases that may be treated according to the present invention include, cardiovascular diseases, disorders of the peripheral and central nervous system, inflammation, urological diseases, developmental disorders, cancer, metabolic diseases, endocrinological diseases and disorders of the gastroenterology system in a mammal.
The present invention provides a method for the treatment of a disease mediated by PTH-I receptors, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drag thereof, substantially as described hereinbefore. In particular, the present invention provides a method for the prophylaxis or treatment of cancer, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore. ha particular, the present invention provides a method for the prophylaxis or treatment of osteoporosis, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore. hi particular, the present invention provides a method for the prophylaxis or treatment of an inflammatory disease, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore.
In particular, the present invention provides a method for the prophylaxis or treatment of an autoimmune disease, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drag thereof, substantially as described hereinbefore. In particular, the present invention provides a method for the prophylaxis or treatment of metastases, particularly bone metastases, by administration to a subject of- a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore.
In particular, the present invention provides a method for the treatment of lack of hair eruption, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore.
Specific diseases that may be treated or prevented according to the present invention include osteoporosis, anaemia, renal impairment, ulcers, myopathy, neuropathy, hypercalcemia, hyperparathyroidism, parathyroid gland adenoma, parathyroid gland hyperplasia, parathyroid gland carcinoma, squamous carcinoma, renal carcinoma, breast carcinoma, prostate carcinoma, lung carcinomas, osteosarcomas, clear cell renal carcinoma, prostate cancer, lung cancer, breast cancer, gastric cancer, ovarian cancer, bladder cancer, bone fracture, severe bone pain, spinal cord compression, cachexia, malnutrition, muscle wasting, net protein loss, arthritis, rheumatoid arthritis, diabetes, congestive heart failure and wound healing. The present invention also provides the use of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described hereinbefore, in the manufacture of a medicament for the prophylaxis or treatment of any of the diseases described hereinbefore.
The compounds of the present invention may also be present in the form of pharmaceutical acceptable salts. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." FDA approved pharmaceutical acceptable salt forms (International J. Pharm. 1986, 33,201-217; J. Pharm. Sci., 1977, Jan, 66 (1), pi) include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
Pharmaceutically acceptable salts of the acidic or basic compounds of the invention can of course be made by conventional procedures, such as by reacting the free base or acid with at least a stoichiometric amount of the desired salt-forming acid or base.
Pharmaceutically acceptable salts of the acidic compounds of the invention include salts with inorganic cations such as sodium, potassium, calcium, magnesium, zinc, and ammonium, and salts with organic bases. Suitable organic bases include N-methyl-D-glucamine, arginine, benzathine, diolamine, olamine, procaine and tromethamine. Pharmaceutically acceptable salts of the basic compounds of the invention include salts derived from organic or inorganic acids. Suitable anions include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, pamoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, tosylate and triethiodide. Hydrochloride salts of compound (I) are particularly preferred. The invention also comprehends derivative compounds ("pro-drugs") which are degraded in vivo to yield the species of formula (T). Pro-drugs are usually (but not always) of lower potency at the target receptor than the species to which they are degraded. Pro-drugs are particularly useful when the desired species has chemical or physical properties which make its administration difficult or inefficient. For example, the desired species may be only poorly soluble, it may be poorly transported across the mucosal epithelium, or it may have an undesirably short plasma half-life. Further discussion of pro-drags may be found in Stella, V. J. et al, "Prodrugs", Drug Delivery Systems, 1985, pp. 112-176, Drugs, 1985, 29, pp. 455-473 and "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
Pro-drag forms of the pharmacologically-active compounds of the invention will generally be compounds according to formula (T) having an acid group which is esterified or amidated. Included in such esterified acid groups are groups of the form -COORa, wherein Ra is Ci-6 alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, or one of the following:
Figure imgf000040_0001
Amidated acid groups include groups of the formula -CONRbR°, wherein Rb is H, C1-5 alkyl, phenyl, substituted phenyl, benzyl, or substituted benzyl, and Rc is -OH or one of the groups just recited for Rb.
Compounds of formula (T) having an amino group may be derivatised with a ketone or an aldehyde such as formaldehyde to form a Mannich base. This will hydrolyse with first order kinetics in aqueous solution. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject.
Pharmaceutically acceptable ester derivatives in which one or more free hydroxy groups are esterified in the form of a pharmaceutically acceptable ester are particularly pro-drug esters that may be convertible by solvolysis under physiological conditions to the compounds of the present invention having tree hydroxy groups.
It is anticipated that the compounds of the invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration, and inhalation.
For oral administration, the compounds of the invention will generally be provided in the form of tablets or capsules or as an aqueous solution or suspension.
Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate and lactose. Corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatine. The lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
Capsules for oral use include hard gelatine capsules in which the active ingredient is mixed with a solid diluent and soft gelatine capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
Effective doses of the compounds of the present invention may be ascertained be conventional methods. The specific dosage level required for any particular patient will depend on a number of factors, including severity of the condition being treated, the route of administration and the weight of the patient. In general, however, it is anticipated that the daily dose (whether administered as a single dose or as divided doses) will be in the range 0.001 to 5000 mg per day, more usually from 1 to 1000 mg per day, and most usually from 10 to 200 mg per day. Expressed as dosage per unit body weight, a typical dose will be expected to be between 0.01 μg/kg and 50 mg/kg, especially between 10 μg/kg and 10 mg/kg, between 100 μg/kg and 2 mg/kg. Where reference is made to dialkyl groups [e.g. N(C1-6 alkyl)2], it is understood that the two alkyl groups may be the same or different.
Formulaic representation of apparent orientation of a group within the backbone is not necessarily intended to represent actual orientation. Thus, a divalent amide group represented as C(O)NH is also intended to cover NHC(O).
In the interests of simplicity, terms which are normally used to refer to monovalent groups (such as "alkyl" or "phenyl") are also used herein to refer to divalent bridging groups which are formed from the corresponding monovalent group by the loss of one hydrogen atom. Whether such a term refers to a monovalent group or to a divalent group will be clear from the context. For example, when R3 is -(CR16R17)m 3-X-R18, it is clear that X must be a divalent group. Thus, when X is defined as NCi-6 alkylC(O), for example, this refers to a divalent group having the structure:
Chalky!
O
Where a divalent bridging group is formed from a cyclic moiety, the linking bonds may be on any suitable ring atom, subject to the normal rules of valency.
Where any particular moiety is substituted, for example a pyrrolyl group comprising a substituent on the heteroaryl ring, unless specified otherwise, the term "substituted on the backbone" contemplates all possible isomeric forms. For example, pyrrolyl substituted on the backbone includes all of the following permutations:
Figure imgf000042_0001
Figure imgf000042_0002
where one of the bonds shown is to the rest of the molecule or another moiety, and the other bond is to the defined substituent. This applies correspondingly to groups having a plurality of substituents.
The term "halogen" or "halo" is used herein to refer to any of fluorine, chlorine, bromine and iodine. Most usually, however, halogen substituents in the compounds of the invention are chlorine, bromine and fluorine substituents. Groups such as 1IaIo(C1-6 alkyl) includes mono-, di- or tri-halo substituted Ci-6 alkyl groups. Moreover, the halo substitution may be at any position in the alkyl chain. "Perhalo" means completely halogenated, e.g., trihalomethyl and pentachloroethyl. The terms "comprising" and "comprises" means "including" as well as "consisting" e.g. a composition "comprising" X may consist exclusively of X or may include something additional e.g. X + Y.
The word "substantially" does not exclude "completely" e.g. a composition which is "substantially free" from Y may be completely free from Y. Where necessary, the word "substantially" may be omitted from the definition of the invention.
"Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
"May" means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form or individual enantiomers may be prepared by standard techniques known to those skilled in the art, for example, by enantiospecific synthesis or resolution, formation of diastereomeric pairs by salt formation with an optically active acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. The term "solvate" means a compound of as defined herein, or a pharmaceutically acceptable salt of a compound of structure (I), wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a hydrate.
As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds. In one embodiment, preferably the groups R1, R3, R4, R5, R7, R8, R10, R14, R15, R16, R17, R18 and R19 are unsubstituted, in or on the backbone. hi one embodiment, preferably the group R1 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein. hi one embodiment, preferably the group R3 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 3 or 4, more preferably by 1 substituent, as defined herein. hi one embodiment, preferably the group R4 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
In one embodiment, preferably the group R5 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein. hi one embodiment, preferably the group R7 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein. hi one embodiment, preferably the group R8 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein. hi one embodiment, preferably the group R10 is substituted, in or on the backbone, by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein. hi one embodiment, preferably the group R14 is substituted, in or on the backbone, by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein. In one embodiment, preferably the group R15 is substituted, in or on the backbone, by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
In one embodiment, preferably the group R16 is substituted, in or on the backbone, by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein. In one embodiment, preferably the group R17 is substituted, in or on the backbone, by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
In one embodiment, preferably the group R18 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein. hi one embodiment, preferably the group R19 is substituted, in or on the backbone, by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
Reference to the "backbone" preferably means the carbon backbone of the group being referred to. However, the term "backbone" includes the possibility for substitution on a heteroatom, such as nitrogen, which is located in the carbon backbone.
As used herein, the term "in the backbone" when referring to a substitution, means that the backbone is interrupted by one or more of the groups indicated. Where more than one substitution occurs, they may be adjacent to one another or remote, i.e., separated by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more carbon atoms.
Furthermore, "in the backbone" comprehends a substitution that may be adjacent or remote to the point of attachment of the group being substituted to the rest of the molecule. It also comprehends the group being the point of attachment to the rest of the molecule. For the sake of clarity, both "ethylaminocarbonyl" and "methylaminocarbonylbutyl" fall under the scope of the definition "C1-6 alkyl group substituted with an NHC(O) group". In the former, the NHC(O) group links the ethyl group to the rest of the molecule, hi the latter, the NHC(O) group interrupts the carbon chain, and the butyl moiety links the methylaminocarbonyl moiety to the rest of the molecule.
As used herein, the term "on the backbone" when referring to a substitution, means that one or more hydrogen atoms on the backbone is replaced by one or more of the groups indicated. Where more than one substitution occurs, they may be on the same, adjacent or remote carbon atoms, i.e., located on carbon atoms that are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more carbon atoms apart.
Where a group comprises two or more moieties defined by a single carbon atom number, for example, C2-20 alkoxyalkyl, the carbon atom number indicates the total number of carbon atoms in the group. As used herein, the term "heteroatom" includes N, O, S, P, Si and halogen (including F, Cl, Br and I).
As used herein, the term "hydrocarbyl group" refers to a monovalent hydrocarbon radical, having the number of carbon atoms as indicated, which contains a carbon backbone comprising one or more hydrogen atoms. The term "hydrocarbyl group" is intended to cover alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, cycloalkynyl, aralkyl, alkaryl, aryl, all of which are further defined herein. This list is non-exhaustive, and the skilled person will readily understand other groups and combinations of the above-mentioned groups fall under the scope of the term "hydrocarbyl group". As used herein, the term "heterocarbyl group" refers to a monovalent hydrocarbon radical, having the number of carbon atoms as indicated, which contains a carbon backbone comprising one or more heteroatoms in or on the carbon backbone, and optionally containing one or more hydrogen atoms. The term "heterocarbyl group" is intended to cover alkoxyalkyl, alkoxyaryl, heteroaryl, heterocyclyl, heteroaralkyl, heterocyclylalkyl, aryloxyalkyl, alkoxy, cycloalkyloxy, aryloxy, alkylamino, cycloalkylamino, arylamino, alkylaminoalkyl, aralkylamino, alkarylamino, aminoalkyl, aminoaryl, aminoaralkyl, aminoalkaryl, guanidinyl, guanidinylalkyl, alkylguanidinyl, alkylguanidinylalkyl, ureayl, ureaylalkyl, alkylureayl and alkylureaylalkyl, all of which are further defined herein. This list is non-exhaustive, and the skilled person will readily understand other groups and combinations of the above-mentioned groups fall under the scope of the term "heterocarbyl group".
As used herein, the term "alkyl" refers to a straight or branched saturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated. By way of non-limiting example, suitable alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, dodecyl and eicosyl. As used herein, the term "alkenyl" refers to a straight or branched unsaturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated, and the distinguishing feature of a carbon-carbon double bond. By way of non-limiting example, suitable alkenyl groups include ethenyl, propenyl, butenyl, penentyl, hexenyl, octenyl, nonenyl, dodecenyl and eicosenyl, wherein the double bond may be located any where in the carbon backbone. As used herein, the term "alkynyl" refers to a straight or branched unsaturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated, and the distinguishing feature of a carbon-carbon triple bond. By way of non-limiting example, suitable alkynyl groups include ethynyl, propynyl, butynyl, penynyl, hexynyl, octynyl, nonynyl, dodycenyl and eicosynyl, wherein the triple bond may be located any where in the carbon backbone. As used herein, the teπn "cycloalkyl" refers to a cyclic saturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated. By way of non-limiting example, suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl, trimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, spiroundecyl, bicyclooctyl and adamantyl.
As used herein, the term "(cycloalkyl)alkyl" refers to an alkyl group with a cycloalkyl substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated. By way of non-limiting example, suitable (cycloalkyl)alkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentyhnethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, methylcyclohexylmethyl, dimethylcyclohexylmethyl, trimethylcyclohexyhnethyl, cycloheptyhnethyl, cycloheptylethyl, cycloheptylpropyl, cycloheptylbutyl and adamantylmethyl.
As used herein, the terms "cycloalkenyl" and "cycloalkynyl" refer to cyclic unsaturated monovalent hydrocarbon radicals. A "cycloalkenyl" is characterized by a carbon-carbon double bond and a "cycloalkynyl" is characterized by a carbon-carbon triple bond. Such groups have the number of carbon atoms as indicated. By way of non-limiting example, suitable cycloalkenyl groups include cyclohexene and cyclohexadiene.
Alkoxy refers to the group "alkyl-O-", where alkyl is as defined above. By way of non-limiting example, suitable alkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
Aryloxy refers to the group "aryl-O", where aryl is as defined herein. By way of non-limiting example, suitable aryloxy groups include phenoxy, tolyloxy and xylyloxy.
As used herein, the term "alkoxyalkyl" refers to an alkyl group having an alkoxy substituent. Binding is through the alkyl group. The alkyl group and/or the alkoxy group has the number of carbon atoms as indicated. The alkyl moiety may be straight or branched. The alk and alkyl moieties of such a group may be substituted as defined above, with regard to the definition of alkyl. By way of non-limiting example, suitable alkoxyalkyl groups include methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxypropyl and ethoxypropyl. As used herein, the term "alkoxyaryl" refers to an aryl group having an alkoxy substituent. Binding is through the aryl group. The aryl group and/or the alkoxy group have the number of carbon atoms as indicated. The alkoxy and aryl moieties of such a group may be substituted as defined herein, with regard to the definitions of alkoxy and aryl. The alkyl moiety may be straight or branched. By way of non-limiting example, suitable alkoxyaryl groups include methoxyphenyl, ethoxyphenyl, dimethoxyphenyl and trimethoxyphenyl.
As used herein, the term "aryl" refers to monovalent unsaturated aromatic carbocyclic radical having one, two, three, four, five or six rings, preferably one, two or three rings, which may be fused or bicyclic. Preferably, the term "aryl" refers to an aromatic monocyclic ring containing 6 carbon atoms, which may be substituted on the ring with 1, 2, 3, 4 or 5 substituents as defined herein; an aromatic bicyclic or fused ring system containing 7, 8, 9 or 10 carbon atoms, which may be substituted on the ring with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents as defined herein; or an aromatic tricyclic ring system containing 10, 11, 12, 13 or 14 carbon atoms, which may be substituted on the ring with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 substituents as defined herein. By way of non-limiting example, suitable aryl groups include phenyl, biphenyl, binaphthyl, indanyl, phenanthryl, fluoryl, flourenyl, stilbyl, benzphenanthryl, acenaphthyl, azulenyl, phenylnaphthyl, benzfluoryl, tetrahydronaphthyl, perylenyl, picenyl, chrysyl, pyrenyl, tolyl, chlorophenyl, dichlorophenyl, trichlorophenyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, fluorophenyl, difluorophenyl, trifluorophenyl, nitrophenyl, dinitrophenyl, trinitrophenyl, aminophenyl, diaminophenyl, triaminophenyl, cyanophenyl, chloromethylphenyl, tolylphenyl, xylylphenyl, chloroethylphenyl, trichloromethylphenyl, dihydroindenyl, benzocycloheptyl and trifluoromethylphenyl.
The teπn "heteroaryl" refers to a monovalent unsaturated aromatic heterocyclic radical having one, two, three, four, five or six rings, preferably one, two or three rings, which may be fused or bicyclic. Preferably, "heteroaryl" refers to an aromatic monocyclic ring system containing five members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms, an aromatic monocyclic ring having six members of which one, two or three members are a N atom, an aromatic bicyclic or fused ring having nine members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms or an aromatic bicyclic ring having ten members of which one, two or three members are a N atom. By way of non-limiting example, suitable heteroaryl groups include furanyl, pyranyl, pyridyl, phthalimido, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, pyronyl, pyrazinyl, tetrazolyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxadinyl, chromenyl, chromanyl, isochromanyl, carbolinyl, thiazolyl, isoxazolyl, isoxazolonyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, benzodioxepinyl and pyridazyl. The term "heterocyclyl" refers to a saturated or partially unsaturated ring having three members of which at least one member is a N, O or S atom and which optionally contains one additional O atom or additional N atom; a saturated or partially unsaturated ring having four members of which at least one member is a N, O or S atom and which optionally contains one additional O atom or one or two additional N atoms; a saturated or partially unsaturated ring having five members of which at least one member is a N, O or S atom and which optionally contains one additional O atom or one, two or three additional N atoms; a saturated or partially unsaturated ring having six members of which one, two or three members are an N, O or S atom and which optionally contains one additional O atom or one, two or three additional N atoms; a saturated or partially unsaturated ring having seven members of which one, two or three members are an N, O or S atom and which optionally contains one additional O atom or one, two or three additional N atoms; a saturated or partially unsaturated ring having eight members of which one, two or three members are an N, O or S atom and which optionally contains one additional O atom or one, two or three additional N atoms; a saturated or partially unsaturated bicyclic ring having nine members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms; or a saturated or partially unsaturated bicyclic ring having ten members of which one, two or three members are an N, O or S atom and which optionally contains one additional O atom or one, two or three additional N atoms. Preferably, heterocycles comprising peroxide groups are excluded from the definition of hetercyclyl. By way of non-limiting example, suitable heterocyclyl groups include pyrrolinyl, pyrrolidinyl, dioxolanyl, tetrahydrofuranyl, morpholinyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrothiopyranyl and piperazinyl.
The term "heterocyclylalkyl" refers to an alkyl group with a heterocyclyl substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated. The heterocyclyl and alkyl moieties of such a group may be substituted as defined herein, with regard to the definitions of heterocyclyl and alkyl. The alkyl moiety may be straight or branched. By way of non-limiting example, suitable heterocyclylalkyl groups include methyl, ethyl, propyl, butyl, pentyl and hexyl substituted with one or more of the heterocyclyl groups indicated immediately above.
As used herein, the term "alkaryl" refers to an aryl group with an alkyl substituent. Binding is through the aryl group. Such groups have the number of carbon atoms as indicated. The alkyl and aryl moieties of such a group may be substituted as defined herein, with regard to the definitions of alkyl and aryl. The alkyl moiety may be straight or branched. Particularly preferred examples of alkaryl include tolyl, xylyl, butylphenyl, mesityl, ethyltolyl, methylindanyl, methylnaphthyl, methyltetrahydronaphthyl, ethylnaphthyl, dimethylnaphthyl, propylnaphthyl, butylnaphthyl, methylfluoryl and methylchrysyl.
As used herein, the term "aralkyl" refers to an alkyl group with an aryl substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated. The aryl and alkyl moieties of such a group may be substituted as defined herein, with regard to the definitions of aryl and alkyl. The alkyl moiety may be straight or branched. Particularly preferred examples of aralkyl include benzyl, methylbenzyl, ethylbenzyl, dimethylbenzyl, diethylbenzyl, methylethylbenzyl, methoxybenzyl, chlorobenzyl, dichlorobenzyl, trichlorobenzyl, phenethyl, phenylpropyl, diphenylpropyl, phenylbutyl, biphenylmethyl, fluorobenzyl, difluorobenzyl, trifluorobenzyl, phenyltolylmethyl, trifluoromethylbenzyl, bis(trifluoromethyl)benzyl, propylbenzyl, tolyhnethyl, fluorophenethyl, fluorenyhnethyl, methoxyphenethyl, dimethoxybenzyl, dichlorophenethyl, phenylethylbenzyl, isopropylbenzyl, diphenyhnethyl, propylbenzyl, butylbenzyl, dimethylethylbenzyl, phenylpentyl, tetramethylbenzyl, phenylhexyl, dipropylbenzyl, triethylbenzyl, cyclohexylbenzyl, naphthylmethyl, diphenylethyl, triphenyhnethyl and hexamethylbenzyl.
The term "heteroaralkyl" refers to an alkyl group with a heteroaryl substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated. The heteroaryl and alkyl moieties of such a group may be substituted as defined herein, with regard to the definitions of heteroaryl and alkyl. The alkyl moiety may be straight or branched. By way of non-limiting example, suitable heteroaralkyl groups include methyl, ethyl, propyl, butyl, pentyl and hexyl substituted with one or more of the specific heteroaryl groups indicated above.
The term "alkylamino" refers to an amine group with an alkyl substituent. Binding is through the amine group. Such groups have the number of carbon atoms as indicated. The alkyl moiety of such a group may be substituted as defined herein, with regard to the definition of alkyl. The alkyl moiety may be straight or branched. By way of non-limiting example, suitable alkylamino groups include methylamino, ethylamino, propylamino, butylamino, pentylamino and hexylamino.
The term "cycloalkylamino" refers to an amine group with a cycloalkyl substituent. Binding is through the amine group. Such groups have the number of carbon atoms as indicated. The cycloalkyl moiety of such a group may be substituted as defined herein, with regard to the definition of cycloalkyl. The alkyl moiety may be straight or branched. By way of non-limiting example, suitable cycloalkylamino groups include cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino, cyclononylamino and cyclododecylamino. The term "aminoalkyl" refers to an alkyl group with an amine substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated. The alkyl moiety of such a group maybe substituted as defined herein, with regard to the definition of alkyl. By way of non-limiting example, suitable aminoalkyl groups include aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl and aminohexyl.
The term "arylamino" refers to an amine group with an aryl substituent. Binding is through the amine group. Such groups have the number of carbon atoms as indicated. The aryl moiety of such a group may be substituted as defined herein, with regard to the definition of aryl. By way of non-limiting example, suitable arylamino groups include phenylamino, biphenylamino, methylphenylamino, methoxyphenylamino, tolylamino and chlorophenylamino.
The term "alkarylamino" refers to an amine group with an alkaryl substituent. Binding is through the amine group. Such groups have the number of carbon atoms as indicated. The alkaryl moiety of such a group may be substituted as defined herein, with regard to the definition of alkaryl. The alkyl moiety may be straight or branched. The term "aminoaralkyl" refers to an aralkyl group with an amine substituent. Binding is through the aralkyl group. Such groups have the number of carbon atoms as indicated. The aralkyl moiety of such a group may be substituted as defined herein, with regard to the definition of aralkyl. The alkyl moiety may be straight or branched.
The term "aminoalkaryl" refers to an alkaryl group with an amine substituent. Binding is through the alkaryl group. Such groups have the number of carbon atoms as indicated. The alkaryl moiety of such a group may be substituted as defined herein, with regard to the definition of alkaryl. The alkyl moiety may be straight or branched.
The term "guanidinyl" refers to a guanidine group that has had one or more hydrogen atoms removed to form a radical. The term "ureayl" refers to a urea group that has had one or more hydrogen atoms removed to form a radical.
Other 'compound' group definitions will be readily understandable by the skilled person based on the previous definitions and the usual conventions of nomenclature.
With regard to one or more substiruents which are referred to as being on the carbon backbone of a group with a compound definition, for example, "alkaryl", the substituent may be on either or both of the component moieties, e.g., on the alkyl and/or aryl moieties. With regard to one or more substituents which are referred to as being in the carbon backbone of a group with a compound definition, for example, "heteroaralkyl", the substituent may interrupt either or both of the component moieties, e.g., in the alkyl and/or aryl moieties.
Reference to cyclic systems, e.g., cycloalkyl, aryl, heteroaryl, etc., contemplates monocyclic and polycyclic systems. Such systems comprise fused, non-fused and spiro conformations, such as bicyclooctyl, adamantyl, biphenyl and benzofuran.
Compounds were tested at human PTHl receptors which have been cloned into an HEK293 cell line as follows:
Step a: Subcloning and engineering of IMAGE clones encoding the human PTHlR into a mammalian expression vector
The NCBI database (http://www.ncbi.nlm.nih.gov) contained 4 mRNA sequences for the human PTHl receptor, having the accession numbers L04308 (Schipani et al. Endocrinology 132, 2157-2165 (1993)), U17418 (Adams et al. Biochemistry, 34, 10553-10559 (1995)), X68596 (Schneider et al. Eur. J. Pharmacol. 246, 149-155 (1993)) and NM_000316 (Hoey et al. Br J Cancer 2003, 88, 567-573). Alignment of these sequences revealed that all four sequences had 100% amino acid identity. The consensus sequence, as represented by L04308, was taken as the wild type (WT) sequence. IMAGE clones (Integrated Molecular Analysis of Genomes and their Expression) (Lennon et al. Genomics 33, 151-152 (1996)), 5183607 and 5186838, were purchased from the HGMP (Human Genome Mapping Project, Cambridge, U.K.). Plasmid DNA was prepared using EndoFree™ plasmid Maxi-prep columns (Qiagen). The DNA was then sequenced using primers 1-5 (see Table 1). The Maxi-prep plasmid DNAs for clones 5183607 and 5186838 were amplified by PCR (polymerase chain reaction) from the start codon to the stop codon using primers 6 and 7, containing Eco Rl (Promega) and Xba I (Promega) restriction sites, respectively. The PCR was performed in 2OmM Tris-HCl (pH 8.8), 1OmM KCl, 1OmM (NHO2SO4, 2mM MgCl2, 0.2mM dNTP containing 0.1 μM of each primer and Ing of the template DNA. A hot start PCR was used: the reactions were denatured for 2min at 950C, cooled to 750C, then IU of Taq Polymerase (hivitrogen) was added and the reactions were cycled 30 times at 950C for lmin, 550C for 30sec and 720C for 3min. After a final extension at 720C for 5min, the samples were cooled to 40C and analysed by electrophoresis.
The PCR products from IMAGE clones 5183607 and 5186838 were purified separately using the MinElute™ PCR purification kit. 5μg of the 1.8kb PCR product generated from IMAGE clone 5183607 (N138S mutation) was restriction-digested with Eco Rl and Kpn I in buffer E (Promega, 6mM Tris-HCl, 6mM MgCl2, 10OmM NaCl, pH 7.5, ImM DTT) containing O.lμg/μl BSA at 370C for Ih 40min. The products were separated using an ethidium bromide stained 1% agarose/TBE gel and the 337bp fragment was isolated and purified using the MinElute™ gel extraction kit. Similarly, 5μg of the 1.8kb from PCR product generated from IMAGE clone 5186838 (E49G mutation) was restriction digested with Xba I and Kpn I in mulitcore buffer (Promega, 25mM Tris -acetate pH 7.5, 10OmM potassium acetate, 1OmM magnesium acetate, ImM DTT) containing O.lμg/μl BSA at 370C for Ih 40min. The 1.4kb fragment was isolated as above.
Both PCR fragments (i.e. 60ng of the 337bp fragment and 280ng of the 1.4kb fragment) were ligated together in a single ligation reaction in the presence of lOOng of Eco Rl I Xba I digested and shrimp alkaline phosphatase (Promega) treated mammalian expression vector using the QuickStick™ DNA Ligation kit (Bioline). After 15 min at room temperature, 2.5μl of the ligation mix was transformed into lOOμl XLl -Blue competent cells (Stratagene).
DNA from eleven of the resulting transformed colonies was prepared using plasmid Mini prep columns (Qiagen) according to the manufacturer's instructions. Of the ten clones that were positive (as determined by restriction digestion of the miniprep DNA), DNA was prepared from one positive clone using the plasmid Maxi-prep columns. The resulting DNA was then fully sequenced by MWG-Biotech AG (Ebersberg, Germany) on both strands using primers 2 and 8-12 (see Table 1). Sequence analysis revealed 100% amino acid identity within the coding region compared to sequence L04308 (WT human PTHlR).
Table 1: Oligonucleotides used for Sequence or PCR analysis
Figure imgf000054_0001
Restriction sites are in bold. Start codon is underlined. Stop codon is in italics and underlined. Step b: Generation of Stable Cell Line
HEK293 cells from the European Collection of Cultures (ECACC) were cultured in Minimal Essential Media (with Earle's Salts) (hivitrogen), containing 2mM Glutamaxl (Invitrogen), 10% heat-inactivated foetal bovine serum (Invitrogen), Ix non-essential amino acids (hivitrogen). Cells (2.1 x 106) were seeded into 100mm x 20mm dishes (Corning) and transfected the following day using the Transfast™ reagent (Promega), using either 13, 26 or 31μg of the plasmid DNA containing the engineered hPTHlR per dish, at a ratio of 1:1 (Transfast™ reagentDNA). After 48h the cells were trypsinised (Culture of Animal Cells, a Manual of Basic Techniques; 4th ed.; Freshney, R. Wiley Press) and seeded in duplicate 35mm x 10mm dishes at low densities (10,000, 2,500 or 500 cells/dish) in media containing 800μg/ml G-418. The remainder of the cells were kept for whole cell radioligand binding analyses. The plated cells were selected for 20 days, with media changes every 3-4 days, using 10% conditioned media from untransfected HEK293 cells, until individual colonies appeared visible to the naked eye. Cloning rings were used to isolate individual, well-separated colonies and trypsinisation was used to transfer the cells in each colony to a suitable vessel for expansion. The cells were expanded and analysed by RT-PCR and radioligand binding analysis. Media, containing 400μg/ml G-418, was used for routine culture of the HEK293/hPTHlR cell lines. Cells were trypsinised and used straight away for whole cell radioligand binding assays or frozen as a pellet on dry ice then stored at -8O0C for membrane-based radioligand binding assays.
Step c: Clonal selection Stable clones, with the greatest expression of the human PTHj receptor, were selected by establishing the specific binding of [125I]-[NIe8'18, Tyr34]-hPTH(l-34) at a range of cell concentrations (2.5 x 104 - 7.5 x 105 cell ml"1) using assay conditions previously described (ORLOFF, J.G., WU, T.L., HEATH, H. W., BRADY, T.G., BRINES, M.L. & STEWART, A.F. J. Biol. Chem., (1989), 264, 6097-6103). Of the clones examined, clone 9B3 was selected because it gave the highest amount of specific binding (74% and 4911cpm) at an added cell concentration of 1 x 105 cell niTW [125I]-[NIe8'18, Tyr34]-hPTH(l-34) concentration of 2OpM. hi addition, there was a linear relationship between cell concentration and specific binding.
Step d: Membrane preparation
Harvested clone 9B3 cells were stored as pellets at -700C. When required, aliquots were thawed, by mixing with ice-cold buffer A. (5OmM Tris-HCl, ρH7.2 at 21°C; 3mM MgCl2,
3mM CaCl2, 3mM KCl and 3mg ml'1 bacitracin). The cell/membrane suspension was centrifuged (20min, 20,00Og @ 4°C; Hettich microfuge) and the final cell pellet resuspended by homogenisation (Polytron PTlO, setting 7, 1 x Is), to a membrane concentration equivalent to 3 x 104 cells ml"1 added, in buffer A (210C; containing lOμM chymostatin and lμM 1,10-phenanthroline).
Step e: Incubation conditions
For competition, saturation and kinetic studies, membranes were prepared as described in step d and used at a concentration of 3 x 104 cells ml"1. Non-specific binding was defined with PTH(J-34) (50μl; lOμM). For competition and saturation studies, membranes were incubated for 210min at 210C, in final volume of 0.5ml, [125I]-[NIe8'18, Υy^\-hFTH(l-34) (50μl; competition =200pM; saturation =2pM-300nM). To establish that the binding of [125I]-[NIe8'18, Tyr34]-hPTH(l-34) reached equilibrium, kinetic studies were performed. Membranes were incubated with [125I]-[NIe8'18, Tyr34]-hPTH(l-34) (50μl; 20OpM) for increasing time intervals (l-1200min). To establish the time-course of the dissociation, specific binding was determined at increasing time intervals times (2-1200min) after addition of lμM PTH(I -34). The assays were terminated by rapid filtration through Whatman GF/B filter mats or GF/B Unifilters (0.3% polyethyleneimine). Filters were washed with ice-cold 5OmM Tris-HCl (pH7.4) and counted on a Wallac gamma counter (lmin) or TopCount (3min). Step f: Saturation and kinetic analysis
The binding of [125I]-[NIe8'18, Tyr34]-hPTH(l-34) to the human PTH1 receptor reached equilibrium after 70min at 21°C (n=3) and was saturable (PKD=8.84 ; nH=1.35; n=l). The binding was dissociated by lμM PTH.
Step g: Competition studies A number of reference compounds and compounds of the invention were tested for their ability to compete for human PTH1 receptors labelled with [125I]-[NIe8'18, Tyr34]-hPTH(l-34). Compounds were diluted and added to 96 well plates together with radioligand and membranes using a Beckman Biomek. The ability of compounds to inhibit specific binding was determined in at least two experiments, in triplicate and over a range of concentrations at half-log unit intervals. Compound affinity values (pICso; mid-point curve location) and mid-point slope parameter (nu) were derived through fitting competition data to the Hill equation (Graph-Pad Prism). Dissociation constants (Kj) were determined using the Cheng & Prusoff equation (1973) to correct for the receptor occupancy of the ligand. In practice pIC5o values are equivalent to pKj values due to the low occupancy of the radioligand. The PK1 values for reference compounds are shown in the table below.
Figure imgf000056_0001
Alternatively, compounds can be tested at human PTHl receptors in a SaOS-2 cell-based assay as follows:
Step a: Cell culture and harvesting
Human SaOS2 cells obtained from the ATCC were seeded into Tl 75 cm2 dishes and grown in McCoys 5 A medium containing 2mM glutamax and 10% foetal bovine serum (FBS) (1.7 million cells). Cells were maintained at 370C in 5% Cθ2/humidified air the media being changed every 3-4days. On the 13th day of culture the media was changed to OptiMEM medium. The following day the cell culture medium was removed and the monolayer briefly washed in 1OmL Hank's buffered salt solution (HBSS). Hanks based cell dissociation medium (1OmL) was added and left for 5min at 370C and cell detachment was aided by gently tapping the culture flask. McCoy's 5 A medium (1OmL) containing 2mM glutamax and 1% FBS was added and mixed by pipetting over the bottom of the flask to prevent receptor degradation. Cells were removed from the flask into a 5OmL centrifuge tube and subsequently centrifuged at 20Og for 5min at 150C to allow a pellet to form. The supernatant was removed and the cells resuspended in McCoy's 5A medium containing 2mM glutamax and 1% FBS. The cell number and viability was determined using a nucleocounter. Cells were aliquoted into appropriate size aliquots and re-centrifuged before being resuspended in 0.5mL of cell freezing medium (CFM), containing DMSO and stored in polypropylene boxes at -8O0C. Finally, cells were removed from the boxes and stored at -8O0C in the freezer. Step b: Preparation of drug solutions hHPTH(l-34), hPTHrP(l-34), [Nle30]-hTIP(7-39) and hTIP(l-39) were dissolved in 20% ultra high purity (UHP) water and 80% ethanol to provide a stock concentration of ImM. Subsequent dilutions were made into RPMI medium containing 25mM HEPES and 5mM IBMX. Test compounds were dissolved in 10% DMF and 90% ethanol to a stock concentration of ImM. Intermediate dilutions were made into 10% DMF and 90% ethanol and final dilutions were made in RPMI containing 25mM HEPES and 5mM IBMX. IBMX was made up fresh daily in DMSO to an initial stock concentration 0.1M. Bacitracin was made up fresh daily in DMSO to an initial concentration of lOOnig/mL. Rolipram was made up in DMSO to an initial stock concentration of 0.2M and stored in lOOμl aliquots at -2O0C. Step c: Cell preparation for LANCE™ cAMP experiments
Aliquots of cells were thawed rapidly at 370C in a water bath. OptiMEM containing 25mM HEPES was slowly added drop- wise (1OmL over 2 min), stopping frequently to mix, then added a little faster, gradually diluting the cells and the preservative. A further 1OmL of medium was added and the cells were centrifuged at 200 x g for 5min to form a pellet. The pellet was resuspended in fresh medium a total and the viable cell count performed. The required number of cells was then re-centrifuged and resuspended in stimulation buffer by repeated pipetting.
Step d: Opimisation of cell concentration for PTH induced accumulation of cAMP Initial experiments were conducted to establish a cell concentration at which PTH produced a large increase in cAMP relative to basal but at the same time where all changes in cAMP could be interpolated from the linear part of the cAMP standard curve. hHPTH(l-34) was diluted in RPMI containing 25mM HEPES (20pM-20μM) and aliquoted in triplicate (5μl) into 384-well OptiPlates prior to the addition of SaOS-2 whole cells (5μl, 3x105, 6XlO5HiL'1). The assay was terminated by addition of detection buffer after 120min at 21±3°C. TopSEAL-A film was affixed to each plate and the plate was placed on a plate shaker for 90min. Following a 16h incubation the plates were counted on an EnVision (PerkinElmer) counter. A cell concentration of 6x105 cells mL"1 was chosen for the experiments.
Step e: Establishing optimal assay stimulation times Basal and hPTH(l-34)-stimulated cAMP accumulation was determined by incubating whole cells at 21+30C (5μl, 6xlO5 cells mL"1) for increasing time intervals with RPMI containing 25mM HEPES (5μl) and hPTH(l-34) (5μl, 20pM-20mM) respectively. The assay was terminated by addition of detection buffer, Alexa Fluor® 647-anti cAMP antibody, 2.5mM IBMX and 0.2-0.5% BSA was added to the cells to stop degradation or further productin of cAMP. TopSEAL-A film was affixed to each plate and the plate was placed on a plate shaker for 90min. Following a 16h incubation the plates were counted on an EnVision (PerkinElmer) counter. cAMP formation in response to PTH-R ligands was measured in whole cells seeded in 384-well Optiplates plates using FRET-based LANCE technology (PerkinElmer). Briefly, cells, 3xlO3 per well were incubated in stimulation buffer consisting of RPMI containing 25mM HEPES (pH7.4), bacitracin O.SmgmL"1, IBMX 2.5mM and rolipram ImM and actiated by 120 min exposure to the PTH-R ligands. Antagonist potency was determined by pre- incubating the cells with antagonist for 30min before addition to 384-well Optiplates plates containing PTH-R agonists. Finally, detection mix containing the Alexa Fluor® 647-anti cAMP antibody, 2.5mM IBMX and 0.2-0.5% BSA was added to the cells to stop degradation or further production of cAMP.
Step f: Assay characterisation with PTH-R ligands
In order to establish that the cAMP accumulation seen in SaOS2 whole cells on addition of hPTH(l-34) was only induced by activation of PTH1 receptors, the effect of several PTH1 and PTH2 receptor selective ligands on cAMP accumulation was examined. Ligands (hPTH(l-34), hTIP(l-39), hPTHrP(l-34) and [Nle30]-hTIP(7-39)) were serially diluted into RPMI containing 25mM HEPES and aliquoted (5μl) in triplicate into Optiplates (2XlO"11^XIO-5M) prior to the addition of whole cells resuspended in RPMI containing 25mM HEPES, 5mM IBMX and 2mM rolipram (5μl; 5x106 cells/ mL). A cAMP standard curve, defined in triplicate was included in each assay.In order to demonstrate that the cAMP accumulation induced by the PTH receptor agonists is mediated by the PTH1 we chose to examine the ability of PTHi receptor peptide antagonists namely hPTHrP(7-34) and [Nle30]-hTIP(7-39) to inhibit hPTH(l- 34)- and hPTHrP(l-34)-stimulated cAMP production. Antagonists were preincubated with cells for a standard 30min. Whole cells (450μl, 6.7xlO5 cells mL"1) resuspended in RPMI containing 5mM IBMX, 2.22mM Rolipram & l.l lmg/mL bacitracin were incubated in Eppendorf tubes with peptide antagonists (50μl) or test compounds for 30min at 21+30C. Following this incubation period, cells (5μl) were aliquoted in triplicate into Optiplates containing either hPTH(l-34) (5μl; 2xl0-n-2xl0-5M) or buffer (5μl, basal). Final concentrations of 2.5mM IBMX, ImM rolipram & 0.5mg/mL bacitracin was achieved in the wells. After the appropriate incubation time, PerkinElmer detection mix containing the Alexa Fluor® 647-anti cAMP antibody, 2.5mM IBMX and 0.2-0.5% BSA was added to the cells to stop degradation or further production of cAMP. TopSealsTM were airfixed and each plate was incubated for 16h, with gentle mixing for the first 90min at 210C. The plates were counted on an EnVision counter (PerkinElmer). A cAMP standard curve defined in triplicate was included in each assay.All data was analysed using GraphPad Prism software to determine P[A]5O, upper asymptote (α) and mid-point slope parameter (nπ - equivalent to the Hill slope). The values below are estimated by logistic fitting of the mean data (triplicates) obtained from n experiments where p[A]5o is the midpoint location of the agonist concentration-effect curve and nH is the midpoint slope parameter of the curve.
Figure imgf000059_0001
Affinity estimates (pA2 and pKβ values) were mathematically derived from either single (JpA2) or multiple concentrations (pKβ) of antagonist.
Figure imgf000059_0002
Figure imgf000060_0002
The following compounds have been synthesised in accordance with the present invention.
Figure imgf000060_0001
Figure imgf000061_0001
Compounds of formula I were found to inhibit the stimulatory effect of hPTH(l-34) or hPTHrp(l-34) on cAMP production in SaOS-2 cell-based assay when added at concentrations ranging form 10"5-10"9M.
We also provide data on compounds of the invention as follows:-
Figure imgf000062_0001
The synthesis of the above-identified compounds shall now be described in detail. Experimental
Commercially available dichloromethane (DCM), 1,2-dichloroethane (DCE), ethyl acetate (EtOAc), tetrahydrofuran (THF) and N,N-dimethylformamide (DMF) were used. Column chromatography was performed on Merck silica gel 60(40-63 μm) using the reported solvent systems. 1H NMR spectra were recorded on a Bruker DRX-300 instrument at 300MHz and the chemical shifts (δH) were recorded relative to an internal standard.
Example 1 l-(5-((l-Arnmo-cyclopentyhnethyl)-amino)-pyridin-2-yl)-5-cyclohexyl-8-methyl-3- (tetrahydro-pyran-4-yl)-lH-l , 3, 4-benzotriazepin-2(3H)-one Step a (2-Amino-4-methyl-phenyl)-cyclohexyl-methanone
To a solution of m-toluidine (66.ImL, 0.6mol) and cyclohexanecarbonitrile (32.76g, 35.6mL, 0.3mol) in dry toluene (1.5L) at O0C, BCl3 (IN in xylene, 30OmL, 0.3mol) was added dropwise, at such a rate as to keep the internal temperature below 5°C. Upon completion of the addition, the mixture was allowed to warm to ambient temperature and stirred for Ih. The reaction mixture was cooled to O0C and AlCl3 (4Og, 0.3mol) was added in portions over 30 min. The cooling bath was removed and the mixture was heated at reflux for 5h and allowed to stand at ambient temperature overnight. The reaction mixture was cooled to 0°C and 2N HCl (45OmL) was added dropwise. Upon completion of the addition, the cooling bath was removed and the mixture was heated at reflux for 2.5h. On cooling to ambient temperature the mixture was extracted with EtOAc (3 x 50OmL). The combined extracts were washed with H2O (IL), brine (500 mL) and dried (MgSO4). Filtration and evaporation of the solvent afforded a red gum which solidified on standing. The crystalline mass was triturated with hexane (10OmL) at -4O0C and quickly filtered to afford pale yellow crystals of the desired compound (29.63g, 45%). The product was dried at ambient temperature in vacuo. 1H NMR (CDCl3) 7.66-6.46 (3H, m), 6.25 (2H, br s), 3.25 (IH, m), 2.27 (3H, s), 1.87-1.28 (1OH, m)
Step b N'-(Tetrahydro-pyran-4-yl)-hydrazinecarboxylic acid tert-butyl ester
A mixture of tetrahydro-4H-pyran-4-one (31.7mL, 0.34mol) and tert-butylcarbazate (47.7g, 0.36mol) in EtOH (50OmL) was stirred at ambient temperature overnight. The reaction mixture was evapotrated and the reisdue suspended in HOAc-H2O (1:1 / 50OmL). NaCNBH3 (22.64g,
0.36mol) was added and the mixture was stirred at ambient temperature for 2.5hr. The reaction mixture was suspended in EtOAc-10% K2CO3 (2:1 / 75OmL). The organic layer was separated, washed with brine (2 x 40OmL) and dried (MgSO4). Filtration and evaporation of the solvent and trituration of the residue with hexane afforded the product as a white amorphous solid
(47.5g, 64%). 1H NMR (CDCl3) 6.10 (IH, br s), 3.99-3.35 (5H, m), 3.06 (IH, m), 1.79-1.35
(4H, m), 1.46 (9H, s)
Step c 5-Cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l, 3, 4-benzotriazepin-2(3H)-one
A solution of the product from step a (9.Og, 41.4mmol) and NEt3 (12.73mL, 91.1mmol) in DCM (30OmL) was added dropwise to a solution of triphosgene (4.06g, 13.7mmol) in DCM
(16OmL) at -4O0C. The reaction mixture was stirred at this temperature for 20min whereupon a solution of the product from step b (8.97g, 41.4mmol) in DCM (16OmL) was added dropwise.
The reaction mixture was allowed to warm to ambient temperature and was washed with H2O
(40OmL), saturated NaHCO3 (40OmL), brine (40OmL) and dried (MgSO4). The residue, obtained following filtration and evaporation, was dissolved in DCM (5OmL) and TFA (5OmL) and stirred for lhr. The mixture was evaporated to dryness and the residue dissolved in DCM
(10OmL), washed with 10% aqueous K2CO3 (10OmL), and dried (MgSO4). Filtration and evaporation of the solvent afforded the product (13.47g, 95%). 1H NMR (CDCl3) 7.25-6.38
(4H, m), 4.15 (IH, m), 4.02 (2H, m), 3.48 (2H, m), 2.70 (IH, m), 2.33 (3H, s), 2.25-1.25 (14H, m)
Step d 5-Cyclohexyl-8-methyl-l-(5-nitro-pyridin-2-yl)-3-(tetrahydro-pyran-4-yl)-lH-l, 3, 4- benzotriazepin-2(3H)-one
Sodium hydride (60% suspension in mineral oil: 60mg, 1.5 mmol) was added to a solution of the product from step c (340mg, l.Ommol) in DMF (1OmL) at ambient temperature and the reaction mixture stirred for Ih. Thereafter, 2-fluoro-5-nitro-pyridine (A. Wissner. et ah, Bioorg. Med. Chem. Lett, (2004), 14, 1411-1416) (180mg, 1.25mmol) was added and the reaction mixture stirred for 16h at 90°C. On cooling, the reaction mixture was diluted with EtO Ac-brine (1:1 / 10OmL). The organic layer was separated and washed with brine (2 x 5OmL), dried (MgSO4), filtered and the solvent evaporated. The residue was dissolved in EtOAc (2mL) and following addition of hexane (1OmL) a brown solid was obtained which was isolated by filtration and dried in vacuo (460mg, 99%). 1H NMR (CDCl3) 8.99 (IH, d), 8.34 (IH, dd), 7.50 (IH, d), 7.41 (IH, d), 7.29 (IH, d), 7.19 (IH, s), 4.35 (IH, m), 4.14 (IH, m), 3.95 (IH, m), 3.56 (IH, m), 3.40 (IH, m), 2.84 (IH, m), 2.40 (3H, s), 2.11-1.16 (14H, m). Step e l-(5-Amino-pyridin-2-yl)-5-cyclohe^l-8-methyl-3-(tetrafψdro-pyran-4-yl)-lH-ly 3, 4- benzotriazepin-2(3H)-one
A suspension of the product from step d (460mg, 0.99mmol) and SnCl2.2H2O (2.24g, lOmmol) in EtOAc (8OmL) was heated at reflux for 16h. On cooling, the reaction mixture was poured into a saturated NaHCO3 solution (2OmL). Further solid sodium bicarbonate (1Og) was added and the suspension was stirred for Ih then filtered through a pad of Celite. The organic layer was separated, washed with brine (5OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography (acetone-DCM (1:5- 1:2) (202mg, 47%). 1B. NMR (CDCl3) 7.89 (IH, s), 7.39 (IH, d), 7.25 (IH, d), 7.00 (2H, m), 6.71 (IH, s), 4.03 (3H, m), 3.76 (2H, brm), 3.46 (2H, m), 2.79 (IH, m), 2.27 (3H, s), 1.95-1.25 (14H, m).
Step f l-ft-tfl-N-tert-Butotycarbonylamino-cyclopentylmethylJ-aminoJ-pyridin^-yty-S- cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one
A mixture of the product from step e (150mg, 0.35mmol), NaBH(OAc)3 (127mg, O.δmmol), 1- N-fert-butoxycarbonylamino cyclopentanecarboxaldehyde (96mg, 0.46mmol) and HOAc (lOOμL, 1.6mmol) in DCE (1OmL) was stirred for 16h at rt. The reaction mixture was diluted with DCM (1OmL), washed with saturated NaHCO3 solution (1OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography (EtOAc-DCM (2:3)) (120mg, 55%). 1H NMR (CDCl3) 7.86 (IH, s), 7.34 (IH, d), 7.23 (IH, d), 6.96 (2H, m), 6.73 (IH, s), 4.63 (2H, brm), 3.97 (3H, m), 3.46 (2H, m), 3.32 (2H, s), 2.79 (IH, m), 2.22 (3H, s), 1.91-1.31 (3 IH, m).
Step g
The product from step f (120mg, 0.12mmol) was dissolved in 4N HCl in dioxan (1OmL) and stirred at ambient temperature for Ih. The solvent was removed at reduced pressure and the residue was diluted with DCM (2OmL) and reconcentrated. Et2O was added and the solvent was evaporated to afford the title compound as the HCl salt (75mg, 34%). 1H NMR (DMSO- d6/D2O) 8.32 (IH, br s), 7.92 (IH, s), 7.47 (IH, d), 7.28 (2H, m), 7.06 (IH, d), 6.64 (IH, s), 3.83 (3H, m), 3.32 (6H, m), 2.94 (IH, m), 2.19 (3H, s), 1.77-1.17 (22H, m). Found: C 58.89, H 7.55, N 12.28%; C3iH42N6O2«2.7HCl«0.7C4H8O2 requires: C 58.76, H 7.34, N 12.16%. Example 2 5-Cyclohexyl-8-methyl-l-(5-((piperidin-4-ylmethyl)-amino)-pyndin-2-yl)-3- (tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one
The HCl salt of the title compound was obtained using steps f and g of example 1 except that 4-formyl-piperidine-l-carboxylic acid tot-butyl ester was used in step f in place of l-N-tert- butoxycarbonylamino cyclopentanecarboxaldehyde. 1H NMR (DMSO-d6/D2O) 7.76 (IH, s), 7.43 (IH, d), 7.23 (IH, d), 7.00 (2H, m), 6.62 (IH, s), 3.81 (4H, m), 3.28 (5H, m), 2.96-2.81 (6H, m), 2.17(3H, s), 1.89-1.10 (18H, m). Found: C 58.39, H 7.31, N 12.37%; C3iH42N6θ2»2.9HCl»0.4C4H8θ2 requires: C 58.29, H 7.22, N 12.51%.
Example 3 5-Cyclohexyl-8-methyl-l-(5-(2-methy]amino-eihylamino)-pyridm-2-yl)-3- (tetrahydro-pyran-4-y I)-IH-1 , 3, 4-benzotriazepin-2(3H)-one
The HCl salt of the title compound was obtained using steps f and g of example 1 except that methyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester was used in step f in place of \-N-tert- butoxycarbonylamino cyclopentanecarboxaldehyde. 1HNMR (CDCl3) (free base) 7.89 (IH, d), 7.39 (IH, d), 7.26 (IH, d), 6.97-6.93 (2H, m), 6.73 (IH, m), 4.28 (IH, brm), 4.07-3.96 (3H, m), 3.46 (2H, t), 3.20 (2H, m), 2.87 (2H, t), 2.80 (IH, m), 2.46 (3H, s), 2.24 (3H, s), 2.05-1.24 (15H, m). Found: C 58.85, H 7.25, N 14.35%; C3iH42N6O2«2.3HCl-requires: C 58.58, H 7.07, N 14.64%.
Example 4 δ-Chloro-δ-cyclohexyl-l-^-β-methylamino-ethylaminoJ-pyridin^-ylJ-S- (tetrahydro-pyran-4-y I)-IH-1 , 3, 4-benzotήazepin-2(3H)-one Step a l-(5-Amino-pyridin-2-yl)-8-chloro-5-cycloheocyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4- benzotriazepin-2(3H)-one was obtained using steps a, and steps c-e of example 1 except that 3- chloro aniline was used in step a in place of m-toluidine. 1H NMR (CDCl3) 7.92 (IH, d), 7.40 (IH, d), 7.32-7.27 (2H, m), 7.15 (IH, dd), 7.03 (IH, dd), 4.07 (IH, t), 4.03 (2H, dd), 3.72 (2H, brs), 3.43 (2H, m), 2.77 (IH, m), 2.00-1.24 (14H, m) Step b
The HCl salt of the title compound was obtained using steps f and g of example 1 except that 1 -(5-amino-pyridin-2-yl)-8-chloro-5-cyclohexyl-3-(tetrahydro-pyran-4-yl)- 1 H- 1 ,3 ,4- benzotriazepin-2(3H)-one and methyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester were used in step f in place of l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)- lH-l,3,4-benzotriazepin-2(3H)-one and 1-N-fert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively. 1H NMR (CDCl3) (free base) 7.89 (IH, d), 7.35- 7.29 (2H, d), 7.12 (IH, d), 7.00-6.93 (2H, m), 4.30 (IH, brm), 4.07-3.96 (3H, m), 3.46 (2H, t), 3.27 (2H, bπn), 2.92 (2H, t), 2.78 (IH, m), 2.50 (3H, s), 2.00-1.30 (15H, m). Found: C 53.32, H 6.30, N 13.45%; C31H42N6O2»2.6HC1.0.4MeOH requires: C 53.19, H 6.39, N 13.58%.
Example 5 5-Cyclohexyl-8-methoxyA-(5-(2-methylamino-ethylamino)-pyridin-2-yl)-S- (tetrahydro-pyran-4-yl)-lH-l, 3, 4-benzotriazepin-2(3H)-one Step a 5-Cyclohexyl-8-methoxy-l-(5-nitro--pyήdin-2-yl)-3-(tetrahydro-pyran-4-yl)-lH-l, 3, 4- benzotriazepin-2(3H)-one was obtained using steps a, c and d of example 1 except that 3- methoxy aniline was used in step a in place of m-toluidine. 1H NMR (CDCl3) 9.00 (IH, s), 8.31 (IH, d), 7.43 (2H, m), 7.04 (IH, d), 6.88 (IH, s), 4.37 (IH, m), 4.16-3.81 (5H, m), 3.55- 3.41 (2H, m), 2.88-2.81 (IH, m), 2.05-1.24 (14H, m). Step b l-(5-Amino-pyridin-2-yl)-5-cyclohexyl-8-methoxy-3-(tetrahydro-pyran-4-yl)-lH-l, 3, 4- benzotriazepin-2(3H)-one
The product from step a (1.39g, 2.91mmol) was dissolved in MeOH-THF (1:1 / 12mL) with 10% Pd/C (150mg) and stirred under a hydrogen atmosphere for 16h. After filtration through a pad of Celite, the solvents were removed at reduced pressure. The residue was purified by chromatography (EtOAc-hexane (1:2)) to afford the product (1.23g, 94%). 1H NMR (CDCl3) 7.93 (IH, d), 7.37-7.27 (2H, m), 7.03-6.99 (IH, m), 6.74-6.70 (IH, m), 6.51 (IH, d), 4.16-3.95 (3H, m), 3.69 (5H, s), 3.50-3.42 (2H, m), 2.79-2.74 (IH, m), 2.05-1.24 (14H, m)
Step c l-(5-(2-(N-tert-Butoxycarbonyl)methylamino-ethylamino)-pyridin-2-yl)-5-cyclohexyl-8- methoxy-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin~2(3H)-one was obtained using step f of example 1 except that l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8-methoxy-3- (tetrahydro-pyran-4-yl)- 1 H- 1 ,3 ,4-benzotriazepin-2(3H)-one and methyl-(2-oxo-ethyl)- carbamic acid tert-butyl ester were used in place of l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8- methyl-3-(tetrahydro-pyran-4-yl)-lH- 1 ,3,4-benzotriazepin-2(3H)-one and 1 -N-tert- butoxycarbonylamino cyclopentanecarboxaldehyde respectively. 1H NMR (CDCl3) 7.86 (IH, d), 7.35-7.27 (3H, m), 6.92-6.88 (IH, m), 6.73-6.69 (IH, m), 6.52 (IH, d), 4.12-3.96 (3H, m), 3.69 (3H, s), 3.50-3.42 (4H, m), 3.31-3.25 (2H, m), 2.90 (3H, s), 2.81-2.74 (IH, m), 2.05-1.24 (23H, m)
Step d
The HCl salt of the title compound was obtained using step g of example 1 except that l-(5-(2- (N-tert-butoxycarbonyl)memylamino-ethylamino)-pyridin-2-yl)-5-cyclohexyl-8-methoxy-3- (tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one was used in place of 1-(5-((1-N- te^butoxycarbonylammo-cyclopen1yhiiethyl)-arnmo)-pyridin-2-yl)-5-cyclohexyl-8-methyl-3- (tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one. 1H NMR (DMSO-d6) 9.02 (2H, brs), 7.86 (IH, d), 7.53 (IH, d), 7.32 (IH, d), 7.20-7.16 (IH, m), 6.84-6.80 (IH, m), 3.90-3.81 (3H, m), 3.66 (3H, s), 3.44-3.29 (4H, m), 3.07-3.03 (2H, m), 2.92 (IH, m), 2.57-2.53 (3H, m), 1.74-1.18 (14H, m). Found: C 55.73, H 6.99, N 13.36%; C28H38N6O3«2.6HCl»0.4C4H8O2 requires: C 55.84, H 6.93, N 13.20%. Example 6 5-Cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l-(5-(2-(tetrahydro-pyran-4- ylamino)-ethylamino)-pyridin-2-yl)-lH-l,3,4-benzotriazepin-2(3H)-one
Step a l-(5-(2-Amino-ethylamino)-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4- yl)-lH-l,3,4-benzotriazepin-2(3H)-one was obtained using step f of example 1 except that tert- butyl N-(2-oxoethyl)carbamate was used in step f in place of 1-TV-ter^-butoxycarbonylamino cyclopentanecarboxaldehyde. 1H ΝMR CDCl3 7.89 (IH, d), 7.41 (IH, d), 7.26 (IH, d), 6.95 (2H, m), 6.72 (IH, s), 4.20 (IH, t), 4.04-3.96 (3H, m), 3.46 (2H, t), 3.18 (2H, q), 2.98 (2H, t), 2.81 (IH, m), 2.24 (3H, s), 2.05-1.24 (16H, m)
Step b
The title compound was obtained using step f of example 1 except that l-(5-(2-amino- ethylamino)-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4- benzotriazepin-2(3H)-one and tetrahydro-4H-pyran-4~one were used in place of l-(5-amino- pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lΗ-l,3,4-benzotriazepin- 2(3H)-one and 1-N-fert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively. 1H ΝMR CDCl3 7.89 (IH, d), 7.40 (IH, d), 7.26 (IH, d), 6.95 (2H, m), 6.72 (IH, s), 4.28 (IH, br m), 4.04-3.96 (5H, m), 3.50-3.40 (4H, m), 3.20 (2H, m), 2.93 (2H, t), 2.81 (IH, m), 2.68 (IH, m), 2.24 (3H, s), 1.97-1.11 (19H, m). The compound was further characterised and tested as the HCl salt. Found: C 58.22, H 7.18, Ν 12.62%; C32H44N6O3^JHCl requires: C 58.15, H 7.13, N 12.71%.
Example 7 5-Cyclohexyl-l-(5-(2-isopropylamino-ethylamino)-pyridin-2-yl)-8-methyl-3- (tetrahydro-pyran-4-yl)-lH~l , 3, 4-benzotriazepin-2(3H)-όne
The title compound was obtained using step f of example 1 except that l-(5-(2-amino- ethylamino)-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4- benzotriazepin-2(3H)-one (Example 6, step a) and acetone were used in place of l-(5-amino- pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin- 2(3H)-one and 1-N-fert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively. 1H ΝMR (free base) CDCl3 7.90 (IH, d), 7.37 (IH, d), 7.26 (IH, d), 6.96 (2H, m), 6.72 (IH, s), 4.42 (IH, m), 4.07-3.96 (3H, m), 3.46 (2H, t), 3.23 (2H, m), 2.91 (2H, t), 2.82 (IH, m), 2.24 (3H, s), 2.17-1.24 (15H, m), 1.11 (6H, d). Found: C 59.67, H 7.42, Ν 13.67%; C30H42N6O2^HCl requires: C 59.48, H 7.39, N 13.87%. Example 8 8-Chloro-5-cyclohexyl-l-(5-(2-dimethylamino-ethylamino)-pyridin-2-yl)-3- (tetrahydro-pyran-4-yl)-lH-l , 3, 4-benzotriazepin-2(3H)-one
A mixture of l-(5-amino-pyridin-2-yl)-8-chloro-5-cyclohexyl-3-(tetrahydro-pyran-4-yl)-lH- l,3,4~benzotriazepin-2(3H)-one (example 4, step a) (497mg, l.lmmol), N,N-dimethylglycine (140mg, 1.40mmol), EDCI (190mg, 1.4mmol) and 1-HOBt (203mg, 1.2mmol) in DMF (5mL) was stirred for 72h at rt. The reaction mixture was diluted with EtOAc (2OmL), washed successively with saturated NaHCO3 solution (2OmL), brine (2 x 2OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was dissolved in THF (18mL). Borane-THF complex (IM in THF / 2.7mL, 2.7mmol) was added and the reaction mixture heated to reflux for 16h. MeOH (9mL) was added dropwise and reflux continued for an additional Ih. After cooling, the solvent was removed at reduced pressure and the residue purified by chromatography (DCM-MeOH (19:1)) to afford the product as a yellow oil (0.1 Ig, 17%). 1H NMR (free base) CDCl3 7.89 (IH, d), 7.32 (IH, d), 7.31 (IH, d), 7.28 (IH, d), 7.13 (IH, d), 6.98 (IH, d), 4.01 (IH, m), 3.96 (2H, dd), 3.22 (2H, t), 3.17 (2H, m), 2.77 (IH, t), 2.62 (IH, t), 2.30 (6H, s), 1.96-1.02 (15H, m) The compound was further characterised and tested as the HCl salt. Found: C 51.48, H 6.54, N 12.20%; C28H37ClN6O«3.6HCl»0.4C4H8O2 requires: C 51.41, H 6.38, N 12.15%
Example 9 S-Cyclohexyl-S-methoxy-l^S-fmethyl^-methylarnino-ethyiyaminoypyridin^-yl)- 3-(tetrahydro-pyran-4-yl)-lH-l , 3, 4-benzotriazepin-2(3H)-one The HCl salt of the title compound was obtained using steps f and g of example 1 except that l-(5-(2-(N-te^butoxycarbonyl)methylammo-ethylamino)-pyridin-2-yl)-5-cyclohexyl-8- methoxy-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one (example 5, step c) and formaldehyde were used in step f in place of l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8-methyl- 3 -(tetrahydro-pyran-4-yl)- 1 H- 1 ,3 ,4-benzotriazepin-2(3H)-one and 1 -N-tert- butoxycarbonylamino cyclopentanecarboxaldehyde respectively. 1H ΝMR (DMSO-d6) 8.90 (2H, br s), 7.98 (IH, d), 7.53 (IH, d), 7.41 (IH, d), 7.33-7.29 (IH, m), 6.85-6.81 (IH, m), 6.36 (IH, d), 3.87-3.81 (3H, m), 3.66-3.63 (5H, m), 3.41-3.30 (2H, m), 3.08-3.06 (2H, m), 2.95 (4H, m), 2.55 (3H, t), 1.74-1.33 (14H, m). Found: C 56.33, H 7.15, Ν 13.41%; C29H40Ν6O3*2.7HCl»0. IC4H8O2 requires: C 56.24, H 6.98, N 13.38% Example 10 5-Cyclohexyl-8-methyl-l-(5-((l-methyl-piperidin-4-ylmethyl)-amino)-pyridin-2- yl)-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one
The title compound was obtained using steps f of example 1 except that l-methyl-piperidine-4- carbaldehyde was used in place of 1-N-ter^-butoxycarbonylamino cyclopentanecarboxaldehyde. 1H ΝMR CDCl3 7.85 (IH, d), 7.40 (IH, d), 7.25 (IH, d), 6.97- 6.88 (2H, m), 6.72 (IH, s), 4.05-3.95 (3H, m), 3.82 (IH, t), 3.46 (2H, t), 3.03 (2H, t), 2.88 (2H, d), 2.80 (IH, m), 2.27 (3H, s), 2.14-1.07 (21H, m). The compound was further characterised and tested as the HCl salt. Found: C 57.19, H 7.56, N 12.26%; C32H44N6O2^ .2HCl-LOMeOH requires: C 57.16, H 7.44, N 12.12% Example 11 5-Cyclohexyl-3-isopropyl-8-methyl-l-(5~((l-methyl-piperidin-4-ylmethyl)- amino)-pyridin-2-yl)-lH-l , 3, 4-benzotriazepin-2(3H)-one
Step a N'-Isopropyl-hydrazinecarboxylic acid tert-butyl ester was obtained using step b of example 1 except that acetone was used in place of tetrahydro-4H-pyran-4-one. 1H NMR (CDCl3) 6.12 (IH, br s), 3.85 (IH, br s), 3.12 (IH, m), 1.46 (9H, s), 1.02 (6H, d). Step b 5-Cycloheocyl-3'isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3Hyone was obtained using step c of example 1 except that N'-isopropyl-hydrazinecarboxylic acid tert-butyl ester was used in place of N'-(tetrahydro-pyran-4-yl)-hydrazinecarboxylic acid tert-butyl ester. 1H NMR (CDCl3) 7.25-6.60 (3H, m), 6.14 (IH, br s), 4.32 (IH, m), 2.70 (IH, m), 2.33 (3H, s), 1.86-1.20 (16H, m). Step c l-(5-Amino-pyHdin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin- 2(3H)-one was obtained using steps d and e of example 1 except that 5-cyclohexyl-3- isopropyl-8-methyl-l,2-dihydro-lH-l,3,4-benzotriazepin-2(3H)-one was used in step d in place of 5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one. 1H NMR (CDCl3) 7.90 (IH, d), 7.47 (IH, d), 7.27 (IH, d), 7.04-6.96 (2H, m), 6.74 (IH, s), 4.19 (IH, m), 3.65 (2H, br s), 2.81 (IH, m), 2.25 (3H, s), 1.96-1.21 (16H, m)
Step d
The title compound was obtained using step f of example 1 except that l-(5-amino-pyridin-2- yl)-5-cyclohexyl-3-isopropyl-8-methyllH-l,3,4-benzotriazepin-2(3H)-one and 1-methyl- piperidine-4-carbaldehyde were used in place of l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8- methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one and 1-N-tert- butoxycarbonylamino cyclopentanecarboxaldehyde respectively. 1H NMR (CDCl3) 7.83 (IH, d), 7.44 (IH, d), 7.24 (IH, d), 6.97-6.89 (2H, m), 6.73 (IH, s), 4.19 (IH, sept), 3.75 (IH, brs), 3.04 (2H, t), 2.92-2.81 (3H, s), 2.30 (3H, s), 2.24 (3H, m), 1.95-1.21 (23H, m). The compound was further characterised and tested as the HCl salt. Found: C 57.05, H 7.54, N 12.21%; C30H42N6O»3.5HCl«0.7C4H8O2 requires: C 56.96 H 7.44, N 12.44%.
Example 12 5-Cyclohexyl-3-isopropyl-8-methyl-l-(5-(2-methylamino-ethylamino)-pyndin-2- yl)-lH-l, 3, 4-benzotriazepin-2(3H)-one The HCl salt of the title compound was obtained using steps f and g of example 1 except that l-(5-amino-pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3H)- one (example 11, step c) and methyl-(2-oxo-ethyl)-carbamic acid tert-bvtiyl ester were used in step f in place of l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)- lH-l,3,4-benzotriazepin-2(3H)-one and 1-N-tert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively. 1H ΝMR (DMSO-d6) 7.81 (IH, d), 7.43 (IH, d), 7.35 (IH, d), 7.13 (IH, d), 7.01 (IH, d), 6.64 (IH, s), 3.98 (IH, sept), 3.39 (2H, t), 3.06 (2H, t), 2.94 (IH, m), 2.57 (3H, t), 2.19 (3H, s), 1.74-1.12 (16H, m). Found: C 56.07, H 7.23, Ν 14.43%; C26H36Ν6O2.9HCl«0.4C4H802 requires: C 56.23, H 7.20, N 14.25%. Example 13 5-Cyclohexyl-l-(5-(4, 5-dihydro-lH-imidazol-2-ylmethyl)-pyridin-2-yl)-8-methyl- 3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one
Step a 6-Fluoro-nicotinic acid methyl ester
A mixture of 6-fluoro-nicotinic acid (2.07g, 14.7mmol), K2CO3 (4.48g, 32.4mmol) and MeI (3.2Og, 22.5mmol) in DMF (6OmL) was stirred for 16h at rt. After dilution with H2O (5OmL), the reaction mixture was extracted with EtOAc (5OmL) and the extract washed successively with saturated NaHCO3 solution (2OmL), brine (2 x 2OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the product as an orange solid (1.79g, 78%). 1H (CDCl3) 8.53 (IH, s), 8.12 (IH, m), 6.77 (IH, dd), 3.67 (3H, s)
Step b 6-(5-Cyclohexyl-2, 3-dihydro-8-methyl-2-oxo-3-(tetrahydro-pyran-4-yl)-lH-l, 3, 4- benzotriazepin-l-yl)-nicotinic acid methyl ester was obtained using step d of example 1 except that 6-fluoro-nicotinic acid methyl ester was used in place of 2-fluoro-5-nitro-pyridine. 1H (CDCl3) 8.76 (IH, s), 8.12 (IH, dd), 7.50 (IH, d), 7.33 (IH, d), 7.20 (IH, d), 7.15 (IH, s), 4.31 (IH, m), 4.09 (IH, m), 3.94 (IH, m), 3.87 (3H, s), 3.54 (IH, m), 3.40 (IH, m), 2.82 (IH, m), 2.39 (3H, s), 1.94-1.22 (14H, m) Step c 5-Cyclohetyl-l~(5-hydrotymethyl-pyridin~2-yl)-8-methyl-3-(tetrahydro-pyran-4-yl)-lH- 1, 3, 4-benzotriazepin-2(3H)-one
MeOH (0.8mL) was added dropwise over Ih to a mixture of 6-(5-cyclohexyl-2,3-dihydro-8- methyl-2-oxo-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-l-yl)-nicotinic acid methyl ester (503mg, l.Oόmmol) and NaBH4 (lOOmg, 2.64mmol) in refluxing /-BuOH (1OmL) and the mixture was stirred at this temperature for an additional 1.5h On cooling to ambient temperature, H2O (3OmL) was added and the mixture was concentrated to half the volume and extracted with DCM (2 x 15mL). The extracts were dried (MgSO4), filtered and evaporated. The residue obtained was purified by chromatography (DCM-hexane-EtOAc / 2:2:1) to yield the product as a white solid (294mg, 62%). 1H (CDCl3) 8.16 (IH, s), 7.63 (2H, s), 7.29 (IH, d), 7.08 (IH, dd), 6.93 (IH, s), 4.56 (2H, s), 4.09 (IH, m), 3.98 (2H, m), 3.45 (2H, m), 2.81 (IH, m), 2.74 (IH, m), 2.30 (3H, s), 1.95-1.22 (14H, m)
Step d 6-(5-Cyclohexyl-l, 2-dihydro-8-methyl-2-oxo-3-(tetrahydro-pyran-4-yl)-lH-l, 3, 4- benzotriazepin-l-yl)-pyridine-3-carbaldehyde DMSO (113μL, 1.5mniol) in DCM (5mL) was added dropwise to a solution of oxalyl chloride (108mg, 0.86mmol) in DCM (5mL) at -78°C. The reaction mixture was stirred at this temperature for 0.5h whereupon a solution of 5-cyclohexyl-l-(5-hydroxymethyl-pyridin-2-yi)- 8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one (294mg, 0.66mmol) in DCM (5mL) was added dropwise and stirring continued for 0.5h. A solution OfNEt3 (46OmL, 3.30mmol) in DCM (5mL) was added and the mixture was allowed to reach ambient temperature and diluted with H2O (1OmL). The organic layer was separated and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography (EtOAc to EtO Ac-acetone to acetone) (290mg, 100%). 1H (CDCl3) 9.87 (IH, s), 8.55 (IH, s), 8.00 (IH, dd), 7.48 (IH, d), 7.35 (IH, d), 7.25 (2H, m), 4.32 (IH, m), 3.94 (2H, m), 3.52 (IH, m), 3.38 (IH, m), 2.82 (IH, m), 2.33 (3H, s), 1.96-1.14 (14H, m)
Step e 5-Cyclohexyl-l-(5-(2,2-dibromo-vinyl)-pyridin-2-yl)-8-methyl-3-(tetrahydro-pyran-4- yl)-lH-l, 3, 4-benzotriazepin-2(3H)-one
A solution of 6-(5-cyclohexyl-l,2-dihydro-8-methyl-2-oxo-3-(tetrahydro-pyran-4-yl)-lH- l,3,4-benzotriazepin-l-yl)-pyridine-3-carbaldehyde (295mg, 0.66mmol), PPh3 (692mg, 2.64mmol) and CBr4 (440mg, 1.32mmol) in DCM (2OmL) was stirred at ambient temperature for 16h. The reaction mixture was diluted with DCM (2OmL), washed with H2O (3OmL) and dried (MgSO4). Filtration and evaporation of the solvent afforded the crude product which was purified by chromatography (hexanes-DCM / 3:1 then DCM then EtOAc) (329mg, 83%). 1H (CDCl3) 8.28 (IH, s), 7.93 (IH, dd), 7.64 (IH, d), 7.32 (2H, m), 7.15 (IH, dd), 7.07 (IH, s), 4.26 (IH, m), 4.08 (2H, m), 3.47 (2H, m), 2.82 (IH, m), 2.37 (3H, s), 1.89-1.21 (14H, m)
Step f
5-Cyclohexyl-l-(5-(2,2-dibromo-vinyl)-ρyridin-2-yl)-8-methyl-3-(tetrahydro-pyran-4-yl)-lH- l,3,4-benzotriazepin-2(3H)-one (329mg, 0.55mmol) was stirred in ethylenediamine (15mL) at ambient temperature for 16h. The reaction mixture was diluted with DCM (2OmL), washed with brine (2OmL) and dried (MgSO4). Filtration and evaporation of the solvent afforded the crude product which was purified by chromatography (DCM-EtOH-NEt3 / 8:2:1) (131mg, 39%). 1H (CDCl3) (free base) 8.16 (IH, s), 7.62 (2H5 m), 7.29 (IH, m), 7.10 (IH, d), 6.97 (IH, s), 4.82 (IH, brs), 4.17 (IH, m), 4.00 2H, m), 3.60 (6H, m), 3.48 (2H, m), 2.81 (IH, m), 2.32 (3H, s), 1.88-1.24 (14H, m) The compound was further characterised and tested as the HCl salt. Found: C 59.16, H 6.88, N 13.86%; C29H36N6O2»2.4HCl»0.3C4H8O2 requires: C 59.02, H 6.69, N 13.67%.
Example 14 l-(5-((J-Amino-cyclopentylmethyl)-amino)-pyήdin-2-yl)-5-cyclohexyl-8-methyl- 3-isopropyl-lH-l, 3, 4-benzotήazepin-2(3H)-one Step a l-fS-ffl-N-tert-Butoxycarbonylamino-cyclopentylmethylJ-aminoJ-pyridin^-yfy-S- cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3H)-one was obtained using the method of example 1 step f, except that l-(5-amino-pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8- methyl-lH-l,3,4-benzotriazepin-2(3H)-one (example 11, step c) was used in place of l-(5- amino-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4- benzotriazepin-2(3H)-one. 1H NMR (CDCl3) 7.85 (IH, d), 7.40 (IH, d), 7.25 (IH, d), 6.95- 6.92 (2H, m), 6.74 (IH, s), 4.58 (2H, br s), 4.19 (IH, m), 3.33 (2H, s), 2.81 (IH, m), 2.24 (3H, s), 2.05-1.21 (33H, m).
Step b
A solution of the product from step a (467mg, 0.79mmol) in TFA (5mL) was stirred at ambient temperature for Ih. The solvent was evaporated; the residue was dissolved in DCM (3OmL), washed successively with 10% aqueous K2CO3 solution, (2 xl5mL), brine (15mL) and dried
(MgSO4). Filtration and evaporation of the solvent afforded the title compound (335mg, 86%).
1H NMR (CDCl3) 7.90 (IH, d), 7.41 (IH, d), 7.25 (IH, s), 6.95 (2H, dd), 6.74 (IH, s), 4.37
(IH, br s), 4.19 (IH, m), 3.04 (2H, d), 2.81 (IH, m), 2.24 (3H, s), 1.96-1.21 (26H, m). The compound was further characterised and tested as the HCl salt. Found: C 59.24, H 7.42, N
13.96%; C29H40N6O2»2.8HCl requires: C 59.00, H 7.31, N 14.23%.
Example 15 5-Cyclohexyl-3-isopropyl-8-methyl-l-(5-((l-
(methylamino)cyclopentyl)methylamino)pyridin-2-yl)-JH-l,3,4-benzotriazepin-2(3H)-one
Step a l-(5-((l-(N-tert-Butoxycarbonyl-N-methylamino)cyclopentylmethyl)amino)pyridin-2- yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotTiazepin-2(3H)-one was obtained using the method of example 1 step f, except that l-(5-amino-pyridin-2-yl)-5-cyclohexyl-3- isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3H)-one (example 11, step c) and l-(N-tert- butoxycarbonyl-N-methylamino) cyclopentanecarboxaldehyde were used in place of l-(5- amino-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)- 1 H- 1 ,3 ,4- benzotriazepin-2(3H)-one and 1-iV-tert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively. 1H NMR (CDCl3) 7.82 (IH, d), 7.38 (IH, d), 7.26 (IH, d), 6.95-6.86 (2H, m), 6.74 (IH, s), 4.85 (IH, br s), 4.17 (IH, m), 3.24 (2H, d), 2.87 (3H, s), 2.82 (IH, m), 2.23 (3H, s), 2.05-1.21 (33H, m). Step b
The title compound was obtained using the method of example 14 step b, except that l-(5-((l- (N-tert-butoxycarbonyl-N-methylamino)cyclopentylmethyl)amino)pyridin-2-yl)-5-cyclohexyl- 3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3H)-one was used in place of l-(5-((l-N-tert- butoxycarbonylamino-cyclopentyknethyl)-amino)-pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8- methyl-lH-l,3,4-benzotriazepin-2(3H)-one. 1H NMR (CDCl3) 7.89 (IH, d), 7.39 (IH, d), 7.25 (IH, d), 6.96-6.91 (2H, m), 6.75 (IH, s), 4.55 (IH, br s), 4.19 (IH, m), 2.99 (2H, d), 2.80 (IH, m), 2.28 (3H, s), 2.24 (3H, s), 1.97-1.21 (25H, m). The compound was further characterised and tested as the HCl salt. Found: C 60.48, H 7.62, N 13.90%; C3oH42N602.6HCl requires: C 60.34, H 7.53, N 14.07%.
Example 16 S-Cyclohexyl-S-methyl-S-ftetrahydro-ΣH-pyran^-yiyi-ζS-β-ζtetrahydro^H- pyran-4-ylamino)propylamino)pyridin-2-yl)-lH-l,3,4-benzotriazepin-2(3H)-oiιe
Step a 5-Cyclohexyl-8-methyl-l-(5-(3-(phthalimido)propylamino)pyridin-2-yl)-3-(tetrahydro- 2H-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one was obtained using the method of example 1 step f, except that 3-(l,3-dioxoisoindolin-2-yl)propanal (J. Joossens et al, J. Med. Chem. 2004, 47, 2411) was used in place of 1-N-tert-butoxycarbonylamino cyclopentanecarboxaldehyde. 1H NMR (CDCl3) 7.89-7.85 (3H, m), 7.74 (2H, m), 7.40 (IH, d), 7.26 (IH, d), 6.98-6.94 (2H, m), 6.73 (IH, s), 4.20 (IH, br s), 4.14-3.96 (3H, m), 3.82 (2H, t), 3.46 (2H, t), 3.20 (2H, t), 2.80 (IH, m), 2.25 (3H, s), 2.05-1.24 (16H, m). Step b l-(5-(3-^Anιinopropylamino)pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-2H' pyran-4-yl)-lH-l , 3, 4-benzotriazepin-2(3H)-one
A solution of 5-cyclohexyl-8-methyl-l-(5-(3-(phthalimido)propylarnino)pyridin-2-yl)-3- (tetrahydro-2H-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one (740mg, 1.2mmol) and hydrazine hydrate (300DL, 6.0mmol) in EtOH (3OmL) was refluxed for Ih. On cooling to ambient temperature the suspension was filtered, the filter cake was washed with CHCl3 and the filtrate was evaporated to dryness. The residue was taken into EtOAc (8OmL) and was washed with water (5OmL) and brine (5OmL). The organic phase was separated and dried (MgSO4). Filtration and evaporation of the solvent afforded the product (473mg, 80%). 1H NMR (CDCl3) 7.88 (IH5 d), 7.37 (IH, d), 7.26 (IH, d), 6.97-6.90 (2H, m), 6.72 (IH, s), 4.30 (IH, br), 4.06-3.95 (3H, m), 3.46 (2H, t), 3.23 (2H, t), 2.89 (2H, t), 2.80 (IH, m), 2.24 (3H, s), 2.20-1.20 (18H, m). Step c
The title compound was obtained by the method of example 1 step f, except that l-(5-(3- ammopropylamino)pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-2H-pyran-4-yl)-lH- l,3,4-benzotriazepin-2(3H)-one and tetrahydropyran-4-one were used in place of l-(5-amino- pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-
2(3H)-one and 1-N-ter^butoxycarbonylamino cyclopentanecarboxaldehyde respectively. 1H NMR (CDCl3) 7.85 (IH, d), 7.36 (IH, d), 7.25 (IH, d), 6.96-6.88 (2H, m), 6.72 (IH, s), 4.03- 3.95 (6H, m), 3.49-3.35 (4H, m), 3.22 (2H, t), 2.81 (3H, t), 2.67 (IH, m), 2.23 (3H, s), 1.96- 1.13 (2 IH, m). The compound was further characterised and tested as the HCl salt. Found: C 57.63, H 7.29, N 11.98%; C33H46N6O3^lHCl requires: C 57.48, H 7.18, N 12.19%.
Example 17 5-Cyclohexyl-l-(5-(3-(isopropylamino)propylamino)pyridin-2-yl)-8-methyl-3- (tetrahydro-2H-pymn-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one
The title compound was obtained by the method of example 1 step f, except that l-(5-(3- aminopropylamino)pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-2H-pyran-4-yl)- IH- l,3,4-benzotriazepin-2(3H)-one (example 16, step b) and acetone were used in place of l-(5- amino-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4- benzotriazepin-2(3H)-one and 1-iV-tert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively. 1H NMR (CDCl3) 7.87 (IH, d), 7.32 (IH, d), 7.25 (IH, d), 6.96-6.89 (2H, m), 6.73 (IH, s), 4.80 (IH, br s), 4.05-3.95 (3H, m), 3.46 (2H, t), 3.21 (2H, t), 2.90-2.77 (4H, m), 2.23 (3H, s), 2.02-1.24 (17H, m), 1.11 (6H, d). The compound was further characterised and tested as the HCl salt. Found: C 57.82, H 7.53, N 12.89%; C3IH44N6O2-S-OHCl requires: C 57.86, H 7.37, N 13.06%.
Example 18 5-Cyclohexyl-3-isopropyl-l-(5-(2-((furan-3-yl)methylamino)ethylamino)pyridin- 2-yl)-8-methyl-lH-l , 3, 4-benzotriazepin-2(3H)-one
Step a 5-Cyclohexyl-3-isopropyl-8-methyl-l-(5-(3-(phthalimido)ethylamino)pyridin-2-yl)-lH- l,3,4-benzotriazepin-2(3H)-one was obtained by the method of example 1 step f, except that 1- (5-amino-pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3H)- one (example 11, step c) and 2-(l,3-dioxoisoindolin-2-yl)acetaldehyde (R. Thayumanavan, F. Tanaka and C. F. Barbas III, Organic Letters, 2004, 6, 3541) were used in place of l-(5-amino- pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin- 2(3H)-one and 1-N-tert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively. 1H ΝMR (CDCl3) 7.88-7.84 (3H, m), 7.75-7.72 (2H, m), 7.45 (IH, d), 7.25 (IH, d), 6.99-6.95 (2H, d), 6.71 (IH, s), 4.20-4.12 (2H, m), 3.98 (2H, t), 3.44 (2H, q), 2.84 (IH, m), 2.23 (3H, s), 1.95-1.21 (16H, m).
Step b l-(5-(2-Amifioethylamino)pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l, 3, 4- benzotriazepin-2(3H)-one was obtained by the method of example 16 step b, except that 5- cyclohexyl-3-isopropyl-8-methyl-l-(5-(3-(phthalimido)ethylamino)pyridin-2-yl)-lH-l,3,4- benzotriazepin-2(3H)-one was used in place of 5-cyclohexyl-8-methyl-l-(5-(3- (phthalimido)propylamino)pyridin-2-yl)-3 -(tetrahydro-2H-pyran-4-yl)- 1 H- 1 ,3 ,4- benzotriazepin-2(3H)-one. 1H ΝMR (CDCl3) 7.88 (IH, d), 7.45 (IH, d), 7.25 (IH, d), 6.95 (2H, d), 6.73 (IH, s), 4.24-4.15 (2H, m), 3.18 (2H, t), 2.97 (2H, t), 2.80 (IH, m), 2.24 (3H, s), 1.96-1.21 (18H, m).
Step c The title compound was obtained by the method of example 1 step f, except that l-(5-(2- amdnoethylainino)pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin- 2(3H)-one and 3-furaldehyde were used in place of l-(5-amino-pyridin-2-yl)-5-cyclohexyl-8- methyl-3 -(tetrahydro-pyran-4-yl)- 1 H- 1 ,3 ,4-benzotriazepin-2(3H)-one and 1 -N-tert- butoxycarbonylamino cyclopentanecarboxaldehyde respectively. 1H ΝMR (CDCl3) 7.86 (IH, s), 7.45-7.36 (3H, m), 7.26 (IH, d), 6.93 (2H, m), 6.73 (IH, s), 6.39 (IH, s), 4.19 (2H, m), 3.68 (2H, s), 3.20 (2H, br s), 2.91 (2H, d), 2.80 (IH, m), 2.23 (3H, s), 1.92-1.20 (17H, m). The compound was further characterised and tested as the HCl salt. Found: C 60.12, H 6.82, Ν 13.62%; C30H38Ν6O2«2.4HCl requires: C 59.80, H 6.76, N 13.95%.
Example 19 5-Cyclohexyl-8-methyl-l-(5-(2-(piperidin-4-ylamino)ethylamino)pyridin-2-yl)-3- (tetrahydro-2H-pyran-4~yl)-lH-l,3,4-benzotriazepin-2(3H)-one
Step a 5-Cyclohexyl-8-methyl-l-(5-(3-(phthalimido)ethylammo)pyridin-2-yl)-3-(tetrahydro- 2H-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one was obtained using the method of example 1 step f, except that 2-(l,3-dioxoisoindolin-2-yl)acetaldehyde was used in place of ϊ-N-tert- butoxycarbonylamino cyclopentanecarboxaldehyde. 1H NMR (CDCl3) 7.86 (3H, m), 7.74 (2H, m), 7.40 (IH, d), 7.25 (IH, d), 6.99-6.94 (2H, m), 6.69 (IH, s), 4.22-3.97 (6H, m), 3.49-3.42 (4H, m), 2.79 (IH, m), 2.23 (3H, s), 2.05-1.24 (14H, m).
Step b l-fS^-AminoethylaminoJpyridin^-ylJS-cyclohexyl-S-methyl-S-ftetrahydro^H-pyran-
4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one was obtained using the method of example 16 step b, except that 5-cyclohexyl-8-methyl-l-(5-(3-(phthalimido)ethylamino)pyridin-2-yl)-3- (tetrahydro-2H-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one was used in place of 5- cyclohexyl-8-methyl-l-(5-(3-(phthalimido)propylamino)pyridin-2-yl)-3-(tetrahydro-2H-pyran-
4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one. 1H NMR (CDCl3) 7.89 (IH, d), 7.41 (IH, d), 7.26
(IH, d), 6.95 (2H, m), 6.72 (IH, s), 4.20 (IH, t), 4.04-3.96 (3H, m), 3.46 (2H, t), 3.18 (2H, q), 2.98 (2H, t), 2.81 (IH, m), 2.24 (3H, s), 2.05-1.24 (16H, m).
Step c l-(5-(2-(4-tert-Butyloxycarbonyl-piperazin-l-yl)ethylamino)pyridin-2-yl)-5-cyclohexyl- 8-methyl~3-(tetrahydro-2H-pyran-4-yl)-lH-l,3,4-benzotήazepin-2(3H)-one was obtained using the method of example 1 step f, except that l-(5-(2-aminoethylamino)pyridin-2-yl)-5- cyclohexyl-8-methyl-3-(tetrahydro-2H-pyi-an-4-yl)-lH-l ,3,4-benzotriazepin-2(3H)-one and N- (tert-butyloxycarbonyl)-4-piperidone were used in place of l-(5-amino-pyridin-2-yl)-5- cyclohexyl-8-methyl-3 -(tetrahydro-pyran-4-yl)- 1 H- 1 ,3 ,4-benzotriazepin-2(3 H)-one and 1 -N- tert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively. 1H NMR (CDCl3) 7.88 (IH, d), 7.40 (IH, d), 7.25 (IH, d), 6.98-6.93 (2H, m), 6.72 (IH, s), 4.29 (IH, br s), 4.07-3.96 (5H, m), 3.46 (2H, t), 3.21 (2H, br s), 2.93 (2H, t), 2.80 (3H, t), 2.62 (IH, m), 2.24 (3H, s), 2.03-1.21 (28H, m).
Step d
The title compound was obtained using the method of example 14 step b, except that l-(5-(2- (4-tert-butyloxycarbonyl-piperazin-l-yl)emylamino)pyridin-2-yl)-5-cyclohexyl-8-methyl-3- (tetrahydro-2H-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one was used in place of l-(5-((l- N-tert-butoxycarbonylamino-cyclopentylmethyl)-amino)-pyridin-2-yl)-5-cyclohexyl-3- isopropyl-8-methyl-lH-l,3,4-benzotriazepin-2(3H)-one. 1H NMR (CDCl3) 7.89 (IH, d), 7.39 (IH, d), 7.26 (IH d), 6.97-6.93 (2H, m), 6.72 (IH, s), 4.30 (IH, t), 4.05-3.96 (3H, m), 3.46 (2H, t), 3.20-3.09 (4H, m), 2.92 (2H, t), 2.80 (IH, m), 2.67-2.56 (3H, m), 2.24 (3H, s), 1.96- 1.23 (2OH, m). The compound was further characterised and tested as the HCl salt. Found: C 51.48, H 7.17, N 12.85%; C32H45N7O2-SHCl requires: C 51.85, H 6.80, N 13.23%.
Example 20 5-Cyclohexyl-3-isopropyl-8-methyl-l-(5-(2-(l-methylpiperidin-4- ylamino)ethylamino)pyridin-2-yl)-lH-l,3,4-benzotriazepin-2(3H)-one
The title compound was obtained using the method of example 1 step f, except that l-(5-(2- aminoethylamino)pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin- 2(3H)-one (example 18 step b) and N-methyl-4-piperidone were used in place of l-(5-amino- pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin- 2(3H)-one and l-N-fer^-butoxycarbonylamino cyclopentanecarboxaldehyde respectively. 1H ΝMR (CDCl3) 7.87 (IH, d), 7.42 (IH, d), 7.25 (IH, d), 6.96-6.92 (2H, m), 6.73 (IH, s), 4.31 (IH, br s), 4.19 (IH, m), 3.48 (2H, t), 2.93-2.81 (5H, m), 2.50 (IH, m), 2.29 (3H, s), 2.23 (3H, s), 2.07-1.21 (23H, m). The compound was further characterised and tested as the HCl salt. Found: C 54.56, H 7.44, Ν 13.95%; C3iH45Ν7O4.2HCl requires: C 54.25, H 7.23, N 14.29%.
Example 21 5-Cyclohexyl-3-isopropyl-8-methyl~l-(5-(2-(tetrahydro-2H-pyran-4- ylamino)ethylamino)pyridin-2-yl)-lH-l,3,4-benzotriazepin-2(3H)-one
The title compound was obtained using the method of example 1 step f, except that l-(5-(2- aminoethylamino)pyridin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l,3,4-benzotriazepin- 2(3H)-one (example 18 step b) and tetrahydropyran-4-one were used in place of l-(5-amino- pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin- 2(3H)-one and 1-N-tert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively. 1H ΝMR (CDCl3) 7.88 (IH, d), 7.45 (IH, d), 7.25 (IH, d), 6.95 (2H, d), 6.73 (IH, s), 4.24-4.17 (2H3 m), 3.99 (2H, dt), 3.40 (2H, t), 3.21 (2H, t), 2.93 (2H, t), 2.81 (IH, m), 2.69 (IH, m), 2.24 (3H, s), 1.96-1.22 (21H, m). The compound was further characterised and tested as the HCl salt. Found: C 56.67, H 7.30, Ν 12.46%; C30H42Ν6O2»3.2HCl»0.4C4H8θ2 requires: C 56.60, H 7.27, N 12.53%.
Example 22 5-Cyclohexyl-3-isopropyl-l-(5-(2-(isopropylamino)ethylamino)pyridin-2-yl)-8- mβihyl-lH-1, 3, 4-benzotriazepin-2(3H)-one
The title compound was obtained using the method of example 1 step f, except that l-(5-(2- aminoethylamino)pyridin-2-yl)-5-cyclohexyl-3-isoproρyl-8-methyl-lH-l,3,4-benzotriazephi- 2(3H)-one (example 18 step b) and acetone were used in place of l-(5-amino-pyridin-2-yl)-5- cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one and 1-7V- ter^-butoxycarbonylamino cyclopentanecarboxaldehyde respectively. 1H NMR (CDCl3) 7.88 (IH, d), 7.43 (IH, d), 7.25 (IH, d), 6.95 (2H, dd), 6.73 (IH, s), 4.22 (IH, br s), 4.17 (IH, septet), 3.20 (2H, s), 2.89 (2H, t), 2.86-2.81 (2H, m), 2.24 (3H, s), 1.96-1.22 (17H, m), 1.08 (6H, d). The compound was further characterised and tested as the HCl salt. Found: C 57.05, H 7.60, N 13.53%; C28H40N6O3HCl«0.5C4H802 requires: C 57.19, H 7.52, N 13.34%.
Example 23 8-Chloro-5-cyclohexyl-3-isopropyl-l-(5-(2-(tetrahydro-2H-pyran-4- ylamino)ethylammo)pyridin-2-yl)-lH-l,3,4-benzotriazepin-2(3H)-one Step a (2~Amino-4-chlorophenyl)(cyclohexyl)methanone was obtained using the method of example 1 step a, except that 3-chloroaniline was used in place of rø-toluidine. 1H NMR (CDCl3) 7.68 (IH, d), 6.66-6.59 (2H, m), 6.37 (2H, br m), 3.21 (IH, m), 1.87-1.73 (5H, m), 1.57-1.24 (5H, m). Step b 8-Chloro-5-cyclohexyl-3-isopropyl-lH-l,3,4-benzotriazepin-2(3H)-one was obtained using the method of example 1 step c, except that (2-amino-4- chlorophenyl)(cyclohexyl)methanone and N'-isopropyl-hydrazinecarboxylic acid tert-butyl ester were used in place of (2-amino-4-methyl-phenyl)-cyclohexyl-methanone and N'- (tetrahydro-pyran-4-yl)-hydrazinecarboxylic acid tert-butyl ester respectively. 1H NMR (CDCl3) 7.26 (IH, d), 7.07 (IH, d), 6.83 (IH, s), 6.39 (IH, s), 4.33 (IH, septet), 2.67 (IH, m), 1.84-1.28 (1OH, m), 1.22 (6H, d).
Step c 8~Chloro-5-cyclohexyl-3-isopropyl-l-(5-nitropyridin-2-yl)-lH-l, 3, 4-benzotriazepin- 2(3H)-one was obtained using the method of example 1 step d, except that 8-chloro-5- cyclohexyl-3-isopropyl-lH-l,3,4-benzotriazepin-2(3H)-one was used in place of 5-cyclohexyl- 8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one. 1H NMR (CDCl3) 8.99 (IH, d), 8.35 (IH, d), 7.59 (IH, d), 7.44 (IH, s), 7.41 (2H, d), 4.48 (IH, septet), 2.82 (IH, m), 1.97-0.95 (16H, m).
Step d l-(5-Aminopyridin~2-yl)-8-chloro-5-cyclohexyl-3-isopropyl-lH-l, 3, 4-benzotriazepin- 2(3H)-one was obtained using the method of example 1 step e, except that 8-chloro-5- cyclohexyl-3-isopropyl-l-(5-nitropyridin-2-yl)-lH-l,3,4-benzotriazepin-2(3H)-one was used in place of 5-cyclohexyl-8-methyl-l-(5-nitro-pyridin-2-yl)-3-(tetrahydro-pyran-4-yl)-lH-l,3,4- benzotriazepin-2(3H)-one. 1H NMR (CDCl3) 7.91 (IH, d), 7.43 (IH, d), 7.30 (IH, d), 7.13 (IH, d), 7.03 (IH, dd), 5.97 (IH, d), 4.21 (IH, septet), 3.70 (2H, br s), 2.78 (IH, m), 1.95-1.21 (16H, m). Step e 8-Chloro-5-cyclohexyl-3-isopropyl-l-(5-(3-(phthalimido)ethylamino)pyridin-2-yl)-lH- l,3,4-benzotriazepin-2(3H)-one was obtained using the method of example 1 step f, except that l-(5-aminopyridin-2-yl)-8-chloro-5-cyclohexyl-3-isopropyl-lH-l,3,4-benzotriazepin-2(3H)- one and 2-(l,3-dioxoisoindolin-2-yl)acetaldehyde were used in place of l-(5-amino-pyridin-2- yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-lH-l,3,4-benzotriazepin-2(3H)-one and 1-iV-tert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively. 1H NMR (CDCl3) 7.88-7.85 (3H5 m), 7.75-7.72 (2H, m), 7.39 (IH, d), 7.30 (IH, d), 7.12 (IH, d), 6.94 (IH, dd), 6.93 (IH, s), 4.23 (IH, septet), 4.00 (2H, t), 3.43 (2H, q), 2.76 (IH, m), 1.94-1.20 (17H, m).
Step f l^S^-Aminoethylaminojpyridin^-yiyS-chloroS-cyclohexylS-isopropyl-lH-l.SA- benzotriazepin-2(3H)-one was obtained using the method of example 16 step b, except that 8- cMoro-5-cyclohexyl-3-isopropyl-l-(5-(3-(phthalimido)ethylamino)pyridin-2-yl)-lH-l,3,4- benzotriazepin-2(3H)-one was used in place of 5-cyclohexyl-8-methyl-l-(5-(3- (phthalimido)propylamino)pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-lH-l,3,4- benzotriazepin-2(3H)-one. 1H NMR (CDCl3) 7.90 (IH, d), 7.40 (IH, d), 7.28 (IH, d), 7.12 (IH, d), 6.98-6.94 (2H, m), 4.25-2.16 (2H, m), 3.19 (2H, q), 2.99 (2H, t), 2.78 (IH, m), 1.95- 1.20 (18H, m).
Step g
The title compound was obtained using the method of example 1 step f, except that l-(5-(2- aminoethylamino)pyridin-2-yl)-8-chloro-5-cyclohexyl-3-isopropyl-lH-l,3,4-benzotriazepin- 2(3H)-one and tetrahydropyran-4-one were used in place of l-(5-amino-pyridm-2-yl)-5- cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)- IH-1 ,3 ,4-benzotriazepin-2(3H)-one and 1 -N- tert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively. 1H NMR (CDCl3) 7.89 (IH, d), 7.39 (IH, d), 7.29 (IH, d), 7.11 (IH, d), 6.98-6.94 (2H, m), 4.33 (IH, br s), 4.20 (IH, septet), 4.00 (2H, dd), 3.40 (2H, t), 3.21 (2H, t), 2.94 (2H, t), 2.78-2.69 (2H, m), 1.95-1.21 (2 IH, m). The compound was further characterised and tested as the HCl salt. Found: C 53.14, H 6.65, N 12.59%; C29H39N6O2Cl-S .2HOO^C4H8O2 requires: C 53.15, H 6.56, N 12.48%.
Example 24 5-Cyclohexyl-34sopropyl-8-methyl-l-(5-(2-(methylamino)ethylamino)pyrimidin- 2-yl)-lH-l, 3, 4-benzotriazepin-2(3H)-one
Step a 2-Hydroxy~5-nitropyrimidine 2-Hydroxypyrimidine HCl (25.92g, 0.20mol) was added in portions to concentrated sulphuric acid (20OmL), then potassium nitrate (39.1 Ig, 0.40mol) was added to the resulting solution and the mixture was stirred for 3 days at 95°C. The mixture was poured slowly into Et2O (3L) with vigorous stirring, the Et2O was repeatedly decanted and then replaced until a solid was obtained. The solid was isolated by filtration, washed with Et2O and was taken up in EtOH. Solid NaHCO3 was added and the mixture was filtered once more. The filtrate was concentrated at reduced pressure to obtain the product (10.72g, 39%). 1H NMR (CDCl3) 12.00-10.00 (IH, br s), 9.15 (2H, s).
Step b 2-Chloro-5-nitropyrimidine
A mixture of 2-hydroxy-5-nitropyrimidine (1.Og, 7.1mmol) and N,N-dimethylaniline (0.9mL, 7.1mmol) in POCl3 (1OmL) was refiuxed for 2h, then was poured onto crushed ice (~100g) and stirred for Ih. The mixture was extracted with DCM (3 x 10OmL), the combined organic layers were dried (MgSO4). Filtration and evaporation of the solvent afforded the product (615mg, 54%). 1HNMR (CDCl3) 9.39 (2H, s). 19
Step c 5-Cyclohexyl-3-isopropyl-8-methyl-l-(5-nitropyrimidin-2-yl)-lH-l, 3, 4-benzotriazepin- 2(3H)-one
Sodium hydride (74mg, 1.85mmol) was added to a solution of 5-cyclohexyl-3-isopropyl-8- methyl-lH-l,3,4-benzotriazepin-2(3H)-one (example 11, step b) (500mg, 1.67mmol) in DMF (2OmL) and the mixture was stirred at ambient temperature for 30 min. 2-Choro-5- nitropyrimidine (290mg, 1.84mmol) was then added and the mixture was stirred at ambient temperature for 17h. The mixture was diluted with EtOAc (10OmL) and was washed with water (5OmL) and brine (2 x 5OmL). The organic layer was separated and dried (MgSO4).
Filtration and evaporation of the solvent gave the crude product which was purified by chromatography (1% MeOH/DCM) (539mg, 64%). 1H NMR (CDCl3) 9.15 (2H, s), 7.46-7.25
(3H, m), 4.69 (IH, m), 2.84 (IH, m), 2.48 (3H, s), 2.10-1.00 (16H, m).
Step d l-(5-Aminopyrimidin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH-l, 3, 4- benzotriazepin-2(3H)-one
A mixture of 5-cyclohexyl-3-isopropyl-8-methyl-l-(5-nitropyrimidin-2-yl)-lH-l,3,4- benzotriazepin-2(3H)-one (539mg, 1.27mmol), and 10% Pd-C (54mg) in MeOH/THF (1:1,
1OmL) was stirred under an atmosphere of hydrogen at ambient temperature for 16h. The mixture was purged with nitrogen then was filtered through Celite, the filtrate was concentrated at reduced pressure and the residue obtained was purified by flash chromatography (4% MeOH / DCM) to afford the product (275mg, 78%). 1H NMR (CDCl3) 8.01-7.14 (5H, m), 4.56 (IH, m), 3.40 (2H, br s), 2.81 (IH, m), 2.40 (3H, s), 2.00-1.10 (16H, m).
Step e
The HCl salt of the title compound was obtained using steps f and g of the method of example 1, except that except that l-(5-aminopyrimidin-2-yl)-5-cyclohexyl-3-isopropyl-8-methyl-lH- l,3,4-benzotriazepin-2(3H)-one and methyl-(2-oxo-ethyl)-carbamic acid tert-bntyl ester were used in place of l-(5-arnino-pyridin-2-yl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)- lH-l,3,4-benzotriazepin-2(3H)-one and 1-iV-fert-butoxycarbonylamino cyclopentanecarboxaldehyde respectively in step f. 1H NMR (CDCl3) 9.71 (IH, br s), 8.39 (IH, s), 7.35-7.15 (4H, m), 4.50-3.10 (8H, m), 2.78 (3H, br s), 2.36 (3H, br s), 2.10-0.90 (16H, m). Found: C 54.10, H 6.97, N 17.57%; C25H35N7O«2.9HC1 requires: C 54.11, H 6.88, N 17.67%.

Claims

Claims
1. A compound of formula (I) :
Figure imgf000081_0001
CO or a salt, solvate or pro-drug thereof; wherein: one of the carbon atoms labelled 6, 7, 8 or 9 may be replaced by a nitrogen atom;
R1, R4 and R5 are independently selected from H, COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH, S(C1-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(Ci-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(C1-6 alkyl), 0(C6-20 aryl), 0(C7-20 alkaryl), 0(C7-20 aralkyl), NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), NH(C7-20 alkaryl), NH(C7-20 aralkyl), N(C1-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-20 alkaryl), N(C1-6 alkyl)(C7-20 aralkyl), N(C6-20 aryl)2, N(C6-20 aryl)(C7-20 alkaryl), N(C6-20 aryl)(C7-20 aralkyl), NHC(O)(C1-6 alkyl), NHC(O)(C6-20 aryl), NHC(O)(C7-20 alkaryl), NHC(O)(C7-20 aralkyl), N(C1-6 alkyl)C(O)(C6-20 aryl), N(C1-6 alkyl)C(O)(C7-20 alkaryl), N(C1-6 alkyl)C(O)(C7-20 aralkyl), C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)2, C(O)NH(C6-20 aryl), C(O)N(C6-20 aryl)2, C(O)NH(C7-20 aralkyl), C(O)N(C7-20 aralkyl)2, C(O)NH(C7-20 alkaryl), C(O)N(C7-20 alkaryl)2, C(O)N(C1-6 alkyl)(C6-20 aryl), C(O)N(C1-6 alkyl)(C7-20 alkaryl), C(O)N(C1-6 alkyl)(C7-20 aralkyl), C(O)N(C6-20 aryl)(C7-20 alkaryl), C(O)N(C6-20 aryl)(C7-20 aralkyl), NO2, CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(C1-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, SO2N(C1-6 alkyl)(C6-20 aryl), SO2N(C1-6 alkyl)(C7-20 alkaryl), SO2N(C1-6 alkyl)(C7-20 aralkyl), SO2N(C6-20 aryl)(C7-20 alkaryl), SO2N(C6-20 aryl)(C7-20 aralkyl), C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl), C(O)(C7-20 aralkyl), OC(O)(C1-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 aralkyl), OC(O)(C7-20 alkaryl) and Ci-30 hydrocarbyl or C1-30 heterocarbyl groups, wherein any of the Ci-30 hydrocarbyl or Ci-30 heterocarbyl groups are optionally substituted with one or more of the groups, preferably 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (a), (b) and (c): (a) -CH=CH-, -C≡C-, S, N, -N=, Si(Cj-6 alkyl)2, Si(OH)2, Si(OC1-6 alkyl)2, C(O)NH, C(O)N(C1-6 alkyl), C(O)O, N(C1-6 alkyl)C(O)N(C1-6 alkyl), NHC(O)N(C1-6 alkyl), N(C1-6 alkyl)C(0)0, NHC(O)NH, NHC(O)O, NH, N(C1-6 alkyl), N(C6-20 aryl), N(C7-20 alkaryl),
. N(C7-20 aralkyl), 0, CO, SO2, NHSO2, NHSO2NH, N(C1-6 alkyl)SO2NH, N(C1-6 alkyl)SO2N(C1-6 alkyl), N(C6-20 aryl)SO2NH, SO, C(O)N(C6-20 aryl), N(Ci-6 alkyl)SO2,
N(C6-20 aryl)SO2, C(O)NHNHC(O), =N-N- and C(O)NHNH in the backbone;
(b) COOH, COO(Ci-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH, S(C1-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(Ci-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(C1-6 alkyl), 0(C6-20 aryl),
0(C7-20 alkaryl), 0(C7-20 aralkyl), =0, NH2, =NH, NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), NH(C7-20 aralkyl), NH(C7-20 alkaryl), N(C1-6 alkyl)(C6-20 aryl), N(Cj-6 alkyl)(C7-20 aralkyl), N(Ci-6 alkyl)(C7-20 alkaryl), =N(C1-6 alkyl), =N(C6-20 aryl), =N(C7-20 aralkyl), =N(C7-20 alkaryl), NHC(O)(Ci-6 alkyl), NHC(O)(C6-20 aryl), NHC(O)(C7-20 aralkyl), NHC(O)(C7-20 alkaryl), N(Ci-6 alkyl)C(O)(C6-20 aryl), N(Cj-6 alkyl)C(O)(C7-20 aralkyl),
N(Ci-6 alkyl)C(O)(C7-20 alkaryl), NO2, CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(C1-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, SO2NH(C7-20 aralkyl), SO2NH(C7-20 alkaryl), SO2N(C1-6 alkyl)(C6-20 aryl), SO2N(C1-6 alkyl)(C7-20 aralkyl), SO2N(C1-6 alkyl)(C7-20 alkaryl), NHSO2(C1-6 alkyl), NHSO2(C6-20 aryl), NHSO2(C7-20 aralkyl), NHSO2(C7-20 alkaryl), N(C1-6 alkyl)SO2(C1-6 alkyl), N(Ci-6 alkyl)SO2(C6-20 aryl), N(C1-6 alkyl)SO2(C7-20 aralkyl), N(Cj-6 alkyl)SO2(C7-20 alkaryl), C(O)H, C(O)(Cj-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl), C(O)(C7-20 aralkyl), OC(O)(C1-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 aralkyl), OC(O)(C7-20 alkaryl), C(O)NH(Ci-6 alkyl), C(O)NH(C6-20 aryl), C(O)NH(C7-20 aralkyl), C(O)NH(C7-20 alkaryl), C(O)N(C1-6 alkyl)2, C(O)N(C1-6 alkyl)(C6-20 aryl), C(O)N(Ci-6 alkyl)(C7-20 aralkyl) and C(O)N(C1-6 alkyl)(C7-20 alkaryl) on the backbone; and,
(c) groups independently selected from the group consisting of C1-I0 alkyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, Ci2-20 aryloxyaryl, C7-20 aryloxyalkyl, C1-10 alkoxy, C6-20 aryloxy, C2-10 alkenyl, C2-10 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl and C6-20 aryl on the backbone;
Rla and R5a are independently selected from H, COOH, COOCH3, COOCH2CH3, halo, OH, OCH3, OCH2CH3, OCF3, CF3, CH3, OCCl3, CCl3, OCF2CF3, CF2CF3, NH2, NH(CH3), N(CH3)2, NHC(O)(CH3), NO2, CN, OC(O)CH3 and C(O)H; or R1 is joined to R5, R5a or Rla to form a 5, 6, 7, 8, 9 or 10-membered saturated, unsaturated or aromatic, heterocyclic or carbocyclic ring which is optionally substituted with one or more of the groups, preferably, 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (b) and (c) above; or R5 is joined to R5a or Rla to form a 5, 6, 7, 8, 9 or 10-membered saturated, unsaturated or aromatic, heterocyclic or carbocyclic ring which is optionally substituted with one or more of the groups, preferably, 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (b) and (c) above;
R3 is selected from H, COOH, COO(C1-20 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), CN, SO2NH2, SO2NH(Ci-6 alkyl), SO2N(Ci-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, SO2NH(C7-20 aralkyl), SO2NH(C7-20 alkaryl), SO2N(C1-6 alkyl)(C6-20 aryl), SO2N(C1-6 alkyl)(C7-20 aralkyl), SO2N(Ci-6 alkyl)(C7-20 alkaryl), SO2N(C6-20 aryl)2, SO2N(C6-20 aryl)(C7-2o aralkyl), SO2N(C6-20 aryl)(C7-20 alkaryl), C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl), C(O)(C7-20 aralkyl), C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(Ci-6 alkyl)2, C(O)NH(C6-20 aryl), C(O)N(C6-20 aryl)2, C(O)NH(C7-20 aralkyl), C(O)N(C7-20 aralkyl)2, C(O)NH(C7-20 alkaryl), C(O)N(C7-20 alkaryl)2, C(O)N(C1-6 alkyl)(C6-20 aryl), C(O)N(C1-6 alkyl)(C7-20 aralkyl), C(O)N(C1-6 alkyl)(C7-2o alkaryl), C(O)N(C6-20 aryl)(C7-20 aralkyl), C(O)N(C6-20 aryl)(C7-20 alkaryl) and C1-30 hydrocarbyl or C1-30 heterocarbyl groups, wherein any of the C1-30 hydrocarbyl or C1-30 heterocarbyl groups are optionally substituted with one or more of the groups, preferably 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (d), (e) and (f):
(d) -CH-CH-, -C≡C-, S, N, -N=, Si(Ci-6 alkyl)2, Si(OH)2, Si(OC1-6 alkyl)2, C(O)NH, C(O)N(C1-6 alkyl), C(O)O, N(C1-6 alkyl)C(O)N(C1-6 alkyl), NHC(O)N(C1-6 alkyl), N(C1-6 alkyl)C(O)O, NHC(O)NH, NHC(O)O, NH, N(C1-6 alkyl), N(C6-20 aryl), N(C7-20 alkaryl), N(C7-20 aralkyl), O, CO, SO2, NHSO2, NHSO2NH, N(C1-6 alkyl)SO2NH, N(C1-6 alkyl)SO2N(C1-6 alkyl), N(C6-20 aryl)SO2NH, SO, C(O)N(C6-20 aryl), N(C1-6 alkyl)SO2,
N(C6-20 aryl)SO2, C(O)NHNHC(O), =N-N- and C(O)NHNH in the backbone;
(e) COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH, S(C1-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(C1-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(C1-6 alkyl), 0(C6-20 aryl),
0(C7-20 alkaryl), 0(C7-20 aralkyl), =0, NH2, =NH, NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), NH(C7-20 aralkyl), NH(C7-20 alkaryl), N(C1-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-20 aralkyl), N(C1-6 alkyl)(C7-20 alkaryl), =N(C1-6 alkyl), =N(C6-20 aryl), =N(C7-20 aralkyl), =N(C7-2o alkaryl), NHC(O)(C1-6 alkyl), NHC(O)(C6-20 aryl), NHC(O)(C7-20 aralkyl), NHC(O)(C7-20 alkaryl), N(C1-6 alkyl)C(O)(C6-20 aryl), N(C1-6 alkyl)C(O)(C7-20 aralkyl), N(C1-6 alkyl)C(O)(C7-20 alkaryl), NO2, CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(C1-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, SO2NH(C7-20 aralkyl), SO2NH(C7-20 alkaryl), SO2N(C1-6 alkyl)(C6-20 aryl), SO2N(C1-6 alkyl)(C7-20 aralkyl), SO2N(C1-6 alkyl)(C7-20 alkaryl), NHSO2(Ci-6 alkyl), NHSO2(C6-20 aryl), NHSO2(C7-20 aralkyl), NHSO2(C7-20 alkaryl), N(Cj-6 alkyl)SO2(C1-6 alkyl), N(C1-6 alkyl) SO2(C6-20 aryl), N(C1-6 alkyl)SO2(C7-20 aralkyl), N(C1-6 alkyl)SO2(C7-20 alkaryl), C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl), C(O)(C7-20 aralkyl), OC(O)(C1-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 aralkyl), OC(O)(C7-20 alkaryl), C(O)NH(C1-6 alkyl), C(O)NH(C6-20 aryl), C(O)NH(C7-20 aralkyl), C(O)NH(C7-20 alkaryl), C(O)N(C1-6 alkyl)2, C(O)N(C1-6 alkyl)(C6-20 aryl), C(O)N(C1-6 alkyl)(C7-20 aralkyl) and C(O)N(C1-6 alkyl)(C7-20 alkaryl) on the backbone; and,
(f) groups independently selected from the group consisting of C1-10 alkyl, C2-I0 alkoxyalkyl, C7-20 alkoxyaryl, Ci2-20 aryloxyaryl, C7-20 aryloxyalkyl, Ci-10 alkoxy, C6-20 aryloxy, C2-10 alkenyl, C2-10 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl and C6-20 aryl on the backbone;
R2 is a group
Figure imgf000084_0001
wherein:
Z, Z1 and Z2 are selected from the group consisting of C and N, wherein Z and Z1 are not the same; n is an integer of O, 1, 2, 3, 4 or 5; m is an integer of 0, 1, 2, 3, 4 or 5; n1 is an integer of O or 1 ; m1 is an integer of O or 1 ; m2 is an integer of 0, 1, 2, 3, 4 or 5; wherein the groups -(CH2)m- and — (CH2)m 2- are optionally independently substituted by 1 or more -OH groups on the CH2 backbone, preferably 1 -OH group; wherein the -(O)n,1- and -(O)n 1- groups are not directly linked to one another;
R7 and R8 are independently selected from the group consisting of H, COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH, S(C1-6 alkyl), SO2H, SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(C1-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(Ci-6 alkyl), NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NHC(O)(C1-6 alkyl), NO2, CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(C1-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, C(O)H, C(O)(C1-6 alkyl),. C(O)(C6-20 aryl), C(O)(C7-20 alkaryl) and C(O)(C7-20 aralkyl), and hydrocarbyl or heterocarbyl groups selected from C1-20 alkyl, C2-20 alkenyl, Ci-20 alkoxy, C2-20 alkoxyalkyl, C6-30 aryloxy, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, C1-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl and C3-30 heterocyclylalkyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups, preferably 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (g), (h) and (i): (g) -CH=CH-, -C≡C-, S, N, -N=, Si(C1-6 alkyl)2, Si(OH)2, Si(OCj-6 alkyl)2, C(O)NH, C(O)N(C1-6 alkyl), C(O)O, N(C1-6 alkyl)C(O)N(C1-6 alkyl), NHC(O)N(C1-6 alkyl), N(C1-6 alkyl)C(O)O, NHC(O)NH, NHC(O)O, NH, N(C1-6 alkyl), N(C6-20 aryl), N(C7-20 alkaryl), N(C7-20 aralkyl), O, CO, SO2, NHSO2 and C(O)NHNH in the backbone;
(h) COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH, S(C1-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H, SO2(C1-6 alkyl),
SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(C1-6 alkyl), SO(C6-20 aryl),
SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(C1-6 alkyl), 0(C6-20 aryl),
0(C7-20 alkaryl), 0(C7-20 aralkyl), =0, NH2, =NH, NH(C1-6 alkyl), N(C1-6 alkyl)2, =N(C1-6 alkyl), NHC(O)(C1-6 alkyl), NO2, CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(C1-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl),
C(O)(C7-20 alkaryl) and C(O)(C7-20 aralkyl) on the backbone; and,
(i) groups independently selected from the group consisting of C1-10 alkyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, C12-20 aryloxyaryl, C7-20 aryloxyalkyl, C1-10 alkoxy, C6-20 aryloxy, C2-10 alkenyl, C2-10 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl and C6-20 aryl on the backbone; when n is 1 or more, -(O)n,1 -(CR2)m-(0)n -(CH2)m 2-R6 is located in the ortho, meta or para position relative to the -(CH2)n- group; when n is O, -(O)n,1 -(CH2)H1-(O)n 1 -(CH2)m 2-R6 is located in the meta or para position relative to the N1 atom (the N1 atom being shown in the representative structure of compound of formula (T) above); R6 is selected from the group consisting of NR9R10, CONR9R10, NR9COR10, R19, NR9C(=NR15)N(R14)2 and N=C(NR15R9)N(R14)2; wherein:
R9 is selected from the group consisting of H and Ci-6 alkyl, C3-2O cycloalkyl, C4-20 (cycloalkyl)alkyl, C6-20 aryl, C7-20 aralkyl, C7-20 alkaryl, C1-20 heteroaryl and C2-20 heterocyclyl;
R10 is selected from the group consisting of, H, C1-20 alkyl, C2-20 alkenyl, C2-20 alkoxyalkyl, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, Ci-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, C9-30 heterocyclylalkaryl, C4-30 heterocyclylalkoxyalkyl, C4-30 heterocyclylalkylaminoalkyl, C4-30 heterocyclylaminoalkyl, C8-30 heteroarylalkaryl, C3-30 heteroarylalkoxyalkyl, C3-30 heteroarylalkylaminoalkyl, C7-30 aryloxyalkyl, C7-30 arylaminoalkyl, C7-30 alkylaminoaryl, Ci-20 aminoalkyl, C7-20 aminoaralkyl, C7-20 aminoalkaryl, C2-20 alkylguanidinylalkyl and ureayl Ci-I0 alkyl; or, in the groups NR9R10 and CONR9R10, R9 and R10 may be joined to form a 3, 4, 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring; any of the groups defined as R10 (except H) being optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from Ci-10 alkyl, C1-20 haloalkyl, Ci-20 perhaloalkyl, Ci-20 hydroxyalkyl, C3-10 cycloalkyl, halo, OH, OCi-6 alkyl, NH2, OC(C1-6 alkyl), OC(C6-20 aryl), OC(C7-20 aralkyl), OC(C7-20 alkaryl), OCO(Ci-6 alkyl), OCO(C6-20 aryl), OCO(C7-20 aralkyl), OCO(C7-20 alkaryl), COOH, COO(Ci-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), N(C6-20 aryl)2, NH(C7-20 aralkyl), N(C7-20 aralkyl)2, NH(C7-20 alkaryl), N(C7-20 alkaryl)2, N(C1-6 aUsyl)(C6-20 aryl), N(Ci-6 alkyl)(C7-20 alkaryl), N(C1-6 alkyl)(C7-20 aralkyl), N(C6-20 aryl)(C6-20 aryl), N(C6-20 aryl)(C7-20 alkaryl), N(C6-20 aryl)(C7-20 aralkyl), NO2, CN, C(O)H, C(O)(Ci-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 aralkyl) and C(O)(C7-20 alkaryl); any of the groups defined as R10 (except H) being optionally substituted in the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from -CH=CH-, -C=C-, S, N, -N=, Si(C1-6 alkyl)2, Si(OH)2, Si(OC1-6 alkyl)2, C(O)NH, C(O)N(C1-6 alkyl), C(O)O, N(C1-6 alkyl)C(O)N(C1-6 alkyl), NHC(O)N(Cj-6 alkyl), N(Ci-6 alkyl)C(O)O, NHC(O)NH, NHC(O)O, NH, N(C1-6 alkyl), N(C6-20 aryl), N(C7-20 alkaryl), N(C7-20 aralkyl), O, CO, SO2, NHSO2, NHSO2NH, N(C1-6 alkyl)SO2NH, N(C1-6 alkyl)SO2N(Ci-6 alkyl), N(C6-20 aryl)SO2NH, SO, C(O)N(C6-20 aryl), N(C1-6 alkyl)SO2, N(C6-20 aryl)SO2, C(O)NHNHC(O), =N-N- and C(O)NHNH; each R14 is independently selected from the group consisting of H, Ci-20 alkyl, C2-20 alkenyl, C2- 20 alkoxyalkyl, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-S0 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, Ci-30 heteroaryl and C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, Ci-10 aminoalkyl, C6-20 aminoaryl, guanidinyl Ci-I0 alkyl, C2-20 alkylguanidinylalkyl, ureayl Ci-10 alkyl and C2-20 alkylureaylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, OH, OCi-6 alkyl, NH2, COOH, COO(Ci-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), OC(O)(Ci-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 aralkyl), OC(O)(C7-20 alkaryl), NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), N(C6-20 aryl)2, NH(C7-20 aralkyl), N(C7-20 aralkyl)2, NH(C7-20 alkaryl), N(C7-20 alkaryl)2, N(C1-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-20 aralkyl), N(Ci-6 alkyl)(C7-20 alkaryl), N(C6-20 aryl)(C7-20 aralkyl), N(C6-20 aryl)(C7-20 alkaryl), NO2, CN, C(O)H and C(O)(Ci-6 alkyl), or each R14 is joined to one another to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring; R15 is selected from the group consisting of H, CN, Ci-20 alkyl, C2-20 alkenyl, C2-20 alkoxyalkyl, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, Cs-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, Ci-30 heteroaryl and C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, Ci-I0 aminoalkyl, C6-20 aminoaryl, guanidinyl Ci-10 alkyl, C2-20 alkylguanidinylalkyl, ureayl C1-10 alkyl and C2-20 alkylureaylalkyl, any of which (except H) are optionally on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, OH, OCi-6 alkyl, NH2, COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), N(C6-20 aryl)2, NH(C7-20 aralkyl), N(C7-20 aralkyl)2, NH(C7-20 alkaryl), N(C7-20 alkaryl)2, NO2, CN, C(O)H and C(O)(Ci-6 alkyl); or R15 and one of R14 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R14not joined to R15 is H or C1-6 alkyl; and,
R19 is selected from the group consisting of, H, -C(=NH)NH2, -C(=NH)NHCi-20 alkyl, -C(=NH)N(Ci-20 alkyl)2, -C(=NH)NHC3-30 cycloalkyl, -C(=NH)N(C3-30 cycloalkyl)2, -C(=NH)NHC6-30 aryl, -C(=NH)N(C6-30 aryl)2, -C(=NH)NHC6-30 alkaryl, -C(=NH)N(C6-30 alkaryl)2, -C(=NH)NHC6-30 aralkyl, -C(=NH)N(C6-30 aralkyl)2, -C(=NH)NHC2-30 heterocyclyl, -C(=NH)N(C2-30 heterocyclyl)2, -C(=NH)NHCi-30 heteroaryl, -C(=NH)N(Ci-30 heteroaryl)2, -C(=NCi.2o alkyl)NH2, -C(=NCi-20 3UCyI)NHC1-20 alkyl, -C(=NCi-20 alkyl)N(Ci-20 alkyl)2, -C(=NCi-20 alkyl)NHC3-30 cycloalkyl, -C(=NC1-20 alkyl)N(C3-30 cycloalkyl)2, -C(=NCi-20 alkyl)NHC6-30 aryl, -C(=NCi_20 alkyl)N(C6-30 aryl)2, -C(=NCi-20 alkyl)NHC6-30 alkaryl, alkyl)N(C6-30 alkaryl)2, -C(=NCi-20 alkyl)NHC6-30 aralkyl, -C(=NC1-20 alkyl)N(C6-30 aralkyl)2, -C(=NC1-20 alkyl)NHC2.30 heterocyclyl, -C(=NCi-20 alkyl)N(C2-30 heterocyclyl)2, -C(=NC1-20 alkyl)NHC1-30 heteroaryl, -C(=NCi-20 alkyl)N(C1-30 heteroaryl)2, C1-20 alkyl, C2-20 alkenyl, C2-20 alkoxyalkyl, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, Ci-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, Cg-30 heterocyclylalkaryl, C4-30 heterocyclylalkoxyalkyl, C4-30 heterocyclylalkylaminoalkyl, C8-30 heteroarylalkaryl, C3-30 heteroarylalkoxyalkyl, C3-30 heteroarylalkylaminoalkyl, C7-30 aryloxyalkyl, C7-30 arylaminoalkyl, C7-30 alkylaminoaryl, Ci-10 aminoalkyl, C7-20 aminoaralkyl, C7-20 aminoalkaryl, C2-20 alkylguanidinylalkyl and ureayl C1-I0 alkyl; any of the groups defined as R19 (except H) being optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from C1-I0 alkyl, Ci-20 haloalkyl, Ci-20 perhaloalkyl, Ci-20 hydroxyalkyl, C3-I0 cycloalkyl, halo, OH, OCi-6 alkyl, NH2, OC(C1-6 alkyl), OC(C6-20 aryl), OC(C7-20 aralkyl), OC(C7-20 alkaryl), OCO(C1-6 alkyl), OCO(C6-20 aryl), OCO(C7-20 aralkyl), OCO(C7-20 alkaryl), COOH, COO(Ci-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), N(C6-20 aryl)2, NH(C7-20 aralkyl), N(C7-20 aralkyl)2, NH(C7-20 alkaryl), N(C7-20 alkaryl)2, N(C1-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-20 alkaryl), N(Ci-6 alkyl)(C7-20 aralkyl), N(C6-20 aryl)(C6-20 aryl), N(C6-20 aryl)(C7-20 alkaryl), N(C6-20 aryl)(C7-20 aralkyl), NO2, CN, C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 aralkyl) and C(O)(C7-20 alkaryl); any of the groups defined as R19 (except H) being optionally substituted in the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from -CH=CH-, -C≡C-, S, N, -N=, Si(C1-6 alkyl)2, Si(OH)2, Si(OCj-6 alkyl)2, C(O)NH, C(O)N(Ci-6 alkyl), C(O)O, N(Ci-6 alkyl)C(O)N(C1-6 alkyl), NHC(O)N(C1-6 alkyl), N(Ci-6 alkyl)C(O)O, NHC(O)NH, NHC(O)O, NH, N(C1-6 alkyl), N(C6-20 aryl), N(C7-20 alkaryl), N(C7-20 aralkyl), O, CO, SO2, NHSO2, NHSO2NH, N(Ci-6 alkyl)SO2NH, N(C1-6 alkyl)SO2N(Ci-6 alkyl), N(C6-20 aryl)SO2NH, SO, C(O)N(C6-20 aryl), N(Ci-6 alkyl)SO2, N(C6-20 aryl)SO2, C(O)NHNHC(O), =N-N- and C(O)NHNH.
2. A compound according to claim 1, wherein R2 is selected from the group consisting of the structures structures (i), (ii) and (iii):
Figure imgf000089_0001
3. A compound according to claim 1 or claim 2, wherein R7 and R8 are independently selected from the group consisting of H, Cj-6 alkyl, halo, haloCi-6 alkyl, perhaloCi-6 alkyl, OH, NH2, NO2, CN, COOH, C(O)H, C(O)O(C1-6 alkyl) and C(O)(C1-6 alkyl), n is O or 1 and m is O or l.
4. A compound according to claim 1 or claim 2, wherein n is 1 or more and R7 and/or R8 are located in the ortho or meta position relative to the -(CH2)n- group.
5. A compound according to claim 1 or claim 2, wherein n is O and R7 and/or R8 are located in the ortho or meta position relative to the N1 atom.
6. A compound according to claim 1 or claim 2, wherein n is 0.
7. A compound according to claim 1, claim 2 or claim 6, wherein m is 0.
8. A compound according to any of claims 1-3 and 5-7, wherein R2 is a group having the structure (id) or (iid):
Figure imgf000089_0002
(iid)
Figure imgf000089_0003
9. A compound according to any preceding claim, wherein R9 is selected from H, methyl, ethyl and propyl, phenyl, phenylethyl, benzyl, tolyl and xylyl, preferably H.
10. A compound according to any preceding claim, wherein R10 is selected from the group consisting of C1-15 heteroaryl, C2-I5 heterocyclyl, C2-15 heteroaralkyl, C3-15 heterocyclylalkyl, C1-15 alkyl, Cg-20 aryl, C7-2O aralkyl, C3-15 cycloalkyl and C4-I5 cycloalkylalkyl, any of which are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from NH2, NH(C1-4 alkyl), N(Ci-4 alkyl)2, NH(C6-I6 aryl), N(C6-I6 aryl)2, NH(C7-16 aralkyl), N(C7-16 aralkyl)2, NH(C7-I6 alkaryl), N(C7-16 alkaryl)2, N(C1-4 alkyl)(C6-i6 aryl), N(Cj-4 alkyl)(C7-i6 alkaryl), N(C1-4 alkyl)(C7.16 aralkyl), N(C6-I6 aryl)(C7-i6 alkaryl), N(C6-J6 aryl)(C7-i6 aralkyl), NH(C2-15 heterocyclyl), NH(C3-I5 heterocyclylalkyl), N(C1-4 alkyl)(C2-i5 heterocyclyl), N(C1-4 alkyl)(C3-i5 heterocyclylalkyl), S(C1-6 alkyl), NO2, CN, OH, SH, OC1-6 alkyl, C(O)H and C(O)(C1-6 alkyl).
11. A compound according to any preceding claim, wherein R10 is selected from the group consisting of Ci-10 alkyl, C3-15 cycloalkyl, C4-15 cycloalkylalkyl, C7-20 aralkyl, furanyl, furanyl(C1-3 alkyl), pyridyl, pyridyl(Ci-3 alkyl), phthalimido, phthalimido(C1-3 alkyl), thienyl, thienyl(Ci-3 alkyl), pyrrolyl, pyrrolyl(C1-3 alkyl), imidazolyl, imidazolyl(Ci-6 alkyl), pyrazolyl, pyrazolyl(Ci-3 alkyl), thiazolyl, IMaZoIyI(C1-3 alkyl), isothiazolyl, isothiazolyl(C1-3 alkyl), thiazolyhnethyl, isothiazolyhnethyl, oxazolyl, oxazolyl(Ci-3 alkyl), pyrrolidinyl, pyrrolidinyl(Ci.3 alkyl), pyrrolinyl, pyrrolinyl(C1-3 alkyl), imidazolidinyl, imidazolidinyl(C1-3 alkyl), imidazohnyl, imidazolinyl(Ci-3 alkyl), imidazolemethyl, dihydroimidazolyl, dihydroimidazolyl(C1-3 alkyl), dihydroimidazolyhαethyl, tetrahydropyrimidinyl, tefrahydropyrimidinyl(C1-3 alkyl), benzimidazolyl, benzimidazolyl(Ci-3 alkyl), tetrahydroisoquinolinyl, tetrahydroisoquinolyl(C1-3 alkyl), pyrazolidinyl, pyrazolidinyl(C1-3 alkyl), tefrahydrofuranyl, tetrahyrdofuranyl(Ci-3 alkyl), pyranyl, pyranyl(C1-3 alkyl), pyridonyl, pyridonyl(C1-3 alkyl), pyronyl, pyronyl(Ci-3 alkyl), pyrazinyl, PyTaZUIyI(C1-3 alkyl), pyridazinyl, pyridazinyl(C1-3 alkyl), piperidinyl, piperidinyl(C1-3 alkyl), piperazinyl, piperazinyl(Ci-3 alkyl), moφholinyl, morpholiny^d^ alkyl), thionaphthyl, thionaphthyl(C1-3 alkyl), benzofuranyl, benzofuranyl(C1-3 alkyl), isobenzofuryl, isobenzofuryl(Ci-3 alkyl), indolyl, indolyl(C1-3 alkyl), oxyindolyl, oxyindonlyl(C1-3 alkyl), isoindolyl, isoindolyl(C1-3 alkyl), indazolyl, indazolyl(Ci-3 alkyl), indolinyl, indolinyl(Ci-3 alkyl), isoindolinyl, isoindolinyl(C1-3 alkyl), isoindazolyl, isoindazolyl(Ci-3 alkyl), benzopyranyl, benopyranyl(C1-3 alkyl), coumarinyl, coumarinyl(Ci-3 alkyl), isocoumarinyl, isocoumarinyl(C1-3 alkyl), quinolyl, quinoly^C^ alkyl), isoquinolyl, isoquinolyl(C1-3 alkyl), napthridinyl, naphthridinyl(C1-3 alkyl), cinnolinyl, cinnolinyl(C1-3 alkyl), quinazolinyl, quinazolinyl(C1-3 alkyl), pyridopyridyl, pyridopyridyl(C1-3 alkyl), benzoxazinyl, benzoxazinyl(Ci-3 alkyl), quinoxadinyl, quinoxadinyl(C1-3 alkyl), chromenyl, chromeny^C^ alkyl), chromanyl, chromanyl(Ci-3 alkyl), isochromanyl, isocnromanyl(Ci-3 alkyl), carbolinyl, carbolinyl(C1-3 alkyl), thiophenyl, thiophenyl(Ci-3 alkyl), thiazolyl, thiazolinyl(C1-3 alkyl), isoxazolyl, isooxazolyl(Ci-3 alkyl), isoxazolonyl, isoxazolonyl(C1-3 alkyl), isothiazolyl, isothiazolyl(C1-3 alkyl), triazolyl, triazolyl(C1-3 alkyl), oxadiazolyl, oxadiazolyl(Ci-3 alkyl), thiadiazolyl, thiadiazolyl(C1-3 alkyl), pyridazyl, pyridazyl(Ci-3 alkyl), any of which are optionally substituted on the backbone with one or more groups independently selected from =O, COOH, SH, SO2H, P(OH)(O)2, halo, trihalomethyl, OH, NH2, =NH, NH(C1-6 alkyl), =N(C1-6 alkyl), NO2, CN, OCH3, SO2NH2 and C(O)H, C1-6 alkyl, C2-6 alkoxyalkyl, C7-io alkoxyaryl, C3-Io cycloalkyl, C4-i5 (cycloalkyl)alkyl, C7-12 aralkyl, C7-12 alkaryl, C1-I2 heteroaryl and C6-I2 aryl.
12. A compound according to claim 11, wherein R10 comprises a lH-imidazol-2-yl(Ci-6 alkyl) group which may be substituted with 1 or more groups independently selected from Ci-6 alkyl, halo, haloC1-6 alkyl, hydroxyC1-6 alkyl, perhaloC1-6 alkyl, OH, NH2, NO2, CN, COOH, C(O)H, C(O)O(Ci-6 alkyl), 0(Q-6 alkyl), OC(O)(Ci-6 alkyl) and C(O)(Cx-6 alkyl).
13. A compound according to any of claims 1 to 10, wherein R10 is selected from the group consisting of cyclopentylmethyl, piperidylmethyl, methylaminoethyl, aminocyclopentylmethyl, methylaminocyclopentyhnethyl, methylaminoethyl, tetrahydro-pyranylaminoethyl, tetrahydro- pyranylaminopropyl, propylaminoethyl, propylaminopropyl, dimethylaminoethyl, furanyhnethylaminoethyl, piperidinylmethyl and l-methyl-piperidin-4-ylmethyl, any of which may be substituted with 1 or more groups independently selected from Ci-6 alkyl, halo, haloCi-6 alkyl, hydroxyCi-6 alkyl, perhaloC1-6 alkyl, OH, NH2, NO2, CN, COOH, C(O)H, C(O)O(C1-6 alkyl), 0(Ci-6 alkyl), OC(O)(Ci-6 alkyl) and C(O)(C1-6 alkyl).
14. A compound according to any of claims 1 to 7, wherein each R14 is independently selected from the group consisting of H, Ci_io alkyl, C2-1O alkenyl, C2-1O alkoxyalkyl, C7-20 alkoxyaryl, C2-io alkynyl, C3-20 cycloalkyl, C4-2O (cycloalkyl)alkyl, C5-20 cycloalkenyl, C7-20 cycloalkynyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, Ci-20 heteroaryl and C2-20 heterocyclyl, C2-20 heteroaralkyl, C3-20 heterocyclylalkyl, C1-10 aminoalkyl, C6-I0 aminoaryl, guanidinyl Ci-6 alkyl, C2-I2 alkylguanidinylalkyl, ureayl Ci-6 alkyl and C2-I2 alkylureaylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, OH, OCH3, OCH2CH3 and NH2, or each R14 is joined to one another to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring.
15. A compound according to any of claims 1 to 7, wherein R15 is selected from the group consisting of H, CN, Ci-I0 alkyl, C2-10 alkenyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, C2-I0 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C5-20 cycloalkenyl, C7-20 cycloalkynyl, C7-20 aralkyl, C7-20 alkaryl, C6-2Q aryl, C1-20 heteroaryl and C2-20 heterocyclyl, C2-20 heteroaralkyl, C3-20 heterocyclylalkyl, Ci-I0 aminoalkyl, C6-I0 aminoaryl, guanidinyl, guanidinyl Ci-6 alkyl, Ci-6 alkylguanidinyl, C2-I2 alkylguanidinylalkyl, ureayl, ureayl Ci-6 alkyl, C1-6 alkylureayl and C2-I2 alkylureaylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, OH, OCH3, OCH2CH3 and NH2.
16. A compound according to any of claims 1 to 7, wherein R15 and one of R14 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R14 not joined to R15 is H or Ci-6 alkyl.
17. A compound according to any of claims 1 to 7, wherein each R14 is independently selected from the group consisting of H and Ci-4 alkyl, or R15 and one of R14 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R14 not joined to R15 is selected from the group consisting of H and Ci-4 alkyl.
18. A compound according to claim 1 or claim 2, wherein R6 comprises a guanidinyl moiety.
19. A compound according to claim 1 , claim 2 or claim 18, wherein R6 is a group
Figure imgf000092_0001
where each R14 and R15 are H.
20. A compound according to any preceding claim, wherein R3 is -(CR16R17)m 3-X-R18; wherein: m3 is 0, 1, 2, 3 or 4; X is a bond, -CH=CH-, -C≡C-, S, N, Si(Ci-6 alkyl)2, Si(OH)2, Si(OCi-6 alkyl)2, C(O)NH, C(O)NC1-6 alkyl, C(O)NC6-20 aryl, C(O)NC7-20 aralkyl, C(O)NC7-20 alkaryl, C(O)O, N(C1-6 alkyl)C(O)N(C1-6 alkyl), NHC(O)N(C1-6 alkyl), OC(O)N(Ci-6 alkyl), NHC(O)NH, NHC(O)O, NH, N(Cj-6 alkyl), O, CO, SO2, SO2NH3 NHSO2, and C(O)NHNH;
R16 and R17 are independently selected from the group consisting of H, C1-20 alkyl, C2-20 alkenyl, C2-20 alkoxyalkyl, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, Ci-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, Ci-10 aminoalkyl and C6-20 aminoaryl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from COOH, COO(C1-6 alkyl), SH, S(C1-6 alkyl), SO2H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), P(OH)(O)2, halo, haloC1-6 alkyl, perhaloC1-6 alkyl, OH, 0(Ci-6 alkyl), =0, NH2, =NH, NH(Cj-6 alkyl), N(C1-6 alkyl)2, =N(Ci-6 alkyl), NHC(O)(C1-6 alkyl), NO2, CN, SO2NH2, C(O)H and C(O)(C1-6 alkyl), C1-10 alkyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, C2-10 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, Ci-20 heteroaryl and C6-20 aryl; or R16 and R17 are joined to form a 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20-membered, saturated, unsaturated or aromatic ring; and,
R18 is selected from the group consisting of H, Ci-20 alkyl, C2-20 alkenyl, C2-20 alkoxyalkyl, C7-30 alkoxyaryl, Ci2-30 aryloxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, C1-30 heteroaryl and C2-30 heterocyclyl, C2-30 heteroaralkyl and C3-30 heterocyclylalkyl, Ci-I0 aminoalkyl, C6-20 aminoaryl, guanidine Ci-10 alkyl, C2-20 alkylguanidinylalkyl, urea Ci-I0 alkyl and C2-20 alkylureaylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from COOH, COO(Ci-6 alkyl), SH, S(CJ-6 alkyl), SO2H, SO2(Ci-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), P(OH)(O)2, halo, haloCi-6 alkyl, perhaloCi-6 alkyl, OH, 0(Ci-6 alkyl), =0, NH2, =NH, NH(Ci-6 alkyl), N(Ci-6 alkyl)2, =N(C1-6 alkyl), NHC(O)(C1-6 alkyl), C(O)NH2, C(O)NH(Ci-6 alkyl), C(O)N(Ci-6 alkyl)2, C(O)NH(C6-I2 aryl), C(O)N(C6-12 aryl)2, C(O)NH(C7-I2 aralkyl), C(O)N(C7-I2 aralkyl)2, C(O)NH(C7-I2 alkaryl), C(O)N(C7-12 alkaryl)2, NO2, CN, SO2, SO2NH2, C(O)H and C(O)(C1-6 alkyl), Ci-I0 alkyl, C2-I0 alkoxyalkyl, C7-20 alkoxyaryl, C2-I0 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, Ci-20 heteroaryl and C6-20 aryl.
21. A compound according to claim 20, wherein m3 is O, 1 or 2.
22. A compound according to claim 20 or claim 21, wherein X is a bond, C(O)NH, C(O)N(C1-6 alkyl), C(O)N(C6-20 aryl), NH, N(Cj-6 alkyl) or O.
23. A compound according to any of claims 20, 21 or 22, wherein R18 is selected from the group consisting of methyl, ethyl, propyl, butyl, phenyl, benzyl, biphenyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, quinolinyl, naphthyl, tetramethylcyclohexyl, benzocycloheptyl, benzodioxepinyl, bicyclooctyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetramethyltetrahydropyranyl, cyclohexylmethyl, phenylethylbenzyl, phenoxybenzyl, phenylethynylbenzyl, cyclohexylbenzyl, tolyl, ethylbenzyl, xylyl, isopropylbenzyl, cyclohexylmethyl, methoxyphenyl, diphenylmethyl, phenethyl, pyridylmethyl, butylphenyl, binaphthyl, adamantyl, propylbenzyl, mesitylyl, ethyltolyl, butylbenzyl, indanyl, diethylbenzyl, methylindanyl, dimethylethylbenzyl, phenylpentyl, tetramethylbenzyl, phenylhexyl, dipropylben2yl, triethylbenzyl, tetrahydronaphthyl, cyclohexylbenzyl, methyhiaphthyl, naphthyhnethyl, methyltetrahydronaphthyl, ethylnaphthyl, dimethylnaphthyl, diphenylethyl, diphenylmethyl, propylnaphthyl, butylnaphthyl, phenanthryl, fluoryl, stilbyl, methylfluoryl, benzphenanthryl, triphenylmethyl, acenaphthyl, azulenyl, phenylnaphthyl, methylchrysyl, benzfluoryl, pyrenyl, hexamethylbenzyl, perylenyl, picenyl, dihydroisoxazolyl, furanyl, pyridyl, phthalimido, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chiOmanyl, isocbxomanyl, carbolinyl, thiophenyl, thiazolyl, isoxazolyl, isoxazolonyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridazyl, tetrahydrobenzoannulenyl, phenylcyclohexyl, benzoylpiperidinyl, benzylpiperidinyl, cyclopropyhnethyl and tetrahydrothiopyranyl, any of which are optionally substituted with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from =0, COOH, SH, SO2H, P(OH)(O)2, halo, trihalomethyl, OH, NH2, =NH, NH(C1-6 alkyl), =N(C1-6 alkyl), NO2, CN, OCH3, SO2NH2 and C(O)H, C1-6 alkyl, C2-6 alkoxyalkyl, C7-10 alkoxyaryl, C3-10 cycloalkyl, C4-15 (cycloalkyl)alkyl, C7-12 aralkyl, C7-12 alkaryl, C1-12 heteroaryl and C6-12 aryl.
24. A compound according to any of claims 1 to 19, wherein R3 comprises a benzyl group, optionally substituted with 1, 2 or 3 groups, independently selected from COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), halo, trihalomethyl, OH, NH2, 0(C1-6 alkyl), 0(C6-20 aryl), 0(C7-20 aralkyl), 0(C7-20 alkaryl), C1-6 alkyl, C6-J2 aryl, C7-12 aralkyl, C7-12 alkaryl, C7-12 aralkynyl, C6-J2 aryloxy, C1-12 heteroaryl, Cs-12 cycloalkyl and C(O)(C1-6 alkyl) on the backbone.
25. A compound according to any of claims 1 to 19, wherein R3 comprises a methyl, ethyl, propyl, butyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, quinolinyl, naphthyl, benzocycloheptyl, tetrahydropyranyl, dihydropyranyl, tetramethyltetrahydropyranyl, or benzodioxepinyl group, optionally substituted with 1, 2, 3 or 4 groups independently selected from COO(C1-6 alkyl), halo, trihalomethyl, OH, NH2, 0(C1-6 alkyl), C1-6 alkyl, C6-12 aryl, C7-12 aralkyl, C7-12 alkaryl, C6-12 aryloxy, C1-12 heteroaryl, C5-12 cycloalkyl and C(O)(C1-6 alkyl) on the backbone.
26. A compound according to any preceding claim, wherein R1 and R5 are independently selected from the group consisting of H, COOH, SH, SO2H, P(OH)(O)2, F, Cl, Br, I, OH, NH2, NO2, CN, SO2NH2, C(O)H, and hydrocarbyl or heterocarbyl groups selected from C1-6 alkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, C7-20 alkoxyaryl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, C1-20 heteroaryl and C2-20 heterocyclyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups, preferably 1, 2, 3 or 4 groups, independently selected from the groups defined in (a), (b) and (c):
(a) C(O)NH, C(O)NMe, C(O)O, NHC(O)NH, NHC(O)O, NH, O, CO, SO2, NHSO2, and C(O)NHNH in the backbone; (b) =0, COOH, SH, SO2H, SO3H, P(OH)(O)2, F, Cl, Br, I, OH, NH2, =NH, NH(C1-6 alkyl), =N(Ci-6 alkyl), NO2, CN, SO2NH2, and C(O)H on the backbone; and,
(c) groups independently selected from the group consisting of C1-6 alkyl, C2-6 alkoxyalkyl, C7-Io alkoxyaryl, C3-1O cycloalkyl, C4-12 (cycloalkyl)alkyl, C7-I2 aralkyl, C7-12 alkaryl, Cj-I2 heteroaryl and C6-12 aryl on the backbone.
27. A compound according to any preceding claim, wherein R5 is H and R1 is selected from the group consisting of H, F, Cl, Br, methoxy, methyl, tolyl, xylyl, pyridinyl, pyridiyl, furanyl, hydroxyphenyl, phenylamino, acetamido, oxopyrrolidinyl, dibenzylamido, piperidinylcarbonyl, benzylamido, benzylamino, OH, NH2 and N(CH3)2.
28. A compound according to any of claims 1 to 27, wherein R5 is H and R1 is selected from methyl, Cl and methoxy.
29. A compound according to any preceding claim, wherein R4 is selected from the group consisting of H, hydrocarbyl or heterocarbyl groups selected from Ci-I0 alkyl, C2-io alkoxyalkyl, C12-2O aryloxyaryl, C7-2O aryloxyalkyl, C1-1O alkoxy, C7-2O alkoxyaryl, C4-20 alkoxycycloalkyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, Ci-20 heteroaryl, C2-2O heteroaralkyl and C2-20 heterocyclyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups, preferably 1, 2 or 3 groups, independently selected from (a), (b) and (c):
(a) S, C(O)NH, C(O)NMe, C(O)O, NHC(O)NH, NHC(O)O, NH, O, CO, SO2, SO2NH, NHSO2 and C(O)NHNH in the backbone; (b) =O, COOH, SH, SO2H, P(OH)(O)2, F, Cl, Br, I, OH, NH2, =NH, NH(C1-6 alkyl), =N(C1-6 alkyl), NO2, CN, SO3H, SO2NH2, C(O)(C1-6 alkyl) and C(O)H on the backbone; and,
(c) groups independently selected from the group consisting of C1-6 alkyl, C2-6 alkoxyalkyl, C7-I0 alkoxyaryl, C3-10 cycloalkyl, C4-12 (cycloalkyl)alkyl, C7-I2 aralkyl, C7-12 alkaryl and C6-12 aryl on the backbone.
30. A compound according to any preceding claim, wherein R4 is selected from the group consisting of C1-6 alkyl, C3-I2 cycloalkyl, C6-12 aryl, C1-12 heteroaryl, C2-I2 heterocyclyl, C2-6 alkoxyalkyl, Cs-12 alkoxycycloalkyl, C2-Io alkylthioalkyl, C4-I2 alkylthiocycloalkyl, C2-io alkylsulfonylalkyl, C6-I2 alkylsulfonylcycloalkyl and C6-I2 alkylaminocycloalkyl.
31. A compound according to any preceding claim, wherein R4 is selected from the group consisting of methyl, tetrahydropyranyl, cyclohexyl, phenyl, isopropyl, fluorophenyl, cyclohexylmethyl, cyclohexyl, adamantyl, pyranyl, piperidinylmethyl, cyclohexylsulfanylmethyl, cyclohexanesulfonyhnethyl, phenoxymethyl, cyclohexylphenoxymethyl, methoxyphenoxymethyl, naphthalenyloxymethyl, ethanoylphenoxymethoxy, aminoacetylaminophenoxymethyl, cyanophenoxymethyl, acetylaminophenoxymethyl, cyclohexylidenemethyl and aminoacetylphenoxymethyl.
32. A compound according to any preceding claim, wherein Rla and R5a are independently selected from H, CH3, F, Cl, Br and OH.
33. A compound according to any preceding claim, wherein R19 is selected from the group consisting of -C(=NH)NH2, -CC=NH)NHC1-I0 alkyl, -C(=NH)N(C1-10 alkyl)2, -C(=NH)NHC3-12 cycloalkyl, -C(=NH)N(C3-12 cycloalkyl)2, -C(=NH)NHC6-12 aryl, -C(=NH)N(C6-12 aryl)2, -C(=NH)NHC6-15 alkaryl, -C(=NH)N(C6-i5 alkaryl)2, -CC=NH)NHC6-15 aralkyl, -C(=NH)N(C6-i5 aralkyl)2, -C(=NH)NHC2-12 heterocyclyl, -C(=NH)N(C2-12 heterocyclyl)2, -Q=NH)NHC1-12 heteroaryl, -C(=NH)N(C1-12 heteroaryl)2, -CC=NC1-10 alkyl)NH2, -C(=NC1-lo alkyl)NHC1-10 alkyl, -C(=NC1-lo alkyl)N(C1-lo alkyl)2, C1-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, CQ-30 heterocyclylalkaryl, C4-30 heterocyclylalkoxyalkyl, C4-30 heterocyclylalkylaminoalkyl, Cg-30 heteroarylalkaryl, C3-30 heteroarylalkoxyalkyl, C3-30 heteroarylalkylaminoalkyl, C7-30 aryloxyalkyl, C7-30 arylaminoalkyl, C7-30 alkylaminoaryl, C1-10 aminoalkyl, C7-20 aminoaralkyl, C7-20 aminoalkaryl, C2-20 alkylguanidinylalkyl and ureayl C1-10 alkyl, and is linked to the rest of the compound of formula (I) by a carbon atom of one of these groups; any of the groups defined as R19 being optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from C1-10 alkyl, C1-20 haloalkyl, C1-20 perhaloalkyl, C1-20 hydroxyalkyl, C3-10 cycloalkyl, halo, OH, OC1-6 alkyl, NH2, OC(C1-6 alkyl), OC(C6-20 aryl), OC(C7-20 aralkyl), OC(C7-20 alkaryl), OCO(C1-6 alkyl), OCO(C6-20 aryl), OCO(C7-20 aralkyl), OCO(C7-20 alkaryl), COOH, COO(Ci-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), N(C6-20 aryl)2, NH(C7-20 aralkyl), N(C7-20 aralkyl)2, NH(C7-20 alkaryl), N(C7-20 alkaryl)2, N(C1-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-20 alkaryl), N(C1-6 alkyl)(C7-20 aralkyl), N(C6-20 aryl)(C6-20 aryl), N(C6-20 aryl)(C7-20 alkaryl), N(C6-20 aryl)(C7-20 aralkyl), NO2, CN, C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 aralkyl) and C(O)(C7-20 alkaryl).
34. A compound according to any preceding claim, wherein R 9 is selected from the group consisting of -C(=NH)NH2, -C(=NH)NHC1-6 alkyl, -C(=NH)N(C1-6 alkyl)2, -C(=NH)NHC3-12 cycloalkyl, -C(=NH)N(C3-12 cycloalkyl)2, -Q=NH)NHC6-10 aryl, -C(=NH)N(C6-10 aryl)2, -C(=NH)NHC6-12 alkaryl, -C(=NH)N(C6-12 alkaryl)2, -C(=NH)NHC6-i2 aralkyl, -C(=NH)N(C6-12 aralkyl)2, -C(=NH)NHC2-10 heterocyclyl, -C(=NH)N(C2-i0 heterocyclyl)2, -C(=NH)NHCi-10 heteroaryl, -C(=NH)N(CMo heteroaryl)2, -C(=NC1-6 alkyl)NH2, -C(=NC1-6 alkyl)NHC1-6 alkyl, alkyl)N(Ci-6 alkyl)2, C]-J5 heteroaryl and C2-I5 heterocyclyl, and is linked to the rest of the compound of formula (I) by a carbon atom of one of these groups; any of the groups defined as R19 being optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from NH2, NH(Ci-4 alkyl), N(Ci-4 alkyl)2, NH(C6-16 aryl), N(C6-I6 aryl)2, NH(C7-I6 aralkyl), N(C7-16 aralkyl)2, NH(C7-I6 alkaryl), N(C7-J6 alkaryl)2, N(C1-4 alkyl)(C6-i6 aryl), N(C1-4 alkyl)(C7-i6 alkaryl), N(C1-4 alkyl)(C7-i6 aralkyl), N(C6-I6 aryl)(C7-i6 alkaryl), N(C6-16 aryl)(C7-i6 aralkyl), S(Ci-6 alkyl), NO2, CN, OH, SH, OCi-6 alkyl, C(O)H and C(O)(C1-6 alkyl).
35. A compound according to any preceding claim, wherein R19 is selected from the group consisting of -C(=NH)NH2, Ci-I5 heteroaryl and C2-I5 heterocyclyl, and is linked to the rest of the compound of formula (I) by a carbon atom of one of these groups; any of the groups defined as R19 being optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from NH2, NH(Ci-4 alkyl) or N(Ci-4 alkyl)2.
36. A pharmaceutical composition comprising a compound, salt, solvate or pro-drug according to any preceding claim and a pharmaceutically acceptable diluent or carrier.
37. A method of making a pharmaceutical composition according to claim 36, comprising mixing said compound, salt, solvate or pro-drug with a pharmaceutically acceptable diluent or carrier.
38. A compound salt, solvate or pro-drug according to any of claims 1 to 35, for use in therapy.
39. A method for the treatment of a disease, selected from the group consisting of cardiovascular diseases, disorders of the peripheral and central nervous system, inflammation, urological diseases, developmental disorders, cancer, metabolic diseases, endocrinological diseases and disorders of the gastroenterology system in a mammal, comprising administering to a patient in need thereof a therapeutically effective amount of a compound, salt, solvate or pro-drug according to any of claims 1 to 35 or a pharmaceutical composition according to claim 36.
40. A method for the treatment of a disease mediated by PTH-I receptors, by administration to a subject of a compound, salt, solvate or pro-drug according to any of claims 1 to 35, or a pharmaceutical composition according to claim 36.
41. A method according to any of claims 39 or 40, wherein the disease is cancer.
42. A method according to any of claims 39 or 40, wherein the disease is osteoporosis.
43. A method according to any of claims 39 or 40, wherein the disease is an inflammatory disease.
44. A method according to any of claims 39 or 40, wherein the disease is an autoimmune disease.
45. A method according to any of claims 39 or 40, wherein the disease is metastases following a primary tumour.
46. A method according to any of claims 39 or 40, wherein the condition is lack of hair eruption.
47. A method according to any of claims 39 or 40, wherein the disease is disease selected from the group consisting of anaemia, renal impairment, ulcers, myopathy, neuropathy, hypercalcemia, hyperparathyroidism, parathyroid gland adenoma, parathyroid gland hyperplasia, parathyroid gland carcinoma, squamous carcinoma, renal carcinoma, breast carcinoma, prostate carcinoma, lung carcinomas, osteosarcomas, clear cell renal carcinoma, prostate cancer, lung cancer, breast cancer, gastric cancer, ovarian cancer, bladder cancer, bone fracture, severe bone pain, spinal cord compression, cachexia, malnutrition, muscle wasting, net protein loss, arthritis, rheumatoid arthritis, diabetes, congestive heart failure and wound healing.
48. Use of a compound, salt, solvate or pro-drug according to any of claims 1 to 35, or a pharmaceutical composition according to claim 36, in the manufacture of a medicament for the prophylaxis or treatment of a disease as defined in any of claims 39 to 47.
PCT/GB2006/004512 2006-05-19 2006-12-04 Benzotriazepinone derivatives Ceased WO2007135350A1 (en)

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