WO2008009963A2 - Pyrimidine derivatives as modulators of parathyroid hormone receptors - Google Patents

Pyrimidine derivatives as modulators of parathyroid hormone receptors Download PDF

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WO2008009963A2
WO2008009963A2 PCT/GB2007/002767 GB2007002767W WO2008009963A2 WO 2008009963 A2 WO2008009963 A2 WO 2008009963A2 GB 2007002767 W GB2007002767 W GB 2007002767W WO 2008009963 A2 WO2008009963 A2 WO 2008009963A2
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alkyl
aryl
alkaryl
aralkyl
phenyl
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WO2008009963A3 (en
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Caroline Minli Rachel Low
Lain Mair Mcdonald
Michael John Pether
John Spencer
Patrizia Tisselli
Paul Trevor Wright
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James Black Foundation Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom

Definitions

  • the present invention is concerned with pyrimidine 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.
  • 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 be 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 auotoimmune diseases such as rheumatoid arthritis.
  • 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 , £>-Trp 12 , Tyr 34 ]bPTH(7-34)NH 2 , (BIM-44002)), (Rosen, H. N. et al, Calcif. Tissue Int.
  • R 3 and R 4 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, S(C -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 (Ci -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), 0(C 6-20 aryl), 0(C 7-20 alkaryl), 0(C 7-20 aralkyl), NH 2 , NH(C
  • R 1 and R 2 groups independently selected from the group consisting of Cj -I0 alkyl, C 2-I0 alkoxyalkyl, C 7-20 alkoxyaryl, Ci 2-20 aryloxyaryl, C 7-20 aryloxyalkyl, C -]0 alkoxy, C 6-20 aryloxy, C 2- I 0 alkenyl, C 2-I0 alkynyl, C 3-20 cycloalkyl, C 4-20 (cycloalkyl)alkyl, C 7-20 aralkyl, C 7-20 alkaryl and C 6-20 aryl on the backbone; at least one of R 1 and R 2 has a structure independently selected from the group consisting of (a), (b) and (c),
  • R 5 and R 7 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(Ci -6 alkyl), SO 2 H, SO 3 H, SO 2 (Ci -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 alkaryl), SO(C 7-20 aralkyl), P(OH)(O) 2 , halo, OH, 0(Ci -6 alkyl), NH 2 , NH(Ci -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
  • R 9 is selected from the group consisting of H, C 1-6 alkyl, Ci -6 aminoalkyl, C 1-I2 alkylaminoalkyl, C 1-I8 dialkylaminoalkyl, C 3-20 cycloalkyl, C 3-20 aminocycloalkyl, C 4-20 (cycloalkyl)alkyl, C 4-20 (aminocycloalkyl)alkyl, C 6-20 aryl, C 6-20 aminoaryl, C 7-20 aralkyl, C 7-20 aminoaralkyl, C 7-20 alkaryl, C 7-20 aminoalkaryl, Ci -20 heteroaryl and C 2-20 heterocyclyl;
  • R 10 is 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 cycloal
  • R 1 is selected from the group consisting of the structures (a), (b), and (c) and and R 2 is independently selected from the same group as R 3 , as defined above.
  • -(CH 2 ) m -R 6 is located in the ortho, meta or para position relative to the -(O) n - group. More preferably, -(CH 2 ) m -R 6 is located in the meta or para position relative to the to the -(O) n -. Most preferably, -(CH 2 ) m -R 6 is located in the para position relative to the -(O) n - group.
  • n 0.
  • R 5 and/or R 7 are preferably located in the ortho or meta position relative to the -(O) n - group, most preferably the meta position.
  • R 1 and/or R 2 is a group having the structure (ai) shown below:
  • R 5 and R 7 are independently selected from the group consisting of H, Ci -6 alkyl, halo, haloCi -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)(C 1-6 alkyl), and R 6 is as defined above.
  • R 1 and/or R 2 is a group having the structure (a 2 ) or (a 3 ) shown below:
  • R 6 is as defined above.
  • R 1 and/or R 2 is a group having the structure (a 2 ).
  • R 1 is a group having the structure (a 2 ) and R 2 is independently selected from the same group as R 3 .
  • R 1 and R 2 are both selected from the group consisting of (a), (b), (c), (ai), (a 2 ) and (a 3 ), they may be the same or different, i.e., they are both independently selected from these groups and the definitions of R 5 , R 6 and R 7 may differ between groups R 1 and R 2 .
  • R 5 and/or R 7 are preferably located in the ortho or meta position relative to the -(O) n - group, most preferably the meta position.
  • R 5 is H and R 7 is H, Cl, Br, or F, preferably H.
  • R 5 and R 7 are both H.
  • R and/or R is selected from
  • R 9 is selected from H, methyl, ethyl, propyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, phenyl, phenylethyl, benzyl, tolyl and xylyl, more preferably H or methyl, most preferably H.
  • R 10 is selected from the group consisting of H, C 1-15 heteroaryl, C 2-I5 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(C 1-4 alkyl) 2 , NH(C 6-16 aryl), N(C 6 - I6 aryl) 2 , NH(C 7-16 aralkyl), N(C 7- , 6 aralkyl) 2 , NH(C 7-16 alkaryl), N(C 7-16 alkaryl) 2 , N(C 1-4 alkyl)(C 6 -i
  • R 10 is selected from the group consisting Of C 6-20 aryl, C 7-20 aralkyl, C 3-I5 cycloalkyl, C 4- i 5 cycloalkylalkyl, Ci -I5 heteroaryl, C 2-15 heterocyclyl, C 2-I5 heteroaralkyl, C 3-I5 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(Cj -4 alkyl), N(Ci -4 alkyl) 2 , guanidinyl and guanidinyl Ci -6 alkyl.
  • R 10 is selected from the group consisting of Ci -]o heteroaryl, C 2- io heterocyclyl, C 3-I0 heteroaralkyl, 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), N(Ci -4 alkyl) 2 , guanidinyl and guanidinyl Ci -6 alkyl.
  • R 10 is selected from the group consisting of of C] -I0 alkyl, C 3-I5 cycloalkyl, C 4-I5 cycloalkylalkyl, C 7-20 aralkyl, furanyl, furanyl(Ci -3 alkyl), pyridyl, pyridyl(Ci. 3 alkyl), phthalimido, phthalimido(Ci -3 alkyl), thienyl, thienyl(Ci -3 alkyl), pyrrolyl, pyrrolyl(Ci -3 alkyl), imidazolyl, imidazolyl(Ci.
  • R 10 is selected from the group consisting of methyl, ethyl, propyl, pyridyl, pyridyl(Ci -3 alkyl), phthalimido, phthalimido(C 1-3 alkyl), pyrrolyl, pyrrolyl(Ci -3 alkyl), imidazolyl, imidazolyl(Ci.
  • R 10 is selected from the group consisting of guanidinylethyl, di(C 1-6 alkyl)amino(Ci.6 alkyl), amino(Ci -6 alkyl), (4,5-dihydro-lH-imidazol-2-yl, 4,5-dihydro-lH-imidazol-2-yl(Ci -6 alkyl) and lH-imidazol-2-yl(C 1-6 alkyl) group which may be substituted with 1 or more groups independently selected from Ci -6 alkyl, halo, haloC] -6 alkyl, hydroxyC ⁇ alkyl, perhaloCi-6 alkyl, OH, NH 2 , NO 2 , CN, COOH, C(O)H, C(O)O(Ci -6 alkyl), 0(Ci -6 alkyl), OC(O)(Ci -6 alkyl) and C(O)(Ci -6 alkyl) and C(
  • 4,5-dihydro-lH-imidazol-2-yl 4,5-dihydro-lH-imidazol-2-ylmethyl, dimethylaminoethyl, morpholinoethyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl and guanidinylethyl.
  • R 10 is 4,5-dihydro-lH-imidazol-2-yl.
  • R 10 represents a natural or synthetic amino acid residue.
  • the amino acid may be an ⁇ - or ⁇ -amino acid.
  • R 10 represents the residue of a natural amino acid corresponding to an amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, lysine, arginine, histidine, aspartic acid, glutamic acid, asparagine, glutamine, cysteine and methionine.
  • NR 9 R 10 has the structure:
  • R 9 and R !o may be 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 6 comprises the group OR 10
  • m is O or 1 , most preferably O.
  • R 6 comprises the group OR 10
  • R 10 is selected from the group consisting of Ci -1O heteroaryl, C 2-1 O heterocyclyl, C 3-I o heteroaralkyl, C 3-10 heterocyclylalkyl, Ci -6 alkylamino Ci -6 alkyl, (Ii(Ci -6 alkyl)amino Ci -6 alkyl 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(Cj -4 alkyl) or N(C 1-4 alkyl) 2 .
  • R 6 comprises the group OR 10
  • R 10 is selected from the group consisting of 1 H-imidazol-2-ylmethyl, 1 H-imidazol-2-ylethyl, 1 H-imidazol-2-ylpropyl,
  • R 11 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 1 ' is not substituted in the backbone.
  • R 1 ' is not substituted on the backbone.
  • R 12 is selected from the group consisting of H, C 1-I0 alkyl, C 2-10 alkenyl, C 2-10 alkoxyalkyl, C 7-20 alkoxyaryl, C 2-10 alkynyl, C 3-20 cycloalkyl, C 4-20 (cycloalkyl)alkyl, C 5-20 cycloalkenyl, C 7-20 cycloalkynyl, C 7-20 aralkyl, C 7-20 alkaryl, C 6 - 2 o aryl, Ci -20 heteroaryl, C 2-20 heterocyclyl, C 2-20 heteroaralkyl, C 3-20 heterocyclylalkyl, Ci -I0 aminoalkyl, C 6-I0 aminoaryl, guanidinyl Cj -6 alkyl, C 2-I2 alkylguanidinylalkyl, ureayl Ci -6 alkyl and C 2-I2 alkylureaylalkyl, any of which (except H) are optionally substitute
  • each R 13 is independently selected from the group consisting of H, Ci -I0 alkyl, C 2-10 alkenyl, C 2-I0 alkoxyalkyl, C 7-20 alkoxyaryl, C 2-I0 alkynyl, C 3-20 cycloalkyl, C 4-20 (cycloalkyl)alkyl, C 5-20 cycloalkenyl, C 7-20 cycloalkynyl, C 7-20 aralkyl, C 7-20 alkaryl, C 6-20 aryl, C] -20 heteroaryl and C 2-20 heterocyclyl, C 2-20 heteroaralkyl, C 3-20 heterocyclylalkyl, Ci -I0 aminoalkyl, C 6-I0 aminoaryl, guanidinyl Ci -6 alkyl, C 2-I2 alkylguanidinylalkyl, ureayl C] -6 alkyl and C 2-I2 alkylureaylalkyl, any of which (except H) are optional
  • each R 13 is independently selected from the group consisting of H and C 1-4 alkyl, or R 12 and one of R 13 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R 13 not joined to R 12 is selected from the group consisting of H and Ci -4 alkyl.
  • R 12 and one of R 13 are joined to form a group selected from imidazole, dihydroimidazole, tetrahydropyrimidinyl, benzimidazole and triazole.
  • each R 13 is independently selected from the group consisting of H and methyl.
  • R 12 and one of R 13 are joined to form a group selected from imidazole, dihydroimidazole and tetrahydropyrimidinyl.
  • R 6 comprises a guanidinyl moiety.
  • R 6 is a group
  • R 12 and each R 13 are H.
  • R 6 is preferably a group -NHCO(Ci -6 alkyl)guanidine or -NHCO(Ci -6 alkyl)amine, more preferably, -NHCO(CH 2 ) 2 guanidine, -NHCOCH 2 NH 2 , -NHCOCH(NH 2 )(CH(CH 3 ) 2 ) or -NHCOCH 2 CH 2 NH 2 .
  • R 6 is preferably a group -CH 2 NHCH 2 CH 2 N(CH 3 ) 2 , -CH 2 NHCH 2 CH 2 morpholine, -CH 2 NHCH 2 CH 2 CH 2 NH 2 or -CH 2 NH 2 .
  • R 1 and/or R 2 is selected from the group consisting of ((lH-imidazol-2-yl)methylamino)-phenyl, ((lH-imidazol-2-yl)ethylamino)-phenyl,
  • R 1 is selected from the group consisting of (( 1 H-imidazol-2-yl)methylamino)-phenyl, (( 1 H-imidazol-2-yl)ethylamino)-phenyl,
  • both of R 1 and R 2 are selected from the group consisting of (a), (b), (c), (ai), (a 2 ) and (a 3 ), they may be the same or different, preferably different.
  • both of R 1 and R 2 is selected from the group consisting of (a), (b), (c), (ai), (a 2 ) and (a 3 ), they are both (a), (ai) or (a 2 ), more preferably both (a 2 ).
  • both of R 1 and R 2 are (a), (ai) or (a 2 ), they may be the same or different, preferably different.
  • R 1 is 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(C 1-6 alkyl), C(O)N(Ci -6 alkyl) 2 , C(O)NH(C 6- I 5 aryl), C(O)N(C 6-15 aryl) 2 , C(O)NH(C 7-I5 aralkyl), C(O)N(C 7-I5 aralkyl) 2 , C(O)NH(C 7-I5 alkaryl), C(O)N(C 7-15 alkaryl) 2 and hydro
  • (ix) groups independently selected from the group consisting of C 1-10 alkyl, C 2-I0 alkoxyalkyl, C 7-20 alkoxyaryl, C 12-20 aryloxyaryl, C 7-20 aryloxyalkyl, C 1-I0 alkoxy, C 6-20 aryloxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-20 cycloalkyl, C 4-20 (cycloalkyl)alkyl, C 7-20 aralkyl, C 7-20 alkaryl and C 6-20 aryl on the backbone.
  • R 1 is not selected from the group consisting of (a), (b), (c), ( ⁇ ), (a 2 ) and (a 3 ), R 1 is not H.
  • R 1 is selected from the group consisting of (a), (b), (c), (a ⁇ , (a 2 ) and (a 3 ), R 1 is selected from the group consisting of Ci -10 alkyl, Ci -10 alkyloxy, C 1-I5 heteroaryl, C 2-I5 heterocyclyl, C 6-20 aryl, C 7-20 aralkyl, C 3-15 cycloalkyl, C 6-20 aryloxy, C 7-20 aralkyloxy, C 3-I5
  • R 1 is selected from the group consisting of (a), (b), (c), (& ⁇ ), (a 2 ) and (a 3 ), R 1 is selected from the group consisting of C 7-2O aralkyl, C 7-2O aralkyloxy, C 7-2O aralkylamino, C 3- i 5 (cycloalkyl)alkyloxy, Ci -1S heteroaryl and C 2-I5 heterocyclyl.
  • R 1 is not selected from the group consisting of (a), (b), (c), (ai), (a 2 ) and (a 3 ), R 1 is selected from the group consisting of phenylethyloxy, phenylethylamino, and cyclohexylethyloxy.
  • R 2 is selected from the group consisting of H, COOH, COO(C 1-6 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(C 1-6 alkyl), C(O)N(C -6 alkyl) 2 , C(O)NH(C 6-I5 aryl), C(O)N(C 6-15 aryl) 2 , C(O)NH(C 7-15 aralkyl), C(O)N(C 7-15 aralkyl) 2 , C(O)NH(C 7-15 alkaryl), C(O)N(C 7-15 alkaryl) 2 and hydrocarbyl or heterocarbyl groups selected
  • (xii) groups independently selected from the group consisting Of C 1-10 alkyl, C 2-10 alkoxyalkyl, C 7-20 alkoxyaryl, C 12-20 aryloxyaryl, C 7-20 aryloxyalkyl, C 1-10 alkoxy, C 6-20 aryloxy, C 2-10 alkenyl, C 2-I0 alkynyl, C 3-20 cycloalkyl, C 4-20 (cycloalkyl)alkyl, C 7-20 aralkyl, C 7-20 alkaryl and C 6-20 aryl on the backbone.
  • R 2 is not selected from the group consisting of (a), (b), (c), (ai), (a 2 ) and (a 3 ), R 2 is not H.
  • R 2 is not selected from the group consisting of (a), (b), (c), (a]), (a 2 ) and (a 3 )
  • R 2 is a group -(CR 16 R 17 ) ra -X-R 18 ; wherein: m' is O, 1, 2, 3 or 4;
  • R 16 and R 17 are independently selected from the group consisting of H, Ci -2O 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, Cs -30 cycloalkenyl, C 7-30 cycloalkynyl, C 7-30 aralkyl, C 7-30 alkaryl, C 6-30 aryl, Ci -30 heteroaryl, C 2-30 heterocyclyl, C 2-30 heteroaralkyl, C 3-30 heterocyclylalkyl, Ci -I0 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 -6 alkyl), SH, S(C -6 alkyl), SO 2 H, SO 2 (C -6 alkyl
  • R 18 is selected from the group consisting of H, C] -20 alkyl, C 2-20 alkenyl, C 2-20 alkoxyalkyl, C 7-30 alkoxyaryl, C] 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, Cj -30 heteroaryl, C 2-30 heterocyclyl, C 2-30 heteroaralkyl, C 3-30 heterocyclylalkyl, C] -I0 aminoalkyl, C] -I0 alkylaminoalkyl, C 6-20 aminoaryl, guanidine C -I0 alkyl, C 2-20 alkylguanidinylalkyl, urea C] -I0 alkyl and C 2-20 alkylure
  • m' is O, 1 or 2, more preferably O or 1, most preferably O.
  • X is a bond, NH, N(C 1-6 alkyl) or O.
  • R 16 and R 17 are independently selected from the group consisting of H, C 1-10 alkyl, C 2-20 alkoxyalkyl, C 7-20 alkoxyaryl, Ci 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 2-2O heteroaralkyl and C 3-2O 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-J0 cycloalkyl, C 4-10 heterocyclyl or C 1-I0 heteroaryl group.
  • R 16 and R 17 are both H; or R 16 is H and R 17 is C 1-]0 alkyl, preferably methyl.
  • R 18 is selected from the group consisting of H, Ci -1O alkyl, C 2-I0 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, Ci -20 heteroaryl, C 2-20 heterocyclyl, C 2-20 heteroaralkyl and C 3-20 heterocyclylalkyl, any of which
  • groups preferably 1, 2 or 3 groups, most preferably 1 group, independently
  • 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, cyclohexyhnethyl, phenylethylbenzyl, phenoxybenzyl, phenylethynylbenzyl, cyclohexylbenzyl, pyranyl, tolyl, ethylbenzyl, xylyl
  • m' is O, X is a bond and R 18 is a C 5-I2 cycloalkyl group.
  • m' is 1, X is a bond and R 18 is a C 5-I2 cycloalkyl group.
  • m' is 1, R 16 is H, R 17 is C 1-1O alkyl, X is a bond and R 18 is a C 5-12 cycloalkyl group. In this embodiment, R 17 is preferably methyl and R 18 is preferably hexyl.
  • n is 1
  • X is a bond and R 18 is a Cs -I2 heterocyclyl group which is optionally substituted on the backbone with a group selected from SO 2 (Ci -3 alkyl) and SO 2 (C 6-10 aryl).
  • m' is 0,
  • X is N(Ci -3 alkyl) and R 18 is a (Ci -3 alkyl)N(CH 2 CH 2 )(S0 2 (C 6- io aryl)) group.
  • m' is 0, X is a bond and R 18 is a Ci -I4 alkyl group. In another preferred embodiment, m' is 0, X is N(Ci -6 alkyl) and R 18 is a Ci -6 alkyl group.
  • m' is 0, X is N(Ci -6 alkyl) and R 18 is a Ci -6 hydroxyalkyl group.
  • m' is 0, X is O and R 18 is a Cj -6 alkyl group. In another preferred embodiment, m' is 0, X is O and R 18 is a Ci -I2 alkoxyalkyl group. In another preferred embodiment, m' is 0, X is O and R 18 is a C 6-I2 cycloalkylalkyl group.
  • X is a bond and R 18 is selected from the group consisting of cyclohexyl, cyclohexylmethyl, cyclopentyl, cycloheptyl, cyclododecyl, cyclodecyl, adamantyl, butyl, bycycloheptyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, tetramethylcyclohexyl, morpholinyl, piperidyl, piperazinyl phenyl, toluyl, benzyl, naphthyl, pyranyl, tetramethyltetrahydropyranyl, tetrahydropyranyl, dihydropyrany
  • R 3 and R 4 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 (Ci -6 alkyl), SO 2 (C 6-20 aryl), SO 2 (C 7-20 alkaryl), SO 2 (C 7-20 aralkyl), SO(C ]-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(Ci -6 alkyl), N(C 1-6 alkyl) 2 , NHC(O)(C 1-6 alkyl), NO 2 , CN, SO 2 NH 2 , C(O)H and C
  • NHC(O)O NH, N(C 1-6 alkyl), O, CO, SO 2 , NHSO 2 and C(O)NH in the backbone;
  • (xv) groups independently selected from the group consisting of Ci -I0 alkyl, C 2-I0 alkoxyalkyl, C 7-20 alkoxyaryl, C 12-20 aryloxyaryl, C 7-20 aryloxyalkyl, Ci -I0 alkoxy, C 6-20 aryloxy, C 2-I0 alkenyl, C 2-I0 alkynyl, C 3-20 cycloalkyl, C 4-20 (cycloalkyl)alkyl, C 7-20 aralkyl, C 7-20 alkaryl and C 6-20 aryl on the backbone.
  • R 3 and R 4 are independently selected from the group consisting of H, COOH, SH, 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, Cj -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, Ci -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 (xvi), (xvii) and (xviii):
  • (xviii) groups independently selected from the group consisting of Ci -6 alkyl, C 2-6 alkoxyalkyl, C 7-10 alkoxyaryl, C 3-I0 cycloalkyl, C 4-I2 (cycloalkyl)alkyl, C 7-I2 aralkyl, C 7-I2 alkaryl, Ci -]2 heteroaryl and C 6-I2 aryl on the backbone.
  • R 4 is selected from the group consisting of H, Q -6 alkyl, Ci -4 alkoxyalkyl, C 7- I 0 aralkyl, C 7-!0 alkaryl, C 6- Io aryl, C J-I0 heteroaryl and C 2- io heterocyclyl.
  • R 4 is selected from the group consisting of H, methyl, ethyl, propyl, butyl, hexyl, ethoxyethyl and benzyl.
  • R 4 is H.
  • R 3 is selected from the group consisting of H, Ci -6 alkyl, Cs -I0 cycloalkyl, C 6-I4 (cycloalkyl)alkyl, Ci -4 alkoxy, C 5- io cycloalkyloxy, C 5- I 0 cycloalkyloxyalkyl, C 6- I 4 (cycloalkyl)oxyalkyl, C 7-I6 aralkyloxy, C 8-I6 aralkyloxyalkyl, C 7- I 6 aryloxyalkyl, C 7-]6 aryloxy, C 7-I2 aralkyl, C 7-I2 alkaryl, C 6-I0 aryl, Ci -I0 heteroaryl and C 2- I 0 heterocyclyl.
  • R 3 is selected from the group consisting of H, phenylethyl, phenylpropyl, phenylbutyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclohexyl optionally substituted with 1, 2, 3 or 4 methyl groups, (cyclohexyl)Ci -3 alkyl wherein the cycloalkyl moiety is optionally substituted with 1, 2, 3 or 4 methyl groups, (cyclohexyl)oxy(C ]-3 alkyl) wherein the cycloalkyl moiety is optionally substituted with 1, 2, 3 or 4 methyl groups, (cycloheptyl)oxy Ci -3 alkyl, adamantyl, adamantylmethyl, adamantylethyl, adamantylpropyl, adamantylbutyl, naphthyl, phenyl, pyridyl, benz
  • R 3 is phenylpropyl. In other preferred embodiments, R 3 is benzyloxymethyl.
  • R 4 is H, R 3 is phenylpropyl, R 1 is (4,5-dihydro-lH-imidazol-2-ylamino)-phenyl or guanidinylphenyl, and R 2 is C 4-20 alkyl or C 5- I 6 cycloalkyl.
  • R 4 is H, R 3 is phenylpropyl, R 1 is (4,5-dihydro-lH-irnidazol-2-ylamino)-phenyl, and R 2 is C 6-I3 alkyl.
  • 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.
  • Pyrimidines (III) are prepared by reaction of a suitable 1,3-difunctional reagents, and a suitable amidine (Scheme 1) (wherein R 2 ' and R 3 ' represent R 2 and R 3 respectively or a suitable precursor thereof).
  • a suitable 1,3-difunctional reagent chlorination of the pyrimidine (III) with phosphorus oxychloride or other suitable chlorinating agent affords the chloropyrimidine (IV).
  • Suzuki reaction with an aromatic boronic acid or boronic acid ester affords the aryl substituted pyrimidine (V) (wherein R 6 ' represents R 6 or a suitable precursor thereof). Modification of R 2 ', R 3 ' and/or R 6 ' affords the desired pyrimidines (VII).
  • R 6 ' substituents 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 by 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 carboxylic acid esters that can be converted to amide derivatives via the corresponding acid.
  • R 6 ' substitents include CHO that can be further modified to the required R 6 group by, amongst others, reductive amination or converted to ethers via reduction to the corresponding alcohol.
  • 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).
  • 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).
  • 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 .
  • Suitable R 3 ' substituents include carboxylic acid esters that can be converted to amide derivatives via the corresponding acid.
  • R 3 substituent is an amine or alkoxy substituent linked to the pyrimidine ring by nitrogen or oxygen respectively
  • these can be obtained via the intermediate chloropyrimidine (XII), prepared by an analogous route to the preparation of (IV) (Scheme 3).
  • Treatment of the chloropyrimidine (XIII) with a suitable amine or alcohol affords the amino or alkoxy- substituted pyrimidine (XIV).
  • Modification of R 1 ', R 2 ' and/or R 3 'X affords the desired pyrimidines (XVI).
  • R substituent is an amine or alkoxy substituent linked to the pyrimidine ring by nitrogen or oxygen respectively
  • R substituent is an amine or alkoxy substituent linked to the pyrimidine ring by nitrogen or oxygen respectively
  • R substituent is an amine or alkoxy substituent linked to the pyrimidine ring by nitrogen or oxygen respectively
  • R substituent is an amine or alkoxy substituent linked to the pyrimidine ring by nitrogen or oxygen respectively
  • R substituent is an amine or alkoxy substituent linked to the pyrimidine ring by nitrogen or oxygen respectively
  • XVII can be prepared by reaction of a suitable 1,3-difunctional reagent (I) and thiourea, in an analogous route to the preparation of (IV) (Scheme 1).
  • Oxidation of the thiomethylpyrimidine intermediate (XIX) to the methylsufonylpyrimidine (XX) can be achieved with m- chloroperoxybenzoic acid or other suitable oxidising agent.
  • Treatment of (XX) with a suitable amine or alcohol affords the amino or alkoxy-substituted pyrimidine (XXI).
  • Modification of R 1 ', R 2 'X and/or R 6 ' affords the desired pyrimidines (XXIII).
  • R 2 substituent is an amine or alkoxy substituent linked to the pyrimidine ring by nitrogen or oxygen respectively
  • R 2 substituent is an amine or alkoxy substituent linked to the pyrimidine ring by nitrogen or oxygen respectively
  • these can be obtained via the chloropyrimidine intermediate (XXVI) (Scheme 5).
  • (XXVI) can be obtained from 2,4,6- tiichloropyrimidine (XXIV) via (XXV) by sequential Suzuki reactions.
  • Treatment of (XXVI) with a suitable amine or alcohol affords the amino or alkoxy-substituted pyrimidine (XXVII), following which, R 6 ', R 2 'X and/or R 3 " can be modified to obtain the desired pyrimidines (XXIII) according to the method of scheme 4.
  • the 4,6-dichloropyrimidine intermediate (XXX) can be obtained from the substituted malonic acid diester (XXVIII) (Scheme 6).
  • the desired pyrimidines (XXIII) can be obtained from (XXX) by sequential Suzuki reactions (as in scheme 5), or when the R 3 and/or R 1 substituent is an amine or alkoxy substituent linked to the pyrimidine ring by nitrogen or oxygen respectively, by base-catalysed reaction using a suitable amine or alcohol (as in scheme 3), or by a combination of methods thereof.
  • 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 herein before, 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 herein before, 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 herein before, 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-drug thereof, substantially as described herein before.
  • 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 herein before.
  • 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 herein before.
  • 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 herein before.
  • 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-drug thereof, substantially as described herein before.
  • 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 herein before.
  • 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 herein before.
  • 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 herein before, in the manufacture of a medicament for the prophylaxis or treatment of any of the diseases described herein before.
  • 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. ScL, 1977, Jan, 66 (1), pi
  • pharmaceutically acceptable acidic/anionic or basic/cationic salts 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 tiOmethamine.
  • 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 (I).
  • 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-drugs may be found in Stella, V. J. et al, "Prodrugs", Dmg Delivery System, 1985, pp. 112-176, Drugs, 1985, 29, pp. 455-473 and "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • Pro-drug forms of the pharmacologically-active compounds of the invention will generally be compounds according to formula (I) 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 c , wherein R b is H, C 1-S alkyl, phenyl, substituted phenyl, benzyl, or substituted benzyl, and R c is -OH or one of the groups just recited for R b .
  • Compounds of formula (I) 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 free 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.
  • 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.
  • 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.
  • dialkyl groups e.g. N(Ci -6 a lkyl) 2
  • the two alkyl groups may be the same or different.
  • reference to other dihydrocarbyl or diheterocarbyl groups should be interpreted such that the two groups may be the same or different.
  • 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 halo(Ci- 6 alkyl) includes mono-, di- or tri-halo substituted Cj -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.
  • composition 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.
  • the compounds possess two or more chiral centers they may additionally exist as diastereomers.
  • 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.
  • 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 3 , R 4 , R 5 , R 7 , R 10 , R 11 , R 12 , R 13 , R 16 , R 17 and R 18 are unsubstituted, in or on the backbone.
  • 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 10 is substituted, in or on the backbone, by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably by 1 substir ⁇ ent, as defined herein.
  • the group R 11 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 12 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 13 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 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.
  • 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 "Ci -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, and 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.
  • 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.
  • 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.
  • 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.
  • 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, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, methylcyclohexylmethyl, dimethylcyclohexylmethyl, trimethylcyclohexylmethyl, cycloheptylmethyl, cycloheptylethyl, cycloheptylpropyl, cycloheptylbutyl and adam
  • 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, tolylmethyl, fluorophenethyl, fluorenylmethyl, methoxyphenethyl, dimethoxybenzyl, dichlorophenethyl, phenylethylbenzyl, isopropylbenzyl, diphenylmethyl, propylbenzy
  • 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 may be 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.
  • the terai "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.
  • 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 (NH 4 ) 2 SO 4 , 2mM MgCl 2 , 0.2mM dNTP containing O.l ⁇ 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 (Invitrogen) 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.
  • the 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.
  • the products were separated using an ethidium bromide stained 1% agarose/TBE gel and the 337bp fragment was isolated and purified using the MinEluteTM gel extraction kit.
  • 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/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-B iotech 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) (Invitrogen), containing 2mM Glutamaxl (Invitrogen), 10% heat-inactivated foetal bovine serum (Invitrogen), Ix non-essential amino acids (Invitrogen).
  • 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.
  • Stable clones with the greatest expression of the human PTH] 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 mr'and [ 125 I]-[NIe 8 ' 18 , Tyr 34 ]-hPTH(l-34) concentration of 2OpM. In 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 -7O 0 C. When required, aliquots were thawed, by mixing with ice-cold buffer A. (5OmM Tris-HCl, pH7.2 at 21 0 C; 3mM MgCl 2 , 3mM CaCl 2 , 3mM KCl and 3mg ml '1 bacitracin).
  • the cell/membrane suspension was centrifuged (20min, 20,00Og @ 4 0 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 10 4 cells ml "1 added, in buffer A (21 0 C; containing lO ⁇ M chymostatin and l ⁇ M 1 , 10-phenanthroline) .
  • 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( I-34) (50 ⁇ l; lO ⁇ M).
  • competition 200pM
  • saturation 2pM-300nM
  • Membranes were incubated with [ 125 I]-[NIe 8 ' 18 , Tyr 34 ]-hPTH(l-34) (50 ⁇ l; 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 l ⁇ M PTH(l-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
  • Step d fyN'-bis-ftert-ButoxycarbonylJ- ⁇ -fi-cyclohexyl- ⁇ - ⁇ henyl ⁇ ropylJ ⁇ yiiinidin ⁇ -ylJ- phenyl ⁇ -(4,5-dihydro-lH-imidazol-2yl)-amine
  • Step e A solution of iV,7V-6/>s-(tert-butoxycarbonyl)- ⁇ 4-[2-cyclohexyl-6-(3-plienyl- propyl)-pyrimidin-4-yl]-phenyl ⁇ -(4,5-dihydro-lH-imidazol-2yl)-amine (435mg,
  • Example 5 ⁇ 4-[2-tert-Butyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -(4,5-dihydro-lH- imidazol-2-yl)-amine
  • the title compound was obtained as its HCl salt using the procedure described in example 1, except that te/t-butylamidine.HCl was used instead of cyclohexylamidine.HCl in step a.
  • the title compound was obtained as its TFA salt using the procedure described in example 1, except that 3,3,5, 5-tetramethylcyclohexylamidine.HCl was used instead of cyclohexylamidine.HCl in step a and TFA was used instead of HCl in dioxan in step e.
  • Example 11 (4,5-Dihydro-lH-imidazol-2-yl)- ⁇ 4-[2-(l-hexyl-heptyl)-6-(3-phenyl-propyl)- pyrimidin-4-yl] -phenylj-amine
  • the title compound was obtained as its HCl salt using the procedure described in example 1, except that 1-hexyl-heptylamidine.HCl was used instead of cyclohexylamidine.HCl in step a.
  • Example 13 N- ⁇ 4-[2-Cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -guanidine
  • the title compound was obtained as its HCl salt using the procedure described in example 1, except that l,3- ⁇ w('te?t-butoxycarbonyl)-2-methyl-thiopseudourea instead of N,N-bis-(tert- butoxycarbonyl)-imidazolidine-2-thione in step d.
  • the title compound was obtained as its TFA salt using the procedure described in example 1 , except that n-heptylamidine.HCl was used instead of cyclohexylamidine.HCl in step a, 1,3- ⁇ te7 ⁇ -butoxycarbonyl)-2-methyl-thiopseudourea was used instead of N,N'-bis-(tert- butoxycarbonyl)-imidazolidine-2-thione in step d and TFA was used instead of HCl in dioxan in step e.
  • the title compound was obtained as its TFA salt using the procedure described in example 1, except that cyclopentylamidine.HCl was used instead of cyclohexylamidine.HCl in step a, 1,3- ⁇ zs(W ⁇ butoxycarbonyl)-2-methyl-thiopseudourea was used instead of N,N'-bis-(tevt- butoxycarbonyl)-imidazolidine-2-thione in step d and TFA was used instead of HCl in dioxan in step e.
  • the title compound was obtained as its HCl salt using the procedure described in example 1, except that isobutylamidine.HCl was used instead of cyclohexylamidine.HCl in step a, and 1,3- 6w(?er ⁇ -butoxycarbonyl)-2-methyl-thiopseudourea was used instead of N,N-bis-(tert- butoxycarbonyl)-imidazolidine-2-thione in step d.
  • the title compound was obtained as its TFA salt using the procedure described in example 1, except that 3.3,5,5-tetramethylcyclohexylamidine.HCl was used instead of cyclohexylamidine.HCl in step a, l,3 ⁇ &zsffer£-butoxycarbonyl)-2-methyl-thiopseudourea was used instead of N,N- ⁇ -(1fe/t-butoxycarbonyl)-imidazolidme-2-thione in step d and TFA was used instead of HCl in dioxan in step e.
  • the title compound was obtained as its HCl salt using the procedure described in example 1, except that cyclododecylamidine.HCl was used instead of cyclohexylamidine.HCl in step a and l,3-£» ⁇ fte7 ⁇ -butoxycarbonyl)-2-methyl-thiopseudourea was used instead of N,N'-bis-(tert- butoxycarbonyl)-imidazolidine-2-thione in step d.
  • the title compound was obtained as its TFA salt using the procedure described in example 1 , except that 4-naphthalen-2-yl-3-oxo-butyric acid ethyl ester was used instead of 3-oxo-6- phenyl-hexanoic acid ethyl ester in step a, l,3- ⁇ zsftert-butoxycarbonyl)-2-methyl- thiopseudourea was used instead of N,N- ⁇ z5-(?e ⁇ -butoxycarbonyl)-imidazolidine-2-thione in step d and TFA was used instead of HCl in dioxan in step e.
  • Example 26 ⁇ 4-[2-Cyclohexyl-6-(3, 3, 5, 5-tetramethyl-cyclohexyloxymethyl)-pyrim.idin-4-yl]- phenyl ⁇ -(4,5-d ⁇ hydro-lH-imidazol-2-yl)-amine
  • the title compound was obtained as its HCl salt using the procedure described in example 1, except that 3-oxo-4-(3,3,5,5-tetramethyl-cyclohexyloxy)-butyric acid ethyl ester was used instead of 3-oxo-6-phenyl-hexanoic acid ethyl ester in step a.
  • the title compound was obtained as its HCl salt using the procedure described in example 1, except that 4-benzyloxy-3-oxo-butyric acid ethyl ester and 1-adamantylamidine.HCl were used instead of 3-oxo-6-phenyl-hexanoic acid ethyl ester and cyclohexylamidine.HCl respectively in step a.
  • the title compound was obtained as its HCl salt using the procedure desciibed in example 1, except that cycloheptylamidine.HCl was used instead of cyclohexylamidine.HCl in step a, 3- (4,4,5, 5,-tetramethyl-l,3,2,-dioxaborolan-2-yl)aniline was used instead of 4-(4,4,5,5- tetramethyl-l,3,2,-dioxaborolan-2-yl)aniline in step c and l,3-t ⁇ ffcrt-butoxycarbonyl)-2- methyl-thiopseudourea was used instead of N,N- ⁇ -fte/t-butoxycarbonyl)-imidazolidine-2- thione in step d.
  • Example 30 N- ⁇ 4-[2-Cyclohexyl-5-isobutyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ - guanidine
  • the title compound was obtained as its TFA salt using the procedure described in example 1, except that 2-isobutyl-3-oxo-6-phenyl-hexanoic acid ethyl ester was used instead of 3-oxo-6- phenyl-hexanoic acid ethyl ester in step a, l,3- ⁇ w( ⁇ ert-butoxycarbonyl)-2-methyl- thiopseudourea was used instead of N,N- ⁇ -(?ert-butoxycarbonyl)-imidazolidine-2-thione in step d and TFA was used instead of HCl in dioxan in step e.
  • Example 31 N- ⁇ 4-[2-Cyclohexyl ⁇ 5-isopropyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ - guanidine
  • the title compound was obtained as its TFA salt using the procedure described in example 1, except that 2-isopropyl-3-oxo-6-phenyl-hexanoic acid ethyl ester was used instead of 3-oxo-6- phenyl-hexanoic acid ethyl ester in step a, l,3-t ⁇ ffer ⁇ butoxycarbonyl)-2-methyl- thiopseudourea was used instead of N,N- ⁇ w-(?e7 ⁇ -butoxycarbonyl)-imidazolidine-2-thione in step d and TFA was used instead of HCl in dioxan in step e.
  • Example 32 N- ⁇ 4-[2-Cyclohexyl-5-(4-methyl-pentyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl] ⁇ phenylj-guanidine
  • the title compound was obtained as its HCl salt using the procedure described in example 1, except that 6-methyl-2-(4-phenyl-butyryl)-heptanoic acid ethyl ester was used instead of 3- oxo-6-phenyl-hexanoic acid ethyl ester in step a and l,3- ⁇ zs(? ⁇ 2r£-butoxycarbonyl)-2-methyl- thiopseudourea was used instead of N 1 N - ⁇ w-fte ⁇ -butoxycarbonyl)-imidazolidine-2-thione in step d.
  • Example 33 ⁇ 4-[2-Cyclohexyl-5-(2-ethoxy-ethyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ - (4,5-dihydro-lH-imidazol-2-yl)-amine
  • the title compound was obtained as its HCl salt using the procedure described in example 1, except that 2-(2-ethoxy-ethyl)-3-oxo-6-phenyl-hexanoic acid ethyl ester was used instead of 3- oxo-6-phenyl-hexanoic acid ethyl ester in step a.
  • the title compound was obtained as its TFA salt using the procedure described in example 1 , except that 2-benzyl-3-oxo-6-phenyl-hexanoic acid ethyl ester was used instead of 3-oxo-6- phenyl-hexanoic acid ethyl ester in step a and TFA was used instead of HCl in dioxan in step e.
  • Example 36 (4, 5 ⁇ Dihydro-lH-imidazol-2-yl)- ⁇ 4-[2-(l ⁇ hexyl-heptyl)-6-(3, 3, 5, 5-tetramethyl- cyclohexyl)-pyrimidin-4-yl]-phenyl ⁇ -a ⁇ nine
  • the title compound was obtained as its HCl salt using the procedure described in example 1, except that 1-hexyl-heptylamidine.HCl and 3-oxo-3-(3,3,5,5-tetramethyl-cyclohexyl)- propionic acid ethyl ester were used instead of cyclohexylamidine.HCl and 3-oxo-6-phenyl- hexanoic acid ethyl ester respectively in step a.
  • Example 37 (4, 5-Dihydro-lH-imidazol-2-yl) ⁇ 4-[2-(l-hexyl-heptyl)-5-isobutyl-6-(3, 3, 5, 5- tetramethyl-cyclohexylmethyl)-pyrimidin-4 ⁇ yl]-phenyl ⁇ -mnine
  • the title compound was obtained as its HCl salt using the procedure described in example 1, except that 1-hexyl-heptylamidine.HCl and 4-methyl-2-[2-(3,3,5,5-tetramethyl-cyclohexyi)- acetyl]-pentanoic acid ethyl ester were used instead of cyclohexylamidine.HCl and 3-oxo-6- phenyl-hexanoic acid ethyl ester respectively in step a..
  • Example 38 N'-[2-(l-Hexyl-heptyl)-6-(3-phenyl-propyl)-pyrimidin-4-ylmethylJ-N,N-dimethyl- ethane- 1, 2-diamine
  • Step a 4-[2-(l-Hexyl-heptyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-benzaldehyde was obtained using steps a-c of the procedure described in example 1, except that 1-hexyl- heptylamidine.HCl was used instead of cyclohexylamidine.HCl in step a., and 4- formyl- phenylboronic acid was used instead of 4-(4,4,5,5-tetramethyl-l,3,2,-dioxaborolan-2-yl)aniline in step c.
  • Step b 4-[2-(l-Hexyl-heptyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-benzaldehyde (388mg, lmmol), N,iV-dimethylethylenediamine (128 ⁇ L, 1.2mmol) and HOAc (172 ⁇ L, 3mmol) were stirred in DCE (5mL) and NaBH(OAc) 3 (318mg, 1.5mmol) was added. The mixture was stirred at rt for 16h, diluted with EtOAc (2OmL) and washed with saturated aqueous NaHCO 3 (3OmL).
  • Example 39 ⁇ 4-[2-(l-Hexyl-heptyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-benzyl ⁇ -(2-morpholin- 4-yl-ethyl)-amine
  • N- (2-aminoethyl)-morpholine was used instead of N,N dimethylethylenediamine in step b.
  • Example 40 N'- ⁇ 4-[2-(l-Hexyl-heptyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-benzyl ⁇ -propane- 1,3-diamine.
  • Step a (3- ⁇ 4-[2-(l-Hexyl-heptyl)-6-(3-phenyl-propyl)-pyrimidin-4 ⁇ yl]-benzylamino ⁇ -propyl)- carbamic acid tert-butyl ester was obtained using step b of example 38, except that fe/t-butyl- 7V-(3-aminopropyl)carbamate was used instead of N,N-dimethylethylenediamine.
  • Step b A solution of (3- ⁇ 4-[2-(l-hexyl-heptyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]- benzylamino ⁇ -propyl)-carbamic acid tert-butyl ester (160mg, 0.25mmol) in 4M HCl in dioxan (3mL) and MeOH (ImL) was stirred at rt for 2h. The solution was evaporated and the residue triturated with Et 2 O to afford the title compound as its HCl salt (116mg, 81%).
  • Example 41 4-[2-Cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-benzylamine Step a ⁇ 4-[2-Cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -methanol was obtained using steps a-c of example 1 except that 4-(hydroxymethyl)-phenylboronic acid was used instead of 4-(4,4,5,5-tetramethyl-l,3,2,-dioxaborolan-2-yl)aniline in step c.
  • Step c A solution of 2- ⁇ 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-benzyl ⁇ -isoindole-l,3- dione (783mg, 1.52mmol), and hydrazine hydrate (380 ⁇ L, 7.6mmol) in EtOH (1OmL) was refluxed for 2h. On cooling the white precipitate was removed by filtration and the filtrate was evaporated. The residue obtained was suspended partitioned H 2 O-DCM (2:3 / 5OmL). The organic layer was separated and dried (MgSO 4 ). Filtration and evaporation of the solvent afforded the product (445mg, 73%).
  • Example 43 (lH-Imidazol-2-ylmethyl)- ⁇ 4 ⁇ [2-(l-methyl-octyl)-6-(3-phenyl-propyl)-pyrimidin- 4-yl] -phenyl ⁇ -amine
  • Step a 4-[2-(l-Methyl-octyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine was obtained using steps a-c of example 1, except that 1-methyl-octylamidine.HCl was used instead of cyclohexylamidine.HCl in step a.
  • Step b (l-Trityl-lH-imidazol-2-ylmethyl)- ⁇ 4-[2-(l-methyl-octyl)-6-(3-phenyl-propyl)- pyrimidin-4-yl] -phenyl ⁇ -amine
  • Step c A solution of (l-trityl-lH-imidazol-2-ylmethyl)- ⁇ 4-[2-(l-methyl-octyl)-6-(3-phenyl- propyl)-pyrimidin-4-yl]-phenyl ⁇ -amine (315mg, 0.435mmol) in TFA (3mL) was stirred at rt for 2h. The solution was evaporated and the residue suspended in EtOAc-saturated NaHCO 3 (2:1 / 3OmL). The organic layer was separated, dried (MgSO 4 ), filtered and the solvent evaporated. The residue was purified by chomatography (DCM-MeOH (9:1)) to afford the title compound (160mg, 75%).
  • Example 44 (4, 5-Dihydro-lH-imidazol-2-ylmethyl)- ⁇ 4-[2-isobutyl-6-(3-phenyl-propyl)- pyrimidin-4-yl] -phenyl ⁇ -amine.
  • Step a 4-[2-(2-methyl-propyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine was obtained using steps a-c of example 1, except that 2-methyl-propylamidine.HCl was used instead of cyclqhexylamidine.HCl in step a.
  • Step b The title compound was obtained using steps b and c of example 43, except that 4-[2- (2-methyl-propyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine was used in step b instead 4-[2-(l-methyl-octyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine.
  • Step a 4-[2-cyclopentyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine was obtained using steps a-c of example 1, except that cyclopentylamidine.HCl was used instead of cyclohexylamidine.HCl in step a.
  • Step b The title compound was obtained using steps b and c of example 43, except that 4-[2- cyclopentyl-6-(3-phenyl- ⁇ ropyl)-pyrimidin-4-yl]-phenylamine was used in step b instead 4-[2- (l-methyl-octyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine.
  • Example 46 N- ⁇ 4-[2-Cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yloxy) ' -phenyl) -guanidine Step a 2-Cyclohexyl-4-(4-nitro-phenoxy)-6-(3-phenyl-propyl)-pyrimidine
  • Step c The title compound was obtained as its TFA salt using steps d and e of example 1, except that 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yloxy]-phenylamine and 1,3- t ⁇ (?ert-butoxycarbonyl)-2-methyl-thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3- phenyl-propyl)-pyrimidin-4-yl]-phenylamine and N.N- ⁇ z.s-fte/t-butoxycarbonyl)- imidazolidine-2-thione respectively in step d and TFA was used instead of HCl in dioxan in step e.
  • the title compound was obtained as its HCl salt using steps d and e of example 1, except that 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yloxy]-phenylamine was used instead of 4- [2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine in step d.
  • Example 48 N- ⁇ 3-[2-Cyclohexyl-6-(3-phenyl-propyl)-pyrhnidin-4-yloxy]-phenyl ⁇ -guanidine Step a 3-[2-Cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yloxy]-phenylamine was obtained using steps a and b of example 46, except that 3-nitrophenol was used instead of 4-nitrophenol in step a.
  • Step b The title compound was obtained as its HCl salt using steps d and e of example 1, except that 3-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yloxy]-phenylamine and 1,3- ⁇ (? ⁇ rt-butoxycarbonyl)-2-methyl-thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3- phenyl-propyl)-pyrimidin-4-yl]-phenylamine and N,N-t ⁇ -(fer£-butoxycarbonyi) ⁇ imidazolidine-2-thione respectively in step d.
  • Step a 4-Chloro-6-cyclohexyl-2-(4-nitro-phenyl)-pyrimidine was obtained using steps a and b of example 1, except that 3-cyclohexyl-3-oxo-propionic acid ethyl ester and 4- nitrophenylamidine.HCl were used instead of 3-oxo-6-phenyl-hexanoic acid ethyl ester and cyclohexylamidine.HCl respectively in step a.
  • Step c 4-(4-Cyclohexyl ⁇ 6-phenethyloxy-pyrimidin-2-yl)-phenylamine was obtained using step b of example 46, except that 4-cyclohexyl-2-(4-nitro-phenyl)-6-phenethyloxy-pyrimidine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3-phenyl-propyl)-pyrimidine.
  • Step d The title compound was obtained as its HCl salt using steps d and e of example 1, except that 4-(4-cyclohexyl-6-phenethyloxy-pyrimidin-2-yl)-phenylamine was used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine in step d.
  • the title compound was obtained as its HCl salt using the procedure described in example 1, except that 4-hexyl-3-oxo-decanoic acid ethyl ester and 4-phenylbutyl amidine.HCl were used instead of 3-oxo-6-phenyl-hexanoic acid ethyl ester cyclohexylamidine.HCl repectively in step a.
  • Step b The title compound was obtained as its HCl salt using step e of example 1 except that N-te7 ⁇ -butoxycarbonyl-2-amino-N- ⁇ 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]- phenyl ⁇ -acetamide was used in place of i ⁇ N- ⁇ w-(ter ⁇ -butoxycarbonyl)- ⁇ 4-[2-cyclohexyl-6-(3- phenyl-propyl)-pyrimidm-4-yl]-phenyl ⁇ -(4,5-dihydro-lH-imidazol-2yl)-amine.
  • step e of example 1 The title compound was obtained as its HCl salt using step a of example 51, except that 4-[2- adamantan-l-yl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine (example 2, step c) and N- valine were used instead of 4-[2-cyclohexyl-6-(3 ⁇ phenyl-propyl)- pyrimidin-4-yl]-phenylamine and JV-fer£-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N- ⁇ > ⁇ -(tert-butoxycarbonyl)- ⁇ 4-[2-cyclohexyl- 6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -(4,5-dihydro-lH-imidazol-2yl)-amine, according to step e of example 1.
  • the title compound was obtained as its HCl salt using step a of example 51, except that 4-[2- cyclopentyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine (example 4 step c) and N-tert- butoxycarbonyl valine were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4- yl]-phenylamine and /V-te/t-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of 7V,N- ⁇ w-(te7 ⁇ -butoxycarbonyl)- ⁇ 4-[2-cyclohexyl-6-(3-phenyl- propyl)-pyrimidin-4-yl]-phenyl ⁇ -(4,5-dihydro-lH-imidazol-2yl)-amine, according to step e of example 1.
  • the title compound was obtained as its HCl salt using step a of example 51, except that N,N- ⁇ -tert-butoxycarbonyl-guanidino-propionic acid was used instead of N-tert-butoxycarbonyl glycine, followed by reaction of the product obtained, in place of 7 ⁇ N- ⁇ z ⁇ -(ter ⁇ - butoxycarbonyl)- ⁇ 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -(4,5-dihydro- lH-imidazol-2yl)-amine, according to step e of example 1.
  • Step a 4-Chloro-2-(3-nitrophenyl)-(3-phenyl-propyl)-pyrimidine was obtained using steps a and b of example 1 except that 3-nitrophenyl amidine.HCl was used instead of cyclohexylamidine.HCl in step a.
  • Step b 4-[2-(3-Nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine was obtained using c of example 1 except that 4-chloro-2-(3-nitrophenyl)-(3-phenyl-propyl)-pyrimidine was used instead of 4-chloro-2-cyclohexyl-(3-phenyl-propyl)-pyrimidine.
  • Step c N ⁇ N''-bis-tef-t-Butoxycarbonyl-N- ⁇ 4-[2-(3-nitro-phefiyl)-6-(3-phenyl-propyl)-py7"imidin- 4-yl] -phenyl ⁇ -guanidine was obtained using step d of example 1 except that 4-[2-(3-nitro- phenyl)-6-(3-phenyl-propyl)-pyiimidin-4-yl]-phenylamine and 1 ,3- ⁇ z,s(fert-butoxycarbonyl)-2- methyl-thiopseudourea were used instead of 4-[2-cyclohexyl-6 ⁇ (3-phenyl-propyl)-pyrimidin-4- yl]-phenylamine and N,7y- ⁇ z5-( ⁇ ert-butoxycarbonyl)-imidazolidine-2-thione respectively.
  • Step d N',N"-bis-tert-Butoxycarbonyl-N- ⁇ 4-[2-(3-amino-phenyl)-6-(3-phenyl-propyl)- pyrimidin-4-yl] -phenyl ⁇ -guanidine was obtained using step b of example 46 except that N',N"- bis-tert-butoxycarbonyl-N- ⁇ 4-[2-(3-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]- phenyl ⁇ -guanidine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6 ⁇ (3-phenyl-propyl)- pyrimidine.
  • Step e N',N"-bis-tert-butoxycarbonyl-2-tert-butoxycarbonylamino-N- ⁇ 3-[4-(4-guanidino- phenyl) -6-(3-phenyl-propyl)-pyrimidin-2-yl]-phenyl ⁇ -acetamide was obtained using step a of example 51 except that 7Y'iV / -bis-tert-butoxycarbonyl-N- ⁇ 4-[2-(3-amino-phenyl)-6-(3-phenyl- propyl)-pyrimidin-4-yl]-phenyl ⁇ -guanidine was used instead of 4 ⁇ [2-cyclohexyl-6-(3-phenyl- propyl)-pyrimidin-4-yl]-phenylamine.
  • Step f The title compound was obtained as its TFA salt using step e of example 1, except that iV'N / -Z?zj-fer ⁇ -butoxycarbonyl-2-ter ⁇ -butoxycarbonylamino-N- ⁇ 3-[4-(4-guanidino-phenyl)-6- (3-phenyl-propyl)-pyrimidin-2-yl]-phenyl ⁇ -acetamide and TFA were used instead of ⁇ iV- ⁇ - (ter?-butoxycarbonyl)- ⁇ 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -(4,5- dihydro-lH-imidazol-2yl)-amine and HCl in dioxan respectively.
  • Step a N',N"-bis-tert-Butoxycarbonyl-3-tert-butoxycarbonylamino-N- ⁇ 3-[4-(4-guanidino- phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]-phenyl ⁇ -propionmnide was obtained using step a of example 51 except that N'N / -& ⁇ -?ert-butoxycarbonyl-iV- ⁇ 4-[2-(3-ammo-phenyl)-6-(3- phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -guanidine (example 56, step d) and 3-tert- butoxycarbonylamino-propionic acid were used instead of 4-[2-cyclohexyl-6-(3-phenyl- propyl)-pyrimidin-4-yl]-phenylamine and N-fert-butoxycarbonyl glycine respectively.
  • Step b The title compound was obtained as its TFA salt using e of example 1, except that iV'N'- ⁇ -ter ⁇ -butoxycarbonyl-3-tert-butoxycarbonylamino-N- ⁇ 3-[4-(4-guanidino-phenyl)-6- (3-phenyl-pro ⁇ yl)-pyrimidin-2-yl]-phenyl ⁇ -propionamide and TFA were used instead of N 1 N'- ⁇ w-(tert-butoxycarbonyl)- ⁇ 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -(4,5- dihydro-lH-imidazol-2yl)-amine and HCl in dioxan respectively.
  • Step a 2-tert-Butoxycarbonylamino-N- ⁇ 4-[2-(3-nitro-phenyl)-6-(3-phenyl-propyl)-py ⁇ midin-4- ylj-phenyl ⁇ -acetamide was obtained using step d of example 51, except that 4-[2-(3-nitro- phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine (example 56, step b) was used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine.
  • Step b 2-tert-Butoxycarbonylamino-N- ⁇ 4-[2-(3-arnino-phenyl)-6-(3-phenyl-propyl)-pyrimidin- 4-yl] -phenyl ⁇ -acetamide was obtained using step b of example 46, except that 2-tert- butoxycarbonylamino-iV- ⁇ 4-[2-(3-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ - acetamide was used instead of 2-cyclohexyl ⁇ 4-(4-nitro-phenoxy)-6-(3-phenyl-propyl) ⁇ pyrimidine.
  • Step c 3-tert-Butoxycarbonylamino-N- ⁇ 3-[4-[4 ⁇ (2-tert ⁇ butoocycarbonylamino-acetylamino)- phenyl]-6-(3-phenyl-propyl)-pyrimidin-2-yl]-phenyl ⁇ propionamide was obtained using step d of example 51, except that 2-tert-butoxycarbonylammo-N- ⁇ 4-[2-(3-amino-phenyl)-6-(3- phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -acetamide and 3-tert-butoxycarbonylamino-propionic acid were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and JV-fert-butoxycarbonyl glycine respectively.
  • Step d The title compound was obtained as its HCl salt using step e of example 1 except that 3-ter ⁇ -butoxycarbonylamino-N- ⁇ 3-[4-[4-(2-tert-butoxycarbonylamino-acetylamino)-phenyl]-6- (3-phenyl-propyl)-pyrimidin-2-yl]-phenyl ⁇ propionamide was used in place of N,N'-bis-(tert- butoxycarbonyl)- ⁇ 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -(4,5-dihydro- lH-imidazol-2yl)-amine.
  • Step b 3-tert-Biitoxycarbonylamino-N- ⁇ 4-[2-(3-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4- ylj-phenylj-propion ⁇ nide was obtained using step d of example 51, except that 3-[2-(3-nitro- phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and 3-fert-butoxycarbonylamino- propionic acid were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]- phenylamine and N-fe/t-butoxycarbonyl glycine respectively.
  • Step c 3-tert-Butoxycarbo7iylamino-N- ⁇ 4-[2-(3-amino-phenyl)-6-(3-phenyl-propyl)-pyrimidin- 4-yl] -phenylj-propionamide was obtained using step b of example 46, except that 3-tert- butoxycarbonylamino-iV- ⁇ 4-[2-(3-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ - propionamide was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3-phenyl-propyl)- pyrimidine.
  • Step d N',N"-bis-tert-Butoxycarbonyl-N- ⁇ 3-[4-[3-(3-tert-butoxycarbonylamino- propionylamino)-phenyl]-6-(3-phenyl-propyl)-pyrimidm ⁇ 2-yl]-phenyl ⁇ -3-guanidino- propionamide was obtained using step d of example 51, except that 3-ter ⁇ - butoxycarbonylamino-iV- ⁇ 3-[2-(3-ammo-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]- phenyl ⁇ -propionamide and N,N- ⁇ -te ⁇ butoxycarbonyl-3-guanidino-propionic acid were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and N-tert- butoxycarbonyl glycine respectively.
  • Step e The title compound was obtained as its TFA salt using step e of example 1, except that 7V'N'- ⁇ w-tert-butoxycarbonyl-N- ⁇ 3-[4-[3-(3-tert-butoxycarbonylamino-propionylamino)- phenyl]-6-(3-phenyl-propyl)- ⁇ yrimidin-2-yl]-phenyl ⁇ -3-guanidino-propionamide and TFA were used instead of N,N- ⁇ z5-(t ⁇ 'f-butoxycarbonyl)- ⁇ 4-[2-cyclohexyl-6-(3-phenyl-propyl)- ⁇ yrimidin-4-yl]-phenyl ⁇ -(4,5-dihydro-lH-imidazol-2yl)-amine and HCl in dioxan respectively.
  • Step a N',N"-bis-tert-Butoxycarbonyl-N- ⁇ 3-[2-(3-nitro-phenyl)-6-(3 ⁇ phenyl-propyl)-pyrimidin- 4-ylj '-phenylJ-3-guanidino propionamide was obtained using step d of example 51, except that 3-[2-(3-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and (example 59, step a) and N,N-£zs-fe ⁇ butoxycarbonyl ⁇ 3-guamdino-propiomc acid were used instead of 4-[2- cyclohexyl-6-(3 -phenyl-propyl)-pyrimidin-4-yl]-phenylamine and iV-te/t-butoxycarbonyl glycine respectively.
  • Step b N',N f '-bis-tert-Butoxycarbonyl-N- ⁇ 3-[2-(3-amino-phenyl)-6-(3-phenyl-propyl)- pyrimidin-4-yl] -phenyl) -3-guanidino propionamide was obtained using step b of example 46, except that N'N'- ⁇ w-ter ⁇ -butoxycarbonyl- ⁇ - ⁇ 3-[2-(3-nitro-phenyl)-6-(3-phenyl-propyl)- pyrimidin-4-yl] -phenyl ⁇ -3-guanidino propionamide was used instead of 2-cyclohexyl-4-(4- nitro-phenoxy)-6-(3-phenyl-propyl)-pyrimidine.
  • Step c N',N"-bis-tert-Butoxycarbonyl-N- ⁇ 3-[2-[3-(3-tert-butoxycarbonylamino- propionylamino)-phenyl]-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -3-guanidino- propionamide was obtained using step d of example 51, except that N'N'- ⁇ w-tert- butoxycarbonyl-iV- ⁇ 3-[2-(3-amino-phenyl)-6-(3-phenyl-propyl)-pyrimidm-4-yl]-phenyl ⁇ -3- guanidino propionamide and 3-ter ⁇ -butoxycarbonylamino-propionic acid were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and iV-fert-butoxycarbonyl glycine respectively
  • Step d The title compound was obtained as its TFA salt using e of example 1, except that N r 'N'-ow-?e ⁇ -butoxycarbonyl-N- ⁇ 3-[2-[3-(3-tert-butoxycarbonylamino-propionylamino)- phenyl]-6-(3-phenyl-pro ⁇ yl)-pyrimidin-4-yl]-phenyl ⁇ -3-guanidino-propionamide and TFA were used instead of N,N- ⁇ -(tert-butoxycarbonyl)- ⁇ 4-[2-cyclohexyl-6-(3-phenyl-propyl)- pyrimidin-4-yl]- ⁇ henyl ⁇ -(4,5-dihydro-lH-imidazol-2yl)-amine and HCl in dioxan respectively.
  • Step a 4-Chloro-6-(3-methyl-butyl)-2-(3-nitro-phenyl)-pyrimidine was obtained using steps a and b of example 1 except that 6-methyl-3-oxo ⁇ heptanoic acid ethyl ester and 3- nitrophenylamidine HCl were used in place of 3-oxo-6-phenyl-hexanoic acid ethyl ester and cyclohexylamidine.HCl respectively in step a.
  • Step c [2-(3-Amino-phenyl)-6-(3-methyl-butyl)-pyrimidin-4-yl]-phenethyl-amine was obtained using step b of example 46, except that [6-(3-methyl-butyl)-2-(3-nitro-phenyl)-pyrimidin-4-yl]- phenethyl-amine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3-phenyl-propyl)- pyrimidine.
  • Step d The title compound was obtained as its HCl salt using steps d and e of example 1 except that [2-(3-amino-phenyl)-6-(3-methyl-butyl)-pyrimidin-4-yl]- ⁇ henethyl-amine and 1,3- 6z5(1fe ⁇ -butoxycarbonyl)-2-methyl-thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3- phenyl-propyl)-pyrimidin-4-yl]-phenylamine and N,N'-bis-(tertAmtoxycdxh(my ⁇ )- imidazolidine-2-thione respectively.
  • Example 63 3-Amino-N- ⁇ 3-[4-(3-guanidino-phenyl)-6-(3-methyl-butyl)-pyrimidin-2-yl]- phenylj-propionamide.
  • Step a 4-[2-(3-Nitro-phenyl)-6-(3-methyl-butyl)-pyrimidin-4-yl] ⁇ phenylamme was obtained using steps a-c of example 1 except that 6-methyl-3-oxo-heptanoic acid ethyl ester and 3- nitrophenyl amidine.HCl were used instead of 3-oxo-6-phenyl-hexanoic acid ethyl ester and cyclohexylamidine.HCl respectively in step a and 3-(4,4,5,5-tetramethyl-l,3,2,dioxaborolan-2- yl)aniline was used instead of 4-(4,4,5,5-tetramethyl-l,3,2,-dioxa
  • Step b N',N''-bis-tert-Butoxycarbonyl-N- ⁇ 4-[2-(3 ⁇ nitr-o-phenyl)-6-(3-methyl-butyl)-pyrimidin- 4-yl]-phenyl ⁇ -guanidine was obtained using step d of example 1 except that 4-[2-(3-nitro- phenyl)-6-(3-methyl-butyl)-pyrimidin-4-yl]-phenylamine and l,3-Z?z5(?er ⁇ -butoxycarbonyl)-2- methyl-thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4- yl]-phenylamine and N,N- ⁇ z5-(?ert-butoxycarbonyl)-imidazolidine-2-thione respectively.
  • Step c N',N''-bis-tert-Butoxycarbonyl-N- ⁇ 4-[2-(3-amino-phenyl)-6-(3-methyl-butyl)-pyrimidin- 4-yl] -phenyl) -guanidine was obtained using step b of example 46 except that N'N'- ⁇ -ter?- butoxycarbonyl-N- ⁇ 4-[2-(3-nitro-phenyl)-6-(3-methyl-butyl)-pyrimidin-4-yl]-phenyl ⁇ - guanidine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3-phenyl-propyl)- pyrimidine.
  • Step d N',N"-bis-tert-Butoxycarbonyl-3-tert-butoxycarbonylammo-N- ⁇ 3-[4-(4-guanidino- phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-ylJ-phenyl ⁇ -propionamide was obtained using step a of example 51 except that N'N'- ⁇ -tert-butoxycarbonyl-N- ⁇ 4-[2-(3-amino-phenyl)-6-(3- methyl-butyl)-pyrimidin-4-yl]-phenyl ⁇ -guanidine and 3-f ⁇ rt-butoxycarbonylamino-propionic acid were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and N-tert-butoxycarbonyl glycine respectively.
  • the title compound was obtained as its TFA salt using step e of example 1, except that TV'N'- &/5-te7t-butoxycarbonyl-3-tert-butoxycarbonylamino-iV- ⁇ 3-[4-(4-guanidino-phenyl)-6-(3- phenyl-propyl)-pyrimidin-2-yl]-phenyl ⁇ -propionamide and TFA were used instead of N,N'-bis- dihydro-lH-imidazol-2yl)-amine and HCl in dioxan respectively.
  • Step a 4-(3-Methyl-butyl)-2-(3-nitro-phenyl)-6-phenethyloxy-pyrimidine was obtained using step b of example 49 except that 4-chloro-6-(3-methyl-butyl)-2-(3-nitro-phenyl)-pyrimidine (example 61 step a) was used instead of 4-chloro-6-cyclohexyl-2-(4-nitro-phenyl)-pyrimidine.
  • Step b 3-[4-(3-Methyl-butyl)-6-phenethyloxy-primidin-2-yl]-phenylamine was obtained using step b of example 46, except that 4-(3-methyl-butyl)-2-(3-nitro ⁇ phenyl)-6-phenethyloxy- pyrimidine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3-phenyl-propyl)- pyrimidine.
  • Step c The title compound was obtained as its HCl salt using step a of example 51, except that 3-[4-(3-methyl-butyl)-6-phenethyloxy-primidin-2-yl]-phenylamine and N.N'-bis-tert- butoxycarbonyl-guanidino-propionic acid were used instead of 4-[2-cyclohexyl-6-(3-phenyl- propyl)-pyrimidin-4-yl]-phenylamine and N-tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-b ⁇ toxycs ⁇ onyl)- ⁇ 4-[2- cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -(4,5-dihydro-lH-imidazol-2yl)- amine, according to step e of example 1.
  • Step a [6-(3-Phenyl-propyl)-2-(3-nitro-phenyl)-pyrimidin-4-yl]-phenethyl-amine was obtained using step b of example 61 except that 4-chloro-2-(3-nitrophenyl)-(3-phenyl-propyl)- pyrimidine (example 56, step a) was used in place of 4-chloro-6-(3-methyl-butyl)-2-(3-nitro- phenyl)-pyrimidine.
  • Step b [2-(3-Amino-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenethyl-amine was obtained using step b of example 46, except that [6-(3-phenyl-propyl)-2-(3-nitro-phenyl)- pyrimidin-4-yl]-phenethyl-amine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3- phenyl-propyl)-pyrimidine.
  • the title compound was obtained as its HCl salt using steps d and e of example 1 except that [2-(3-amino-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenethyl-amine and 1 ,3-bi$(tert- butoxycarbonyl)-2-methyl-thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3-phenyl- propyl)-pyrimidin-4-yl]-phenylamine and N,N-t ⁇ -ffer ⁇ butoxycarbonyl)-imidazolidine-2- thione respectively.
  • Step a 4-(2-Cyclohexyl-ethoxy-2-(3-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine was obtained using step b of example 49 except that 4-chloro-2-(3-nitrophenyl)-(3-phenyl-propyl)- pyrimidine (example 56, step a) and 2-cyclohexylethanol were used instead of 4-chloro-6- cyclohexyl-2-(4-nitro-phenyl)-pyrimidine and 2-phenethylalcohol respectively.
  • Step b 3-[4-(2-Cyclohexyl-ethoxy)-6-(3-phenyl-propyl)-prii7iidin-2-ylJ-phenylamine was obtained using step b of example 46, except that 4-(2-cyclohexylethoxy-2-(3-nitro-phenyl)-6- (3-phenyl-propyl)-pyrimidine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3- phenyl-propyl)-pyrimidine.
  • Step c N',N''-bis-tert-buto3cycarbonyl-N- ⁇ 3-[4-(2-cycloheyyl-ethoxy)-6-(3-phenyl-propyl)- pyrimidin-2-ylJ-phenyl ⁇ -propionamide was obtained using step a of example 51, except that 3- [4-(2-cyclohexyl-ethoxy)-6-(3-phenyl-propyl)-primidin-2-yl]-phenylamine and N,N'-bis-tert- butoxycarbonyl-guanidino-propionic acid were used instead of 4-[2-cyclohexyl-6 ⁇ (3-phenyl- propyl)-pyrimidin-4-yl]-phenylamine and N-tert-butoxycarbonyl glycine respectively.
  • Step d The title compound was obtained as its TFA salt using step e of example 1 except that N'iV'- ⁇ -tert-butoxycarbonyl-iV ; - ⁇ 3-[4-(2-cyclohexyl-ethoxy)-6-(3-phenyl-propyl)-pyrimidm- 2-yl]-phenyl ⁇ -propionamide and TFA were used in place of N,N - ⁇ w-(ter ⁇ -butoxycarbonyl)- ⁇ 4- [2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -(4,5-dihydro-lH-imidazol-2yl)- amine and HCl in dioxan respectively.
  • Step a 4-Phenethyloxy-2-(3-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine was obtained using step b of example 49 except that 4-chloro-2-(3-nitrophenyl)-(3-phenyl-propyl)-pyrimidine (example 56, step a) was used instead of 4-chloro-6-cyclohexyl-2-(4-nitiO-phenyl)-pyrimidine.
  • Step b 3-[4-Phenethyloxy-6-(3-phenyl-propyl)-primidin-2-yl]-phenylamine was obtained using step b of example 46, except that 4-phenethyloxy-2-(3-nitro-phenyl)-6-(3-phenyl-propyl)- pyrimidine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3-phenyl-propyl)- pyrimidine.
  • Step c N',N"-bis-tert-butoxycarbonyl-N- ⁇ 3-[4-phenethyloxy-6-(3-phenyl-propyl)-pyrimidin-2- yl]-phenyl ⁇ -propionamide was obtained using step a of example 51, except that 3-[4- phenethyloxy-6-(3 -phenyl-propyl)-primidin-2-yl]-phenylamine and N,N'-bis-tert- butoxycarbonyl-guanidino-propionic acid were used instead of 4-[2-cyclohexyl-6-(3-phenyl- propyl)-pyrimidin-4-yl]-phenylamine and N-ter ⁇ -butoxycarbonyl glycine respectively.
  • Step d The title compound was obtained as its TFA salt using step e of example 1 except that N'N'- ⁇ w-tert-butoxycarbonyl-N- ⁇ 3-[4-phenethyloxy-6-(3-phenyl-piOpyl)-pyiimidin-2-yl]- phenyl ⁇ -propionamide and TFA were used in place of N,N- ⁇ >z,s-(fert-butoxycarbonyl)- ⁇ 4-[2- cyclohexyl-6-(3-phenyl-propyl)- ⁇ yrimidin-4-yl]-phenyl ⁇ -(4,5-dihydro-lH-imidazol-2yl)- amine and HCl in dioxan respectively.
  • Step a 4-Chloro-2-(4-nitrophenyl)-(3-phenyl-propyl)-pyrimidine was obtained using steps a and b of example 1 except that 4-nitrophenyl amidine.HCl was used instead of cyclohexylamidine.HCl in step a.
  • Step b [6-(3-Phenyl-propyl)-2-(4-nitro-phenyl)-pyrimidin-4-yl]-phenethyl-amine was obtained using step b of example 61 except that 4-chloro-2-(4-nitrophenyl)-(3-phenyl-propyl)- pyrimidine was used in place of 4-chloro-6-(3-methyl-butyl)-2-(3-nitro-phenyl)-pyrimidine.
  • Step c [2-(4-Amino-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenethyl-amine was obtained using step b of example 46, except that [6-(3-phenyl-propyl)-2-(4-nitro-phenyl)- pyrimidin-4-yl]-phenethyl-amine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3- phenyl-propyl)-pyrimidine.
  • Step d The title compound was obtained as its HCl salt using steps d and e of example 1 except that [2-(4-amino-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenethyl-amine and 1,3- ⁇ ftert-butoxycarbonyl)-2-methyl-thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3- phenyl-propyl)-pyrimidin-4-yl]-phenylamine and N,JV-t ⁇ -(?er£-butoxycarbonyl)- imidazolidine-2-thione respectively.
  • Step a 4-Phenethyloxy-2-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine was obtained using step b of example 49 except 4-chloro-2-(4-nitrophenyl)-(3-phenyl-propyl)-pyrimidine (example 68, step a) was used instead of 4-chloro-6-cyclohexyl-2-(4-nitro-phenyl)-pyrimidine.
  • Step b 4-[4-Phenethyloxy-6-(3-phenyl-propyl)-primidin-2-yl]-phenylamine was obtained using step b of example 46, except that 4-phenethyloxy-2-(4-nitro-phenyl)-6-(3-phenyl-pro ⁇ yl)- pyrimidine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3-phenyl-propyl)- pyrimidine.
  • Step c The title compound was obtained as its HCl salt using steps d and e of example 1 except that 4-[4-phenethyloxy-6-(3-phenyl-propyl)-primidin-2-yl]-phenylamine and l,3-bis(tert- butoxycarbonyl)-2-methyl-thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3-phenyl- propyl)-pyrimidin-4-yl]-phenylamine and N,N-t ⁇ -(?er ⁇ butoxycarbonyl)-imidazolidine-2- thione respectively.
  • Example 70 3-Guanidino-N- ⁇ 4-[4-phenethyloxy-6-(3-phenyl-propyl)-pyrimidin-2-yl] -phenyl ⁇ - propionamide
  • the title compound was obtained as its HCl salt using step a of example 51, except that 4-[4- phenethyloxy-6-(3-phenyl-propyl)-primidin-2-yl]-phenylamine (example 69, step b) and N,N'- ⁇ 5-te7t-butoxycarbonyl-guanidino-propionic acid were used instead of 4-[2-cyclohexyl-6-(3- phenyl-propyl)-pyrimidin-4-yl]-phenylamine and iV-tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-&zs-(fe7t-butoxycarbonyl)- ⁇ 4-[2-
  • 3-Oxo-6-phenyl-hexanoic acid ethyl ester (2.18g, 9.3mmol) and 2-methyl-2-thiopseudourea sulfate (2.6g, 9.3mmol) were added to an aqueous NaOH solution (0.4g in 3mL).
  • the reaction mixture was stirred for 48h at rt and the white suspension obtained acidified carefully to pH A- 5 with dilute HCl.
  • the mixture was extracted with DCM (3 x 2OmL) and extracts washed with H 2 O (5OmL) and dried (MgSO 4 ).
  • Step b 2-Methylsulfanyl-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine was obtained using steps b and c of example 1 except that 2-methylsulfanyl-6-(3-phenyl-propyl)-pyrimidin-4-ol was used instead of 2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-ol in step b and 4,4,5,5- tetramethyl-2-(4-nitro-phenyl)-[l,3,2]dioxaborolane was used instead of 4-(4,4,5,5- tetramethyl-l,3,2,-dioxaborolan-2-yl)aniline in step c.
  • Step Q 4-[2-Morpholin-4-yl-6-(3-phenyl-propyl)-py ⁇ midin-4-yl]-phenylamine
  • 4-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]-moipholine 0.2Og, 0.50mmol
  • EtOAc 2OmL
  • Sn(II)Cl 2 -H 2 O 0.57g, 2.5mmol
  • Step f The title compound was obtained as its HCl salt using steps d and e of example 1 except that 4-[2-mo ⁇ holin-4-yl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and was used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine.
  • 1 HNMR (d 6 DMSO) 8.18 (2H, d), 7.36-7.13 (8H, m), 3.77 (4H, s), 3.55 (6H, s), 3.25 (2H, s), 2.64 (4H, t), 1.99 (2H, quintet).
  • Example 72 N- ⁇ 4-[6-(3-Phenyl-propyl)-2-piperidin-l-yl-pyrimidin-4-yl]-phenyl ⁇ -guanidine Step a 4-[2-Piperidin-l-yl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine was obtained using steps d and e of example 71 except that piperidine was used instead of morpholine in step d.
  • Step b N',N"-bis-tert-Butoxycarbonyl-N- ⁇ 4-[2-piperidin-l-yl-6-(3-phenyl-propyl)-pyrimidin-4- yl] -phenyl ⁇ -guanidine was obtained using step d of example 1 except that 4-[2-piperidin-l-yl- 6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and l,3- ⁇ fte7 ⁇ -butoxycarbonyl)-2-methyl- thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]- phenylamine and N, N - ⁇ -(?e7 ⁇ -butoxycarbonyl)-imidazolidine-2-thione respectively.
  • Step c The title compound was obtained as its TFA salt using step e of example 1, except that N'N'-to-fer ⁇ -butoxycarbonyl-N- ⁇ 4-[2-piperidin- 1 -yl-6-(3-phenyl-propyl)-pyrimidin-4-yl]- phenyl ⁇ -guanidine and TFA were used instead of N,JV'-&z,s-(ter£-butoxycarbonyl)- ⁇ 4-[2- cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -(4,5-dihydro- 1 H-imidazol-2yl)- amine and HCl in dioxan respectively.
  • the title compound was obtained as its HCl salt using steps d and e of example 71 except that iV-methylhexylamine was used instead of morpholine in step d, followed by reaction of the product obtained instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine, according to steps d and e of example 1.
  • the title compound was obtained as its HCl salt using steps d and e of example 71 except that dihexylamine was used instead of morpholine in step d, followed by reaction of the product obtained instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidm-4-yl]-phenylamine, according to steps d and e of example 1.
  • Step a 2-Hexyloxy-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine was obtained using step b of example 49 except 2-methanesulfonyl-4-(4-nitro-phenyl) T 6-(3-phenyl-propyl)-pyrimidine (example 71, step d) and hexylalcohol were used instead of 4-chloro-6-cyclohexyl-2-(4-nitro- phenyl)-pyrimidine and 2-phenethylalcohol respectively.
  • Step b 4-[2-Hexyloxy-6 ⁇ (3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine was obtained using step e of example 71 except that 2-hexyloxy-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)- pyrimidine was used instead of 4-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]- morpholine.
  • Step c The title compound was obtained as its HCl salt using steps d and e of example 1 except that 4-[2-hexyloxy-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and was used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine.
  • Example 76 ⁇ 4-[2-(2-Cyclohexyl-ethoxy)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -(4, 5- dihydro-lH-imidazol-2-yl)-amine
  • Step a 2-(2-Cyclohexyl-ethoxy)-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine was obtained using step b of example 49 except 2-methanesulfonyl-4-(4-nitro-phenyl)-6-(3-phenyl- propyl)-pyrimidine (example 71, step d) and 2-cyclohexylethanol were used instead of 4- chloro-6-cyclohexyl-2-(4-nitro-phenyl)-pyi-imidine and 2-phenethylalcohol respectively.
  • Step b 4-[2-(2 ⁇ Cyclohexyl-ethoxy)-6 ⁇ (3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine was obtained using step e of example 71 except that 2-(2-cyclohexyl-ethoxy ) -4-(4-nitro-phenyl)-6- (3-phenyl-propyl)-pyrimidine was used instead of 4-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)- pyrimidin-2-yl]-morpholine.
  • Step c The title compound was obtained as its HCl salt using steps d and e of example 1 except that 4-[2-(2-cyclohexyl-ethoxy)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and was used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine.
  • the title compound was obtained as its HCl salt using steps d and e of example 71 except that 2-(methylamino)ethanol was used instead of morpholine in step d, followed by reaction of the product obtained instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine, according to steps d and e of example 1.
  • the title compound was obtained as its HCl salt using steps d and e of example 71 except that 3-ethoxy-propylamine was used instead of morpholine in step d, followed by reaction of the product obtained instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine, according to steps d and e of example 1.
  • Example 79 (4, 5-Dihydro-lH-imidazol-2-yl)- ⁇ 4-[2-(2-ethoxy-ethoxy)-6-(3-phenyl-propyl)- pyrimidin-4-yl] -phenyl ⁇ -amine
  • Step a 2-(2-Ethoxy-ethoxy)-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine was obtained using step b of example 49 except 2-methanesulfonyl-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)- pyrimidine (example 71, step d) and 2-ethoxyethanol were used instead of 4-chloro-6- cyclohexyl-2-(4-nitro-phenyl)-pyrimidine and 2-phenethylalcohol respectively.
  • Step b 4-[2-(2-Ethoxy-ethoxy)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine was obtained using step e of example 71 except that 2-(2-ethoxy-ethoxy)-4-(4-nitro-phenyl)-6-(3-phenyl- propyl)-pyrimidine was used instead of 4-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2- yl]-morpholine.
  • Step c The title compound was obtained as its HCl salt using steps d and e of example 1 except that 4-[2-(2-ethoxy-ethoxy)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and was used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)- ⁇ yrimidin-4-yl]-phenylamine.
  • Step a 2-(2-Butoxy-l-butoxymethyl-ethoxy)-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine was obtained using step b of example 49 except 2-methanesulfonyl-4-(4-nitro-phenyl)-6-(3- phenyl ⁇ propyl)-pyrimidine (example 71, step d) and l,3-dibutoxy-propan-2-ol were used instead of 4-chloro-6-cyclohexyl-2-(4-nitro-phenyl)-pyrimidine and 2-phenethylalcohol respectively.
  • Step b 4-[2-(2-Butoxy-l-butoxymethyl-ethoxy)-6-(3-phenyl-propyl)-pyrimidin-4-yl]- phenylamine was obtained using step e of example 71 except that 2-(2-butoxy-l- butoxymethyl-ethoxy)-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine was used instead of 4-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]-morpholine.
  • Step c The title compound was obtained as its HCl salt using steps d and e of example 1 except that 4-[2-(2-butoxy-l-butoxymethyl-ethoxy)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and was used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine.
  • the title compound was obtained as its HCl salt using steps d and e of example 71 except that 1-benzenesulfonyl-piperazine was used instead of morpholine in step d, followed by reaction of the product obtained instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]- phenylamine, according to steps d and e of example 1.
  • Example 82 N-(2- ⁇ [4-[4-(4,5-Dihydro-lH-imidazol-2-ylamino)-phenyl]-6-(3-phenyl-propyl)- pyrimidin-2-yl]-methyl-amino ⁇ -ethyl)-N-methyl-benzenesulfonamide Step a N,N' ⁇ dimethyl-N-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl] ⁇ ethane-l, 2- diamine was obtained using steps d of example 71 except that ⁇ N'-dimethylethylenediamine was used instead of morpholine.
  • Step b N-Methyl-N-(2- ⁇ methyl-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]- amino ⁇ -ethyl) -benzenesulfonamide
  • Benzenesulfonylchloride (0.17mL, 1.3mmol) was added to a solution of iV,N'-dimethyl- ⁇ ' ' -[4- (4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidm-2-yl]-ethane-l,2-diamine (0.44g, 1.21mmol), NEt 3 (0.25mL, 1.8mmol) in DCM (3mL). The reaction mixture was stirred for 2 h and then diluted with DCM (5OmL).
  • Step c The title compound was obtained as its HCl salt using step e of example 71 except that N-methyl-N-(2- ⁇ methyl-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]-amino ⁇ - ethyl)-benzenesulfonamide was used instead of 4-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)- pyrimidin-2-yl]-morpholine, followed by reaction of the product obtained instead of 4-[2- cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine, according to steps d and e of example 1.
  • Step a l-[4-(4-Nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]-piperazine was obtained using steps d of example 71 except that piperazine was used instead of morpholine.
  • Step b 4-Methanesulfonyl- 1 -[4-(4-Nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]- piperazine was obtained using step b of example 82 except that l-[4-(4-nitro-phenyl)-6-(3- phenyl-propyl)-pyrimidin-2-yl]-piperazine and methanesulfonylchloride were used instead of N ⁇ -dimethyl-N-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]-ethane-l,2-diamine and benzenesulfonylchloride respectively
  • Step c The title compound was obtained as its HCl salt using step e of example 71 except that 4-methanesulfonyl-l-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]-piperazine was used instead of 4-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]-morpholine, followed by reaction of the product obtained instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)- pyrimidin-4-yl]-phenylamine, according to steps d and e of example 1.
  • Step b 2-Chloro ⁇ 4-(4-nitro-phenyl)-6-phenyl-pyrimidine was obtained using step a of example 84 except that 2,4-dichloro-6-phenyl-pyrimidine and 4,4,5,5-tetramethyl-2-(4-nitro-phenyl)- [l,3,2]dioxaborolane were used in place of 2,4,6-trichloropyrimidine and phenylboronic acid repectively.
  • 1 H NMR (CDCl 3 ) 8.43-8.32 (4H, m), 8.19-8.15 (2H, dd), 8.08 (IH, s), 7.62-7.52 (3H, m).
  • Step c The title compound was obtained as its HCl salt using steps d and e of example 71 except that 2-chloro-4-(4-nitro-phenyl)-6-phenyl-pyrimidine and 7V-methyl-hexylamine were used instead of 2-methanesulfonyl-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine and morpholine respectively in step d, followed by reaction of the product obtained instead of 4-[2- cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine, according to steps d and e of example 1.
  • Step b 2-Cyclohexyl-5-methyl-6-(4-nitro-phenyl)-pyrimidine-4-carboxylic acid ethyl ester was obtained using steps b and c of example 1 except that 2-cyclohexyl-6-hydroxy-5-methyl- pyrimidine-4-carboxylic acid ethyl ester was used instead of 2-cyclohexyl-6-(3-phenyl- propyl)-pyrimidin-4-ol in step b and 4,4,5, 5-tetramethyl-2-(4-nitro-phenyl)- [l,3,2]dioxaborolane was used instead of 4-(4,4,5,5-tetramethyl-l,3,2,-dioxaborolan-2- yl)aniline in step c.
  • Step d 2-Cyclohexyl-5-methyl-6-(4-nitro-phenyl)-pyrimidine-4-carboxylic acid benzylamide was obtained using step a of example 51, except that benzylamine and 2-cyclohexyl-5-methyl- 6-(4-nitro-phenyl)-pyrimidine-4-carboxylic acid were used instead of 4-[2-cyclohexyl-6-(3- phenyl-propyl)-pyrimidin-4-yl]-phenylamine and N-tert-butoxycarbonyl glycine respectively.
  • Step e 2-Cyclohexyl-5-methyl-6-(4-amino-phenyl)-pyrimidine-4-carboxylic acid benzylamide was obtained using step b of example 46, except that 2-cyclohexyl-5-methyl-6-(4-nitro- phenyl)-pyrimidine-4-carboxylic acid benzylamide was used instead of 2-cyclohexyl-4-(4- nitro-phenoxy)-6-(3-phenyl-propyl)-pyrimidine.
  • Step f N',N"-bis-tert-Butoxycarbonyl-N- ⁇ 6-(4-amino-phenyl)-2-cyclohexyl-5-methyl- pyrimidine-4-carboxylic acid benzylamide ⁇ -guanidine was obtained using step d of example 1 except that 2-cyclohexyl-5-methyl-6-(4-amino-phenyl)-pyrimidine-4-carboxylic acid benzylamide and l,3-t ⁇ fter ⁇ butoxycarbonyl)-2-methyl-thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and N,N'-bis-(tert- butoxycarbonyl)-imidazolidine-2-thione respectively.
  • Step g The title compound was obtained as its TFA salt using step e of example 1, except that N'iV-6z5-ter ⁇ -butoxycarbonyl-N- ⁇ 6-(4-amino-phenyl)-2-cyclohexyl-5-methyl-pvrimidine-4- carboxylic acid benzylamide ⁇ -guanidine and TFA were used instead of N,N-bis-(tert ⁇ butoxycarbonyl)- ⁇ 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -(4,5-dihydro- lH-imidazol-2yl)-amine and HCl in dioxan respectively.
  • Step b Benzyl-(6-chloro-2-cyclohexyl-5-ethyl-pyrimidin-4-yl)-amine was obtained using step b of example 61 except that 4,6-dichloro-2-cyclohexyl-5-ethyl-pyrimidine and benzylamine were used in place of 4-chloro-6-(3-methyl-butyl)-2-(3-nitro-phenyl)-pyrimidine and phenethylamine respectively.
  • Step c The title compound was obtained as its HCl salt using steps c-e of example 1, except that benzyl-(6-chloro-2-cyclohexyl-5-ethyl-pyrimidin-4-yl)-amine was used instead of 4- chloro-2-cyclohexyl-(3-phenyl-propyl)-pyrimidine in step c.
  • Step a N'(tert-Butoxycarbonyl)-N"- ⁇ 4-[2-(l-methyl-octyl)-6-(3-phenyl-propyl)-pyrimidin-4- yl] -phenyl ⁇ -ethane-l ,2-diamine
  • the title compound was obtained as its HCl salt using step b of example 43 except that N-(tert- butoxycarbonyl)-glycinaldehyde was used instead of l-trityl-imidazole-2-carboxaldehyde, followed by reaction of the product obtained instead of N,N-t ⁇ -(fer£-butoxycarbonyl)- ⁇ 4-[2- cyclohexyl-6-(3 -phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -(4,5-dihydro- 1 H-imidazol-2yl)- amine, according to step e of example 1.
  • the title compound was obtained as its HCl salt using step b of example 43 except that 2- ⁇ tert- butoxycarbonylamino)-propionaldehyde was used instead of l-trityl-imidazole-2- carboxaldehyde, followed by reaction of the product obtained instead of N,N'-bis-(tert- butoxycarbonyl)- ⁇ 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -(4,5-dihydro- lH-imidazol-2yl)-amine, according to step e of example 1.
  • step e of example 1 The title compound was obtained as its HCl salt using step b of example 43 except that N-(tert- butoxycarbonyl)-prolinal was used instead of l-trityl-miidazole-2-carboxaldehyde, followed by reaction of the product obtained instead of ⁇ N-6w-(tert-butoxycarbonyl)- ⁇ 4-[2- cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -(4,5-dihydro-lH-imidazol-2yl)- amine, according to step e of example 1.
  • step b of example 43 The title compound was obtained as its HCl salt using step b of example 43 except that two equivalents of N-(?ert-butoxycarbonyl)-glycinaldehyde were used instead of 1-tiityl-imidazole- 2-carboxaldehyde, followed by reaction of the product obtained instead of N,7V- ⁇ w-(tert- butoxycarbonyl)- ⁇ 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl ⁇ -(4,5-dihydro- lH-imidazol-2yl)-amine, according to step e of example 1.
  • Step a 4-[2-(l-Methyl-octyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-benzaldehyde was obtained using steps a-c of the procedure described in example 1, except that 1-methyl- octylamidine.HCl was used instead of cyclohexylamidine.HCl in step a., and 4-formyl- phenylboronic acid was used instead of 4-(4,4,5,5-tetramethyl-l,3,2,-dioxaborolan-2-yl)aniline in step c.
  • Step c A solution of 4-[4-(2,2-dibromo-vinyl)-phenyl]-2-(l-methyl-octyl)-6-(3-phenyl- propyl)-pyrimidine (0.225g, 0.39mmol) in ethylenediamine (2mL) was stirred at rt for 2h. The reaction mixture was diluted with EtAOc (2OmL), washed with H 2 O (3 x 20ml) and dried (MgSO 4 ). Filtration and evaporation of the solvent gave the crude product which was purified by chomatography (DCM-MeOH-NH 4 OH (9:1:0.1)) to (0.13Og, 69%).
  • Step a 2-Methyl-6-(3-phenylpropyl)pyrimidin-4-ol was obtained using the procedure described in example 1 step a, except that methylamidine.HCl was used instead of cyclohexylamidine.HCl.
  • Step c 2-(4-Bromostyryl)-4-chloro-6-(3-phenylpropyl)pyrimidine was obtained using the procedure described in examplel step b, except that 2-(4-bromostyryl)-6-(3- phenylpropyl)pyrimidin-4-ol was used instead of 2-cyclohexyl-6-(3- phenylpropyl)pyrimidin-4-ol.
  • 1 H NMR (CDCl 3 ) 7.95 (IH, d), 7.50 (4H, m), 7.33-7.13 (6H, m), 7.00 (IH, s), 2.73 (4H, m), 2.12 (2H, m).
  • Step d 4-(2-(4-Bromostyryl)-6-(3-phenylpropyl)pyrimidin-4-yl)phenylamine was obtained using the procedure described in example 1 step c, except that 2-(4-bromostyryl)-4-chloro- 6-(3-phenylpropyl)pyrimidine (example 92, step c) was used instead of 4-chloro-2- cyclohexyl-6-(3-phenylpropyl)pyrimidine.
  • Step e The title compound was obtained as its TFA salt using the procedure described in example 1, step d except that 4-(2-(4-bromostyryl)-6-(3-phenylpropyl)pyrimidin-4- yl)phenylamine and N,N'-bis-tert-butoxycarbonyl-2-methyl-2-thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]- ⁇ henylamine and N 5 N'- bis-(tert-butoxycarbonyl)- imidazolidine-2-thione respectively, followed by treatment of the product obtained, in place of N',N"-bis-tert-butoxycarbonyl-N- ⁇ 6-(4-amino-phenyl)-2- cyclohexyl-5-methyl-pyrimidine-4-carboxylic acid benzylamide ⁇ -guanidine, according to the method of example 85, step h.
  • the title compound was obtained as the HCl salt using the procedure described in example 1, except that 4-benzyloxy-3-oxo-butyric acid ethyl ester and 2-methylnonanamidine.HCl were used instead of 3-oxo-6-phenyl-hexanoic acid ethyl ester and cyclohexylamidine. HCl respectively.

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Abstract

The present invention is concerned with pyrimidine 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.

Description

PYRIMIDINE DERIVATIVES Field of the Invention
The present invention is concerned with pyrimidine 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. In 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. In 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 al., 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. In 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 al, 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 be 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 auotoimmune 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(l-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 amino 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(l-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, £>-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, bTIP(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 D-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). 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:
R3 and R4 are independently selected from H, COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH, S(C-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(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), 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)(C7-2o 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 C1-30 hydrocarbyl or C1-3O 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 (i), (ii) and (iii):
(i) -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(C1-6 alkyl), N(C1-6 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, 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(C1-6 alkyl)SO2, N(C6-20 aryl)SO2, C(O)NHNHC(O), =N-N- and C(O)NHNH in the backbone;
(ii) COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH, S(C-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(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 aUcaryl), 0(C7-20 aralkyl), =O, 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(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(Ci-6 alkyl)(C7-20 alkaryl), NHSO2(C-6 alkyl), NHSO2(C6-20 aryl), NHSO2(C7-20 aralkyl),
NHSO2(C7-20 alkaryl), N(C-6 alkyl)SO2(C-6 alkyl), N(C-6 alkyl)SO2(C6-20 aryl), N(C-6 alkyl)SO2(C7-20 aralkyl), N(C-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(C-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(C-6 alkyl)(C7-20 alkaryl) on the backbone; and,
(iii) groups independently selected from the group consisting of Cj-I0 alkyl, C2-I0 alkoxyalkyl, C7-20 alkoxyaryl, Ci2-20 aryloxyaryl, C7-20 aryloxyalkyl, C-]0 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; at least one of R1 and R2 has a structure independently selected from the group consisting of (a), (b) and (c),
Figure imgf000007_0001
n is O or 1; m is O, 1, 2, 3, 4, 5 or 6;
R5 and R7 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(Ci-6 alkyl), 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(Ci-6 alkyl), NH2, NH(Ci-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, 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 C3-3O 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 (iv), (v) and (vi):
(iv) -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 alkaryl), N(C7-20 aralkyl), O, CO, SO2, NHSO2 and C(O)NHNH in the backbone; (v) 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,
(vi) groups independently selected from the group consisting Of C]-1O 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;
R6 is selected from the group consisting of -NR9R10, -CONR9R10, -NR9COR10, -OR10, -R11, - NR9C(=NR12)N(R13)2 and -N=C(NR12 R9)N(R13)2; wherein:
R9 is selected from the group consisting of H, C1-6 alkyl, Ci-6 aminoalkyl, C1-I2 alkylaminoalkyl, C1-I8 dialkylaminoalkyl, C3-20 cycloalkyl, C3-20 aminocycloalkyl, C4-20 (cycloalkyl)alkyl, C4-20 (aminocycloalkyl)alkyl, C6-20 aryl, C6-20 aminoaryl, C7-20 aralkyl, C7-20 aminoaralkyl, C7-20 alkaryl, C7-20 aminoalkaryl, Ci-20 heteroaryl and C2-20 heterocyclyl; R10 is 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, Ci-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, Cc1-30 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, C]-I0 aminoalkyl, C1-12 alkylaminoalkyl, Ci-I8 dialkylaminoalkyl, 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-I0 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(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(Ci-6 alkyl), N(C1-6 alkyl)2i 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)(C7.2o 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), C(O)(C7-20 alkaryl), guanidinyl and guanidinyl Ci-I0 alkyl; 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(Ci-6 alkyl)2, Si(OH)2, Si(OC1-6 alkyl)2, C(O)NH, C(O)N(Cj-6 alkyl), C(O)O, N(CJ-6 alkyl)C(O)N(Ci-6 alkyl), NHC(O)N(C1-6 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, NHSO2NH, N(Ci-6 alkyl)SO2NH, N(C w 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; R1Ms selected from the group consisting of H, -C(=NH)NH2, -C(=NH)NHC1-20 alkyl, -C(=NH)N(Ci.2o alkyl)2, -C(=NH)NHC3-3o cycloalkyl, -C(=NH)N(C3-3o cycloalkyl)2, -C(=NH)NHC6-30 aryl, -CeNH)N(C6-30 aryl)2, -C(=NH)NHC5-30 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)NHC1-30 heteroaiyl, -C(=NH)N(C3o heteroaryl)2, -CC=NC20 alkyl)NH2, -C(=NC1-20 alkyl)NHCi-20 alkyl, -C(=NCi-20 alkyl)N(Ci-20 alkyl)2, -C(=NC1-20 alkyl)NHC3-30 cycloalkyl, -C(=NCi.2O alkyl)N(C3-30 cycloalkyl)2, -C(=NC1-20 alkyl)NHC6-30 aryl, -C(=NC1-20 alkyl)N(C6-30 aryl)2, -CC=NC20 alkyl)NHC6-30 alkaryl, -C(=NCi-20 alkyl)N(C6-30 alkaryl)2, -C(=NCi-20 alkyl)NHC6-30 aralkyl, -C(=NCi.2o alkyl)N(C6-30 aralkyl)2, -C(=NCi-20 alkyl)NHC2-30 heterocyclyl,
Figure imgf000009_0001
alkyl)N(C2-30 heterocyclyl)2, -CC=NCL20 alkyl)NHC1-30 heteroaryl, -CC=NCL20 alkyl)N(C1-30 heteroaryl)2, 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, 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 aiyloxyalkyl, C7-30 arylaminoalkyl, C7-30 alkylaminoaryl, Ci-I0 aminoalkyl, C7-20 aminoaralkyl, C7-20 aminoalkaryl, C2-20 alkylguanidinylalkyl and ureayl CLIO alkyl; any of the groups defined as R11 (except H) being optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from Ci-I0 alkyl, C]-20 haloalkyl, Ci-20 perhaloalkyl, C1-20 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(C1-5 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); any of the groups defined as R11 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(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, 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; R12 is 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, Ci-30 heteroaryl and C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, Ci-I0 aminoalkyl, C6-20 aminoaryl, guanidinyl Ci-I0 alkyl, C2-20 alkylguanidinylalkyl, ureayl Ci-I0 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(Ci-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, NO2, CN, C(O)H and C(O)(Cj-6 alkyl); and each R13 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, 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, C]-I0 aminoalkyl, C6-20 aminoaryl, guanidinyl Ci-I0 alkyl, C2-20 alkylguanidinylalkyl, ureayl 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 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)(C1-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 aralkyl), OC(O)(C7-20 alkaryl), NH(Ci-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(C-6 alkyl)(C6-20 aryl), N(Ci-6 alkyl)(C7-20 aralkyl), N(C1-6 alkyl)(C7-20 alkaryl), N(C6-20 aryl)(C7-20 ^alkyl), N(C6-20 aryl)(C7-20 alkaryl), NO2, CN, C(O)H and C(O)(C1-6 alkyl), or each R12 is joined to one another to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring; or R12 and one of R13 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R13 not joined to R12 is H or C1-6 alkyl; and where one of R1 and R2 is not a group (a), (b), and (c), it is independently selected from the same group as R3, as defined above.
Preferably, R1 is selected from the group consisting of the structures (a), (b), and (c) and and R2 is independently selected from the same group as R3, as defined above.
Preferably, -(CH2)m-R6 is located in the ortho, meta or para position relative to the -(O)n- group. More preferably, -(CH2)m-R6 is located in the meta or para position relative to the to the -(O)n-. Most preferably, -(CH2)m-R6 is located in the para position relative to the -(O)n- group.
Preferably, n = 0.
R5 and/or R7 are preferably located in the ortho or meta position relative to the -(O)n- group, most preferably the meta position. Preferably, R1 and/or R2 is a group having the structure (ai) shown below:
Figure imgf000011_0001
wherein R5 and R7 are independently selected from the group consisting of H, Ci-6 alkyl, halo, haloCi-6 alkyl, perhaloC1-6 alkyl, OH, NH2, NO2, CN, COOH, C(O)H, C(O)O(C1-6 alkyl) and C(O)(C1-6 alkyl), and R6 is as defined above. Preferably, R1 and/or R2 is a group having the structure (a2) or (a3) shown below:
Figure imgf000011_0002
wherein R6 is as defined above. Preferably, R1 and/or R2 is a group having the structure (a2). Preferably, R1 is a group having the structure (a2) and R2 is independently selected from the same group as R3.
Where R1 and R2 are both selected from the group consisting of (a), (b), (c), (ai), (a2) and (a3), they may be the same or different, i.e., they are both independently selected from these groups and the definitions of R5, R6 and R7 may differ between groups R1 and R2.
With regard to the structure (a{), R5 and/or R7 are preferably located in the ortho or meta position relative to the -(O)n- group, most preferably the meta position.
Preferably, R5 is H and R7 is H, Cl, Br, or F, preferably H. Preferably, R5 and R7 are both H. Preferably, R6 is selected from the group consisting of -NR9R10, -NR9COR10 and -NR9C(=NR12)N(R13)2.
Preferably, R and/or R is selected from
Figure imgf000012_0001
and
Figure imgf000012_0002
Preferably, R9 is selected from H, methyl, ethyl, propyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, phenyl, phenylethyl, benzyl, tolyl and xylyl, more preferably H or methyl, most preferably H.
Preferably, R10 is selected from the group consisting of H, C1-15 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(C1-4 alkyl)2, NH(C6-16 aryl), N(C6-I6 aryl)2, NH(C7-16 aralkyl), N(C7-,6 aralkyl)2, NH(C7-16 alkaryl), N(C7-16 alkaryl)2, N(C1-4 alkyl)(C6-i6 aryl), N(C1-4 alkyl)(C7-16 alkaryl), N(Ci-4 alkyl)(C7.i6 aralkyl), N(C6-16 aryl)(C7-i6 alkaryl), N(C646 aryl)(C7-16 aralkyl), S(C1-6 alkyl), NO2, CN, OH, SH, OCj-6 alkyl, C(O)H, C(O)(C1-6 alkyl), guanidinyl and guanidinyl C1-6 alkyl.
Preferably, R10 is selected from the group consisting Of C6-20 aryl, C7-20 aralkyl, C3-I5 cycloalkyl, C4-i5 cycloalkylalkyl, Ci-I5 heteroaryl, C2-15 heterocyclyl, C2-I5 heteroaralkyl, C3-I5 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(Cj-4 alkyl), N(Ci-4 alkyl)2, guanidinyl and guanidinyl Ci-6 alkyl.
Preferably, R10 is selected from the group consisting of Ci-]o heteroaryl, C2-io heterocyclyl, C3-I0 heteroaralkyl, 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), N(Ci-4 alkyl)2, guanidinyl and guanidinyl Ci-6 alkyl.
Preferably, R10 is selected from the group consisting of of C]-I0 alkyl, C3-I5 cycloalkyl, C4-I5 cycloalkylalkyl, C7-20 aralkyl, furanyl, furanyl(Ci-3 alkyl), pyridyl, pyridyl(Ci.3 alkyl), phthalimido, phthalimido(Ci-3 alkyl), thienyl, thienyl(Ci-3 alkyl), pyrrolyl, pyrrolyl(Ci-3 alkyl), imidazolyl, imidazolyl(Ci.6 alkyl), pyrazolyl, pyrazolyl(Ci-3 alkyl), thiazolyl, thiazolyl(Ci-3 alkyl), isothiazolyl, isothiazolyl(Ci-3 alkyl), thiazolylmethyl, isothiazolylmethyl, oxazolyl, oxazolyl(Ci-3 alkyl), pyrrolidinyl, pyrrolidinyl(Ci-3 alkyl), pyrrolinyl, pyrrolinyl(C1-3 alkyl), imidazolidinyl, imidazolidinyl(C]-3 alkyl), imidazolinyl, imidazolinyl(Ci-3 alkyl), imidazolemethyl, dihydroimidazolyl, dihydroimidazolyl(C1-3 alkyl), dihydroimidazolylmethyl, tetrahydropyrimidinyl, tetrahydropyrimidinyl(Ci-3 alkyl), benzimidazolyl, benzimidazolyl(Ci-3 alkyl), tetrahydroisoquinolinyl, tetrahydroisoquinolyl(Ci-3 alkyl), pyrazolidinyl, pyrazolidinyl(C]-3 alkyl), tetrahydrofuranyl, tetrahyrdofuranyl(Ci-3 alkyl), pyranyl, pyranyl(Ci-3 alkyl), pyridonyl, pyridonyl(Ci-3 alkyl), pyronyl, pyronyl(Ci-3 alkyl), pyrazinyl, pyrazinyl(Ci-3 alkyl), pyridazinyl, pyridazinyl(Ci-3 alkyl), piperidinyl, piperidinyl(Ci-3 alkyl), piperazinyl, piperazinyl(Ci-3 alkyl), morpholinyl, morpholinyl(Ci..3 alkyl), thionaphthyl, thionaphthyl(Ci-3 alkyl), benzofuranyl, benzofuranyl(Ci-3 alkyl), isobenzofuryl, isobenzofuryl(Ci-3 alkyl), indolyl, indolyl(Ci-3 alkyl), oxyindolyl, oxyindonlyl(Ci-3 alkyl), isoindolyl, isoindolyl(C]-3 alkyl), indazolyl, indazolyl(Ci-3 alkyl), indolinyl, indolinyl(Ci-3 alkyl), isoindolinyl, isoindolinyl(Ci-3 alkyl), isoindazolyl, isoindazolyl(C]-3 alkyl), benzopyranyl, benopyranyl(Ct-3 alkyl), coumarinyl, coumarinyl(Ci-3 alkyl), isocoumarinyl, isocoumarinyl(Ci-3 alkyl), quinolyl, quinolyl(C]-3 alkyl), isoquinolyl, isoquinolyl(Ci-3 alkyl), napthridinyl, naphthridinyl(Ci-3 alkyl), cinnolinyl, cinnolinyl(Ci-3 alkyl), quinazolinyl, quinazolinyl(Ci-3 alkyl), pyridopyridyl, pyridopyridyl(Ci-3 alkyl), benzoxazinyl, benzoxazinyl(Ci-3 alkyl), quinoxadinyl, quinoxadinyl(Ci.3 alkyl), chromenyl, chromenyl(Ci-3 alkyl), chromanyl, chromanyl(C]-3 alkyl), isochromanyl, isochromanyl(Ci-3 alkyl), carbolinyl, carbolinyl(Ci-3 alkyl), thiophenyl, thiophenyl(Ci-3 alkyl), thiazolyl, thiazolinyl(Ci-3 alkyl), isoxazolyl, isooxazolyl(Ci-3 alkyl), isoxazolonyl, isoxazolonyl(Ci-3 alkyl), isothiazolyl, isothiazolyl(C1-3 alkyl), triazolyl, triazolyl(C1-3 alkyl), oxadiazolyl, oxadiazolyl(C1-3' alkyl), thiadiazolyl, thiadiazolyl(C1-3 alkyl), pyridazyl and pyridazyl(C1-3 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), guanidinyl, guanidinyl(Ci-3 alkyl), NO2, CN, OCH3, SO2NH2 and C(O)H, Ci-6 alkyl, C2-6 alkoxyalkyl, C7-io alkoxyaryl, C3-io cycloalkyl, C4-I5 (cycloalkyl)alkyl, C7-I2 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, NH2, guanidinyl and guanidinyl Ci-6 alkyl.
Preferably, R10 is selected from the group consisting of methyl, ethyl, propyl, pyridyl, pyridyl(Ci-3 alkyl), phthalimido, phthalimido(C1-3 alkyl), pyrrolyl, pyrrolyl(Ci-3 alkyl), imidazolyl, imidazolyl(Ci.6 alkyl), pyrazolyl, pyrazolyl(Ci-3 alkyl), thiazolyl, thiazolyl(Ci_3 alkyl), isothiazolyl, isothiazolyl(Ci-3 alkyl), thiazolylmethyl, isothiazolylmethyl, oxazolyl, oxazolyl(Ci_3 alkyl), pyrrolidinyl, pyiτolidinyl(Ci-3 alkyl), pyrrolinyl, pyrrolinyl(Ci-3 alkyl), imidazolidinyl, imidazolidinyl(Ci-3 alkyl), imidazolinyl, imidazolinyl(Ci-3 alkyl), imidazolemethyl, dihydroimidazolyl, dihydroimidazolyl(Ci-3 alkyl), dihydroimidazolylmethyl, tetrahydiOpyrimidinyl, tetrahydropyrimidinyl(Ci-3 alkyl), benzimidazolyl, benzimidazolyl(C]-3 alkyl), tetrahydroisoquinolinyl, tetrahydroisoquinolyl(Ci-3 alkyl), pyrazolidinyl, pyrazolidinyl(Ci-3 alkyl), pyridonyl, pyridonyl(Ci-3 alkyl), pyrazinyl, pyrazinyl(Ci-3 alkyl), pyiidazinyl, pyridazinyl(Ci-3 alkyl), piperidinyl, piperidinyl(Ci-3 alkyl), piperazinyl, piperazinyl(Ci-3 alkyl), morpholinyl, morpholinyl(Ci-3 alkyl), indolyl, indolyl(C]-3 alkyl), oxyindolyl, oxyindonlyl(Ci-3 alkyl), isoindolyl, isoindolyl(C]-3 alkyl), indazolyl, indazolyl(Ci-3 alkyl), indolinyl, indolinyl(Ci_3 alkyl), isoindolinyl, isoindoliny^C]^ alkyl), isoindazolyl, isoindazolyl(Ci-3 alkyl), quinolyl, quinolyl(C]-3 alkyl), isoquinolyl, isoquinolyl(C]-3 alkyl), quinazolinyl, quinazolinyl(C1-3 alkyl), pyridopyridyl, pyridopyridyl(Ci-3 alkyl), benzoxazinyl, benzoxazinyl(Ci-3 alkyl), quinoxadinyl, quinoxadinyl(Ci-3 alkyl), carbolinyl, carbolinyl(Ci-3 alkyl), thiophenyl, thiophenyl(Ci-3 alkyl), thiazolyl, thiazolinyl(Ci-3 alkyl), isoxazolyl, isooxazolyl(C]-3 alkyl), isoxazolonyl, isoxazolonyl(Ci-3 alkyl), isothiazolyl, isothiazolyl(Ci-3 alkyl), triazolyl, triazolyl(C1-3 alkyl), oxadiazolyl, oxadiazolyl(Ci-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(C,-6 alkyl), NO2, CN, OCH3, SO2NH2 and C(O)H, C1-6 alkyl, C2-6 alkoxyalkyl, C7-10 alkoxyaryl, C3-I0 cycloalkyl, C4-15 (cycloalkyl)alkyl, C7-12 aralkyl, C7-12 alkaryl, C1-12 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, NH2, guanidinyl and guanidinyl Ci-6 alkyl.
In a particularly preferred embodiment, R10 is selected from the group consisting of guanidinylethyl, di(C1-6 alkyl)amino(Ci.6 alkyl), amino(Ci-6 alkyl), (4,5-dihydro-lH-imidazol-2-yl, 4,5-dihydro-lH-imidazol-2-yl(Ci-6 alkyl) and lH-imidazol-2-yl(C1-6 alkyl) group which may be substituted with 1 or more groups independently selected from Ci-6 alkyl, halo, haloC]-6 alkyl, hydroxyC^ alkyl, perhaloCi-6 alkyl, OH, NH2, NO2, CN, COOH, C(O)H, C(O)O(Ci-6 alkyl), 0(Ci-6 alkyl), OC(O)(Ci-6 alkyl) and C(O)(Ci-6 alkyl). In a preferred embodiment, R10 is selected from the group consisting of 1 H-imidazol-2-ylmethyl, 1 H-imidazol-2-ylethyl, 1 H-imidazol-2-ylpropyl,
4,5-dihydro-lH-imidazol-2-yl, 4,5-dihydro-lH-imidazol-2-ylmethyl, dimethylaminoethyl, morpholinoethyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl and guanidinylethyl.
In a particularly preferred embodiment, R10 is 4,5-dihydro-lH-imidazol-2-yl. In a preferred embodiment, R10 represents a natural or synthetic amino acid residue. The amino acid may be an α- or β-amino acid. Particularly preferably, R10 represents the residue of a natural amino acid corresponding to an amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, lysine, arginine, histidine, aspartic acid, glutamic acid, asparagine, glutamine, cysteine and methionine. For the sake of clarity, where R10 represents an amino acid residue corresponding to glycine, NR9R10 has the structure:
Figure imgf000015_0001
In the embodiment where R9 and R!o may be 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. When R6 comprises the group OR10, preferably m is O or 1 , most preferably O. When R6 comprises the group OR10, preferably R10 is selected from the group consisting of Ci-1O heteroaryl, C2-1O heterocyclyl, C3-Io heteroaralkyl, C3-10 heterocyclylalkyl, Ci-6 alkylamino Ci-6 alkyl, (Ii(Ci-6 alkyl)amino Ci-6 alkyl 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(Cj-4 alkyl) or N(C1-4 alkyl)2.
When R6 comprises the group OR10, preferably R10 is selected from the group consisting of 1 H-imidazol-2-ylmethyl, 1 H-imidazol-2-ylethyl, 1 H-imidazol-2-ylpropyl,
4, 5 -dihydro- 1 H-imidazol-2-ylmethyl, 4, 5-dihydro- 1 H-imidazol-2-ylethyl,
4, 5 -dihydro- 1 H-imidazol-2-ylpropyl, dimethylaminoethyl, methylaminoethyl, methylaminomethyl, diethylaminoethyl, ethylaminoethyl, diethylaminomethyl, ethylaminomethyl, piperidinylethyl, pyrrolidinylmethyl, morpholinylmethyl, pyrrolidinylethyl, morpholinylethyl, piperidinylmethyl, pyrrolidinylpropyl, morpholinylpropyl and piperidinylpropyl.
Preferably, R11 is selected from the group consisting of -C(=NH)NH2, -C(=NH)NHC1-10 alkyl, -C(=NH)N(Ci-10 alkyl)2, -C(=NH)NHC3-i2 cycloalkyl, -C(=NH)N(C3-i2 cycloalkyl)2,
-C(=NH)NHC6-i2 aryl, -C(=NH)N(C6-12 aryl)2, -C(=NH)NHC6-15 alkaryl, -C(=NH)N(C6-i5 alkaryl)2, -C(=NH)NHC6-i5 aralkyl, -C(=NH)N(C6-i5 aralkyl)2, -C(=NH)NHC2-12 heterocyclyl,
-C(=NH)N(C2-i2 heterocyclyl)2, -C(=NH)NHCM2 heteroaryl, -C(=NH)N(C,.12 heteroaryl)2,
-C(=NCi.io alkyl)NH2, -C(=NC,-10 alkyl)NHC1-K) alkyl, -C(=NC,-10 alkyl)N(C1-10 alkyl)2, C1-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, Cg-30 heterocyclylalkaryl, C4-30 heterocyclylalkoxyalkyl, C4-30 heterocyclylalkylaminoalkyl, C8-3O heteroarylalkaryl, C3-30 heteroarylalkoxyalkyl, C3-30 heteroarylalkylaminoalkyl, C7-30 aryloxyalkyl, C7-30 arylaminoalkyl, C7-30 alkylaminoaryl, C1-I0 aminoalkyl, C7-20 aminoaralkyl,
C7-20 aminoalkaryl, C2-20 alkylguanidinylalkyl and ureayl C1-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 R1 ' 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, Ci-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(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, 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). Preferably, R14s not H.
Preferably, R11 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-i2 cycloalkyl, -C(=NH)N(C3-i2 cycloalkyl)2, -C(=NH)NHC6-10 aryl, -C(=NH)N(C6-io aryl)2, -C(=NH)NHC6-12 alkaryl, -C(=NH)N(C6-I2 alkaryl)2, -C(=NH)NHC6-12 aralkyl, -C(=NH)N(C6-12 aralkyl)2, -C(=NH)NHC2-i0 heterocyclyl, -CC=NH)N(C2-I0 heterocyclyl)2, -C(=NH)NHCM0 heteroaryl, -C(=NH)N(Ci-10 heteroaryl)2, -C(=NC1-6 alkyl)NH2, -C(=NCi-6 alkyl)NHCI-6 alkyl, -C(=NC1-6 alkyl)N(Ci-6 alkyl)2, C1-15 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 R11 being optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from NH2, NH(C-4 alkyl), N(Ci-4 alkyl)2, NH(C6-I6 aryl), N(C6-16 aryl)2, NH(C7-16 aralkyl), N(C7-16 aralkyl)2, NH(C7-16 alkaryl), N(C7-16 alkaryl)2, N(C1-4 alkyl)(C6-16 aryl), N(C1-4 alkyl)(C7-16 alkaryl), N(C1-4 alkyl)(C7-16 aralkyl), N(C6-16 aryl)(C7-16 alkaryl), N(C6-16 aryl)(C7-16 aralkyl), S(C6 alkyl), NO2, CN, OH, SH, OC1-6 alkyl, C(O)H and C(O)(C1-6 alkyl).
Preferably, Rπ is selected from the group consisting of -C(=NH)NH2, Cj-I5 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 R11 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(Ci-4 arkyl)2.
Preferably, R11 is selected from the group consisting of -C(=NH)NH2, C]-10 heteroaryl and C2-io heterocyclyl, which are linked to the rest of the compound of formula (I) by a carbon atom of one of these groups.
Preferably, R11 is selected from the group consisting of -C(=NH)NH2, C2-4 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, R11 is selected from the group consisting of -C(=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 R11 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(d-6 alkyl), NO2, CN, OCH3, SO2NH2 and C(O)H, C1-6 alkyl, C2-6 alkoxyalkyl, C7-I0 alkoxyaryl, C3-io cycloalkyl, C4-I5 (cycloalkyl)alkyl, C7-I2 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, R11 is selected from the group consisting of -C(=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 R1 ] 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(C,-6 alkyl), NO2, CN, OCH3, SO2NH2 and C(O)H, Ci-6 alkyl, C2-6 alkoxyalkyl, C7-io alkoxyaryl, C3-io cycloalkyl, C4-I5 (cycloalkyl)alkyl, C7-I2 aralkyl, C7-I2 alkaryl, C]-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, R11 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, R1 ' is not substituted in the backbone. Preferably, R1 ' is not substituted on the backbone.
Throughout the specification, in respect of the group R11, 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 R11.
Preferably, R12 is selected from the group consisting of H, C1-I0 alkyl, C2-10 alkenyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, C2-10 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C5-20 cycloalkenyl, C7-20 cycloalkynyl, C7-20 aralkyl, C7-20 alkaryl, C6-2o aryl, Ci-20 heteroaryl, C2-20 heterocyclyl, C2-20 heteroaralkyl, C3-20 heterocyclylalkyl, Ci-I0 aminoalkyl, C6-I0 aminoaryl, guanidinyl Cj-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 R12 is joined to one another to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring; and,
Preferably, each R13 is independently selected from the group consisting of H, Ci-I0 alkyl, C2-10 alkenyl, C2-I0 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, C6-20 aryl, C]-20 heteroaryl and C2-20 heterocyclyl, C2-20 heteroaralkyl, C3-20 heterocyclylalkyl, Ci-I0 aminoalkyl, C6-I0 aminoaryl, guanidinyl Ci-6 alkyl, C2-I2 alkylguanidinylalkyl, ureayl C]-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 R12 and one of R13 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R13 not joined to R12 is H or Ci-6 alkyl.
Preferably, each R13 is independently selected from the group consisting of H and C1-4 alkyl, or R12 and one of R13 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R13 not joined to R12 is selected from the group consisting of H and Ci-4 alkyl. Preferably R12 and one of R13 are joined to form a group selected from imidazole, dihydroimidazole, tetrahydropyrimidinyl, benzimidazole and triazole.
Preferably, each R13 is independently selected from the group consisting of H and methyl.
Preferably, R12 and one of R13 are joined to form a group selected from imidazole, dihydroimidazole and tetrahydropyrimidinyl. Preferably, R6 comprises a guanidinyl moiety. Preferably, R6 is a group
Figure imgf000020_0001
where R12 and each R13 are H.
Alternatively, R6 is preferably a group -NHCO(Ci-6 alkyl)guanidine or -NHCO(Ci-6 alkyl)amine, more preferably, -NHCO(CH2)2guanidine, -NHCOCH2NH2, -NHCOCH(NH2)(CH(CH3)2) or -NHCOCH2CH2NH2.
Alternatively, R6 is preferably a group -CH2NHCH2CH2N(CH3)2, -CH2NHCH2CH2morpholine, -CH2NHCH2CH2CH2NH2 or -CH2NH2.
In a preferred embodiment, R1 and/or R2 is selected from the group consisting of ((lH-imidazol-2-yl)methylamino)-phenyl, ((lH-imidazol-2-yl)ethylamino)-phenyl,
((lH-imidazol-2-yl)propylamino)-phenyl, (4,5-dihydro-lH-imidazol-2-ylamino)-phenyl,
((4,5-dihydro-lH-imidazol-2-yl)methylamino)-phenyl,
(( 1 H-imidazol-2-yl)methylamino)-phenyloxy, (( 1 H-imidazol-2-yl)ethylamino)-phenyloxy, (( 1 H-imidazol-2-yl)propylamino)-phenyloxy, (4,5-dihydro- 1 H-imidazol-2-ylamino)-phenyloxy,
((4,5-dihydro- 1 H-imidazol-2~yl)memylamino)-phenyloxy, guanidinylphenyloxy and guanidinylphenyl. In the above groups, preferably the phenyl and phenyloxy moieties of the R1 and R2 groups are substituted with the named substituents in the para position relative to the point of attachment of the R1 and R2 groups to the rest of the compound of formula (I). In a preferred embodiment, R1 is selected from the group consisting of (( 1 H-imidazol-2-yl)methylamino)-phenyl, (( 1 H-imidazol-2-yl)ethylamino)-phenyl,
(( 1 H-imidazol-2-yl)propylamino)-phenyl, (4,5-dihydro- 1 H-imidazol-2-ylamino)-phenyl,
((4,5-dihydro-lH-imidazol-2-yl)methylamino)-phenyl and guanidinylphenyl and R1 and R2 are different. In the above groups, preferably the phenyl moiety of the R1 group is substituted with the named substituents in the para position relative to the point of attachment of the R1 group to the rest of the compound of formula (I).
Preferably, when both of R1 and R2 are selected from the group consisting of (a), (b), (c), (ai), (a2) and (a3), they may be the same or different, preferably different. Preferably, when both of R1 and R2 is selected from the group consisting of (a), (b), (c), (ai), (a2) and (a3), they are both (a), (ai) or (a2), more preferably both (a2). When both of R1 and R2 are (a), (ai) or (a2), they may be the same or different, preferably different. Preferably, when R1 is not selected from the group consisting of (a), (b), (c), (at), (a2) and (a3), R1 is 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(C1-6 alkyl), C(O)N(Ci-6 alkyl)2, C(O)NH(C6-I5 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-I5 alkaryl), C(O)N(C7-15 alkaryl)2 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, 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 or 4 groups, independently selected from the groups defined in (vii), (viii) and (ix):
(vii) -CH=CH-, -C≡C-, S, N, -N=, Si(Ci-6 alkyl)2, Si(OH)2, C(O)NH, C(O)N(Cj-6 alkyl), C(O)O, N(Ci-6 alkyl)C(O)N(Ci-6 alkyl), NHC(O)N(C1-6 alkyl), N(C1-6 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;
(viii) COOH, COO(C1-6 alkyl), SH, S(Ci-6 alkyl), SO2H, SO3H, SO2(Ci-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(Ci-6 alkyl), OC(O)(C1-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 alkaryl), OC(O)(C7-20 aralkyl), =O, 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(C7-15 aralkyl), C(O)N(C7-15 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,
(ix) groups independently selected from the group consisting of C1-10 alkyl, C2-I0 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.
Preferably, when R1 is not selected from the group consisting of (a), (b), (c), (Ά{), (a2) and (a3), R1 is not H.
Preferably, when R1 is not selected from the group consisting of (a), (b), (c), (aθ, (a2) and (a3), R1 is selected from the group consisting of Ci-10 alkyl, Ci-10 alkyloxy, C1-I5 heteroaryl, C2-I5 heterocyclyl, C6-20 aryl, C7-20 aralkyl, C3-15 cycloalkyl, C6-20 aryloxy, C7-20 aralkyloxy, C3-I5
(cycloalkyl)alkyl, C3-15 (cycloalkyl)alkyloxy, C6-20 arylamino, C7-20 aralkylamino, C3-!5
(cycloalkyl)alkylamino and C3-I5 (cycloalkyl)amino, 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(C1-4 alkyl)2, NH(C6-16 aryl), N(C6-16 aryl)2, NH(C7-16 aralkyl), N(C7-16 aralkyl)2, NH(C7-16 alkaryl), N(C7-I6 alkaryl)2, N(C1-4 alkyl)(C6-16 aryl), N(C1-4 alkyl)(C7-i6 alkaryl), N(C1-4 alkyl)(C7-16 aralkyl), N(C6-16 aryl)(C7-16 alkaryl), N(C6-16 aryl)(C7-16 aralkyl), S(C1-6 alkyl), NO2, CN, OH, SH, OC)-6 alkyl, C(O)H and C(O)(C1-6 alkyl).
Preferably, when R1 is not selected from the group consisting of (a), (b), (c), (&{), (a2) and (a3), R1 is selected from the group consisting of C7-2O aralkyl, C7-2O aralkyloxy, C7-2O aralkylamino, C3-i5 (cycloalkyl)alkyloxy, Ci-1S heteroaryl and C2-I5 heterocyclyl.
Preferably, when R1 is not selected from the group consisting of (a), (b), (c), (ai), (a2) and (a3), R1 is selected from the group consisting of phenylethyloxy, phenylethylamino, and cyclohexylethyloxy. Preferably, when R2 is not selected from the group consisting of (a), (b), (c), (ai), (a2) and (a3), R2 is selected from the group consisting of H, COOH, COO(C1-6 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(C1-6 alkyl), C(O)N(C-6 alkyl)2, C(O)NH(C6-I5 aryl), C(O)N(C6-15 aryl)2, C(O)NH(C7-15 aralkyl), C(O)N(C7-15 aralkyl)2, C(O)NH(C7-15 alkaryl), C(O)N(C7-15 alkaryl)2 and hydrocarbyl or heterocarbyl groups selected from C1-20 alkyl, C2-2O 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 (x), (xi) and (xii):
(x) -CH=CH-, -C≡C-, S, N, -N=, Si(C1-6 alkyl)2, Si(OH)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), O, CO, SO2, NHSO2 and C(O)NHNH in the backbone; (xi) COOH, COO(C1-6 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)(Ci-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 alkaryl), OC(O)(C7-20 aralkyl), =0, NH2, =NH, NH(C-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(C7-15 aralkyl), C(O)N(C7-15 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,
(xii) 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-I0 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl and C6-20 aryl on the backbone.
Preferably, when R2 is not selected from the group consisting of (a), (b), (c), (ai), (a2) and (a3), R2 is not H. Preferably, when R2 is not selected from the group consisting of (a), (b), (c), (a]), (a2) and (a3), R2 is a group -(CR16R17)ra-X-R18; wherein: m' is O, 1, 2, 3 or 4;
X is a bond, -CH=CH-, -C≡C-, S, N, Si(Ci-6 alkyl)2, Si(OH)2, Si(OC1-6 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(Ci-6 alkyl), NHC(O)N(Ci-6 alkyl), OC(O)N(Ci-6 alkyl), NHC(O)NH, NHC(O)O, NH, N(Ci-I0 alkyl), O, CO, SO2, SO2NH, NHSO2, and C(O)NHNH;
R16 and R17 are independently selected from the group consisting of H, Ci-2O 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, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, Ci-I0 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(C-6 alkyl), SH, S(C-6 alkyl), SO2H, SO2(C-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), P(OH)(O)2, halo, halod-6 alkyl, perhaloC-6 alkyl, OH, 0(C-6 alkyl), =O, NH2, =NH, NH(C-6 alkyl), N(C-6 alkyl)2, =N(C-6 alkyl), NHC(O)(C-6 alkyl), NO2, CN, SO2NH2, C(O)H and C(O)(C]-6 alkyl), C-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; 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, C]-20 alkyl, C2-20 alkenyl, C2-20 alkoxyalkyl, C7-30 alkoxyaryl, C]2-30 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, Cj-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, C]-I0 aminoalkyl, C]-I0 alkylaminoalkyl, C6-20 aminoaryl, guanidine C-I0 alkyl, C2-20 alkylguanidinylalkyl, urea C]-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(C-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, haloC,-6 alkyl, perhaloC,-6 alkyl, OH, 0(C-6 alkyl), =O, 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(C6-12 aryl), C(O)N(C6-12 atyl)2, C(O)NH(C7-12 aralkyl), C(O)N(C7-12 aralkyl)2, C(O)NH(C7-12 alkaiyl), C(O)N(C7-12 alkaiyl)2, NO2, CN, SO2, SO2NH2, C(O)H and C(O)(C1-6 alkyl), CM0 alkyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, C2-10 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C1-20 heteroaryl and C6-20 aryl.
Preferably, m' is O, 1 or 2, more preferably O or 1, most preferably O.
Preferably, X is a bond, NH, N(C1-6 alkyl) or O. In other preferred embodiments, X is -CH=CH-.
Preferably, R16 and R17 are independently selected from the group consisting of H, C1-10 alkyl, C2-20 alkoxyalkyl, C7-20 alkoxyaryl, Ci2-20 aryloxyaryl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, C1-20 heteroaryl, C2-20 heterocyclyl, C2-2O heteroaralkyl and C3-2O heterocyclylalkyl.
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-J0 cycloalkyl, C4-10 heterocyclyl or C1-I0 heteroaryl group.
In other preferred embodiments, R16 and R17 are both H; or R16 is H and R17 is C1-]0 alkyl, preferably methyl.
Preferably, R18 is selected from the group consisting of H, Ci-1O alkyl, C2-I0 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, SH, SO2H, SO2(C1-3 alkyl), SO2(C6-] o aryl), 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, C,.6 alkyl, C2-6 alkoxyalkyl, C7-I0 alkoxyaryl, C3-,o cycloalkyl,
C4-I5 (cycloalkyl)alkyl, C7-I2 aralkyl, C7-I2 alkaryl, C1-I2 heteroaryl and C6-I2 aryl.
Preferably, R18 is a C6-20 aryl group, which is optionally substituted with one or more groups, preferably 1, 2 or 3 groups, most preferably 1 group, independently selected from =0, COOH, SH, SO2H, SO2(C-3 alkyl), SO2(C6-10 aryl), P(OH)(O)2, halo, trihalomethyl, OH, NH2, =NH, NH(C-6 alkyl), =N(C1-6 alkyl), NO2, CN, OCH3, SO2NH2 and C(O)H, C1-6 alkyl, C2-6 alkoxyalkyl, C7-10 alkoxyaryl, C3-I0 cycloalkyl, C4-15 (cycloalkyl)alkyl, C7-12 aralkyl, C7-12 alkaryl, C1-12 heteroaryl and C6-12 aryl, with halo being preferred.
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, cyclohexyhnethyl, phenylethylbenzyl, phenoxybenzyl, phenylethynylbenzyl, cyclohexylbenzyl, pyranyl, tolyl, ethylbenzyl, xylyl, isopropylbenzyl, cyclohexylmethyl, methoxyphenyl, diphenylmethyl, phenethyl, pyridylmethyl, butylphenyl, binaphthyl, adamantyl, propylbenzyl, mesitylyl, ethyltolyl, butylbenzyl, indanyl, diethylbenzyl, methylindanyl, dimethylethylbenzyl, phenylpentyl, tetramethylbenzyl, phenylhexyl, dipropylbenzyl, triethylbenzyl, tetrahydronaphthyl, cyclohexylbenzyl, methylnaphthyl, naphthylmethyl, methyltetrahydronaphthyl, ethylnaphthyl, dimethylnaphthyl, diphenylethyl, diphenylmethyl, propylnaphthyl, butylnaphthyl, phenanthryl, fluoryl, stilbyl, methylfluoryl, benzphenanthryl, triphenyhnethyl, 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, tetrahydrofliranyl, pyranyl, pyronyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, morpholinyl, tbionaphthyl, 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(Ci-6 alkyl), =N(C1-6 alkyl), NO2, CN, OCH3, SO2, SO2NH2 and C(O)H, C1-6 alkyl, C2-6 alkoxyalkyl, C7-10 alkoxyaryl, C3-I0 cycloalkyl, C4-I5 (cycloalkyl)alkyl, C7-I2 aralkyl, C7-J2 alkaryl, Ci-I2 heteroaryl and' C6-I2 aryl.
Preferably, R18 is a phenyl group, which is optionally substituted with one or more groups, preferably 1, 2, 3 or 4 groups, most preferably 1 group, independently selected from =0, COOH, SH, SO2H, P(OH)(O)2, halo, trihalomethyl, OH, NH2, =NH, NH(Ci-6 alkyl), =N(Ci-6 alkyl), NO2, CN, OCH3, SO2, SO2NH2 and C(O)H, C,-6 alkyl, C2-6 alkoxyalkyl, C7-I0 alkoxyaryl, C3-I0 cycloalkyl, C4-I5 (cycloalkyl)alkyl, C7-I2 aralkyl, C7-I2 alkaryl, Ci-I2 heteroaryl and C6-I2 aryl, with halo being preferred.
In a particularly preferred embodiment, m' is O, X is a bond and R18 is a C5-I2 cycloalkyl group. In another preferred embodiment, m' is 1, X is a bond and R18 is a C5-I2 cycloalkyl group. In another preferred embodiment, m' is 1, R16 is H, R17 is C1-1O alkyl, X is a bond and R18 is a C5-12 cycloalkyl group. In this embodiment, R17 is preferably methyl and R18 is preferably hexyl.
In another preferred embodiment, m' is 0, X is a bond and R18 is a Cs-I2 heterocyclyl group which is optionally substituted on the backbone with a group selected from SO2(Ci-3 alkyl) and SO2(C6-10 aryl).
In another preferred embodiment, m' is 0, X is N(Ci-3 alkyl) and R18 is a (Ci-3 alkyl)N(CH2CH2)(S02(C6-io aryl)) group.
In another preferred embodiment, m' is 0, X is a bond and R18 is a Ci-I4 alkyl group. In another preferred embodiment, m' is 0, X is N(Ci-6 alkyl) and R18 is a Ci-6 alkyl group.
In another preferred embodiment, m' is 0, X is N(Ci-6 alkyl) and R18 is a Ci-6 hydroxyalkyl group.
In another preferred embodiment, m' is 0, X is O and R18 is a Cj-6 alkyl group. In another preferred embodiment, m' is 0, X is O and R18 is a Ci-I2 alkoxyalkyl group. In another preferred embodiment, m' is 0, X is O and R18 is a C6-I2 cycloalkylalkyl group.
In another preferred embodiment, m' is 0, X is a bond and R18 is selected from the group consisting of cyclohexyl, cyclohexylmethyl, cyclopentyl, cycloheptyl, cyclododecyl, cyclodecyl, adamantyl, butyl, bycycloheptyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, tetramethylcyclohexyl, morpholinyl, piperidyl, piperazinyl phenyl, toluyl, benzyl, naphthyl, pyranyl, tetramethyltetrahydropyranyl, tetrahydropyranyl, dihydropyranyl, bicyclooctyl, and methylsulphonylpiperazinyl, 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, 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, R3 and R4 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(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, 0(C1-6 alkyl), NH2, NH(Ci-6 alkyl), N(C1-6 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 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, C2-3O 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 (xiii), (xiv) and (xv):
(xiii) -CH=CH-, -OC-, S, -N=, Si(C1-6 alkyl)2, Si(OH)2, C(O)NH, C(O)N(C1-6 alkyl), C(O)O, N(C1-6 alkyl)C(O)N(C)-6 alkyl), NHC(O)N(Ci-6 alkyl), N(C1-6 alkyl)C(O)O, NHC(O)NH,
NHC(O)O, NH, N(C1-6 alkyl), O, CO, SO2, NHSO2 and C(O)NHNH in the backbone;
(xiv) COOH, COO(C1-6 alkyl), SH, S(Cj-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(Ci-6 alkyl), 0(C6-20 aryl), 0(C7-20 alkaryl), 0(C7-20 aralkyl), =0, NH2, =NH,
NH(Ci-6 alkyl), N(Ci-6 alkyl)2,
Figure imgf000027_0001
alkyl), NHC(O)(Ci-6 alkyl), NO2, CN, SO2NH2, SO2NH(Ci-6 alkyl), SO2N(Cj-6 alkyl)2, C(O)H and C(O)(Ci-6 alkyl) on the backbone; and,
(xv) groups independently selected from the group consisting of Ci-I0 alkyl, C2-I0 alkoxyalkyl, C7-20 alkoxyaryl, C12-20 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.
Preferably, R3 and R4 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 Ci-6 alkyl, Cj-6 alkoxy, C2-6 alkoxyalkyl, C7-20 alkoxyaryl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, Ci-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 (xvi), (xvii) and (xviii):
(xvi) 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;
(xvii) =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,
(xviii) groups independently selected from the group consisting of Ci-6 alkyl, C2-6 alkoxyalkyl, C7-10 alkoxyaryl, C3-I0 cycloalkyl, C4-I2 (cycloalkyl)alkyl, C7-I2 aralkyl, C7-I2 alkaryl, Ci-]2 heteroaryl and C6-I2 aryl on the backbone.
Preferably, R4 is selected from the group consisting of C]-6 alkyl, C5-8 cycloalkyl, C]-4 alkoxy, Ci-8 alkoxyalkyl, C7-I0 aralkyl, C7-I0 alkaryl, C6-I0 aryl, Ci-I0 heteroaryl and C2-I0 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(C1-6 alkyl), NO2, CN and C(O)H;
H, F3 Cl, Br, COOH, SH, SO2H, P(OH)(O)2, OH, NH2, NO2, CN, SO3H, SO2NH2 and C(O)H.
Preferably, R4 is selected from the group consisting of H, Q-6 alkyl, Ci-4 alkoxyalkyl, C7-I0 aralkyl, C7-!0 alkaryl, C6-Io aryl, CJ-I0 heteroaryl and C2-io heterocyclyl.
Preferably, R4 is selected from the group consisting of H, methyl, ethyl, propyl, butyl, hexyl, ethoxyethyl and benzyl.
Most preferably, R4 is H.
Preferably, R3 is selected from the group consisting of Ci-4 alkyl, C5-io cycloalkyl, C6-I4 (cycloalkyl)alkyl, Ci-4 alkoxy, Cs-I0 cycloalkyloxy, Cs-I0 cycloalkyloxyalkyl, C6-I4 (cycloalkyl)oxyalkyl, C7-I6 aralkyloxy, C8-I6 aralkyloxyalkyl, C7-I6 aryloxyalkyl, C7-I6 aryloxy, C7-I2 aralkyl, C7-I2 alkaryl, C6-I0 aryl, Ci-I0 heteroaryl and C2-I0 heterocyclyl, any of which are optionally substituted with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from =0, COOH, F, Cl, Br, I, OH, NH2, NH(C1-6 alkyl), NO2, CN, CH3 and C(O)H; H, F, Cl, Br, COOH, SH, SO2H, P(OH)(O)2, OH, NH2, NO2, CN, SO3H, SO2NH2 and C(O)H.
Preferably, R3 is selected from the group consisting of H, Ci-6 alkyl, Cs-I0 cycloalkyl, C6-I4 (cycloalkyl)alkyl, Ci-4 alkoxy, C5-io cycloalkyloxy, C5-I0 cycloalkyloxyalkyl, C6-I4 (cycloalkyl)oxyalkyl, C7-I6 aralkyloxy, C8-I6 aralkyloxyalkyl, C7-I6 aryloxyalkyl, C7-]6 aryloxy, C7-I2 aralkyl, C7-I2 alkaryl, C6-I0 aryl, Ci-I0 heteroaryl and C2-I0 heterocyclyl. Preferably, R3 is selected from the group consisting of H, phenylethyl, phenylpropyl, phenylbutyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclohexyl optionally substituted with 1, 2, 3 or 4 methyl groups, (cyclohexyl)Ci-3 alkyl wherein the cycloalkyl moiety is optionally substituted with 1, 2, 3 or 4 methyl groups, (cyclohexyl)oxy(C]-3 alkyl) wherein the cycloalkyl moiety is optionally substituted with 1, 2, 3 or 4 methyl groups, (cycloheptyl)oxy Ci-3 alkyl, adamantyl, adamantylmethyl, adamantylethyl, adamantylpropyl, adamantylbutyl, naphthyl, phenyl, pyridyl, benzyl, tolyl, benzyloxymethyl, phenylethyloxy, xylyl, pyridinyl, pyranyl, tetrahydropyranyl, dihydropyranyl, furanyl, hydroxyphenyl, phenylamino, acetamido, benzylamido and benzylamino.
Preferably, R3 is phenylpropyl. In other preferred embodiments, R3 is benzyloxymethyl. In a particularly preferred embodiment, R4 is H, R3 is phenylpropyl, R1 is (4,5-dihydro-lH-imidazol-2-ylamino)-phenyl or guanidinylphenyl, and R2 is C4-20 alkyl or C5-I6 cycloalkyl. In a particularly preferred embodiment, R4 is H, R3 is phenylpropyl, R1 is (4,5-dihydro-lH-irnidazol-2-ylamino)-phenyl, and R2 is C6-I3 alkyl.
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 1-6, or the general methods disclosed in DJ. Brown, "The Chemistry of Heterocyclic Compounds, The Pyrimidines", Wiley, New York, (1970) or by combinations thereof.
Pyrimidines (III) are prepared by reaction of a suitable 1,3-difunctional reagents, and a suitable amidine (Scheme 1) (wherein R2' and R3' represent R2 and R3 respectively or a suitable precursor thereof). When a β-keto ester (I) is used as a suitable 1,3-difunctional reagent, chlorination of the pyrimidine (III) with phosphorus oxychloride or other suitable chlorinating agent affords the chloropyrimidine (IV). Suzuki reaction with an aromatic boronic acid or boronic acid ester affords the aryl substituted pyrimidine (V) (wherein R6' represents R6 or a suitable precursor thereof). Modification of R2', R3' and/or R6' affords the desired pyrimidines (VII).
Reaction scheme 1
Figure imgf000029_0001
R6' substituents 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 by 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 carboxylic acid esters that can be converted to amide derivatives via the corresponding acid. Other suitable R6' substitents include CHO that can be further modified to the required R6 group by, amongst others, reductive amination or converted to ethers via reduction to the corresponding alcohol. 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. Suitable R3' substituents include carboxylic acid esters that can be converted to amide derivatives via the corresponding acid.
When n = 1, treatment of the chloropyrimidine (IV) with a suitable phenol affords the phenoxy substituted pyrimidine (VIII) (Scheme 2). Modification of R2', R3' and/or R6' affords the desired pyrimidines (X).
Reaction scheme 2
M
Figure imgf000031_0001
When the R3 substituent is an amine or alkoxy substituent linked to the pyrimidine ring by nitrogen or oxygen respectively, these can be obtained via the intermediate chloropyrimidine (XII), prepared by an analogous route to the preparation of (IV) (Scheme 3). Treatment of the chloropyrimidine (XIII) with a suitable amine or alcohol affords the amino or alkoxy- substituted pyrimidine (XIV). Modification of R1', R2' and/or R3'X affords the desired pyrimidines (XVI).
Reaction scheme 3
Figure imgf000031_0002
(XIII)
Modify R3X &/or R2' Modify R1'
Figure imgf000031_0003
Figure imgf000031_0004
(XVI)
(XV)
When the R substituent is an amine or alkoxy substituent linked to the pyrimidine ring by nitrogen or oxygen respectively, these can be obtained via the intermediate thioalkylpyrimidine (XVII) (Scheme 4) (J.L. Adams et al., Bioorg. Med. Chem. Letts., (1998), 8, 3111). (XVII) can be prepared by reaction of a suitable 1,3-difunctional reagent (I) and thiourea, in an analogous route to the preparation of (IV) (Scheme 1). Oxidation of the thiomethylpyrimidine intermediate (XIX) to the methylsufonylpyrimidine (XX) can be achieved with m- chloroperoxybenzoic acid or other suitable oxidising agent. Treatment of (XX) with a suitable amine or alcohol affords the amino or alkoxy-substituted pyrimidine (XXI). Modification of R1', R2'X and/or R6' affords the desired pyrimidines (XXIII).
Reaction scheme 4
Figure imgf000032_0001
(XXIII)
(XXII)
Alternatively, when the R2 substituent is an amine or alkoxy substituent linked to the pyrimidine ring by nitrogen or oxygen respectively, these can be obtained via the chloropyrimidine intermediate (XXVI) (Scheme 5). (XXVI) can be obtained from 2,4,6- tiichloropyrimidine (XXIV) via (XXV) by sequential Suzuki reactions. Treatment of (XXVI) with a suitable amine or alcohol affords the amino or alkoxy-substituted pyrimidine (XXVII), following which, R6', R2'X and/or R3" can be modified to obtain the desired pyrimidines (XXIII) according to the method of scheme 4.
Reaction scheme 5
Figure imgf000033_0001
Similarly, the 4,6-dichloropyrimidine intermediate (XXX) can be obtained from the substituted malonic acid diester (XXVIII) (Scheme 6). The desired pyrimidines (XXIII) can be obtained from (XXX) by sequential Suzuki reactions (as in scheme 5), or when the R3 and/or R1 substituent is an amine or alkoxy substituent linked to the pyrimidine ring by nitrogen or oxygen respectively, by base-catalysed reaction using a suitable amine or alcohol (as in scheme 3), or by a combination of methods thereof.
Reaction scheme 6
Figure imgf000033_0002
(XXVIII)
(XXIX) (XXX)
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 herein before, 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 herein before, 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 herein before, 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-drug thereof, substantially as described herein before.
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 herein before.
In 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 herein before.
In 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 herein before. 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-drug thereof, substantially as described herein before.
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 herein before.
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 herein before. 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 herein before, in the manufacture of a medicament for the prophylaxis or treatment of any of the diseases described herein before.
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. ScL, 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 tiOmethamine.
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 (I). 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-drugs may be found in Stella, V. J. et al, "Prodrugs", Dmg Delivery System, 1985, pp. 112-176, Drugs, 1985, 29, pp. 455-473 and "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
Pro-drug forms of the pharmacologically-active compounds of the invention will generally be compounds according to formula (I) 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 imgf000036_0001
Amidated acid groups include groups of the formula -CONRbRc, wherein Rb is H, C1-S alkyl, phenyl, substituted phenyl, benzyl, or substituted benzyl, and Rc is -OH or one of the groups just recited for Rb. Compounds of formula (I) 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 free 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(Ci-6 alkyl)2], it is understood that the two alkyl groups may be the same or different. Similarly, reference to other dihydrocarbyl or diheterocarbyl groups should be interpreted such that the two groups may be the same or different.
Foπnulaic 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 R2 is -(CR16R17V-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:
Figure imgf000038_0001
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 imgf000038_0002
Figure imgf000038_0003
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 halo(Ci-6 alkyl) includes mono-, di- or tri-halo substituted Cj-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 R3, R4, R5, R7, R10, R11, R12, R13, R16, R17 and R18 are unsubstituted, in or on the backbone. In 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.
In 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.
In 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.
In 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 substirαent, as defined herein. In one embodiment, preferably the group R11 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 R12 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 R13 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 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 "Ci-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. In 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 term "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, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, methylcyclohexylmethyl, dimethylcyclohexylmethyl, trimethylcyclohexylmethyl, cycloheptylmethyl, 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 term "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, tolylmethyl, fluorophenethyl, fluorenylmethyl, methoxyphenethyl, dimethoxybenzyl, dichlorophenethyl, phenylethylbenzyl, isopropylbenzyl, diphenylmethyl, propylbenzyl, butylbenzyl, dimethylethylbenzyl, phenylpentyl, tetramethylbenzyl, phenylhexyl, dipropylbenzyl, triethylbenzyl, cyclohexylbenzyl, naphthylmethyl, diphenylethyl, triphenylmethyl 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 may be 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 terai "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.
With regard to one or more 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.
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.
Other 'compound' group definitions will be readily understandable by the skilled person based on the previous definitions and the usual conventions of nomenclature.
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 (NH4)2SO4, 2mM MgCl2, 0.2mM dNTP containing O.lμM 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 (Invitrogen) 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/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-B iotech 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 imgf000049_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) (Invitrogen), containing 2mM Glutamaxl (Invitrogen), 10% heat-inactivated foetal bovine serum (Invitrogen), Ix non-essential amino acids (Invitrogen). 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 PTH] 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 mr'and [125I]-[NIe8'18, Tyr34]-hPTH(l-34) concentration of 2OpM. In 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 -7O0C. When required, aliquots were thawed, by mixing with ice-cold buffer A. (5OmM Tris-HCl, pH7.2 at 210C; 3mM MgCl2, 3mM CaCl2, 3mM KCl and 3mg ml'1 bacitracin). The cell/membrane suspension was centrifuged (20min, 20,00Og @ 40C; 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(I-34) (50μl; lOμM). For competition and saturation studies, membranes were incubated for 210min at 210C, in final volume of 0.5ml, [125I]-[NIe8'18, Tyr34]-hPTH(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(l-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 PTHi receptor reached equilibrium after 70min at 210C (n=3) and was saturable (pKo=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 PTHi 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 (TLH) 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. hi practice pICso values are equivalent to pKi values due to the low occupancy of the radioligand.
The pKi values for reference compounds are shown in the table below.
Figure imgf000051_0001
* error is standard deviation The following compounds have been synthesised in accordance with the present invention.
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
The following compounds have also been synthesised in accordance with the present invention.
Figure imgf000059_0001
5 The synthesis of the above-identified compounds shall now be described in detail. Experimental
Column chomatography 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 (5H) were recorded relative to an internal standard. 0 Example 1 {4-[2-Cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4, 5-dihydro-lH- imidazol-2yl) -amine
Step a 2-Cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-ol
Clean sodium (460mg, 20mmol) was dissolved in dry MeOH (2OmL) under argon. 3-oxo-6- phenyl-hexanoic acid ethyl ester (2.34g, lOmmol) and cyclohexylamidine.HCl (1.62g, 5 lOmmol) were added and the mixture heated at reflux for 2h. The solvent was evaporated and the residue was taken up in H2O (5OmL), the solution acidified to pH 4 with dilute HCl, and extracted with DCM (2 x 4OmL). The organic extract was washed with brine and dried (MgSO4). Filtration and evaporation of the solvent afforded the desired product (2.59g, 84%). 1H NMR ((J6 DMSO) 12.08 (IH, bs), 8.98 (IH, s), 7.29-7.13 (5H, m), 5.95 (IH, s), 2.58 (2H, t), 0 2.48 (IH, m), 2.40 (2H, t), 1.86 (2H, m), 1.80-1.22 (1OH, m). Step b 4-Chloro-2-cyclohexyl-(3-phenyl-propyl)-pyrimidine
A solution of 2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-ol (2.49g, 8.41mmol), and N,N- dimethylaniline (1.08mL, 8.41mmol), in POCl3 (2OmL) was refluxed for 2h. On cooling the mixture was poured into H2O (10OmL) and extracted with EtOAc (10OmL). The extract was washed with H2O (2 x 10OmL) and dried (MgSO4). Filtration and evaporation of the solvent afforded the desired product (2.44g, 92%). 1H NMR (CDCl3) 7.32-7.18 (5H, m), 6.97 (IH, s), 2.83 (IH, m), 2.77-2.67 (4H, m), 2.09 (2H, m), 2.00-1.27 (1OH, m).
Step c 4-[2-Cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine
A mixture of 4-chloro-2-cyclohexyl-(3-phenyl-propyl)-pyrimidine (1.26g, 4mmol), 4-(4,4,5,5- tetramethyl-l,3,2,-dioxaborolan-2-yl)aniline (l.lg, 5mmol), K2CO3 (l.lg, 8mmol) and
Pd(PPh3)4 (200mg) in DME-EtOH (1:1, 4OmL) was heated at reflux under argon for Ih. The mixture was concentrated in vacuo and the residue suspended in between H2O-EtOAc (1:1,
10OmL). The organic layer was separated and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chomatography (DCM-Hexane-EtOAc (9:9:2)) (760mg, 51%). 1H NMR (CDCl3) 7.96 (2H, d), 7.32-7.19 (6H, m), 6.73 (2H, d), 3.92
(2H, bs), 2.78 (IH, m), 2.75-2.13 (4H, m), 2.01 (2H, m), 2.00-1.30 (1OH, m).
Step d fyN'-bis-ftert-ButoxycarbonylJ-^-fi-cyclohexyl-ό-βψhenylψropylJφyiiinidin^-ylJ- phenyl}-(4,5-dihydro-lH-imidazol-2yl)-amine
A mixture of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine (549mg, 1.58mmol), N,N-tø-(fer^butoxycarbonyl)-imidazolidine-2-thione (454mg, 1.5mmol), NEt3
(414μL, 3mmol) and Hg(II)Cl2 (0.4Og, 1.5mmol) in DCM (5mL) was stirred at rt for 3d. The mixture was filtered to remove inorganic salts, and the filtrate was evaporated. The residue was purified by chomatography (Hexane-Me2CO (4:1)) to afford the product, (425mg, 45%). 1H
NMR (CDCl3) 8.03 (2H, d), 7.31-7.19 (6H, m), 7.07 (2H, d), 3.85 (4H, s), 2.88-2.70 (5H, m), 2.13-1.25 (12H, m), 1.34 (18H, s).
Step e A solution of iV,7V-6/>s-(tert-butoxycarbonyl)-{4-[2-cyclohexyl-6-(3-plienyl- propyl)-pyrimidin-4-yl]-phenyl}-(4,5-dihydro-lH-imidazol-2yl)-amine (435mg,
0.67mmol) in 4M HCl in dioxan (5mL) was stirred at rt for 2h. Filtration and evaporation to dryness gave the crude product which on trituration with Et2O afforded the title compound as its HCl salt (284mg, 77%). 1H NMR (d6 DMSO) 11.49 (IH, s), 8.67 (2H, s), 8.33 (2H, d), 8.10 (IH, s), 7.47 (2H, d), 7.28-7.12 (5H, m), 3.69 (4H, s), 3.15 (IH, s), 2.97 (2H, t), 2.68 (2H, t), 2.11 (2H, m), 2.00-1.20 (1OH, m). Found: C 59.71, H 6.77, N 12.16%; C28H33N5-3HC1-H2O requires: C 59.31, H 6.75, N 12.35%.
Example 2 {4-[2-Adamantan-l-yl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4,5-dihydro- lH-imidazol-2-yl) -amine
The title compound was obtained as its HCl salt using the procedure described in example 1, except that 1-adamantylamidine.HCl was used instead of cyclohexylamidine.HCl in step a. 1H NMR (d6 DMSO) 11.32 (IH, s), 8.58 (IH, s), 8.55 (2H, bs), 8.33 (2H, d), 8.10 (IH, s), 7.47 (2H, d), 7.28-7.13 (5H, m), 3.68 (4H, s), 3.16 (IH, m), 2.96 (2H, t), 2.68 (2H, t), 2.14 (3H, s), 2.09 (6H, s), 2.01 (2H, m), 1.75 (6H, m). Found: C 65.71, H 7.20, N 12.16%; C32H37N5^HCl- H2O requires: C 65.97, H 7.09, N 12.02%.
Example 3 {4-[2-Cyclohexylmethyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4,5-dihydro- lH-imidazol-2-yl) -amine
The title compound was obtained as its HCl salt using the procedure described in example 1, except that cyclohexylmethylamidine.HCl was used instead of cyclohexylamidine.HCl in step a. 1H NMR (d6 DMSO) 10.98 (IH, s), 8.50 (2H, s), 8.28 (2H, d), 8.10 (IH, s), 7.40 (2H, d), 7.30-7.14 (5H, m), 3.69 (4H, s), 2.96 (2H, t), 2.80 (2H, d), 2.67 (2H, t), 2.01 (2H, m), 2.00 (IH, m), 1.67-1.00 (1OH, m). Found: C 64.02, H 7.40, N 12.90%; C29H39N5^HCl-H2O requires: C 63.96, H 7.22, N 12.86%. Example 4 {4-[2-Cyclopentyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4, 5-dihydro-lH- imidazol-2-yl) -amine
The title compound was obtained as its HCl salt using the procedure described in example 1, except that cyclopentylamidine.HCl was used instead of cyclohexylamidine.HCl in step a. 1H NMR (d6 DMSO) 11.07 (IH, s), 8.52 (2H, s), 8.26 (2H, d), 7.85 (IH, s), 7.40 (2H, d), 7.30- 7.14 (5H, m), 3.69 (4H, s), 3.46 (IH, m), 2.83 (2H, m), 2.67 (2H, t), 2.01 (2H, m), 1.94-1.67 (8H, m). Found: C 62.85, H 7.01, N 13.61%; C27H3 ,N5-2HC1-H2O requires: C 62.79, H 6.83, N 13.56%.
Example 5 {4-[2-tert-Butyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4,5-dihydro-lH- imidazol-2-yl)-amine The title compound was obtained as its HCl salt using the procedure described in example 1, except that te/t-butylamidine.HCl was used instead of cyclohexylamidine.HCl in step a. 1H NMR (d6 DMSO) 11.18 (IH, s), 8.53 (IH, s), 8.26 (2H, d), 7.77 (IH, s), 7.40 (2H, d), 7.30- 7.14 (5H, m), 3.69 (4H, s), 2.83 (2H, m), 2.67 (2H, t), 2.01 (2H, m), 1.43 (9H, s). Found: C 61.81, H 7.20, N 13.71%; C26H3-N5^HCl-H2O requires: C 61.90, H 7.00, N 13.88%.
Example 6 {4-[2-Bicyclo[2.2. l]hept-2-yl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4, 5- dihydro-lH-imidazol-2-yl)-amine
The title compound was obtained as its HCl salt using the procedure described in example 1, except that 2-norbornylamidine.HCl was used instead of cyclohexylamidine.HCl in step a. 1H NMR (d6 DMSO) 11.02 (IH, s), 8.49 (IH, s), 8.26 (2H, d), 7.81 (IH, s), 7.40 (2H, d), 7.30- 7.14 (5H, m), 3.69 (4H, s), 3.00 (IH, m), 2.83 (2H, m), 2.67 (2H, t), 2.01 (2H, m), 1.85-1.00 (1OH, m). Found: C 64.15, H 6.90, N 12.71%; C29H33N5^HCl-H2O requires: C 64.20, H 6.87, N 12.91%.
Example 7 (4,5-Dihydro-lH-imidazol-2-yl)-{4-[2-isobutyl-6-(3-phenyl-propyl)-pyrimidin-4- yl) ' -phenyl) -amme
The title compound was obtained as its HCl salt using the procedure described in example 1, except that isobutylamidine.HCl was used instead of cyclohexylamidine.HCl in step a. 1H NMR (d6 DMSO) 11.18 (IH, s), 8.54 (IH, s), 8.26 (2H, d), 7.94 (IH, s), 7.40 (2H, d), 7.30- 7.14 (5H, m), 3.69 (4H, s), 3.00 (IH, m), 2.83 (4H, m), 2.64 (2H, t), 2.25 (IH, m), 2.01 (2H, m), 0.92 (6H, d). Found: C 61.81, H 6.90, N 13.70%; C26H31N5 -2HCl-H2O requires: C 61.90, H 7.00, N 13.88%.
Example 8 (4,5-Dihydro-lH-imidazol-2-yl)-{4-[2-heptyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]- phenylj-amine
The title compound was obtained as its HCl salt using the procedure described in example 1, except that n-heptylamidine.HCl was used instead of cyclohexylamidine.HCl in step a. 1H NMR (d6 DMSO) 10.99 (IH, s), 8.49 (IH, s), 8.26 (2H, d), 7.82 (IH, s), 7.40 (2H, d), 7.30- 7.14 (5H, m), 3.66 (4H, s), 2.89 (2H, t), 2.79 (2H, t), 2.61 (2H, t), 2.01 (2H, m), 1.80 (2H, m), 1.29-1.21 (8H, m), 0.80 (3H, t). Found: C 63.62, H 7.65, N 12.75%; C29H37N5-2HC1-H2O requires: C 63.73, H 7.56, N 12.81%. Example 9 {4-[2-Cyclododecyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4, 5-dihydro-lH- imidazol-2-yl)-amine
The title compound was obtained as its TFA salt using the procedure described in example 1, except that cyclododecylamidine.HCl was used instead of cyclohexylamidine.HCl in step a and TFA was used instead of HCl in dioxan in step e. 1H NMR (d6 DMSO) 10.81 (IH, s), 8.55 (IH, s), 8.26 (2H, d), 7.75 (IH, s), 7.40 (2H, d), 7.30-7.14 (5H, m), 3.69(4H, s), 3.09 (IH, m), 2.79 (2H5 1), 2.64 (2H, t), 2.01 (2H, m), 2.00-1.30 (22H, m). Found: C 58.15, H 6.10, N 8.41%; C34H45N5-2.4CF3COOH-0.5dioxan requires: C 58.23, H 6.16, N 8.32%.
Example 10 (4, 5-Dihydro-lH-imidazol-2-yl)-{4-[6-(3-phenyl-propyl)-2-(3, 3, 5, 5-tetramethyl- cyclohexyl)-pyrimidin-4-yl]-phenyl}-amine
The title compound was obtained as its TFA salt using the procedure described in example 1, except that 3,3,5, 5-tetramethylcyclohexylamidine.HCl was used instead of cyclohexylamidine.HCl in step a and TFA was used instead of HCl in dioxan in step e. 1H NMR (d6 DMSO) 11.02 (IH, s), 8.66 (2H, s), 8.26 (2H, d), 7.76 (IH, s), 7.40 (2H, d), 7.30- 7.14 (5H, m), 3.70(4H, s), 3.16 (IH, m), 2.79 (2H, t), 2.66 (2H, t), 2.01 (2H, m), 1.70-1.30 (6H, m), 1.16 (6H, s), 0.93 (6H, s). Found: C 56.85, H 5.68, N 8.38%; C32H4IN5- 2.5CF3COOH-0.5dioxan requires: C 56.79, H 5.80, N 8.49%.
Example 11 (4,5-Dihydro-lH-imidazol-2-yl)-{4-[2-(l-hexyl-heptyl)-6-(3-phenyl-propyl)- pyrimidin-4-yl] -phenylj-amine The title compound was obtained as its HCl salt using the procedure described in example 1, except that 1-hexyl-heptylamidine.HCl was used instead of cyclohexylamidine.HCl in step a. 1H NMR (d6 DMSO) 11.23 (IH, s), 8.56 (IH, s), 8.28 (2H, d), 7.90 (IH, s), 7.42 (2H, d), 7.30- 7.14 (5H, m), 3.69(4H, s), 3.02 (IH, m), 2.87 (2H, t), 2.60(2H, t), 2.06 (2H, m), 1.80 (2H, m), 1.65 (2H, m), 1.15 (16H, m), 0.76 (6H, t). Found: C 64.79, H 8.25, N 10.75%; C34H49N5-SHCl requires: C 64.55, H 8.35, N 10.75%.
Example 12 (4,5-Dihydro-lH-imidazol-2-yl)-{4-[2-(l-methyl-octyl)-6-(3-phenyl-propyl)- pyήrnidin-4-y IJ -phenyl} -amine
The title compound was obtained as its HCl salt using the procedure described in example 1 , except that 1-methyloctylamidine.HCl was used instead of cyclohexylamidine.HCl in step a. 1H NMR (CDCl3) 8.06 (2H, d), 7.32-7.17 (8H, m), 3.78 (4H, s), 3.03 (IH, m), 2.81-2.69 (4H, 2xt), 2.13 (2H, m), 1.90 (IH, m), 1.63 (IH, m), 1.36 (3H, d), 1.30 (1OH, m), 0.86 (3H, t). Found: C 62.99, H 7.59, N 11.60%; C3iH4iN5-2HCl-2H2O requires: C 62.83, H 7.99, N 11.81%.
Example 13 N-{4-[2-Cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-guanidine The title compound was obtained as its HCl salt using the procedure described in example 1, except that l,3-δw('te?t-butoxycarbonyl)-2-methyl-thiopseudourea instead of N,N-bis-(tert- butoxycarbonyl)-imidazolidine-2-thione in step d. 1H NMR (d6 DMSO) 10.03 (IH, s), 8.27 (2H, d), 7.88 (IH, s), 7.72 (4H, bs), 7.40 (2H, d), 7.30-7.16 (5H, m), 2.92 (IH, m), 2.84 (2H, t), 2.69 (2H, t), 2.07 (2H, m), 2.00-1.00 (1OH, m). Found: C 64.23, H 6.94, N 14.51%; C26H3iN5- 2HCl requires: C 64.19, H 6.84, N 14.40%.
Example 14 N-{4-[2-Cycloheptyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-guanidine
The title compound was obtained as its HCl salt using the procedure described in example 1, except that cycloheptylamidine.HCl was used instead of cyclohexylamidine.HCl in step a, and l,3-όώ^ert-butoxycarbonyl)-2-methyl-thiopseudourea was used instead of N,N'-bis-(tert- butoxycarbonyl)-imidazolidine-2-thione in step d. 1H NMR (d6 DMSO) 10.36 (IH, s), 8.28
(2H, d), 7.91 (IH, s), 7.73 (4H, bs), 7.38 (2H5 d), 7.30-7.16 (5H, m), 3.10 (IH, m), 2.86 (2H, t)
2.64 (2H, t), 2.07 (2H, m), 2.00-1.50 (12H, m). Found: C 65.12, H 6.75, N 14.01%; C27H33N5- 2HCl requires: C 65.05, H 6.67, N 14.05%.
Example 15 N-{4-[2-Heptyl-6-(3-phenyl-propyl)-pyrinιidin-4-yl]-phenyl}-guanidine
The title compound was obtained as its TFA salt using the procedure described in example 1 , except that n-heptylamidine.HCl was used instead of cyclohexylamidine.HCl in step a, 1,3- έώ^te7^-butoxycarbonyl)-2-methyl-thiopseudourea was used instead of N,N'-bis-(tert- butoxycarbonyl)-imidazolidine-2-thione in step d and TFA was used instead of HCl in dioxan in step e. 1H NMR (d6 DMSO) 8.24 (2H, d), 7.75 (IH, s), 7.38 (2H, d), 7.30-7.16 (5H, m), 2.85 (2H, t), 2.79 (2H, t), 2.64 (2H, t), 2.04 (2H, m), 1.78 (2H, m), 1.30 (8H, m), 0.80 (3H, t). Found: C 52.32, H 5.37, N 9.77%; C27H35N5-2CF3COOH-0.9DCM requires: C 52.15, H 5.33, N 9.54%. Example 16 N-{4-[2-Cyclopentyl-6-(3-phenyl-propyl)~pyrimidin-4-ylJ-phejiyl}-guanidine
The title compound was obtained as its TFA salt using the procedure described in example 1, except that cyclopentylamidine.HCl was used instead of cyclohexylamidine.HCl in step a, 1,3- έzs(W^butoxycarbonyl)-2-methyl-thiopseudourea was used instead of N,N'-bis-(tevt- butoxycarbonyl)-imidazolidine-2-thione in step d and TFA was used instead of HCl in dioxan in step e. 1H NMR (d6 DMSO) 8.24 (2H, d), 7.73 (IH, s), 7.56 (IH, s), 7.38 (2H, d), 7.30-7.20 (5H, m), 3.38 (IH, m), 2.77 (2H, t), 2.64 (2H, t), 2.04 (2H, t), 2.00-1.66 (1OH, m). Found: C 51.01, H 4.55, N 9.93%; C25H29N5-2.8CF3COOH requires: C 51.13, H 4.46, N 9.74%.
Example 17 N-{4-[2-Isobutyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-guanidine
The title compound was obtained as its HCl salt using the procedure described in example 1, except that isobutylamidine.HCl was used instead of cyclohexylamidine.HCl in step a, and 1,3- 6w(?er^-butoxycarbonyl)-2-methyl-thiopseudourea was used instead of N,N-bis-(tert- butoxycarbonyl)-imidazolidine-2-thione in step d. 1H NMR (d6 DMSO) 11.18 (IH, s), 8.54 (IH, s), 8.26 (2H, d), 7.81 (IH, s), 7.64 (IH, bs), 7.40 (2H, d), 7.30-7.14 (5H, m), 3.00 (IH, m), 2.83 (4H, m), 2.64 (2H, t), 2.25 (IH, m), 2.01 (2H, m), 0.92 (6H, d). Found: C 50.59, H 6.08, N 9.87%; C24H29N5-2HCl-1.9DCM-1.0dioxan requires: C 50.63, H 5.92, N 9.75%.
Example 18 N-ft-ft-Cyclodecyl-ό-β-phenyl-propylJ-pyrimidin^-ylJ-phenylJ-guanidine
The title compound was obtained as its TFA salt using the procedure described in example 1, except that cyclodecylamidine.HCl was used instead of cyclohexylamidine in step a, 1,3- tø(ϊer^butoxycarbonyl)-2-methyl-thiopseudourea was used instead of N,N'-bis-(tert- butoxycarbonyl)-imidazolidine-2-thione in step d and TFA was used instead of HCl in dioxan in step e. 1H NMR (d6 DMSO) 8.26 (2H, d), 7.75 (IH, s), 7.36 (2H, d), 7.30-7.14 (5H, m), 3.26
(IH, m), 2.78 (2H, t), 2.64 (2H, t), 2.01 (2H, m), 2.00-1.30 (18H, m). Found: C 57.82, H 5.92, N 9.50%; C3oH39N5-2.1CF3COOH-0.3dioxan requires: C 57.80, H 5.96, N 9.52%.
Example 19 N-{4-[6-(3-Phenyl-propyl)-2-(3, 3, 5, 5-tetramethyl-cyclohexyl)-pyrimidin-4-yl]- phenylj-guanidine
The title compound was obtained as its TFA salt using the procedure described in example 1, except that 3.3,5,5-tetramethylcyclohexylamidine.HCl was used instead of cyclohexylamidine.HCl in step a, l,3~&zsffer£-butoxycarbonyl)-2-methyl-thiopseudourea was used instead of N,N-έώ-(1fe/t-butoxycarbonyl)-imidazolidme-2-thione in step d and TFA was used instead of HCl in dioxan in step e. 1H ΝMR (d6 DMSO) 8.25 (2H, d), 7.78(1H, s), 7.37 (2H, d), 7.30-7.14 (5H, m), 3.17 (IH, m), 2.79 (2H, t), 2.64 (2H, t), 2.01 (2H, m), 1.66-1.00 (6H, m), 1.05 (6H, s), 0.90 (6H, s). Found: C 56.85, H 5.68, Ν 8.33%; C32RnN5- 2.5CF3COOH-0.5dioxan requires: C 56.79, H 5.80, N 8.49%.
Example 20 N-{4-[2-Cyclododecyl-6-(3-phenyl-propyl)-pyrimidin-4-ylJ-phenyl}-guanidine
The title compound was obtained as its HCl salt using the procedure described in example 1, except that cyclododecylamidine.HCl was used instead of cyclohexylamidine.HCl in step a and l,3-£»ώfte7^-butoxycarbonyl)-2-methyl-thiopseudourea was used instead of N,N'-bis-(tert- butoxycarbonyl)-imidazolidine-2-thione in step d. 1H NMR (d6 DMSO) 10.10 (IH, s), 8.26 (2H3 d), 7.75 (IH, s), 7.62 (4H, bs), 7.36 (2H, d), 7.30-7.14 (5H, m), 3.10 (IH, m), 2.78 (2H, t), 2.64 (2H, t), 2.01 (2H, m), 1.90-1.25 (22H, m). Found: C 64.36, H 7.80, N 11.33%; C32H43N5- 2.8HC1 requires: C 64.04, H 7.69, N 11.66%.
Example 21 {4-[2-Cyclohexyl-6-(3-methyl-butyl)-pyrimidin-4-yl]-phenyl}-(4, 5-dihydro-lH- imidazol-2-yϊ) -amine
The title compound was obtained as its HCl salt using the procedure described in example 1, except that 6-methyl-3-oxo-heptanoic acid ethyl ester was used instead of 3-oxo-6-phenyl- hexanoic acid ethyl ester in step a. 1H NMR (CDCl3) of free base, 8.06 (2H, bs), 7.97 (2H, d), 7.21 (IH, s), 7.14 (2H, d), 3.60 (4H, s), 2.82 (IH, m), 2.69 (2H, t), 2.03-1.25 (13H5 m), 0.94 (6H, d). Found: C 60.58, H 7.59, N 14.68%; C24H33N5-2.3HC1 requires: C 60.63, H 7.48, N 14.73%.
Example 22 {4-[2-Cyclohexyl-6-(3, 3, 5, 5-tetramethyl-cyclohexyl)-pyrimidin-4-yl]-phenyl}-(4, 5- dihydro-lH-imidazol-2-yl)-amine
The title compound was obtained as its HCl salt using the procedure described in example 1, except that 3-oxo-3-(3,3,5,5-tetramethyl-cyclohexyl)-propionic acid ethyl ester was used instead of 3-oxo-6-phenyl-hexanoic acid ethyl ester in step a. 1H NMR (d6 DMSO) 11.06 (IH, s), 8.52 (2H, s), 8.31 (2H, d), 7.85 (IH, s), 7.41 (2H, d), 3.69 (4H, s), 3.20 (IH, m), 2.95 (IH, m), 2.00-1.10 (16H, m), 1.09 (6H, s), 0.94 (6H, s). Found: C 61.26, H 7.99, N 11.95%; C29H4iN5-3HCl requires: C 61.21, H 7.79, N 12.30%.
Example 23 {4-[6-(2-Adamantan-l-yl-ethyl)-2-cyclohexyl-pyrimidin-4-yl]-phenyl}-(4, 5- dihydro-lH-imidazol-2-yl)-amine
The title compound was obtained as its HCl salt using the procedure described in example 1 , except that 5-adamantan-l-yl-3-oxo-pentanoic acid ethyl ester was used instead of 3-oxo-6- phenyl-hexanoic acid ethyl ester in step a. 1H NMR (d6 DMSO) 11.33 (IH, s), 8.61 (2H, s), 8.32 (2H, d), 8.05 (IH, s), 7.44 (2H, d), 3.69 (4H, s), 3.04 (IH, m), 2.81 (2H, m), 2.10-1.25 (27H, m). Found: C 60.89, H 7.66, N 11.15%; C31H41N5-3HC1-H2O requires: C 60.93, H 7.59, N 11.46%. Example 24 {4-[2-Cyclohexyl-6-(3 , 3, 5, 5-tetramethyl-cyclohexylmethyl)-pyrimidin~4-yl]- phenyl}-(4,5-dihydro-lH-imidazol-2-yl)-amine
The title compound was obtained as its HCl salt using the procedure described in example 1 , except that 3-oxo-4-(3,3,5,5-tetramethyl-cyclohexyl)-butyric acid ethyl ester was used instead of 3-oxo-6-phenyl-hexanoic acid ethyl ester in step a. 1H NMR (d6 DMSO) 11.41 (IH, s), 8.63 (2H, s), 8.33 (2H, d), 8.05 (IH, s), 7.45 (2H, d), 3.69 (4H, s), 3.10 (IH, m), 2.76 (2H, m), 2.25 (IH, m), 2.00-0.75 (16H, m), 0.97 (6H, s), 0.83 (6H, s). Found: C 60.31, H 8.13, N 11.45%; C30H43N5-SHCl-H2O requires: C 59.94, H 8.04, N 11.65%.
Example 25 N- [4-(2-Cyclohexyl-6-naphthalen-2-ylmethyl-pyrimidin~4-yl)-phenyl]-guanidine
The title compound was obtained as its TFA salt using the procedure described in example 1 , except that 4-naphthalen-2-yl-3-oxo-butyric acid ethyl ester was used instead of 3-oxo-6- phenyl-hexanoic acid ethyl ester in step a, l,3-όzsftert-butoxycarbonyl)-2-methyl- thiopseudourea was used instead of N,N-όz5-(?eλ^-butoxycarbonyl)-imidazolidine-2-thione in step d and TFA was used instead of HCl in dioxan in step e. 1H ΝMR (d6 DMSO) 10.24 (IH, s), 8.20 (2H, d), 7.86 (5H, m), 7.66 (3H, m), 7.54 (IH, d), 7.48 (2H, m), 7.35 (2H, d), 4.29 (2H, s), 2.87 (IH, m), 1.99-1.27 (1OH, m). Found: C 57.85, H 4.81, N 10.45%; C28H29N5- 2CF3COOH requires: C 57.92, H 4.71, N 10.55%.
Example 26 {4-[2-Cyclohexyl-6-(3, 3, 5, 5-tetramethyl-cyclohexyloxymethyl)-pyrim.idin-4-yl]- phenyl}-(4,5-dϊhydro-lH-imidazol-2-yl)-amine The title compound was obtained as its HCl salt using the procedure described in example 1, except that 3-oxo-4-(3,3,5,5-tetramethyl-cyclohexyloxy)-butyric acid ethyl ester was used instead of 3-oxo-6-phenyl-hexanoic acid ethyl ester in step a. 1H NMR (d6 DMSO) 10.99 (IH, s), 8.49 (2H, s), 8.23 (2H, d), 7.77 (IH, s), 7.44 (2H, d), 4.61 (2H ,s), 3.77 (IH, m), 3.69 (4H, s), 2.90 (IH, m), 2.00-1.20 (16H, m), 0.98 (6H, s), 0.92 (6H, s). Found: C 61.49, H 8.00, N 11.71%; C30H43N5O-2HCl-1.5H2O requires: C 61.11, H 8.25, N 11.88%.
Example 27 [4-(6-Cycloheptyloxymethyl-2-cyclohexyl-pyήmidin-4-yl)-phenyl]-(4, 5-dihydro- lH-imidazol-2-yl)-amine
The title compound was obtained as its HCl salt using the procedure described in example 1, except that 4~cycloheptyloxy-3-oxo-butyric acid ethyl ester was used instead of 3-oxo-6- phenyl-hexanoic acid ethyl ester in step a. 1H NMR (d6 DMSO) 10.96 (IH, s), 8.48 (2H, s), 8.22 (2H, d), 7.75 (IH, s), 7.42 (2H, d), 4.55 (2H, s), 3.69 (4H, s), 3.63 (IH, m), 2.84 (IH, m), 1.94-1.25 (22H, m). Found: C 58.62, H 7.57, N 12.18%; C27H37N5O-2HC1-2H2O requires: C 58.26, H 7.79, N 12.58%.
Example 28 [4-(2-Adamantan~l-yl-6-benzyloxymethyl-pyrimidin-4-yl)-phenyl]-(4,5-dihydro- lH-imidazol-2-yϊ) -amine
The title compound was obtained as its HCl salt using the procedure described in example 1, except that 4-benzyloxy-3-oxo-butyric acid ethyl ester and 1-adamantylamidine.HCl were used instead of 3-oxo-6-phenyl-hexanoic acid ethyl ester and cyclohexylamidine.HCl respectively in step a. 1H NMR (d6 DMSO) 10.93 (IH, s), 8.48 (2H, s), 8.24 (2H, d), 7.79 (IH, s), 7.43-7.30 (7H, m), 4.69 (2H, s), 4.64 (2H, s), 3.69 (4H, s), 2.05 (9H, s), 1.75 (6H, s). Found: C 61.93, H 6.67, N 10.58%; C3 ,H35N5O-SHCl requires: C 61.74, H 6.35, N 10.61%.
Example 29 N-{3-[2-Cycloheptyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-guanidine
The title compound was obtained as its HCl salt using the procedure desciibed in example 1, except that cycloheptylamidine.HCl was used instead of cyclohexylamidine.HCl in step a, 3- (4,4,5, 5,-tetramethyl-l,3,2,-dioxaborolan-2-yl)aniline was used instead of 4-(4,4,5,5- tetramethyl-l,3,2,-dioxaborolan-2-yl)aniline in step c and l,3-tøffcrt-butoxycarbonyl)-2- methyl-thiopseudourea was used instead of N,N-όω-fte/t-butoxycarbonyl)-imidazolidine-2- thione in step d. 1H NMR (d6 DMSO) 8.10 (IH, d), 8.02 (IH, s), 7.67 (IH, s), 7.58(1H, t), 7.39 (IH, d), 7.36-7.15 (5H, m), 3.00 (IH, m), 2.74 (2H, t), 2.63 (2H, t), 2.05 (2H, m), 2.00-1.25 (12H, m). Exact mass found 428, C27H33N5 requires 427.3.
Example 30 N-{4-[2-Cyclohexyl-5-isobutyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}- guanidine The title compound was obtained as its TFA salt using the procedure described in example 1, except that 2-isobutyl-3-oxo-6-phenyl-hexanoic acid ethyl ester was used instead of 3-oxo-6- phenyl-hexanoic acid ethyl ester in step a, l,3-έw(ϊert-butoxycarbonyl)-2-methyl- thiopseudourea was used instead of N,N-έώ-(?ert-butoxycarbonyl)-imidazolidine-2-thione in step d and TFA was used instead of HCl in dioxan in step e. 1H ΝMR (d6 DMSO) 9.94 (IH, s), 7.58 (2H, s), 7.50 (2H, d), 7.32-7.17 (7H, m), 2.72 (4H, m), 2.54 (3H, m), 2.06 (2H, m), 1.90- 1.00 (HH, m), 0.53 (6H, d). Found: C 59.30, H 6.25, Ν 9.25%; C30H39N5- 1.8CF3COOH- 0.8dioxan requires: C 59.30, H 6.38, N 9.39%.
Example 31 N-{4-[2-Cyclohexyl~5-isopropyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}- guanidine The title compound was obtained as its TFA salt using the procedure described in example 1, except that 2-isopropyl-3-oxo-6-phenyl-hexanoic acid ethyl ester was used instead of 3-oxo-6- phenyl-hexanoic acid ethyl ester in step a, l,3-tøffer^butoxycarbonyl)-2-methyl- thiopseudourea was used instead of N,N-έw-(?e7^-butoxycarbonyl)-imidazolidine-2-thione in step d and TFA was used instead of HCl in dioxan in step e. 1H ΝMR (d6 DMSO) 9.83 (IH, s), 7.52 (4H, s), 7.42 (2H, d), 7.32-7.18 (7H, m), 3.16 (IH, m), 2.85 (3H, m), 2.72 (2H, m), 2.06 (2H, m), 1.90-1.00 (1OH, m), 1.11 (6H, d). Found: C 55.51, H 5.35, Ν 8.46%; C29H34N5- 2.4CF3COOH-0.7dioxan requires: C 55.58, H 5.73, N 8.85%.
Example 32 N-{4-[2-Cyclohexyl-5-(4-methyl-pentyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]~ phenylj-guanidine The title compound was obtained as its HCl salt using the procedure described in example 1, except that 6-methyl-2-(4-phenyl-butyryl)-heptanoic acid ethyl ester was used instead of 3- oxo-6-phenyl-hexanoic acid ethyl ester in step a and l,3-όzs(?<2r£-butoxycarbonyl)-2-methyl- thiopseudourea was used instead of N1N -έw-fte^-butoxycarbonyl)-imidazolidine-2-thione in step d. 1H NMR (d6 DMSO) 10.19 (IH, s), 7.62 (4H, s), 7.50 (2H, d), 7.34-7.17 (7H, m), 2.79- 2.71 (5H, m), 2.50 (2H, m), 2.04 (2H, m), 1.94-0.98 (15H, m), 0.71 (6H, d). Found: C 67.16, H 8.00, N 12.03%; C32H43N5-2.07HCl requires: C 67.05, H 7.98, N 12.22%.
Example 33 {4-[2-Cyclohexyl-5-(2-ethoxy-ethyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}- (4,5-dihydro-lH-imidazol-2-yl)-amine The title compound was obtained as its HCl salt using the procedure described in example 1, except that 2-(2-ethoxy-ethyl)-3-oxo-6-phenyl-hexanoic acid ethyl ester was used instead of 3- oxo-6-phenyl-hexanoic acid ethyl ester in step a. 1H NMR (d6 DMSO) 11.39 (IH, s), 8.56 (2H, s), 7.58 (2H, d), 7.40 (2H, d), 7.27-7.16 (5H, m), 3.68 (4H, s), 3.32 (2H, t), 3.23 (2H, q), 2.96 (3H, m), 2.87 (2H, t), 2.69 (2H, t), 2.07 (2H, m), 1.94-1.25 (1OH, m), 0.96 (3H, t). Found: C 62.78, H 7.61, N 10.62%; C32H4iN5O-2.5HCl-0.7dioxan requires: C 62.88, H 7.45, N 10.53%.
Example 34 {4-[5-Benzyl-2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4, 5- dihydro-lH-imidazol-2-yl)-amine
The title compound was obtained as its TFA salt using the procedure described in example 1 , except that 2-benzyl-3-oxo-6-phenyl-hexanoic acid ethyl ester was used instead of 3-oxo-6- phenyl-hexanoic acid ethyl ester in step a and TFA was used instead of HCl in dioxan in step e. 1H NMR (d6 DMSO) 10.76 (IH, s), 8.39 (2H, s), 7.52 (2H, d), 7.31-7.12 (8H, m), 7.06 (2H, d), 6.90 (2H, d), 4.03 (2H, s), 3.65 (4H, s), 2.81 (IH, m), 2.60 (2H, t), 2.50 (2H5 t), 2.00-1.00 (12H, m). Exact mass found 530, C35H39N3 requires 529.3. Example 35 {4-[2-Cyclohexyl-5-methyl-6-(3-phenyl-propyl)-pyrirnidin-4-yl]-phenyl}-(4,5- dihydro-lH-irnidazol~2-yl)-amine
The title compound was obtained as its HCl salt using the procedure described in example 1, except that 2-methyl-3-oxo-6-phenyl-hexanoic acid ethyl ester was used instead of 3-oxo-6- phenyl-hexanoic acid ethyl ester in step a. 1H NMR (d6 DMSO) 11.37 (IH, s), 8.57 (2H, s), 7.66 (2H, d), 7.41 (2H, d), 7.24-7.15 (5H, m), 3.68 (4H, s), 2.97 (3H, m), 2.73 (2H, t), 2.25 (3H,s), 2.00-1.23 (12H, m). Found: C 63.93, H 7.35, N 11.49%; C29H35N5-2.5HCl-0.7H2O requires: C 64.01, H 7.52, N 11.74%.
Example 36 (4, 5~Dihydro-lH-imidazol-2-yl)-{4-[2-(l~hexyl-heptyl)-6-(3, 3, 5, 5-tetramethyl- cyclohexyl)-pyrimidin-4-yl]-phenyl}-aτnine The title compound was obtained as its HCl salt using the procedure described in example 1, except that 1-hexyl-heptylamidine.HCl and 3-oxo-3-(3,3,5,5-tetramethyl-cyclohexyl)- propionic acid ethyl ester were used instead of cyclohexylamidine.HCl and 3-oxo-6-phenyl- hexanoic acid ethyl ester respectively in step a. 1H NMR (d6 DMSO) 11.05 (IH, s), 8.51 (2H, s), 8.28 (2H, d), 7.81 (IH, s), 7.32 (2H,d), 3.69 (4H, s), 3.08 (IH, m), 2.95 (IH, m), 1.79-0.90 (26H, m), 1.09 (6H, s), 0.93 (6H, s), 0.79 (6H, t). Found: C 65.82, H 9.22, N 10.48%; C35H57N5-2HC1-1.5H2O requires: C 65.53, H 9.47, N 10.61%.
Example 37 (4, 5-Dihydro-lH-imidazol-2-yl)~{4-[2-(l-hexyl-heptyl)-5-isobutyl-6-(3, 3, 5, 5- tetramethyl-cyclohexylmethyl)-pyrimidin-4~yl]-phenyl}-mnine The title compound was obtained as its HCl salt using the procedure described in example 1, except that 1-hexyl-heptylamidine.HCl and 4-methyl-2-[2-(3,3,5,5-tetramethyl-cyclohexyi)- acetyl]-pentanoic acid ethyl ester were used instead of cyclohexylamidine.HCl and 3-oxo-6- phenyl-hexanoic acid ethyl ester respectively in step a.. 1H NMR (d6 DMSO) 10.89 (IH, s), 8.44 (2H, s), 7.50 (2H, d), 7.36 (2H, d), 3.68 (4H, s), 2.75 (IH, m), 2.67 (4H, 2xd), 2.45 (IH, m), 1.80-0.76 (26H, m), 0.97 (6H, s), 0.85 (6H, s), 0.78 (6H, t), 0.60 (6H5 d). Found: C 69.74, H 10.13, N 9.97%; C4iH67N5-2HCl requires: C 70.06, H 9.89, N 9.96%.
Example 38 N'-[2-(l-Hexyl-heptyl)-6-(3-phenyl-propyl)-pyrimidin-4-ylmethylJ-N,N-dimethyl- ethane- 1, 2-diamine Step a 4-[2-(l-Hexyl-heptyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-benzaldehyde was obtained using steps a-c of the procedure described in example 1, except that 1-hexyl- heptylamidine.HCl was used instead of cyclohexylamidine.HCl in step a., and 4- formyl- phenylboronic acid was used instead of 4-(4,4,5,5-tetramethyl-l,3,2,-dioxaborolan-2-yl)aniline in step c. 1H NMR (CDCl3) 10.11 (IH, s), 8.25 (2H, d), 8.00 (2H5 d), 7.37 (IH, s), 7.32-7.17 (5H, m), 3.00 (IH, m), 2.86 (2H, t), 2.72 (2H5 t), 2.14 (2H5 m), 1.89 (2H, m), 1.71 (2H, m), 1.27-1.16 (16H5 m), 0.84 (6H5 1).
Step b 4-[2-(l-Hexyl-heptyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-benzaldehyde (388mg, lmmol), N,iV-dimethylethylenediamine (128μL, 1.2mmol) and HOAc (172μL, 3mmol) were stirred in DCE (5mL) and NaBH(OAc)3 (318mg, 1.5mmol) was added. The mixture was stirred at rt for 16h, diluted with EtOAc (2OmL) and washed with saturated aqueous NaHCO3 (3OmL). The organic layer was dried (MgSO4), filtered and evaporated, and the residue purified by chomatography (DCM-MeOH-NH4OH (9:1:0.1)) to afford the title compound (305mg, 55%). 1H NMR (CDCl3) 8.08 (2H, d), 7.45 (2H, d), 7.30-7.19 (6H, m), 3.89 (2H5 s), 3.00 (IH5 m), 2.82 (2H, t), 2.68 (4H5 m), 2.44 (2H5 1), 2.22 (6H, s), 2.12 (2H5 1), 1.90 (2H, m), 1.83 (2H5 m)5 1.70 (2H5 m), 1.25 (16H5 m), 0.83 (6H5 t). The compound was further characterised and tested as its HCl salt. Found: C 66.85, H 9.1O5 N 8.51%; C37H56N4-3HC1 requires: C 66.7O5 H 8.93, N 8.41%.
Example 39 {4-[2-(l-Hexyl-heptyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-benzyl}-(2-morpholin- 4-yl-ethyl)-amine The title compound was obtained using the procedure described in example 38 except that N- (2-aminoethyl)-morpholine was used instead of N,N dimethylethylenediamine in step b. 1H NMR (CDCl3) 8.06 (2H, d), 7.44 (2H5 d), 7.32-7.19 (6H, m), 3.89 (2H, s), 3.70 (4H, m), 2.95 (IH, m), 2.83 (2H, t), 2.70 (4H5 m), 2.52 (2H, m), 2.43 (4H, m), 2.12 (2H, m), 1.93 (2H, m), 1.70 (2H, m), 1.25 (16H, m), 0.83 (6H, t). The compound was further characterised and tested as its HCl salt. Found: C 64.25, H 8.65, N 7.46%; C39H60N4O-SHCl-H2O requires: C 64.49, H 8.74, N 7.71%.
Example 40 N'-{4-[2-(l-Hexyl-heptyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-benzyl}-propane- 1,3-diamine. Step a (3-{4-[2-(l-Hexyl-heptyl)-6-(3-phenyl-propyl)-pyrimidin-4~yl]-benzylamino}-propyl)- carbamic acid tert-butyl ester was obtained using step b of example 38, except that fe/t-butyl- 7V-(3-aminopropyl)carbamate was used instead of N,N-dimethylethylenediamine. 1H ΝMR (CDCl3) 8.05 (2H, d), 7.50 (2H, d), 7.29-7.19 (6H, m), 5.20 (IH, bs), 3.90 (2H, s), 3.25 (3H, m), 3.00 (IH, m), 2.90-2.75 (6H, m), 2.20 (2H, m), 2.00-1.60 (6H, m), 1.45 (9H, s), 1.25 (16H, m), 0.83 (6H, t).
Step b A solution of (3-{4-[2-(l-hexyl-heptyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]- benzylamino}-propyl)-carbamic acid tert-butyl ester (160mg, 0.25mmol) in 4M HCl in dioxan (3mL) and MeOH (ImL) was stirred at rt for 2h. The solution was evaporated and the residue triturated with Et2O to afford the title compound as its HCl salt (116mg, 81%). 1H ΝMR (d6 DMSO) 9.68 (2H, bs), 8.23 (2H, d), 7.84 (IH, s), 7.75 (2H, d), 7.28-7.13 (5H, m), 4.19 (2H, s), 3.38-2.80 (9H, m), 2.26 (2H, t), 2.04 (4H, m), 1.80 (2H, m), 1.70 (2H, m), 1.14 (16H, m), 0.76 (6H, t). Found: C 64.16, H 8.75, Ν 8.31%; C36H56N4-SHCl-H2O requires: C 64.51, H 8.87, N 8.36%.
Example 41 4-[2-Cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-benzylamine Step a {4-[2-Cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-methanol was obtained using steps a-c of example 1 except that 4-(hydroxymethyl)-phenylboronic acid was used instead of 4-(4,4,5,5-tetramethyl-l,3,2,-dioxaborolan-2-yl)aniline in step c. 1H NMR (CDCl3) 8.10 (2H, d), 7.47 (2H, d), 7.32-7.20 (6H, m), 4.77 (2H, d), 2.92 (IH, m), 2.82 (2H, t), 2.71 (2H, t), 2.12 (2H, m), 2.05 (IH, s), 2.00-1.25 (1OH, m). Step b 2-{4-[2-Cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-benzyl}-isoindole-l, 3-dione
Diethyl-azodicarboxylate (455μL, 2.5mmol) was added to a solution of {4-[2-cyclohexyl-6-(3- phenyl-propyl)-pyrimidin-4-yl]-phenyl}-methanol (722mg, 2mmol), PPh3 (655mg, 2.5mmol) and phthalimide (368mg, 2.5mmol) in THF (1OmL). The mixture was stirred at rt for 16h and evaporated to dryness. The residue obtained was purified by chomatography (DCM-hexane- EtOAc (9:9:2)) to afford the product as a colourless oil (783 mg, 74%). 1H NMR (CDCl3) 8.03 (2H, d), 7.86 (2H, m), 7.72 (2H, m), 7.54 (2H, d), 7.31-7.19 (6H, m), 4.91 (2H, s), 2.89 (IH, m), 2.81 (2H, t), 2.71 (2H, t), 2.13-1.27 (12H, m).
Step c A solution of 2-{4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-benzyl}-isoindole-l,3- dione (783mg, 1.52mmol), and hydrazine hydrate (380μL, 7.6mmol) in EtOH (1OmL) was refluxed for 2h. On cooling the white precipitate was removed by filtration and the filtrate was evaporated. The residue obtained was suspended partitioned H2O-DCM (2:3 / 5OmL). The organic layer was separated and dried (MgSO4). Filtration and evaporation of the solvent afforded the product (445mg, 73%). 1H NMR (CDCl3) 8.07 (2H, d), 7.43 (2H, d), 7.32-7.17 (6H, m), 3.95 (2H, s), 2.92 (IH, m), 2.83 (2H, t), 2.73 (2H, t), 2.15-1.25 (12H5 m), 1.77 (2H, bs). The compound was further characterised and tested as its HCl salt. Found: C 60.48, H 7.05, N 8.16%; C26H3 iN3-3HCl-H2O requires: C 60.88, H 7.07, N 8.19%. Example 42 {4-[2-Cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-benzyl}-(4, 5-dihydro-lH- imidazol-2-yϊ) -amine
The title compound was obtained as its HCl salt using steps d and e of example 1, except that 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-benzylamine (example 41) was used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine in step d. 1H NMR (d6 DMSO) 8.93 (IH, bs), 8.22 (2H, d), 7.87 (IH, s), 7.50 (2H, d), 7.29-7.16 (5H, m), 4.51 (2H, d), 3.60 (4H, m), 2.90 (IH, m), 2.84 (2H, t), 2.67 (2H, t), 2.08-1.25 (12H, m). Found: C 59.21, H 6.89, N 11.55%; C29H351N5-3HC1-1.5H2O requires: C 59.03, H 7.00, N 11.86%.
Example 43 (lH-Imidazol-2-ylmethyl)-{4~[2-(l-methyl-octyl)-6-(3-phenyl-propyl)-pyrimidin- 4-yl] -phenyl}-amine Step a 4-[2-(l-Methyl-octyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine was obtained using steps a-c of example 1, except that 1-methyl-octylamidine.HCl was used instead of cyclohexylamidine.HCl in step a. 1H NMR (CDCl3) 7.96 (2H, d), 7.32-7.20 (6H, m), 6.74 (2H, d) 3.91 (2H, bs), 3.04 (IH, m), 2.97 (2H, t), 2.71 (2H, t), 2.11 (2H, m), 1.93 (IH, m), 1.63 (IH, m), 1.35 (3H, d), 1.25 (1OH, m), 0.86 (3H, t). Step b (l-Trityl-lH-imidazol-2-ylmethyl)-{4-[2-(l-methyl-octyl)-6-(3-phenyl-propyl)- pyrimidin-4-yl] -phenyl} -amine
A solution of 4-[2-(l-methyl-octyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine (415mg, lmmol), l-trityl-imidazole-2-carboxaldehyde (338mg, lmmol), HOAc (180μL, 3mmol), and NaBH(OAc)3 (422mg, 2mmol) in DCE (1OmL) was stirred at rt for 48h. The solution was diluted with EtOAc (4OmL) and the mixture washed with saturated NaHCO3 (2OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chomatography (DCM-EtOAc (85:15)) (315mg, 44%). 1H NMR (CDCl3) 7.85 (2H, d), 7.38-7.14 (21H, m), 7.04 (IH, s), 6.85 (IH, s), 6.27 (2H, d), 4.86 (IH, bt), 3.34 (2H, d), 2.99 (IH, m), 2.75 (2H, t), 2.69 (2H, t), 2.08 (2H, m), 1.90 (IH, m), 1.65 (IH, m), 1.34 (3H, d), 1.31-1.23 (1OH, m), 0.85 (3H, t).
Step c A solution of (l-trityl-lH-imidazol-2-ylmethyl)-{4-[2-(l-methyl-octyl)-6-(3-phenyl- propyl)-pyrimidin-4-yl]-phenyl}-amine (315mg, 0.435mmol) in TFA (3mL) was stirred at rt for 2h. The solution was evaporated and the residue suspended in EtOAc-saturated NaHCO3 (2:1 / 3OmL). The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated. The residue was purified by chomatography (DCM-MeOH (9:1)) to afford the title compound (160mg, 75%). 1H NMR (CDCl3) 7.93 (2H, d), 7.28-7.17 (6H, m), 7.01 (2H, s), 6.62 (2H, d), 4.50 (IH, bs), 4.44 (2H, s), 3.00 (IH5 m), 2.76 (2H, t), 2.69 (2H, t), 2.09 (2H, m), 1.95 (IH, m), 1.60 (IH, m), 1.33 (3H, d), 1.23 (1OH, m), 0.85 (3H, t). The compound was further characterised and tested as its HCl salt. Found: C 63.38, H 7.54, N 11.59%; C32H44N5- 3HCl requires: C 63.20, H 7.79, N 11.52%.
Example 44 (4, 5-Dihydro-lH-imidazol-2-ylmethyl)-{4-[2-isobutyl-6-(3-phenyl-propyl)- pyrimidin-4-yl] -phenyl}-amine. Step a 4-[2-(2-methyl-propyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine was obtained using steps a-c of example 1, except that 2-methyl-propylamidine.HCl was used instead of cyclqhexylamidine.HCl in step a.
Step b The title compound was obtained using steps b and c of example 43, except that 4-[2- (2-methyl-propyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine was used in step b instead 4-[2-(l-methyl-octyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine. 1H NMR (CDCl3) 7.92 (2H, d), 7.31-7.19 (6H, m), 7.01 (2H, s), 6.66 (2H, d), 4.49 (2H, s), 2.81 (2H, d), 2.77 (2H, t), 2.67 (2H, t), 2.34 (IH, m), 2.10 (2H, m), 0.98 (6H, d). The compound was further characterised and tested as its HCl salt. Found: C 54.39, H 5.78, N 11.16%; C27H3 iN5-2HCl- 1.6DCM requires: C 54.14, H 5.75, N 11.04%. Example 45 {4-[2-Cyclopentyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4, 5-dihydro-lH- imidazol-2-ylmethyl)-amine
Step a 4-[2-cyclopentyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine was obtained using steps a-c of example 1, except that cyclopentylamidine.HCl was used instead of cyclohexylamidine.HCl in step a. Step b The title compound was obtained using steps b and c of example 43, except that 4-[2- cyclopentyl-6-(3-phenyl-ρropyl)-pyrimidin-4-yl]-phenylamine was used in step b instead 4-[2- (l-methyl-octyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine. 1H NMR (CDCl3) 7.83 (2H, d), 7.30-7.19 (6H, m), 7.05 (2H, s), 6.86 (2H, d), 4.50 (IH, bs), 4.42 (2H, s), 3.34 (IH, m), 2.66 (4H, m) 2.10-1.50 (1OH, m). The compound was further characterised and tested as its HCl salt. Found: C 65.76, H 6.61, N 13.50%; C28H3iN5-2HCl requires: C 65.90, H 6.55, N 13.72%.
Example 46 N-{4-[2-Cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yloxy) ' -phenyl) -guanidine Step a 2-Cyclohexyl-4-(4-nitro-phenoxy)-6-(3-phenyl-propyl)-pyrimidine A mixture of 4-chloro-2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidine (example 1, step b) (1.05g, 3.3mmol), 4-nitrophenol (487mg, 3.5mmol), K2CO3 (482mg, 3.5mmol) and DMF (6mL) was stirred at 140°C for 16h. The mixture was suspended in H2O-EtOAc (3:2 / 5OmL). The organic layer was separated, washed with H2O (2 x 2OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chomatography (Hexane-EtOAc (4:1)) (735mg, 53%). 1H NMR (CDCl3). 8.30 (2H, d), 7.36 (2H, d), 7.33-7.18 (5H, m), 6.57 (IH, s), 2.80-2.69 (5H, m), 2.09 (2H, m) 2.00-1.28 (1OH, m).
Step b 4-[2-Cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yloxy]-phenylamine
A mixture of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3-phenyl-propyl)-pyrimidine (735mg, 1.76mmol), ammonium formate (555mg, 8.8mmol) and 10% palladium on carbon catalyst (lOOmg) in MeOH (1OmL) was refluxed for 30min. The catalyst was removed by filtration through a pad of celite and the filtrate was evaporated. The residue obtained was suspended in H2O-DCM (1:2 / 3OmL) and the organic layer separated and dried (MgSO4). Filtration and evaporation of the solvent gave the product (605mg, 89%). 1H NMR (CDCl3) 7.29-7.15 (5H, m), 6.93 (2H, d), 6.70 (2H, d), 6.26 (IH, s), 3.67 (2H, bs), 2.76 (IH, m), 2.69-2.63 (4H, m), 2.02-1.32 (12H, m).
Step c The title compound was obtained as its TFA salt using steps d and e of example 1, except that 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yloxy]-phenylamine and 1,3- tø(?ert-butoxycarbonyl)-2-methyl-thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3- phenyl-propyl)-pyrimidin-4-yl]-phenylamine and N.N-έz.s-fte/t-butoxycarbonyl)- imidazolidine-2-thione respectively in step d and TFA was used instead of HCl in dioxan in step e. 1H ΝMR (d6 DMSO) 9.78 (IH, s), 7.47 (4H, bs), 7.33-7.14 (9H, m), 6.69 (IH, s), 2.69- 2.50 (5H, m), 1.98 (2H, m), 1.85-1.00 (1OH, m). Found: C 54.62, H 5.25, Ν 10.43%; C26H3,Ν5O-2CF3COOH requires: C 54.79, H 5.05, N 10.65%.
Example 47 {4-[2-Cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yloxy]-phenyl}-(4,5-dihydro- lH-imidazol-2-yl) -amine
The title compound was obtained as its HCl salt using steps d and e of example 1, except that 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yloxy]-phenylamine was used instead of 4- [2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine in step d. 1H NMR (d6 DMSO) 10.83 (IH, s), 8.38 (2H, s), 7.46-7.17 (9H, m), 6.90 (IH, s), 3.66 (4H, s), 2.76 (3H, m), 2.63 (2H, m), 1.98 (2H, m), 1.82-1.25 (1OH, m). Found: C 59.32, H 6.80, N 12.46%; C28H33N5O-SHCl requires: C 59.52, H 6.42, N 12.39%.
Example 48 N-{3-[2-Cyclohexyl-6-(3-phenyl-propyl)-pyrhnidin-4-yloxy]-phenyl}-guanidine Step a 3-[2-Cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yloxy]-phenylamine was obtained using steps a and b of example 46, except that 3-nitrophenol was used instead of 4-nitrophenol in step a.
Step b The title compound was obtained as its HCl salt using steps d and e of example 1, except that 3-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yloxy]-phenylamine and 1,3- έώ(?βrt-butoxycarbonyl)-2-methyl-thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3- phenyl-propyl)-pyrimidin-4-yl]-phenylamine and N,N-tø-(fer£-butoxycarbonyi)~ imidazolidine-2-thione respectively in step d. 1H NMR (d6 DMSO) 10.44 (IH, s), 7.71 (4H, bs), 7.55 (IH, t) 7.28-7.13 (8H, m), 7.07 (IH, s), 2.87 (IH, m), 2.80 (2H, t), 2.62 (2H, t), 2.02 (2H, m) 1.88-1.27 (1OH, m). Found: C 59.33, H 6.68, N 12.91%; C26H31N5O-2HC1-1.5H2O • requires: C 59.25, H 6.40, N 13.28%.
Example 49 [4-(4-Cyclohexyl-6-phenethyloxy-pyrimidin-2-yl)-phenyl]-(4, 5-dihydro-lH- imidazol-2-yl) -amine
Step a 4-Chloro-6-cyclohexyl-2-(4-nitro-phenyl)-pyrimidine was obtained using steps a and b of example 1, except that 3-cyclohexyl-3-oxo-propionic acid ethyl ester and 4- nitrophenylamidine.HCl were used instead of 3-oxo-6-phenyl-hexanoic acid ethyl ester and cyclohexylamidine.HCl respectively in step a. 1H NMR (CDCl3) 8.65 (2H, d), 8.31 (2H, d), 7.17 (IH, s), 2.75 (IH, m), 2.05-1.34 (1OH, m).
Step b 4-Cyclohexyl-2-(4-nitro-phenyl)-6-phenethyloxy-pyrimidine
Sodium hydride (60% dispersion in mineral oil: 200mg, 5.2mmol) was added to a solution of phenethyl alcohol (550μL, 4.6mmol) in dry THF (1OmL) under argon and the mixture heated slowly to 5O0C. A solution of 4-chloro-6-cyclohexyl-2-(4-nitro-phenyl)-pyrimidine (1.22g,
3.84mmol) in THF (1OmL) was added drop-wise and the reaction refluxed for 2h. The solvent was evaporated and the residue suspended in H2O-EtOAc (2:3 / 5OmL) and the organic layer separated and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was re-crystallised from MeOH (1 Mg, 94%). 1H NMR (CDCl3) 8.62 (2H, d), 8.29 (2H, d), 7.33 (5H, m), 6.53 (IH, s), 4.71 (2H, t), 3.16 (2H, t), 2.66 (IH, m), 2.05-1.27 (1OH, m).
Step c 4-(4-Cyclohexyl~6-phenethyloxy-pyrimidin-2-yl)-phenylamine was obtained using step b of example 46, except that 4-cyclohexyl-2-(4-nitro-phenyl)-6-phenethyloxy-pyrimidine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3-phenyl-propyl)-pyrimidine. 1H NMR (CDCl3) 8.30 (2H, d), 7.28 (5H, m), 6.72 (2H5 d), 6.34 (IH, s), 4.67 (2H, t), 3.88 (2H, bs), 3.14 (2H, t), 2.60 (IH, m), 2.02-1.27 (1OH, m).
Step d The title compound was obtained as its HCl salt using steps d and e of example 1, except that 4-(4-cyclohexyl-6-phenethyloxy-pyrimidin-2-yl)-phenylamine was used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine in step d. 1H NMR (d6 DMSO) 11.10 (IH, s), 8.49 (2H, s), 8.39 (2H, d), 7.38 (2H, d), 7.35-7.20 (5H, m), 6.65 (IH, s), 4.65 (2H, t), 3.68 (4H, s), 3.10 (2H, t), 2.65 (IH, m), 1.90-1.29 (1OH, m). Found: C 58.76, H 6.47, N 12.55%; C27H3 ,N5O-2HC1-2H2O requires: C 58.91, H 6.77, N 12.72%. Example 50 (4,5-Dihydro-lH-imidazol-2-yl)-{4-[6-(l-hexyl-heptyl)-2-(3-phenyl-propyl)- pyrimidin~4-y I] -phenyl} -amine
The title compound was obtained as its HCl salt using the procedure described in example 1, except that 4-hexyl-3-oxo-decanoic acid ethyl ester and 4-phenylbutyl amidine.HCl were used instead of 3-oxo-6-phenyl-hexanoic acid ethyl ester cyclohexylamidine.HCl repectively in step a. 1H NMR (CDCl3) 12.50 (IH, bs), 8.07 (2H, d), 7.34-7.15 (8H, m), 3.78 (4H, s), 3.01 (2H, t), 2.75 (3H, m), 2.20 (2H, m), 1.70 (4H, m), 1.24 (16H, m) 0.84 (6H, t). Found: C 66.40, H 8.30, N 10.92%; C35H49N5^HCl-H2O requires: C 66.64, H 8.46, N 11.10%.
Example 51 2-Amino-N-{4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}- acetamide Step a N-tert-Butoxycarbonyl-2-amino-N-{4-[2-cyclohexyl~6-(3-phenyl-propyl)-pyrimidin-4- yl] -phenyl} -acetamide
A solution of 4-[2-cyclohexyl-6-(3-phenyl-ρropyl)-pyrimidin-4-yl]-phenylamine (540mg, 1.45mmol) (example 1, step c), N-fert-butoxycarbonyl-glycine (350mg, 2mmol), EDCI (384mg 2mmol) and 1-HOBt (306mg, 2mmol) in DCM (1OmL) was stirred at rt for 4h. The mixture was diluted with DCM (2OmL), washed successively with saturated NaHCO3 (1OmL), H2O (1OmL), IM HCl (1OmL), H2O (1OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chomatography (DCM-EtOAc (4:1)) (326mg, 45%). 1H NMR (CDCl3) 8.30 (IH, bs) 8.10 (2H, d), 7.65 (2H, d), 7.29-7.19 (6H, m), 5.30 (IH, bs), 3.96 (2H, d), 2.86 (IH, m), 2.78 (2H, t), 2.70 (2H, t), 2.11-1.25 (12H, m), 1.50 (9H, s).
Step b The title compound was obtained as its HCl salt using step e of example 1 except that N-te7^-butoxycarbonyl-2-amino-N-{4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]- phenyl} -acetamide was used in place of i\ζN-έw-(ter^-butoxycarbonyl)-{4-[2-cyclohexyl-6-(3- phenyl-propyl)-pyrimidm-4-yl]-phenyl}-(4,5-dihydro-lH-imidazol-2yl)-amine. 1H NMR (d6 DMSO). 11.21 (IH, s), 8.33 (IH, bs), 8.27 (2H, d), 7.95 (IH, s), 7.82 (2H, d), 7.29-7.13 (5H, m), 3.82 (2H, m), 2.95 (IH, m), 2.90 (2H, t), 2.65 (2H, t), 2.08 (2H, m), 2.00-1.20 (1OH, m). Found: C 62.55, H 6.76, N 10.60%; C27H32N4O-2HC1-H2O requires: C 62.42, H 6.98, N 10.78%. Example 52 N-{4-[2-Adamantan-l-yl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-2-amino-3- methyl-butyramide
The title compound was obtained as its HCl salt using step a of example 51, except that 4-[2- adamantan-l-yl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine (example 2, step c) and N-
Figure imgf000077_0001
valine were used instead of 4-[2-cyclohexyl-6-(3~phenyl-propyl)- pyrimidin-4-yl]-phenylamine and JV-fer£-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-έ>ώ-(tert-butoxycarbonyl)-{4-[2-cyclohexyl- 6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4,5-dihydro-lH-imidazol-2yl)-amine, according to step e of example 1. 1H ΝMR (d6 DMSO) 11.22 (IH, s), 8.42 (3H, bs), 8.24 (2H, d), 7.84 (2H, d), 7.75 (IH, s), 7.29-7.15 (5H, m), 3.95 (IH, t), 2.83 (2H, t), 2.66 (2H, t), 2.08 (HH, m) 1.75 (6H, m), 1.00 (6H, d). Found: C 64.29, H 7.43, Ν 8.59%; C34H42Ν40-3HCl requires: C 64.53, H 7.17, N 8.85%.
Example 53 Z-Amino-N-fø-P-cyclopentyl-ό-β-phenyl-propylJ-pyrimidin^-ylJ-phenylJ-S- methyl-butyramide
The title compound was obtained as its HCl salt using step a of example 51, except that 4-[2- cyclopentyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine (example 4 step c) and N-tert- butoxycarbonyl valine were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4- yl]-phenylamine and /V-te/t-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of 7V,N-έw-(te7^-butoxycarbonyl)-{4-[2-cyclohexyl-6-(3-phenyl- propyl)-pyrimidin-4-yl]-phenyl}-(4,5-dihydro-lH-imidazol-2yl)-amine, according to step e of example 1. 1H NMR (d6 DMSO) 11.22 (IH, s), 8.42 (3H, bs), 8.24 (2H, d), 7.84 (2H, d), 7.75 (IH, s), 7.29-7.15 (5H, m), 3.95 (IH, t), 3.38 (IH, m), 2.83 (2H, t), 2.66 (2H, t), 2.21-1.66 (HH, m), 1.00 (6H, d). Found: C 65.61, H 7.33, N 10.38%; C29H36N4O-2HC1 requires: C 65.78, H 7.23, N 10.58%.
Example 54 2-Amino-N-{4-[2-isobutyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-3-methyl- hutyr amide
The title compound was obtained as its HCl salt using step a of example 51, except that 4- [2- isobutyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-ρhenylamine (example 17, step c) and N-tert- butoxycarbonyl valine were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4- yl]-phenylamine and iV-tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,7Y-όz5-(tert-butoxycarbonyl)-{4-[2-cyclohexyl-6-(3-phenyl- propyl)-pyrimidin-4-yl]-phenyl}-(4,5-dihydro-lH-imidazol-2yl)-amine, according to step e of example 1. 1H NMR (d6 DMSO) 11.22 (IH, s), 8.42 (3H, bs), 8.26 (2H, d), 7.86 (2H, d), 7.75 (IH, s), 7.29-7.15 (5H, m), 3.93 (IH, t), 3.35 (3H, m), 2.85 (2H, t), 2.64 (2H, t), 2.25 (2H, m), 2.06 (2H, m), 1.00 (12H, m). Found: C 64.65, H 7.33, N 10.56%; C28H36N4O-2HC1 requires: C 64.98, H 7.40, N 10.83%.
Example 55 N-ft-ft-Cyclohexyl-ό-β-phenyl-pmpyfy-pyrimidin^-ylJ-phenylj-S-guanidino- propionamide
The title compound was obtained as its HCl salt using step a of example 51, except that N,N- έώ-tert-butoxycarbonyl-guanidino-propionic acid was used instead of N-tert-butoxycarbonyl glycine, followed by reaction of the product obtained, in place of 7ΛζN-έz^-(ter^- butoxycarbonyl)-{4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4,5-dihydro- lH-imidazol-2yl)-amine, according to step e of example 1. 1H NMR (d6DMSO) 10.30 (IH, s), 8.30 (IH, s), 8.18 (2H, d), 7.74 (2H, d), 7.67 (IH, s), 7.52 (2H, m), 7.29-7.15 (6H, m), 3.43 (2H, d), 3.09 (2H, m), 2.73 (3H, m), 2.65 (3H, m) 2.05-1.19 (12H, m). Found: C 62.31, H 6.94, N 15.12%; C29H36N6O^HCl requires: C 62.47, H 6.87, N 15.07%.
Example 56 2-Amino-N-{3-[4-(4-guanidino-phenyl)-6-(3-phenyl-propyl)-pyriinidin-2-yl]- phenylj-acetamide
Step a 4-Chloro-2-(3-nitrophenyl)-(3-phenyl-propyl)-pyrimidine was obtained using steps a and b of example 1 except that 3-nitrophenyl amidine.HCl was used instead of cyclohexylamidine.HCl in step a.
Step b 4-[2-(3-Nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine was obtained using c of example 1 except that 4-chloro-2-(3-nitrophenyl)-(3-phenyl-propyl)-pyrimidine was used instead of 4-chloro-2-cyclohexyl-(3-phenyl-propyl)-pyrimidine. 1H NMR (CDCl3) 9.43 (IH, s), 8.92 (IH, d), 8.30 (IH, d) 8.07 (2H, d), 7.65 (IH, t), 7.37-7.22 (6H, m), 6.78 (2H, d), 4.01 (2H, bs), 2.89 (2H, t), 2.78 (2H, t), 2.22 (2H, m).
Step c N\N''-bis-tef-t-Butoxycarbonyl-N-{4-[2-(3-nitro-phefiyl)-6-(3-phenyl-propyl)-py7"imidin- 4-yl] -phenyl} -guanidine was obtained using step d of example 1 except that 4-[2-(3-nitro- phenyl)-6-(3-phenyl-propyl)-pyiimidin-4-yl]-phenylamine and 1 ,3-όz,s(fert-butoxycarbonyl)-2- methyl-thiopseudourea were used instead of 4-[2-cyclohexyl-6~(3-phenyl-propyl)-pyrimidin-4- yl]-phenylamine and N,7y-έz5-(ϊert-butoxycarbonyl)-imidazolidine-2-thione respectively. 1H NMR (CDCl3) 11.65 (IH, s), 10.56 (IH, s), 9.44 (IH, s), 8.95 (IH, d), 8.32 (IH, d), 8.21 (2H, d), 7.85 (2H, d), 7.68 (IH, t), 7.47 (IH, s), 7.32-7.21 (5H, m) 2.93 (2H, t), 2.79 (2H, t), 2.24 (2H, m), 1.57 (9H, s), 1.54 (9H, s). Step d N',N"-bis-tert-Butoxycarbonyl-N-{4-[2-(3-amino-phenyl)-6-(3-phenyl-propyl)- pyrimidin-4-yl] -phenyl} -guanidine was obtained using step b of example 46 except that N',N"- bis-tert-butoxycarbonyl-N-{4-[2-(3-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]- phenyl} -guanidine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6~(3-phenyl-propyl)- pyrimidine. 1H NMR (CDCl3) 11.65 (IH, s), 10.56 (IH, s), 8.21 (2H, d), 8.02 (IH, d), 7.95 (IH, s), 7.80 (2H, d), 7.38 (IH, s), 7.33-7.21 (5H, m), 6.84 (IH, d), 3.78 (2H, bs), 2.90 (2H, t), 2.77 (2H, t), 2.20 (2H, m), 1.57 (9H, s), 1.55 (9H, s).
Step e N',N"-bis-tert-butoxycarbonyl-2-tert-butoxycarbonylamino-N-{3-[4-(4-guanidino- phenyl) -6-(3-phenyl-propyl)-pyrimidin-2-yl]-phenyl}-acetamide was obtained using step a of example 51 except that 7Y'iV/-bis-tert-butoxycarbonyl-N-{4-[2-(3-amino-phenyl)-6-(3-phenyl- propyl)-pyrimidin-4-yl]-phenyl} -guanidine was used instead of 4~[2-cyclohexyl-6-(3-phenyl- propyl)-pyrimidin-4-yl]-phenylamine. 1H NMR (CDCl3) 11.66 (IH, s), 10.52 (IH, s), 8.44 (IH, s), 8.35 (IH, d), 8.20 (IH, s), 8.16 (2H, d), 7.93 (IH, s), 7.78 (2H, d), 7.47 (IH, t), 7.38 (IH, s), 7.33-7.20 (5H, m), 5.30 (IH, bs), 3.99 (2H, d), 2.88 (2H, t), 2.77 (2H, t), 2.23 (2H, m), 1.57 (9H, s), 1.54 (9H, s), 1.50 (9H, s).
Step f The title compound was obtained as its TFA salt using step e of example 1, except that iV'N/-Z?zj-fer^-butoxycarbonyl-2-ter^-butoxycarbonylamino-N-{3-[4-(4-guanidino-phenyl)-6- (3-phenyl-propyl)-pyrimidin-2-yl]-phenyl}-acetamide and TFA were used instead of ΛζiV-δώ- (ter?-butoxycarbonyl)-{4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4,5- dihydro-lH-imidazol-2yl)-amine and HCl in dioxan respectively. 1H NMR (d6 DMSO) 10.64 (IH, s), 10.21 (IH, s), 8.69 (IH, s), 8.39 (2H, d), 8.26 (IH, d), 8.15-7.18 (17H, m), 3.83 (2H, m), 2.89 (2H, m), 2.71 (2H, m) 2.14 (2H, m). Found: C 54.40, H 4.35, N 13.80%; C32H31N7O- 2CF3COOH requires: C 54.31, H 4.41, N 13.86%.
Example 57 3-Amino-N-{3-[4-(4-guanidino-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]- phenylj-propionamide
Step a N',N"-bis-tert-Butoxycarbonyl-3-tert-butoxycarbonylamino-N-{3-[4-(4-guanidino- phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]-phenyl}-propionmnide was obtained using step a of example 51 except that N'N/-&ώ-?ert-butoxycarbonyl-iV-{4-[2-(3-ammo-phenyl)-6-(3- phenyl-propyl)-pyrimidin-4-yl]-phenyl} -guanidine (example 56, step d) and 3-tert- butoxycarbonylamino-propionic acid were used instead of 4-[2-cyclohexyl-6-(3-phenyl- propyl)-pyrimidin-4-yl]-phenylamine and N-fert-butoxycarbonyl glycine respectively.
Step b The title compound was obtained as its TFA salt using e of example 1, except that iV'N'-όώ-ter^-butoxycarbonyl-3-tert-butoxycarbonylamino-N-{3-[4-(4-guanidino-phenyl)-6- (3-phenyl-proρyl)-pyrimidin-2-yl]-phenyl}-propionamide and TFA were used instead of N1N'- όw-(tert-butoxycarbonyl)-{4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4,5- dihydro-lH-imidazol-2yl)-amine and HCl in dioxan respectively. 1H NMR (d6 DMSO) 10.34 (IH, s), 10.18 (IH, s), 8.67 (IH, s), 8.40 (2H, d), 8.23 (IH, d), 7.91-7.18 (17H, m), 3.12 (2H, q), 2.89 (2H, m), 2.72 (4H, m), 2.11 (2H, m). Found: C 52.21, H 4.67, N 12.57%; C33H33N7O- 2CF3COOH requires: C 52.31, H 4.92, N 12.94%.
Example 58 3-Amino-N-{3-[4-[4-(2-amino-acetylamino)-phenyl]-6-(3-phenyl-propyl)- pyrimidin-2-yl]-phenyl}-propionamide
Step a 2-tert-Butoxycarbonylamino-N-{4-[2-(3-nitro-phenyl)-6-(3-phenyl-propyl)-pyήmidin-4- ylj-phenyl}-acetamide was obtained using step d of example 51, except that 4-[2-(3-nitro- phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine (example 56, step b) was used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine. 1H NMR (CDCl3) 9.41 (IH, s), 8.91 (IH, d), 8.45 (IH, bs), 8.31 (IH, d), 8.19 (2H, d), 7.73-7.63 (3H, m), 7.44 (IH, s), 7.32-7.21 (5H, m), 5.30 (IH, bt), 3.98 (2H, d), 2.91 (2H, t), 2.78 (2H, t), 2.22 (2H, m), 1.51 (9H, s). Step b 2-tert-Butoxycarbonylamino-N-{4-[2-(3-arnino-phenyl)-6-(3-phenyl-propyl)-pyrimidin- 4-yl] -phenyl} -acetamide was obtained using step b of example 46, except that 2-tert- butoxycarbonylamino-iV-{4-[2-(3-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}- acetamide was used instead of 2-cyclohexyl~4-(4-nitro-phenoxy)-6-(3-phenyl-propyl)~ pyrimidine. 1H NMR (CDCl3) 8.35 (IH, bs), 8.18 (2H, d), 8.00 (IH, d), 7.93 (IH, s), 7.68 (2H, d), 7.36-7.20 (7H, m), 6.83 (IH, d), 5.30 (IH, bt), 3.96 (2H, d), 3.80 (2H, bs), 2.89 (2H, t), 2.76 (2H, t), 2,21 (2H, m), 1.51 (9H, s).
Step c 3-tert-Butoxycarbonylamino-N-{3-[4-[4~(2-tert~butoocycarbonylamino-acetylamino)- phenyl]-6-(3-phenyl-propyl)-pyrimidin-2-yl]-phenyl}propionamide was obtained using step d of example 51, except that 2-tert-butoxycarbonylammo-N-{4-[2-(3-amino-phenyl)-6-(3- phenyl-propyl)-pyrimidin-4-yl]-phenyl} -acetamide and 3-tert-butoxycarbonylamino-propionic acid were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and JV-fert-butoxycarbonyl glycine respectively. 1H ΝMR (CDCl3) 8.50 (IH, bs), 8.43 (IH, s), 8.33 (IH, d), 8.10 (2H, d), 7.93 (IH, d), 7.90 (IH, bs), 7.63 (2H, d), 7.42 (IH, t), 7.48-7.20 (6H, m), 5.40 (IH, bt), 5.28 (IH, bt), 3.97 (2H, d), 3.55 (2H, q), 2.84 (2H, t), 2.75 (2H, t), 2.66 (2H, t), 2.17 (2H, m), 1.50 (9H, s), 1.45 (9H, s).
Step d The title compound was obtained as its HCl salt using step e of example 1 except that 3-ter^-butoxycarbonylamino-N-{3-[4-[4-(2-tert-butoxycarbonylamino-acetylamino)-phenyl]-6- (3-phenyl-propyl)-pyrimidin-2-yl]-phenyl}propionamide was used in place of N,N'-bis-(tert- butoxycarbonyl)-{4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4,5-dihydro- lH-imidazol-2yl)-amine. 1H ΝMR (dg DMSO) 11.15 (IH, s), 10.45 (IH, s), 8.71 (IH, s), 8.36- 7.17 (18H, m), 3.86 (2H, d), 3.09 (2H, m), 2.89-2.69 (6H, m), 2.13 (2H, m). Found: C 61.57, H 5.83, N 14.33%; C3oH32N602-2HCl requires: C 61.96, H 5.89, N 14.45%.
Example 59 N-{3-[4-[3-(3-Amino-propionylamino)-phenyl]-6-(3-phenyl-propyl)-pyrimidin-2- yl]-phenyl}-3-guanidino-propionamide Step a 3-[2-(3-Nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4~yl]-phenylamine was obtained using steps a-c of example 1 except that 3-nitrophenyl amidine.HCl was used instead of cyclohexylamidine.HCl in step a and 3-aminophenylboronic acid was used instead of 4- (4,4,5,5-tetramethyl-l,3,2,-dioxaborolan-2-yl)aniline in step c. 1H NMR (CDCl3) 9.44 (IH, t),
8.94 (IH, dd), 8.32 (IH, dd), 7.68 (IH, t), 7.59 (IH, d), 7.51 (IH, d), 7.47 (IH, s), 7.35-7.22 (6H, m), 6.87 (IH, dd), 3.88 (2H, bs), 2.94 (2H, t), 2.79 (2H, t), 2.24 (2H, m).
Step b 3-tert-Biitoxycarbonylamino-N-{4-[2-(3-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4- ylj-phenylj-propionωnide was obtained using step d of example 51, except that 3-[2-(3-nitro- phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and 3-fert-butoxycarbonylamino- propionic acid were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]- phenylamine and N-fe/t-butoxycarbonyl glycine respectively. 1H ΝMR (CDCl3) 9.43 (IH, t),
8.95 (IH, dd), 8.41 (IH, s), 8.33 (IH, dd), 7.98 (IH, d), 7.96 (IH, bs), 7.71 (IH, d), 7.65 (IH, t), 7.52 (2H, m), 7.32-7.21 (6H, m), 5.20 (IH, bs), 5.56 (2H, q), 2.94 (2H, t), 2.79 (2H, t), 2.69 (2H, t), 2.25 (2H, m), 1.45 (9H, s).
Step c 3-tert-Butoxycarbo7iylamino-N-{4-[2-(3-amino-phenyl)-6-(3-phenyl-propyl)-pyrimidin- 4-yl] -phenylj-propionamide was obtained using step b of example 46, except that 3-tert- butoxycarbonylamino-iV-{4-[2-(3-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}- propionamide was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3-phenyl-propyl)- pyrimidine. 1H ΝMR (CDCl3) 8.31 (IH, s), 8.00 (IH, d), 7.95-7.75 (4H, m), 7.50-7.21 (9H, m), 6.81 (IH, dd), 5.10 (IH, bs), 3.81 (2H, bs), 3.54 (2H, q), 2.90 (2H, t), 2.77 (2H, t), 2.67 (2H, t), 2.21 (2H, m), 1.45 (9H, s).
Step d N',N"-bis-tert-Butoxycarbonyl-N-{3-[4-[3-(3-tert-butoxycarbonylamino- propionylamino)-phenyl]-6-(3-phenyl-propyl)-pyrimidm~2-yl]-phenyl}-3-guanidino- propionamide was obtained using step d of example 51, except that 3-ter^- butoxycarbonylamino-iV-{3-[2-(3-ammo-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]- phenyl} -propionamide and N,N-έώ-te^butoxycarbonyl-3-guanidino-propionic acid were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and N-tert- butoxycarbonyl glycine respectively. 1H NMR (CDCl3) 11.44 (IH, s), 8.89 (IH, bt), 8.85 (IH, bs), 8.50 (IH, s), 8.38 (IH, bs), 8.32 (2H,m), 7.88-7.81 (3H, m), 7.46-7.20 (8H, m), 5.25 (IH, bs), 3.84 (2H, q), 3.51 (2H, q), 2.86 (2H, t), 2.76 (4H, t), 2.63 (2H, t), 2.20 (2H, m), 1.48 (18H, s), 1.43 (9H, s). Step e The title compound was obtained as its TFA salt using step e of example 1, except that 7V'N'-έw-tert-butoxycarbonyl-N-{3-[4-[3-(3-tert-butoxycarbonylamino-propionylamino)- phenyl]-6-(3-phenyl-propyl)-ρyrimidin-2-yl]-phenyl}-3-guanidino-propionamide and TFA were used instead of N,N-όz5-(tø'f-butoxycarbonyl)-{4-[2-cyclohexyl-6-(3-phenyl-propyl)- ρyrimidin-4-yl]-phenyl}-(4,5-dihydro-lH-imidazol-2yl)-amine and HCl in dioxan respectively. 1HNMR Cd6DMSO) 10.42 (IH, s), 10.29 (IH, s), 8.63 (IH, s), 8.49 (IH, s), 8.25 (IH, d), 8.00- 7.00 (19H, m), 3.45 (2H, q), 3.12 (2H, q), 2.88 (2H, t), 2.79-2.66 (6H, m), 2.13 (2H, m). Found: C 52.53, H 4.75, N 13.34%; C36H36N8O2^CF3COOH-LSH2O requires: C 52.74, H 5.04, N 13.67%. Example 60 N-{3-[2-[3-(3-Amino-propionylamino)-phenyl]-6-(3-phenyl-propyl)-pyrimidin-4- yl]-phenyl}-3-guanidino-propionamide
Step a N',N"-bis-tert-Butoxycarbonyl-N-{3-[2-(3-nitro-phenyl)-6-(3~phenyl-propyl)-pyrimidin- 4-ylj '-phenylJ-3-guanidino propionamide was obtained using step d of example 51, except that 3-[2-(3-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and (example 59, step a) and N,N-£zs-fe^butoxycarbonyl~3-guamdino-propiomc acid were used instead of 4-[2- cyclohexyl-6-(3 -phenyl-propyl)-pyrimidin-4-yl]-phenylamine and iV-te/t-butoxycarbonyl glycine respectively. Step b N',Nf'-bis-tert-Butoxycarbonyl-N-{3-[2-(3-amino-phenyl)-6-(3-phenyl-propyl)- pyrimidin-4-yl] -phenyl) -3-guanidino propionamide was obtained using step b of example 46, except that N'N'-όw-ter^-butoxycarbonyl-Ν-{3-[2-(3-nitro-phenyl)-6-(3-phenyl-propyl)- pyrimidin-4-yl] -phenyl} -3-guanidino propionamide was used instead of 2-cyclohexyl-4-(4- nitro-phenoxy)-6-(3-phenyl-propyl)-pyrimidine.
Step c N',N"-bis-tert-Butoxycarbonyl-N-{3-[2-[3-(3-tert-butoxycarbonylamino- propionylamino)-phenyl]-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-3-guanidino- propionamide was obtained using step d of example 51, except that N'N'-έw-tert- butoxycarbonyl-iV-{3-[2-(3-amino-phenyl)-6-(3-phenyl-propyl)-pyrimidm-4-yl]-phenyl}-3- guanidino propionamide and 3-ter^-butoxycarbonylamino-propionic acid were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and iV-fert-butoxycarbonyl glycine respectively.
Step d The title compound was obtained as its TFA salt using e of example 1, except that Nr'N'-ow-?e^-butoxycarbonyl-N-{3-[2-[3-(3-tert-butoxycarbonylamino-propionylamino)- phenyl]-6-(3-phenyl-proρyl)-pyrimidin-4-yl]-phenyl} -3-guanidino-propionamide and TFA were used instead of N,N-δώ-(tert-butoxycarbonyl)-{4-[2-cyclohexyl-6-(3-phenyl-propyl)- pyrimidin-4-yl]-ρhenyl}-(4,5-dihydro-lH-imidazol-2yl)-amine and HCl in dioxan respectively. 1R NMR Cd6DMSO) 10.35 (IH, s), 10.31 (IH, s), 8.63 (IH, s), 8.48 (IH, s), 8.26 (IH, d), 8.00- 7.00 (2OH, m), 3.45 (2H, q), 3.14 (2H, q), 2.89 (2H, t), 2.77-2.66 (6H, m), 2.13 (2H, m). Found: C 52.68, H 4.75, N 13.42%; C36H36N8O2^CF3COOH- 1.5H2O requires: C 52.74, H 5.04, N 13.67%.
Example 61 N-{3-[4-(3-Methyl-butyl)-6-phenethylamino-pyrimidin-2-yl]-phenyl}-guanidine.
Step a 4-Chloro-6-(3-methyl-butyl)-2-(3-nitro-phenyl)-pyrimidine was obtained using steps a and b of example 1 except that 6-methyl-3-oxo~heptanoic acid ethyl ester and 3- nitrophenylamidine HCl were used in place of 3-oxo-6-phenyl-hexanoic acid ethyl ester and cyclohexylamidine.HCl respectively in step a. 1H NMR (CDCl3) 9.30 (IH, s), 8.80 (IH, d), 8.35 (IH, d), 7.66 (IH, t), 7.18 (IH, s), 2.84 (2H, m), 1.69 (3H, m), 1.00 (6H, t).
Step b [6-(3-Methyl-butyl)-2-(3-nitro-phenyl)-pyrimidin-4-yl]-phenethyl-amine
A solution of 4-chloro-6-(3-methyl-butyl)-2-(3-nitro-phenyl)-pyrimidine (753mg, 2.5mmol), phenethylamine (627μL, 5mmol), and NEt3 (690μL) in THF (1OmL) was refiuxed for 16h. The solution was diluted with EtOAc (3OmL) and washed with H2O (2 x 2OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chomatography (Hexane-EtOAc (4:1)). 1H NMR (CDCl3) 9.27 (IH, t), 8.75 (IH, d), 8.26 (IH, dd), 7.60 (IH, t), 7.38-7.27 (5H, m), 6.11 (IH, s), 4.95 (IH, bs), 3.72 (2H, q), 2.99 (2H, t), 2.66 (2H, m), 1.65 (3H, m), 0.98 (6H, d). Step c [2-(3-Amino-phenyl)-6-(3-methyl-butyl)-pyrimidin-4-yl]-phenethyl-amine was obtained using step b of example 46, except that [6-(3-methyl-butyl)-2-(3-nitro-phenyl)-pyrimidin-4-yl]- phenethyl-amine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3-phenyl-propyl)- pyrimidine. 1H NMR (CDCl3) 7.80 (IH, d), 7.75 (IH, s), 7.37-7.21 (6H, m), 6.76 (IH, dd), 6.05 (IH, s), 4.90 (IH, bs), 3.67 (2H, q), 3.59 (2H, bs), 2.65 (2H, t), 2.65 (2H, m), 1.65 (3H, m), 0.97 (6H, d).
Step d The title compound was obtained as its HCl salt using steps d and e of example 1 except that [2-(3-amino-phenyl)-6-(3-methyl-butyl)-pyrimidin-4-yl]-ρhenethyl-amine and 1,3- 6z5(1fe^-butoxycarbonyl)-2-methyl-thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3- phenyl-propyl)-pyrimidin-4-yl]-phenylamine and N,N'-bis-(tertAmtoxycdxh(my\)- imidazolidine-2-thione respectively. 1H NMR (CDCl3) 8.05 (IH, d), 7.97 (IH, s), 7.26-7.13 (7H, m), 7.75-6.75 (4H, bm), 3.46 (2H, bs), 2.83 (2H, t), 2.49 (2H, t), 1.53 (3H, m), 0.90 (6H, d). Found: C 55.36, H 6.82, N 16.12%; C24H30N6-2HCl-2.5H2O requires: C 55.38, H 7.17, N 16.15%. Example 62 3-Guanidino-N-{3-[4-(3-methyl-butyl)-6-phenethylamino-pyrimidin-2-yl}- phenylj-propionamide
The title compound was obtained as its HCl salt using step a of example 51, except that [2-(3- amino-phenyl)-6-(3-methyl-butyl)-pyrimidin-4-yl]-phenethyl-amine (example 61, step c) and N,7V-έw-te^-butoxycarbonyl-guanidino-propionic acid were used instead of 4-[2-cyclohexyl- 6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and N-fert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-όw-(tert- butoxycarbonyl)-{4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4,5-dihydro- lH-imidazol-2yl)-amine, according to step e of example 1. 1HNMR (d6 DMSO) 10.72 (IH, s), 9.70 (IH, bs), 8.51 (IH, s), 7.92-7.19 (9H, m), 6.63 (IH, s), 3.78 (2H, m), 3.45 (2H, q), 2.94 (2H, t), 2.78 (2H, m), 2.68 (2H, t), 1.57-1.52 (3H, m), 0.93 (6H, d). Found: C 54.38, H 7.09, N 16.14%; C27H35N7O-2HC1-3H2O requires: C 54.00, H 7.21, N 16.33%.
Example 63 3-Amino-N-{3-[4-(3-guanidino-phenyl)-6-(3-methyl-butyl)-pyrimidin-2-yl]- phenylj-propionamide. Step a 4-[2-(3-Nitro-phenyl)-6-(3-methyl-butyl)-pyrimidin-4-yl]~phenylamme was obtained using steps a-c of example 1 except that 6-methyl-3-oxo-heptanoic acid ethyl ester and 3- nitrophenyl amidine.HCl were used instead of 3-oxo-6-phenyl-hexanoic acid ethyl ester and cyclohexylamidine.HCl respectively in step a and 3-(4,4,5,5-tetramethyl-l,3,2,dioxaborolan-2- yl)aniline was used instead of 4-(4,4,5,5-tetramethyl-l,3,2,-dioxaborolan-2-yl)aniline in step c. 1H NMR (CDCl3) 9.42 (IH, t), 8.93 (IH, dd), 8.32 (IH, dd), 7.67 (IH, t), 7.61 (IH, d), 7.55 (IH, d), 7.50 (IH, s), 7.32 (IH, t), 6.87 (IH, dd), 3.88 (2H, b s), 2.90 (2H, m), 1.75 (3H, m), 1.02 (6H, d).
Step b N',N''-bis-tert-Butoxycarbonyl-N-{4-[2-(3~nitr-o-phenyl)-6-(3-methyl-butyl)-pyrimidin- 4-yl]-phenyl}-guanidine was obtained using step d of example 1 except that 4-[2-(3-nitro- phenyl)-6-(3-methyl-butyl)-pyrimidin-4-yl]-phenylamine and l,3-Z?z5(?erϊ-butoxycarbonyl)-2- methyl-thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4- yl]-phenylamine and N,N-έz5-(?ert-butoxycarbonyl)-imidazolidine-2-thione respectively. 1H ΝMR (CDCl3) 11.66 (IH, s), 10.50 (IH, s), 9.43 (IH, s), 8.95 (IH, d), 8.51 (IH, s), 8.07 (IH, d), 7.80 (IH, d), 7.68 (IH, t), 7.56 (IH, s), 7.50 (IH, t), 2.91 (2H, m), 1.75 (3H, m), 1.58 (9H, s), 1.53 (9H, s), 1.02 (6H, d).
Step c N',N''-bis-tert-Butoxycarbonyl-N-{4-[2-(3-amino-phenyl)-6-(3-methyl-butyl)-pyrimidin- 4-yl] -phenyl) -guanidine was obtained using step b of example 46 except that N'N'-όώ-ter?- butoxycarbonyl-N-{4-[2-(3-nitro-phenyl)-6-(3-methyl-butyl)-pyrimidin-4-yl]-phenyl}- guanidine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3-phenyl-propyl)- pyrimidine. 1H NMR (CDCl3) 11.66 (IH, s), 10.46 (IH, s), 8.42 (IH, s), 8.03 (2H, m), 7.95 (IH, s), 7.80 (IH, d), 7.50 (2H, m), 7.30 (2H, m), 6.83 (IH, d), 3.80 (2H, bs), 2.88 (2H, m), 1.75 (3H, m), 1.57 (9H, s), 1.53 (9H, s), 1.00 (6H, d).
Step d N',N"-bis-tert-Butoxycarbonyl-3-tert-butoxycarbonylammo-N-{3-[4-(4-guanidino- phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-ylJ-phenyl}-propionamide was obtained using step a of example 51 except that N'N'-δώ-tert-butoxycarbonyl-N-{4-[2-(3-amino-phenyl)-6-(3- methyl-butyl)-pyrimidin-4-yl]-phenyl} -guanidine and 3-ført-butoxycarbonylamino-propionic acid were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and N-tert-butoxycarbonyl glycine respectively. 1H ΝMR (d6 DMSO) 11.43 (IH, s), 10.12 (2H, s), 8.59 (IH, s), 8.42 (IH, s), 8.20 (IH, d), 8.13 (IH, d), 7.93 (IH, d), 7.86 (IH, s), 7.80 (IH, d), 7.56 (IH, t), 7.45 (IH, t), 6.80 (IH, t), 2.86 (2H, q), 2.83 (2H, m), 2.50 (2H, m), 1.72 (3H, m), 1.53 (9H, s), 1.39 (9H, s), 1.37 (9H, s), 0.96 (6H, d). Step e
The title compound was obtained as its TFA salt using step e of example 1, except that TV'N'- &/5-te7t-butoxycarbonyl-3-tert-butoxycarbonylamino-iV-{3-[4-(4-guanidino-phenyl)-6-(3- phenyl-propyl)-pyrimidin-2-yl]-phenyl}-propionamide and TFA were used instead of N,N'-bis-
Figure imgf000086_0001
dihydro-lH-imidazol-2yl)-amine and HCl in dioxan respectively. 1H ΝMR (d6 DMSO) 10.37 (IH, s), 10.26 (IH, s), 8.63 (IH, s), 8.24 (3H, t), 8.17 (IH, s), 7.95-7.62 (HH, m), 7.51-7.43 (2H, m), 3.12 (2H, m), 2.87 (2H, m), 1.74-1.62 (3H, m), 0.96 (6H, d). Found: C 48.67, H 5.32, Ν 13.34%; C27H33Ν7O-2CF3COOH-2.5H2O requires: C 48.46, H 4.94, N 13.64%.
Example 64 3-Guanidino-N-{3-[4-(3-methyl-butyl)-6-pherτethyloxy-pyrimidin-2-yl] -phenyl}- propionamide
Step a 4-(3-Methyl-butyl)-2-(3-nitro-phenyl)-6-phenethyloxy-pyrimidine was obtained using step b of example 49 except that 4-chloro-6-(3-methyl-butyl)-2-(3-nitro-phenyl)-pyrimidine (example 61 step a) was used instead of 4-chloro-6-cyclohexyl-2-(4-nitro-phenyl)-pyrimidine. 1H NMR (CDCl3) 9.29 (IH, s), 8.78 (IH, d), 8.32 (IH, d), 7.63 (IH, t), 7.36-7.25 (5H, m), 6.53 (IH, s) 4.73 (IH, t), 3.17 (IH, t), 2.77 (2H, m), 1.67 (3H, m), 0.99 (6H, d).
■ Step b 3-[4-(3-Methyl-butyl)-6-phenethyloxy-primidin-2-yl]-phenylamine was obtained using step b of example 46, except that 4-(3-methyl-butyl)-2-(3-nitro~phenyl)-6-phenethyloxy- pyrimidine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3-phenyl-propyl)- pyrimidine. 1H NMR (CDCl3) 7.87 (IH, d), 7.79 (IH, s), 7.35-7.23 (6H, m), 6.80 (IH, d), 6.44 (IH, s), 4.69 (2H, t), 3.76 (2H, bs), 3.15 (2H, t), 2.75 (2H, m), 1.64 (3H, m), 0.97 (6H, d).
Step c The title compound was obtained as its HCl salt using step a of example 51, except that 3-[4-(3-methyl-butyl)-6-phenethyloxy-primidin-2-yl]-phenylamine and N.N'-bis-tert- butoxycarbonyl-guanidino-propionic acid were used instead of 4-[2-cyclohexyl-6-(3-phenyl- propyl)-pyrimidin-4-yl]-phenylamine and N-tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-bυtoxycsώonyl)-{4-[2- cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4,5-dihydro-lH-imidazol-2yl)- amine, according to step e of example 1. 1H NMR (d6 DMSO) 10.41 (IH5 s), 8.55 (IH, s), 8.06 (IH, d), 7.90 (IH, d), 7.74 (IH, t), 7.42 (IH, t), 7.40-7.22 (5H, m), 6.70 (IH, s), 6.20 (3H, bs), 4.65 (2H, t), 3.40 (2H, m), 3.09 (2H, t), 2.70 (4H, m), 1.58 (3H, m), 0.91 (6H, d). Found: C 53.14, H 6.49, N 13.24%; C27H34N6O2-4HC1 requires: C 52.77, H 6.37, N 13.62%.
Example 65 N-{-3-[4-Pherιethylamino-6-(3-phenyl-propyl)-primidin-2-yl]-phenyl}-guanidine
Step a [6-(3-Phenyl-propyl)-2-(3-nitro-phenyl)-pyrimidin-4-yl]-phenethyl-amine was obtained using step b of example 61 except that 4-chloro-2-(3-nitrophenyl)-(3-phenyl-propyl)- pyrimidine (example 56, step a) was used in place of 4-chloro-6-(3-methyl-butyl)-2-(3-nitro- phenyl)-pyrimidine.
Step b [2-(3-Amino-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenethyl-amine was obtained using step b of example 46, except that [6-(3-phenyl-propyl)-2-(3-nitro-phenyl)- pyrimidin-4-yl]-phenethyl-amine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3- phenyl-propyl)-pyrimidine.
Step c
The title compound was obtained as its HCl salt using steps d and e of example 1 except that [2-(3-amino-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenethyl-amine and 1 ,3-bi$(tert- butoxycarbonyl)-2-methyl-thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3-phenyl- propyl)-pyrimidin-4-yl]-phenylamine and N,N-tø-ffer^butoxycarbonyl)-imidazolidine-2- thione respectively. 1H ΝMR (d6 DMSO) 8.17-7.36 (4H, m) 7.30-7.15 (1OH, m), 6.66 (IH, d), 3.79 (2H, m), 2.95-2.79 (4H, m), 2.67 (2H, t), 1.99 (2H, m). Found: C 55.27, H 6.46, Ν 13.41%; C28H3oΝ6-3HCl-2.75H20 requires: C 54.98, H 6.67, N 13.73%.
Example 66 3-Guanidino- {3-[4-phenethyloxy-6-(3-phenyl-propyl)-pyrimidin-2-yl]-phenyl} - propionamide
Step a 4-(2-Cyclohexyl-ethoxy-2-(3-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine was obtained using step b of example 49 except that 4-chloro-2-(3-nitrophenyl)-(3-phenyl-propyl)- pyrimidine (example 56, step a) and 2-cyclohexylethanol were used instead of 4-chloro-6- cyclohexyl-2-(4-nitro-phenyl)-pyrimidine and 2-phenethylalcohol respectively. 1H NMR (CDCl3) 9.29 (IH, t), 8.80 (IH, dd), 8.30 (IH, dd), 7.63 (IH, t), 7.33-7.20 (5H, m), 6.51 (IH, s), 4.54 (IH, s), 2.82-2.72 (4H, m), 2.15 (2H,m) 1.84-1.00 (13H, m).
Step b 3-[4-(2-Cyclohexyl-ethoxy)-6-(3-phenyl-propyl)-prii7iidin-2-ylJ-phenylamine was obtained using step b of example 46, except that 4-(2-cyclohexylethoxy-2-(3-nitro-phenyl)-6- (3-phenyl-propyl)-pyrimidine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3- phenyl-propyl)-pyrimidine.
Step c N',N''-bis-tert-buto3cycarbonyl-N-{3-[4-(2-cycloheyyl-ethoxy)-6-(3-phenyl-propyl)- pyrimidin-2-ylJ-phenyl}-propionamide was obtained using step a of example 51, except that 3- [4-(2-cyclohexyl-ethoxy)-6-(3-phenyl-propyl)-primidin-2-yl]-phenylamine and N,N'-bis-tert- butoxycarbonyl-guanidino-propionic acid were used instead of 4-[2-cyclohexyl-6~(3-phenyl- propyl)-pyrimidin-4-yl]-phenylamine and N-tert-butoxycarbonyl glycine respectively.
Step d The title compound was obtained as its TFA salt using step e of example 1 except that N'iV'-έώ-tert-butoxycarbonyl-iV;-{3-[4-(2-cyclohexyl-ethoxy)-6-(3-phenyl-propyl)-pyrimidm- 2-yl]-phenyl} -propionamide and TFA were used in place of N,N -έw-(ter^-butoxycarbonyl)- {4- [2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4,5-dihydro-lH-imidazol-2yl)- amine and HCl in dioxan respectively. 1H ΝMR (d6 DMSO) 10.20 (IH, s), 8.52 (IH, s), 8.06 (IH, d), 7.86 (IH, d), 7.49 (IH, t), 7.43 (IH, t), 7.30-7.20 (5H, m), 6.70 (IH, s), 4.47 (2H, t), 3.42 (2H, q), 2.74-2.61 (6H, m), 2.03 (2H, m), 1.77-0.98 (13H, m). Found: C 55.70, H 5.70, Ν 11.41%; C3iH4oΝ6θ2-2CF3COOH requires: C 55.55, H 5.69, N 11.10%.
Example 67 3-Guanidino-N-{3[4-phenethyloxy-6-(3-phenyl-propyl)-pyrimidin-2-yl] -phenyl}- propionamide
Step a 4-Phenethyloxy-2-(3-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine was obtained using step b of example 49 except that 4-chloro-2-(3-nitrophenyl)-(3-phenyl-propyl)-pyrimidine (example 56, step a) was used instead of 4-chloro-6-cyclohexyl-2-(4-nitiO-phenyl)-pyrimidine.
Step b 3-[4-Phenethyloxy-6-(3-phenyl-propyl)-primidin-2-yl]-phenylamine was obtained using step b of example 46, except that 4-phenethyloxy-2-(3-nitro-phenyl)-6-(3-phenyl-propyl)- pyrimidine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3-phenyl-propyl)- pyrimidine. Step c N',N"-bis-tert-butoxycarbonyl-N-{3-[4-phenethyloxy-6-(3-phenyl-propyl)-pyrimidin-2- yl]-phenyl}-propionamide was obtained using step a of example 51, except that 3-[4- phenethyloxy-6-(3 -phenyl-propyl)-primidin-2-yl]-phenylamine and N,N'-bis-tert- butoxycarbonyl-guanidino-propionic acid were used instead of 4-[2-cyclohexyl-6-(3-phenyl- propyl)-pyrimidin-4-yl]-phenylamine and N-ter^-butoxycarbonyl glycine respectively. Step d The title compound was obtained as its TFA salt using step e of example 1 except that N'N'-δw-tert-butoxycarbonyl-N-{3-[4-phenethyloxy-6-(3-phenyl-piOpyl)-pyiimidin-2-yl]- phenyl} -propionamide and TFA were used in place of N,N-έ>z,s-(fert-butoxycarbonyl)-{4-[2- cyclohexyl-6-(3-phenyl-propyl)-ρyrimidin-4-yl]-phenyl}-(4,5-dihydro-lH-imidazol-2yl)- amine and HCl in dioxan respectively. 1H NMR (d6 DMSO) 10.21 (IH, s), 8.52 (IH, s), 8.07 (2H, d), 7.85 (IH, d), 7.54 (IH5 1), 7.43 (IH, t), 7.34-7.20 (1OH, m), 6.69 (IH, s), 4.65 (2H, t), 3.44 (2H, q), 3.09 (2H, t), 2.74-2.61 (6H, m), 2.02 (2H, m). Found: C 55.91, H 4.91, N 11.38%; C35H36N6O2^CF3COOH requires: C 56.00, H 4.83, N 11.20%. Example 68 N-{4-[4-Phenethylamino-6-(3-phenyl-propyl)-pyrimidin-2-yl]-phenyl}-guanidme
Step a 4-Chloro-2-(4-nitrophenyl)-(3-phenyl-propyl)-pyrimidine was obtained using steps a and b of example 1 except that 4-nitrophenyl amidine.HCl was used instead of cyclohexylamidine.HCl in step a.
Step b [6-(3-Phenyl-propyl)-2-(4-nitro-phenyl)-pyrimidin-4-yl]-phenethyl-amine was obtained using step b of example 61 except that 4-chloro-2-(4-nitrophenyl)-(3-phenyl-propyl)- pyrimidine was used in place of 4-chloro-6-(3-methyl-butyl)-2-(3-nitro-phenyl)-pyrimidine.
Step c [2-(4-Amino-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenethyl-amine was obtained using step b of example 46, except that [6-(3-phenyl-propyl)-2-(4-nitro-phenyl)- pyrimidin-4-yl]-phenethyl-amine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3- phenyl-propyl)-pyrimidine.
Step d The title compound was obtained as its HCl salt using steps d and e of example 1 except that [2-(4-amino-phenyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenethyl-amine and 1,3- έώftert-butoxycarbonyl)-2-methyl-thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3- phenyl-propyl)-pyrimidin-4-yl]-phenylamine and N,JV-tø-(?er£-butoxycarbonyl)- imidazolidine-2-thione respectively. 1H ΝMR (d6DMSO) 10.68 (IH, s), 8.33 (2H, d), 7.90 (4H, bs), 7.45 (2H, d), 7.30-7.15 (1OH, m), 6.61 (IH, s), 3.77 (2H, q), 2.93 (2H, m), 2.85 (2H, t), 2.68 (2H, t), 1.98 (2H. m). Found: C 59.15, H 6.32, Ν 15.13%; C28H31Ν6-3HCl-0.5H2O requires: C 59.11, H 6.02, N 14.77%.
Example 69 N-{4-[4-Phenethyloxy-6-(3-phenyl-propyl)-pyrimidin-2-yl]-phenyl}-guanidine
Step a 4-Phenethyloxy-2-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine was obtained using step b of example 49 except 4-chloro-2-(4-nitrophenyl)-(3-phenyl-propyl)-pyrimidine (example 68, step a) was used instead of 4-chloro-6-cyclohexyl-2-(4-nitro-phenyl)-pyrimidine. 1H NMR (CDCl3) 8.63 (2H, d), 8.30 (2H, d), 7.37-7.24 (1OH, m), 6.53 (IH, s), 4.72 (2H, t), 3.16 (2H, t), 2.82-2.71 (4H, m), 2.16 (2H, m).
Step b 4-[4-Phenethyloxy-6-(3-phenyl-propyl)-primidin-2-yl]-phenylamine was obtained using step b of example 46, except that 4-phenethyloxy-2-(4-nitro-phenyl)-6-(3-phenyl-proρyl)- pyrimidine was used instead of 2-cyclohexyl-4-(4-nitro-phenoxy)-6-(3-phenyl-propyl)- pyrimidine. 1H NMR (CDCl3) 8.30 (2H, d), 7.35-7.20 (1OH, m), 6.73 (2H, d), 6.35 (IH, s), 4.68 (2H, t), 3.89 (2H, bs), 3.14 (2H, t), 2.76-2.69 (4H, m), 2.15 (2H, m).
Step c The title compound was obtained as its HCl salt using steps d and e of example 1 except that 4-[4-phenethyloxy-6-(3-phenyl-propyl)-primidin-2-yl]-phenylamine and l,3-bis(tert- butoxycarbonyl)-2-methyl-thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3-phenyl- propyl)-pyrimidin-4-yl]-phenylamine and N,N-tø-(?er^butoxycarbonyl)-imidazolidine-2- thione respectively. 1H ΝMR (CDCl3) 10.05 (IH, s), 8.38 (2H, d), 7.57 (4H, bs), 7.36-7.17 (12H, m), 6.69 (IH, s), 4.65 (2H, t), 3.09 (2H, t), 2.74-2.61 (2H, m), 2.05 (2H, m). Found: C 60.38, H 5.89, Ν 12.31%; C28H29N5 O-3 HCl requires: C 59.95, H 5.75, N 12.48%.
Example 70 3-Guanidino-N-{4-[4-phenethyloxy-6-(3-phenyl-propyl)-pyrimidin-2-yl] -phenyl}- propionamide The title compound was obtained as its HCl salt using step a of example 51, except that 4-[4- phenethyloxy-6-(3-phenyl-propyl)-primidin-2-yl]-phenylamine (example 69, step b) and N,N'- όϋ5-te7t-butoxycarbonyl-guanidino-propionic acid were used instead of 4-[2-cyclohexyl-6-(3- phenyl-propyl)-pyrimidin-4-yl]-phenylamine and iV-tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-&zs-(fe7t-butoxycarbonyl)-{4-[2- cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4,5-dihydro-lH-imidazol-2yl)- amine, according to step e of example 1. 1H ΝMR (CDCl3) 11.38 (IH, s), 8.30 (2H, d), 7.75 (2H, d), 7.57 (IH, bt), 7.33-6.65 (14H, m), 6.63 (IH, s), 4.64 (2H, t), 3.42 (2H, q), 3.08 (2H, t), 2.72-2.62 (6H, m), 2.01 (2H, m). Found: C 59.15, H 6.19, Ν 13.18%; C3iH34Ν6O2-3HCl requires: C 58.81, H 6.05, N 13.28%. Example 71 (4, 5-Dihydro-lH-imidazol-2-yl)-{4-[2~morpholin-4-yl-6-(3-phenyl-propyl)- pyrimidin-4-yl] -phenyl) -amine
Step a.2-Methylsulfanyl-6-(3-phenyl-propyl)-pyrimidin-4-ol
3-Oxo-6-phenyl-hexanoic acid ethyl ester (2.18g, 9.3mmol) and 2-methyl-2-thiopseudourea sulfate (2.6g, 9.3mmol) were added to an aqueous NaOH solution (0.4g in 3mL). The reaction mixture was stirred for 48h at rt and the white suspension obtained acidified carefully to pH A- 5 with dilute HCl. The mixture was extracted with DCM (3 x 2OmL) and extracts washed with H2O (5OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chomatography (Et2O-Hexane (3:2)) to afford desired compound as a white solid (l.llg, 45%). 1H NMR (CDCl3) 12.7 (IH, s), 7.15-7.32 (5H, m), 6.05 (IH, s), 2.51-2.75 (6H, m), 1.97-2.07 (3H, m).
Step b 2-Methylsulfanyl-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine was obtained using steps b and c of example 1 except that 2-methylsulfanyl-6-(3-phenyl-propyl)-pyrimidin-4-ol was used instead of 2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-ol in step b and 4,4,5,5- tetramethyl-2-(4-nitro-phenyl)-[l,3,2]dioxaborolane was used instead of 4-(4,4,5,5- tetramethyl-l,3,2,-dioxaborolan-2-yl)aniline in step c. 1H NMR (CDCl3) 8.34 (2H, d), 8.24 (2H, d), 7.33-7.18 (6H, m), 2.82 (2H, t), 2.74 (2H, t), 2.67 (3H3 s), 2.15 (2H, quintet).
Step c 2-Methanesulfonyl-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)~pyrimidine
To a solution of 2-methylsulfanyl-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine (0.53g, 1.45mmol) in DCM (9mL) at 00C, was added 3-chloroperoxybenzoic acid (0.8 Ig, 3.62mmol) in small portions. The mixture was stirred at 00C for 2.5h. The reaction mixture was then diluted with DCM (10OmL), washed with saturated NaHCO3 solution (2 x 3OmL) and dried
(MgSO4). Filtration and evaporation of the solvent afforded the product as a yellow oil (0.50g,
86%). 1H NMR (CDCl3) 8.37 (2H, d), 8.31 (2H, d), 7.30-7.19 (6H, m), 3.44 (3H, s), 3.02 (2H, t), 2.78 (2H, t), 2.20 (2H, quintet).
Step d 4-[4-(4-Nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]-morpholine
2-Methanesulfonyl-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine (0.22g, 0.56mmol) and morpholine (0.1OmL, l.lmmol) in dioxan (8mL) were heated at reflux for 17h. The reaction mixture was evaporated under reduced pressure and the remaining oil was suspended in DCM (1OmL), washed with H2O (1OmL) and dried over (MgSO4). Filtration and evaporation of the solvent afforded the product as a yellow solid (0.2Og, 90%). 1H NMR (CDCl3) 8.31 (2H, d), 8.18 (2H, d), 7.33-7.18 (5H, m), 6.87 (IH, s), 3.93 (4H, d), 3.81 (4H, d), 2.73 (4H, t), 2.11 (2H, quintet).
Step Q 4-[2-Morpholin-4-yl-6-(3-phenyl-propyl)-pyήmidin-4-yl]-phenylamine To a solution of 4-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]-moipholine (0.2Og, 0.50mmol) in EtOAc (2OmL) was added Sn(II)Cl2-H2O (0.57g, 2.5mmol) and the mixture was heated at reflux for Ih. On cooling, saturated NaHCO3 solution (1.2mL) was added to the reaction mixture followed by solid NaHCO3 and MgSO4 until a precipitate formed. The precipitate was removed by filtration, and evaporation of the solvent from the filtrate afforded the product as a yellow solid (0.15g, 82%). 1H NMR (CDCl3) 7.90 (2H, d), 7.32-7.20 (5H, m), 6.73 (2H, d), 6.71 (IH, s), 3.92-3.88 (6H, m), 3.83-3.78 (4H, m), 2.68 (4H, quintet), 2.09 (2H, quintet).
Step f The title compound was obtained as its HCl salt using steps d and e of example 1 except that 4-[2-moφholin-4-yl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and was used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine. 1HNMR (d6 DMSO) 8.18 (2H, d), 7.36-7.13 (8H, m), 3.77 (4H, s), 3.55 (6H, s), 3.25 (2H, s), 2.64 (4H, t), 1.99 (2H, quintet). Exact mass found 443.23, C26H30N6O requires 442.57.
Example 72 N-{4-[6-(3-Phenyl-propyl)-2-piperidin-l-yl-pyrimidin-4-yl]-phenyl}-guanidine Step a 4-[2-Piperidin-l-yl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine was obtained using steps d and e of example 71 except that piperidine was used instead of morpholine in step d.
Step b N',N"-bis-tert-Butoxycarbonyl-N-{4-[2-piperidin-l-yl-6-(3-phenyl-propyl)-pyrimidin-4- yl] -phenyl} -guanidine was obtained using step d of example 1 except that 4-[2-piperidin-l-yl- 6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and l,3-έώfte7^-butoxycarbonyl)-2-methyl- thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]- phenylamine and N, N -έώ-(?e7^-butoxycarbonyl)-imidazolidine-2-thione respectively.
Step c The title compound was obtained as its TFA salt using step e of example 1, except that N'N'-to-fer^-butoxycarbonyl-N- {4-[2-piperidin- 1 -yl-6-(3-phenyl-propyl)-pyrimidin-4-yl]- phenyl} -guanidine and TFA were used instead of N,JV'-&z,s-(ter£-butoxycarbonyl)-{4-[2- cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl} -(4,5-dihydro- 1 H-imidazol-2yl)- amine and HCl in dioxan respectively. 1H NMR (d6 DMSO) 8.17 (2H, d), 7.35-7.14 (7H, m), 7.05 (IH, s), 3.82 (4H, s), 2.67-2.62 (4H, m), 2.00 (2H, t), 1.62-1.54 (6H, m). Found: C 48.61, H 4.73, N 9.76%; C25H3oN6-3CF3COOH-dioxan requires C 48.53, H 4.65, N 9.76%. Example 73 [4-[4-(4,5-Dihydro-lH-imidazol-2-ylamino)-phenyl]-6-(3-phenyl-propyl)- pyrimidin-2-yl]-hexyl-methyl-amine
The title compound was obtained as its HCl salt using steps d and e of example 71 except that iV-methylhexylamine was used instead of morpholine in step d, followed by reaction of the product obtained instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine, according to steps d and e of example 1. 1H NMR (d6 DMSO) 8.19 (2H, d), 7.37 (2H, d), 7.21- 7.05 (6H, m), 3.68 (4H, s), 3.18 (3H, s), 2.72-2.65 (4H, m), 2.00 (2H, t), 1.58 (2H, bs), 1.26 (7H, bs), 0.80 (4H, bs). Found: C 60.92, H 7.26, N 13.56%; C29H38N6-3HCl-dioxan requires C 60.99, H 7.40, N 13.59%. Example 74 [4~[4-(4, 5-Dihydro-lH-imidazol-2-ylamino)-phenyl]-6-(3-phenyl-propyl)- pyrimidin-2-yl] -dihexyl-amine
The title compound was obtained as its HCl salt using steps d and e of example 71 except that dihexylamine was used instead of morpholine in step d, followed by reaction of the product obtained instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidm-4-yl]-phenylamine, according to steps d and e of example 1. 1H NMR (CDCl3) 8.05 (2H, d), 7.29-7.19 (7H, m), 6.69 (IH, s), 3.72 (4H, s), 3.64 (4H, t), 2.65 (2H, t), 2.71 (2H, m), 2.07 (2H, quintet), 1.66 (4H, t), 1.34 (12H, bs), 0.90 (6H, t). Found: C 65.09, H 8.12, N 12.77%; C34H48N6-2HCl-dioxan requires C 48.53, H 4.65, N 9.76%. Example 75 (4, 5-Dihydro-lH-imidazol-2-yl)-{4-[2-hexyloxy-6-(3-phenyl-propyl)-pyrimidin-4- yl] -phenylj-amine
Step a 2-Hexyloxy-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine was obtained using step b of example 49 except 2-methanesulfonyl-4-(4-nitro-phenyl)T6-(3-phenyl-propyl)-pyrimidine (example 71, step d) and hexylalcohol were used instead of 4-chloro-6-cyclohexyl-2-(4-nitro- phenyl)-pyrimidine and 2-phenethylalcohol respectively. 1H NMR (CDCl3) 8.34 (2H, d), 8.25 (2H, d), 7.32-7.20 (6H, m), 4.47 (2H, t), 2.82 (2H, t), 2.74 (2H, t), 2.15 (2H, quintet), 1.87 (2H, quintet), 1.54-1.50 (2H, m), 1.39-1.28 (4H, m), 0.92 (3H, t).
Step b 4-[2-Hexyloxy-6~(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine was obtained using step e of example 71 except that 2-hexyloxy-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)- pyrimidine was used instead of 4-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]- morpholine.
Step c The title compound was obtained as its HCl salt using steps d and e of example 1 except that 4-[2-hexyloxy-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and was used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine. 1H NMR (CDCl3) 7.93 (2H, d), 7.32-7.13 (7H, m), 7.03 (IH, s), 4.39 (2H, t), 3.71 (4H, s), 2.69 (4H, t), 2.07 (2H, quintet), 1.84 (2H, quintet), 1.50 (2H, quintet), 1.39-1.35 (4H, m), 0.92 (3H, t). Found: C 61.66, H 7.02, N 12.65%; C28H35N5O-2HCl-dioxan requires C 61.58, H 6.95, N 12.64%.
Example 76 {4-[2-(2-Cyclohexyl-ethoxy)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4, 5- dihydro-lH-imidazol-2-yl)-amine Step a 2-(2-Cyclohexyl-ethoxy)-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine was obtained using step b of example 49 except 2-methanesulfonyl-4-(4-nitro-phenyl)-6-(3-phenyl- propyl)-pyrimidine (example 71, step d) and 2-cyclohexylethanol were used instead of 4- chloro-6-cyclohexyl-2-(4-nitro-phenyl)-pyi-imidine and 2-phenethylalcohol respectively. Step b 4-[2-(2~Cyclohexyl-ethoxy)-6~(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine was obtained using step e of example 71 except that 2-(2-cyclohexyl-ethoxy)-4-(4-nitro-phenyl)-6- (3-phenyl-propyl)-pyrimidine was used instead of 4-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)- pyrimidin-2-yl]-morpholine. Step c The title compound was obtained as its HCl salt using steps d and e of example 1 except that 4-[2-(2-cyclohexyl-ethoxy)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and was used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine. 1H NMR (CDCl3) 7.96 (2H, d), 7.13-7.29 (7H, m), 7.06 (IH, s), 4.45 (2H, t), 3.65 (4H, s), 2.71 (4H, t), 2.09 (2H, quintet), 1.29-0.90 (13H, m). Found: C 62.02, H 7.12, N 11.53%; C30H37N5O-3HCl- Et2O requires C 62.01, H 7.12, N 11.59%.
Example 77 2-{[4-[4-(4, 5-Dihydro-lH-imidazol-2-ylamino)-phenylJ-6-(3-phenyl-propyl)- pyrimidin-2-yl]-methyl-amino}-ethanol
The title compound was obtained as its HCl salt using steps d and e of example 71 except that 2-(methylamino)ethanol was used instead of morpholine in step d, followed by reaction of the product obtained instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine, according to steps d and e of example 1. 1H NMR (CDCl3) 7.97 (2H, d), 7.29-7.20 (7H, m), 6.75 (IH, s), 3.87-3.83 (4H, m), 3.76 (4H, s), 3.28 (3H, s), 2.68 (4H, quintet), 2.00 (2H, quintet), LlO (IH, s).
Example 78 [4-[4-(4, 5-Dihydro-lH-imidazol-2-ylamino)~phenylJ-6-(3-phenyl-propyl)- pyrimidin-2-yl]-(3-ethoxy-propyl)-amine
The title compound was obtained as its HCl salt using steps d and e of example 71 except that 3-ethoxy-propylamine was used instead of morpholine in step d, followed by reaction of the product obtained instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine, according to steps d and e of example 1. 1H NMR (CDCl3) 7.97 (2H, d), 7.32-7.14 (7H, m), 6.76 (IH, s), 5.32 (IH, bs), 3.64-3.46 (1OH, m), 2.71 (2H, t), 2.63 (2H, t), 2.07 (2H, quintet), 1.93 (2H, quintet), 1.22 (3H, t). Found: C 57.30, H 6.87, N 14.26%; C27H34N6O-3HCl-dioxan requires C 57.33, H 6.71, N 14.23%.
Example 79 (4, 5-Dihydro-lH-imidazol-2-yl)-{4-[2-(2-ethoxy-ethoxy)-6-(3-phenyl-propyl)- pyrimidin-4-yl] -phenyl} -amine Step a 2-(2-Ethoxy-ethoxy)-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine was obtained using step b of example 49 except 2-methanesulfonyl-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)- pyrimidine (example 71, step d) and 2-ethoxyethanol were used instead of 4-chloro-6- cyclohexyl-2-(4-nitro-phenyl)-pyrimidine and 2-phenethylalcohol respectively. Step b 4-[2-(2-Ethoxy-ethoxy)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine was obtained using step e of example 71 except that 2-(2-ethoxy-ethoxy)-4-(4-nitro-phenyl)-6-(3-phenyl- propyl)-pyrimidine was used instead of 4-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2- yl]-morpholine. Step c The title compound was obtained as its HCl salt using steps d and e of example 1 except that 4-[2-(2-ethoxy-ethoxy)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and was used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-ρyrimidin-4-yl]-phenylamine. 1H NMR (CDCl3) 7.93 (2H, d), 7.32-7.14 (7H, m), 7.05 (IH, s), 4.55 (2H, t), 3.83 (2H, t), 3.66 (4H, s), 3.59 (2H, t), 2.69 (4H, t), 2.07 (2H, quintet), 1.23 (2H, t). 446.26 (M+l). Example 80 {4-[2-(2-Butoxy-l-butoxymethyl-ethoxy)-6-(3-phenyl-propyl)-pyrimidin-4-yl]- phenyl}-(4,5-dihydro-lH-imidazol-2-yl)-amine
Step a.2-(2-Butoxy-l-butoxymethyl-ethoxy)-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine was obtained using step b of example 49 except 2-methanesulfonyl-4-(4-nitro-phenyl)-6-(3- phenyl~propyl)-pyrimidine (example 71, step d) and l,3-dibutoxy-propan-2-ol were used instead of 4-chloro-6-cyclohexyl-2-(4-nitro-phenyl)-pyrimidine and 2-phenethylalcohol respectively.
Step b 4-[2-(2-Butoxy-l-butoxymethyl-ethoxy)-6-(3-phenyl-propyl)-pyrimidin-4-yl]- phenylamine was obtained using step e of example 71 except that 2-(2-butoxy-l- butoxymethyl-ethoxy)-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine was used instead of 4-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]-morpholine.
Step c The title compound was obtained as its HCl salt using steps d and e of example 1 except that 4-[2-(2-butoxy-l-butoxymethyl-ethoxy)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and was used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine. 1H NMR (CDCl3) 8.03 (2H, d), 7.29-7.11 (8H, m), 5.55 (IH, quintet), 3.77 (4H, d), 3.63 (4H, s), 3.51 (4H, t), 2.75-2.71 (4H, m), 2.11 (2H, quintet), 1.54 (6H, quintet), 1.36 (2H, quintet), 0.89 (6H, t).
Example 81 {4-[2-(4-Benzenesulfonyl-piperazin-l-yl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]- phenyl}-(4,5-dihydro-lH-imidazol-2-yl)-amine
The title compound was obtained as its HCl salt using steps d and e of example 71 except that 1-benzenesulfonyl-piperazine was used instead of morpholine in step d, followed by reaction of the product obtained instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]- phenylamine, according to steps d and e of example 1. 1H NMR (CDCl3) 7.97 (2H, d), 7.75 (2H, d), 7.55-7.52 (3H, m), 7.29-7.17 (7H, m), 6.76 (IH, s), 4.04 (4H, t), 3.73 (4H, s), 3.12 (4H, t), 2.68-2.61 (4H, m), 2.05 (2H, quintet). Found: C 55.78, H 5.57, N 13.54%; C32H35N7O2S-SHCl-Et2O requires C 55.62, H 5.78, N 13.67%.
Example 82 N-(2-{[4-[4-(4,5-Dihydro-lH-imidazol-2-ylamino)-phenyl]-6-(3-phenyl-propyl)- pyrimidin-2-yl]-methyl-amino}-ethyl)-N-methyl-benzenesulfonamide Step a N,N'~dimethyl-N-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]~ethane-l, 2- diamine was obtained using steps d of example 71 except that ΛζN'-dimethylethylenediamine was used instead of morpholine.
Step b N-Methyl-N-(2-{methyl-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]- amino} -ethyl) -benzenesulfonamide Benzenesulfonylchloride (0.17mL, 1.3mmol) was added to a solution of iV,N'-dimethyl-Λ''-[4- (4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidm-2-yl]-ethane-l,2-diamine (0.44g, 1.21mmol), NEt3 (0.25mL, 1.8mmol) in DCM (3mL).The reaction mixture was stirred for 2 h and then diluted with DCM (5OmL). The organic layer was washed with 10% aqueous KHSO4 solution (4OmL), 10% aqueous K2CO3 solution (4OmL), brine (4OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chomatography (Hexane-DCM-EtOAc (4:0.5:0.5)) to afford the desired compound as a yellow oil (0.3Og, 45%). 1H NMR (CDCl3) 8.29 (2H, d), 8.20 (2H, d), 7.76 (2H, d), 7.54-7.46 (3H, m), 7.29-7.18 (5H, m), 3.93 (2H, t), 3.35 (2H, t), 3.31 (3H, s), 2.85 (3H, s), 2.73-2.67 (4H, m), 2.10 (2H, quintet). Step c The title compound was obtained as its HCl salt using step e of example 71 except that N-methyl-N-(2-{methyl-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]-amino}- ethyl)-benzenesulfonamide was used instead of 4-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)- pyrimidin-2-yl]-morpholine, followed by reaction of the product obtained instead of 4-[2- cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine, according to steps d and e of example 1. 1H ΝMR (CDCl3) 8.04 (2H, d), 7.74 (2H, d), 7.48-7.45 (3H, m), 7.28-7.17 (7H, m), 6.75 (IH, s), 3.91 (2H, t), 3.73 (4H, s), 3.33 (2H, t), 3.28 (3H, s), 2.84 (3H, s), 2.66 (4H, quintet), 2.09 (2H, quintet). Found: C 54.89, H 5.86, Ν 13.41%; C32H37Ν7O2S-3HCl-Et2O requires C 54.90, H 6.01, N 13.50%.
Example 83 (4,5~Dihydro-lH-imidazol-2-yl)-{4-[2-(4-methanesulfonyl-piperazin-l-yl)-6-(3- phenyl-propyl)-pyrimidin-4-yl]-phenyl}-amine
Step a l-[4-(4-Nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]-piperazine was obtained using steps d of example 71 except that piperazine was used instead of morpholine.
Step b 4-Methanesulfonyl- 1 -[4-(4-Nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]- piperazine was obtained using step b of example 82 except that l-[4-(4-nitro-phenyl)-6-(3- phenyl-propyl)-pyrimidin-2-yl]-piperazine and methanesulfonylchloride were used instead of N^-dimethyl-N-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]-ethane-l,2-diamine and benzenesulfonylchloride respectively
Step c The title compound was obtained as its HCl salt using step e of example 71 except that 4-methanesulfonyl-l-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]-piperazine was used instead of 4-[4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidin-2-yl]-morpholine, followed by reaction of the product obtained instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)- pyrimidin-4-yl]-phenylamine, according to steps d and e of example 1. 1H NMR (CDCl3) 8.03
(2H, d), 7.30-7.20 (7H, m), 6.82 (IH, s), 4.07 (4H, t), 3.79 (4H, s), 3.32 (4H, t), 2.80 (3H, s), 2.69 (3H, quintet), 2.09 (2H, quintet). Found: C 50.95, H 5.96, N 14.81%; C27H33N7O2S-3HC1-
Et2O requires C 50.87, H 5.96, N 14.72%.
Example 84 {4-[4-(4,5-Dihydro-lH-pyrrol-2-ylammo)-phenyl]-6-phenyl-pyrimidin-2-yl}- hexyl-methyl-amine
Step a 2,4-Dichloro-6-phenyl-pyrirnidine 2,4,6-Trichloropyrimidine (1.Og, 5.5mmol) and phenylboronic acid (0.67g, 5.5mmol) were dissolved in DME (5OmL) under an Argon atmosphere. A solution OfNa2CO3 (1.81g, 17.1mmol) in H2O (5mL) was added, followed by palladium acetate (61.2mg) and PPh3 (143mg). The reaction mixture was refluxed for 5-6 h. The solution was evaporated and the residue suspended in between H2O-DCM (3:5 / 8OmL). The separated organic layer was separated, washed with H2O (3OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chomatography (Hexane-EtOAc (4.5:0.5)) (0.725g, 59%). 1H NMR (CDCl3) 8.07 (2H, d), 7.68 (IH, s), 7.61-7.51 (3H, m).
Step b 2-Chloro~4-(4-nitro-phenyl)-6-phenyl-pyrimidine was obtained using step a of example 84 except that 2,4-dichloro-6-phenyl-pyrimidine and 4,4,5,5-tetramethyl-2-(4-nitro-phenyl)- [l,3,2]dioxaborolane were used in place of 2,4,6-trichloropyrimidine and phenylboronic acid repectively. 1H NMR (CDCl3) 8.43-8.32 (4H, m), 8.19-8.15 (2H, dd), 8.08 (IH, s), 7.62-7.52 (3H, m).
Step c The title compound was obtained as its HCl salt using steps d and e of example 71 except that 2-chloro-4-(4-nitro-phenyl)-6-phenyl-pyrimidine and 7V-methyl-hexylamine were used instead of 2-methanesulfonyl-4-(4-nitro-phenyl)-6-(3-phenyl-propyl)-pyrimidine and morpholine respectively in step d, followed by reaction of the product obtained instead of 4-[2- cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine, according to steps d and e of example 1. 1H NMR (d6 DMSO) 10.97 (IH, s), 8.48 (2H, s), 8.32 (2H, d), 8.28-8.24 (2H, m), 7.72 (IH, s), 7.54-7.52 (3H, m), 7.40 (2H, d), 3.76 (2H, t), 3.69 (4H, s), 3.16 (3H, s), 1.65 (2H, m), 1.34-1.27 (6H, m), 0.84 (3H, t). Found: C 56.47, H 6.69, N 15.06%; C26H33N6-SHCl-H2O requires C 56.16, H 6.71, N 15.11%.
Example 85 2-Cyclohexyl-6-(4-guanidino-phenyl)-5-methyl-pyrimidine-4-carboxylic acid benzylamide Step a 2-Cyclohexyl-6-hydroxy-5-methyl-pyrimidine-4-carboxylic acid ethyl ester
Clean sodium metal (0.4g, 18.4mmol) was dissolved in dry EtOH (8mL) under argon and added drop-wise to a solution of cyclohexylamidine.HCl (3.Og, 18.4mmol) in EtOH (13mL). The precipitate formed was removed by filtration. Diethyloxalpropionate (3.5mL, 18.4mmol) was added to the filtrate and the mixture refluxed for 24 h. On cooling, concentration of the solution afforded the product as yellow crystals (1.92g, 40%). 1H NMR (CDCl3) 11.69 (IH, s), 4.43 (2H, q), 2.65 (IH, m), 2.20 (3H, s), 1.99-1.57 (7H, m), 1.44 (3H, t), 1.40-1.25 (3H, m).
Step b 2-Cyclohexyl-5-methyl-6-(4-nitro-phenyl)-pyrimidine-4-carboxylic acid ethyl ester was obtained using steps b and c of example 1 except that 2-cyclohexyl-6-hydroxy-5-methyl- pyrimidine-4-carboxylic acid ethyl ester was used instead of 2-cyclohexyl-6-(3-phenyl- propyl)-pyrimidin-4-ol in step b and 4,4,5, 5-tetramethyl-2-(4-nitro-phenyl)- [l,3,2]dioxaborolane was used instead of 4-(4,4,5,5-tetramethyl-l,3,2,-dioxaborolan-2- yl)aniline in step c. 1H NMR (CDCl3) 8.36 (2H, d), 7.74 (2H, d), 4.50 (2H, q), 2.96 (IH, 3xt), 2.37 (3H, s), 2.05-1.66 (7H, m), 1.45 (3H, t), 1.44-1.27 (3H, m).
Step c 2-Cyclohexyl-5-methyl-6-(4-nitro~phenyl)-pyrimidine-4-carboxylic acid 2-Cyclohexyl-5-methyl-6-(4-nitro-phenyl)-pyrimidine-4-carboxylic acid ethyl ester (0.482g, 1.3mmol) was stirred at rt in MeOH (2OmL) with a IM LiOH (2mL, 2.0mmol) for 1.5 h. The solvent was evaporated and the residue was diluted with H2O (1OmL), acidified carefully to pH 6-7 with dilute HCl, and extracted with DCM (3 x 2OmL). The extract was washed with brine (5OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the product as yellow solid (0.422g, 95%). 1H NMR (CDCl3) 8.38 (2H, d), 7.76 (2H, d), 2.99 (IH, 3xt), 2.72 (3H, s), 2.11-1.34 (1OH, m).
Step d 2-Cyclohexyl-5-methyl-6-(4-nitro-phenyl)-pyrimidine-4-carboxylic acid benzylamide was obtained using step a of example 51, except that benzylamine and 2-cyclohexyl-5-methyl- 6-(4-nitro-phenyl)-pyrimidine-4-carboxylic acid were used instead of 4-[2-cyclohexyl-6-(3- phenyl-propyl)-pyrimidin-4-yl]-phenylamine and N-tert-butoxycarbonyl glycine respectively. 1H ΝMR (CDCl3) 8.49 (IH, t), 8.35 (2H, d), 7.74 (2H, d), 7.40-7.32 (5H, m), 4.68 (2H, d), 2.91 (IH, 3xt), 2.05-1.70 (6H, m), 1.45-1.27 (4H, m). Step e 2-Cyclohexyl-5-methyl-6-(4-amino-phenyl)-pyrimidine-4-carboxylic acid benzylamide was obtained using step b of example 46, except that 2-cyclohexyl-5-methyl-6-(4-nitro- phenyl)-pyrimidine-4-carboxylic acid benzylamide was used instead of 2-cyclohexyl-4-(4- nitro-phenoxy)-6-(3-phenyl-propyl)-pyrimidine. 1H NMR (CDCl3) 8.52 (IH, bs), 7.47 (2H, d), 7.44-7.29 (5H, m), 6.76 (2H, d), 4.67 (2H, d), 3.87 (2H, s), 2.87 (IH, 3xt), 2.71 (3H, s), 2.05- 1.61 (6H, m), 1.44-1.26 (4H, m).
Step f N',N"-bis-tert-Butoxycarbonyl-N-{6-(4-amino-phenyl)-2-cyclohexyl-5-methyl- pyrimidine-4-carboxylic acid benzylamide} -guanidine was obtained using step d of example 1 except that 2-cyclohexyl-5-methyl-6-(4-amino-phenyl)-pyrimidine-4-carboxylic acid benzylamide and l,3-tøfter^butoxycarbonyl)-2-methyl-thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenylamine and N,N'-bis-(tert- butoxycarbonyl)-imidazolidine-2-thione respectively. 1H NMR (CDCl3) 11.7 (IH, s), 10.5 (IH, s), 8.50 (IH, t), 7.77 (2H, d), 7.57 (2H, d), 7.40-7.31 (5H, m), 4.68 (2H, d), 2.91 (IH, 3xt), 2.69 (3H, s), 2.05-1.61 (6H, m), 1.56 ((H, s), 1.53 (9H, s), 1.49-1.24 (4H, m). Step g The title compound was obtained as its TFA salt using step e of example 1, except that N'iV-6z5-ter^-butoxycarbonyl-N-{6-(4-amino-phenyl)-2-cyclohexyl-5-methyl-pvrimidine-4- carboxylic acid benzylamide} -guanidine and TFA were used instead of N,N-bis-(tert~ butoxycarbonyl)-{4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4,5-dihydro- lH-imidazol-2yl)-amine and HCl in dioxan respectively. 1H NMR (CDCl3) 10.20 (IH, m), 8.33 (IH, t), 7.68 (2H, d), 7.42-7.28 (7H, m), 4.68 (2H, d), 2.93 (IH, m), 2.68 (3H, s), 1.95- 1.10 (1OH, m). Found: C 57.69, H 5.59, N 13.56%; C26H30N6O- lTFA-dioxan requires C 57.94, H 5.55, N 13.42%.
Example 86 Benzyl-{2-cyclohexyl-6-[4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl]-5-ethyl- pyrimidin-4-yl} -amine Step a 4,6-Dichloro-2-cyclohexyl-5-ethyl-pyrimidine was obtained using steps a and b of example 1 except that 2-ethyl-malonic acid diethyl ester was used in place of 3-oxo-6-phenyl- hexanoic acid ethyl ester in step a. 1H NMR (CDCl3) 2.86 (2H, q), 2.75 (IH, m), 2.00-1.25 (1OH, m), 1.22 (3H, t).
Step b Benzyl-(6-chloro-2-cyclohexyl-5-ethyl-pyrimidin-4-yl)-amine was obtained using step b of example 61 except that 4,6-dichloro-2-cyclohexyl-5-ethyl-pyrimidine and benzylamine were used in place of 4-chloro-6-(3-methyl-butyl)-2-(3-nitro-phenyl)-pyrimidine and phenethylamine respectively. 1H NMR (CDCl3) 7.32 (5H, m), 5.00 (IH, bt), 4.74 (2H, d), 2.64 (IH, m), 2.55 (2H, q), 2.00-1.27 (1OH, m), 1.14 (3H, t). Step c The title compound was obtained as its HCl salt using steps c-e of example 1, except that benzyl-(6-chloro-2-cyclohexyl-5-ethyl-pyrimidin-4-yl)-amine was used instead of 4- chloro-2-cyclohexyl-(3-phenyl-propyl)-pyrimidine in step c. 1H NMR (CDCl3) 7.44-7.26 (9H, m), 5.20 (IH, bt), 3.79 (4H, s), 2.75 (IH, m), 2.36 (2H, q), 2.00-1.25 (1OH, m), 1.08 (3H, t). Found: C 57.41, H 6.98, N 14.19%; C28H34N6.3HC1.H2O requires C 57.78, H 6.75, N 14.44%.
Example 87 N'-^-β-ζl-Methyl-octyty-δ-β-phenyl-propyty-pyrimidin^-ylJ-phenylj-ethane- 1,2 -diamine
Step a N'(tert-Butoxycarbonyl)-N"-{4-[2-(l-methyl-octyl)-6-(3-phenyl-propyl)-pyrimidin-4- yl] -phenyl}-ethane-l ,2-diamine The title compound was obtained as its HCl salt using step b of example 43 except that N-(tert- butoxycarbonyl)-glycinaldehyde was used instead of l-trityl-imidazole-2-carboxaldehyde, followed by reaction of the product obtained instead of N,N-tø-(fer£-butoxycarbonyl)-{4-[2- cyclohexyl-6-(3 -phenyl-propyl)-pyrimidin-4-yl]-phenyl} -(4,5-dihydro- 1 H-imidazol-2yl)- amine, according to step e of example 1. 1H ΝMR (d6DMSO) 8.33 (3H, bs), 8.19 (2H, d), 8.00 (IH, s), 7.28-7.13 (5H, m), 6.80 (2H, d), 3.48 (2H, t), 3.35 (IH, m), 3.00 (4H, m), 2.68 (2H, t), 2.12 (2H, m), 1.90 (IH, m), 1.60 (IH, m), 1.32 (3H, d), 1.09 (1OH, m), 0.79 (3H, t). Found: C 63.73, H 8.27, Ν 10.01%; C30H42N4JHCl requires C 63.43, H 7.99, N 9.86%.
Example 88 N'~{4-[2-(l-Methyl-octyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phe?iyl}-propane- 1,3 '-diamine. The title compound was obtained as its HCl salt using step b of example 43 except that 2-{tert- butoxycarbonylamino)-propionaldehyde was used instead of l-trityl-imidazole-2- carboxaldehyde, followed by reaction of the product obtained instead of N,N'-bis-(tert- butoxycarbonyl)-{4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4,5-dihydro- lH-imidazol-2yl)-amine, according to step e of example 1. 1H NMR (d6DMSO) 8.16 (5H, bs and d) 7.99 (IH, s), 7.28-7.15 (5H, m), 6.76 (2H, d) 3.30 (IH, m), 3.27 (2H, t), 2.99 (2H, t), 2.89 (2H, q), 2.68 (2H3 1), 2.10 (2H, m), 1.88 (3H, m), 1.60 (IH, m), 1.32 (3H, d), 1.18 (1OH, m), 0.79 (3H, t). Found: C 62.10, H 8.25, N 9.25%; C3IH44N4-SHCLH2O requires C 62.04, H 8.23, N 9.33%.
Example 89 {4-[2-(l-Methyl-octyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-pyrrolidin-2- ylmethyl-amine
The title compound was obtained as its HCl salt using step b of example 43 except that N-(tert- butoxycarbonyl)-prolinal was used instead of l-trityl-miidazole-2-carboxaldehyde, followed by reaction of the product obtained instead of ΛζN-6w-(tert-butoxycarbonyl)-{4-[2- cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4,5-dihydro-lH-imidazol-2yl)- amine, according to step e of example 1. 1H NMR (d6DMSO) 9.72 (lH,bs), 9.37 (IH, bs), 8.17 (2H, d), 7.98 (IH, s), 7.28-7.13 (5H, m), 6.81 (2H, d), 3.70 (IH, m), 3.55 (2H, m), 3.40-3.00 (3H, m), 2.95 (2H,t), 2.68 (2H, t), 2.10 (2H, m), 1.89 (3H, m), 1.55 (2H, m), 1.33 (3H, d), 1.18 (1OH, m), 0.79 (3H, t). Found: C 65.58, H 8.37, N 9.27%; C33H46N4-SHCl requires C 65.18, H 8.12, N 9.21%.
Example 90 N'-(2-Amino-ethyl)-N'-{4~[2-(l-methyl-octyl)-6-(3-phenyl-propyl)-pyrimidin-4- yl]-phenyl}-ethane-l,2-diamine
The title compound was obtained as its HCl salt using step b of example 43 except that two equivalents of N-(?ert-butoxycarbonyl)-glycinaldehyde were used instead of 1-tiityl-imidazole- 2-carboxaldehyde, followed by reaction of the product obtained instead of N,7V-όw-(tert- butoxycarbonyl)-{4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-phenyl}-(4,5-dihydro- lH-imidazol-2yl)-amine, according to step e of example 1. 1H ΝMR (dβDMSO) 8.34 (6H, bs), 8.19 (2H, d), 7.98 (IH, s), 7.29-7.12 (7H, m), 3.76 (4H, m), 3.20 (IH, m), 3.00 (6H, m), 2.67 (2H, t), 2.09 (2H, m), 1.90 (IH, m), 1.62 (IH, m), 1.30 (3H, d), 1.08 (1OH, m), 0.76 (3H, t). Found: C 59.75, H 8.11, Ν 10.90%; C32H47N5^HCl requires C 59.35, H 7.84, N 10.81%.
Example 91 4-[4-(4, 5-Dihydro-lH-imidazol-2-ylmethyl)-phenyl]-2-(l~methyl-octyl)-6-(3- phenyl-propyl)-pyrimidine
Step a 4-[2-(l-Methyl-octyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]-benzaldehyde was obtained using steps a-c of the procedure described in example 1, except that 1-methyl- octylamidine.HCl was used instead of cyclohexylamidine.HCl in step a., and 4-formyl- phenylboronic acid was used instead of 4-(4,4,5,5-tetramethyl-l,3,2,-dioxaborolan-2-yl)aniline in step c. 1H NMR (CDCl3) 10.11 (IH, s), 8.25 (2H, d), 8.00 (2H, d), 7.39 (IH, s), 7.33-7.18 (5H, m), 3.10 (IH, m), 2.86 (2H, t), 2.73 (2H, t), 2.14 (2H, m), 2.00 (IH, m), 1.63 (IH, m), 1.38 (3H, d), 1.24 (1OH, m), 0.85 (3H, t). Step b 4-[4-(2,2-Dibromo~vinyl)-phenyl]-2-(l-methyl-octyl)-6-(3-phenyl-propyl)-pyrimidine
To a stirred solution of 4-[2-(l-methyl-octyl)-6-(3-phenyl-propyl)-pyrimidin-4-yl]- benzaldehyde (0.428g, lmmol) in DCM (2OmL) was added CBr4 (0.398g, 1.2mmol) followed by PPh3 (0.629g, 2.4mmol). The reaction mixture was stirred for 30 min then filtered though a pad of silica which was then washed through with DCM (20OmL). The filtrate was evaporated to afford the product (0.5Og, 86%). 1H NMR (CDCl3) 8.01 (2H, d), 7.65 (2H, d), 7.55 (IH, s), 7.33 (IH, s), 7.31-7.10 (5H, m), 3.07 (IH, m), 2.83 (2H, t), 2.72 (2H5 1), 2.12 (2H, m), 1.93 (IH, m), 1.63 (IH, m), 1.58 (IH, d), 1.36 (2H, d), 1.24 (1OH, m), 0.85 (3H, t).
Step c A solution of 4-[4-(2,2-dibromo-vinyl)-phenyl]-2-(l-methyl-octyl)-6-(3-phenyl- propyl)-pyrimidine (0.225g, 0.39mmol) in ethylenediamine (2mL) was stirred at rt for 2h. The reaction mixture was diluted with EtAOc (2OmL), washed with H2O (3 x 20ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chomatography (DCM-MeOH-NH4OH (9:1:0.1)) to (0.13Og, 69%). 1H NMR (CDCl3) 8.05 (2H, d), 7.40 (2H, d), 7.32-7.17 (6H, m), 4.00 (IH, bs), 3.67 (2H,s), 3.59 (4H, s), 3.06 (IH, m), 2.82 (2H, t), 2.72 (2H, t), 2.12 (2H, m), 1.92 (IH, m), 1.65 (IH, m), 1.35 (3H, d), 1.25 (1OH, m), 0.85 (3H, t). The compound was further characterised and tested as its HCl salt. Found: C 66.88, H 7.90, N 9.71%; C32H42N4^HClH2O requires C 67.00, H 8.08, N 9.76%.
Example 92 (4-(2-(4-Bromostyryl)-6-(3-phenylpropyl)pyrimidin-4-yl)phenyl)guanidine
Step a 2-Methyl-6-(3-phenylpropyl)pyrimidin-4-ol was obtained using the procedure described in example 1 step a, except that methylamidine.HCl was used instead of cyclohexylamidine.HCl. 1H NMR (d6 DMSO) 12.25 (IH, br s), 7.20 (5H, m), 5.96 (IH, s), 2.58 (2H, t), 2.38 (2H, t), 2.23 (3H, s), 1.85 (2H, m).
Step b 2-(4-Bromostyryl)-6-(3~phenylpropyl)pyrimidin-4-ol
A mixture of 2-methyl-6-(3-phenylpropyl)pyrimidin-4-ol (1.14g, 5.0mmol), 4- bromobenzaldehyde (1.1 Ig, ό.Ommol) and AcOH (5mL) was stirred and refluxed for 48 h. After cooling and dilution with MeOH (5mL) the product was isolated by filtration as white crystals (1.2g, 61%). 1H NMR (d6 DMSO) 12.25 (IH, br s), 7.80 (IH, d), 7.57 (4H, m), 7.22 (5H, m), 6.90 (IH, d), 6.05 (IH, s), 2.63 (2H, t), 2.48 (2H, t), 1.90 (2H, m).
Step c 2-(4-Bromostyryl)-4-chloro-6-(3-phenylpropyl)pyrimidine was obtained using the procedure described in examplel step b, except that 2-(4-bromostyryl)-6-(3- phenylpropyl)pyrimidin-4-ol was used instead of 2-cyclohexyl-6-(3- phenylpropyl)pyrimidin-4-ol. 1H NMR (CDCl3) 7.95 (IH, d), 7.50 (4H, m), 7.33-7.13 (6H, m), 7.00 (IH, s), 2.73 (4H, m), 2.12 (2H, m).
Step d 4-(2-(4-Bromostyryl)-6-(3-phenylpropyl)pyrimidin-4-yl)phenylamine was obtained using the procedure described in example 1 step c, except that 2-(4-bromostyryl)-4-chloro- 6-(3-phenylpropyl)pyrimidine (example 92, step c) was used instead of 4-chloro-2- cyclohexyl-6-(3-phenylpropyl)pyrimidine.1H NMR (CDCl3) 8.01 (3H, m), 7.52 (4H5 s), 7.31-7.22 (7H, m), 6.78 (2H, d), 3.96 (2H, br s), 2.85-2.73 (4H, m), 2.16 (2H, m).
Step e The title compound was obtained as its TFA salt using the procedure described in example 1, step d except that 4-(2-(4-bromostyryl)-6-(3-phenylpropyl)pyrimidin-4- yl)phenylamine and N,N'-bis-tert-butoxycarbonyl-2-methyl-2-thiopseudourea were used instead of 4-[2-cyclohexyl-6-(3-phenyl-propyl)-pyrimidin-4-yl]-ρhenylamine and N5N'- bis-(tert-butoxycarbonyl)- imidazolidine-2-thione respectively, followed by treatment of the product obtained, in place of N',N"-bis-tert-butoxycarbonyl-N-{6-(4-amino-phenyl)-2- cyclohexyl-5-methyl-pyrimidine-4-carboxylic acid benzylamide}-guanidine, according to the method of example 85, step h. 1H NMR (d6DMSO) 8.30 (2H, d), 7.77 (IH, d), 7.65 (2H, d), 7.56 (2H, d), 7.30-7.12 (5H, m), 2.79 (2H, t), 2.64 (2H, t), 2.03 (2H, m). Found: C 50.38, H 3.95, N 9.27% C28H26N5Br.2 CF3CO2H.1.2H2O requires: C 50.43, H 4.02 N 9.19%.
Example 93 N-(4-(2-(l-Cyclohexylethyl)-6-(3-phenylpropyl)pyrimidin-4-yl)phenyl)-4, 5- dihydro-lH-imidazol-2-amine
The title compound was obtained using the procedure described in example 1, except that 2-cyclohexylpropanamidine.HCl was used in step a instead of cyclohexylamidine.HCl. 1H NMR (CDCl3) 8.02 (2H, d), 7.31-7.17 (8H, m), 3.72 (4H, s), 2.85-2.65 (5H, m), 2.07 (2H, m), 1.90-1.50 (5H, m), 1.40-0.95 (9H, m). The compound was further characterised and tested as its HCl salt. Found: C 61.82, H 7.33, N 11.80% C30H37N52.4HC1.1.5H2O requires: C 61.89, H 7.34 N 12.03%. Example 94 N-(4-(6-((Benzyloxy)methyl)-2-(nonan-2-yl)pyrimidin-4-yl)phenyl)-4,5- dihydro-lH-imidazol-2-amine
The title compound was obtained as the HCl salt using the procedure described in example 1, except that 4-benzyloxy-3-oxo-butyric acid ethyl ester and 2-methylnonanamidine.HCl were used instead of 3-oxo-6-phenyl-hexanoic acid ethyl ester and cyclohexylamidine. HCl respectively. 1H NMR (CDCl3) 8.09 (2H, d), 7.65 (IH, s), 7.44-7.00 (9H, m), 4.70 (2H, s), 4.63 (2H, s), 3.65 (4H, s), 3.03 (IH, m), 1.90 (IH, m), 1.62 (IH3 m), 1.40-1.20 (13H, m), 0.86 (3H, t). ). Found: C 62.98, H 7.35, N 11.81% C30H39N3O.2.5HCl requires: C 62.67, H 7.27 N 12.18%.

Claims

CLAIMS 1. A compound of formula (I) :
Figure imgf000104_0001
(I) or a salt, solvate or pro-drug thereof; wherein:
R3 and R4 are independently selected from H, COOH, COO(Cj-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 C1-30 hydrocarbyl or Ci-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 (i), (ii) and (iii):
(i) -CH=CH-, -C≡C-5 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(Q-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 in the backbone;
(ii) 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(Ci-6 alkyl), 0(C6-20 aryl), 0(C7-20 alkaryl), 0(C7-20 aralkyl), =0, NH2, =NH, NH(Ci-6 alkyl), N(Ci-6 alkyl)2, NH(C6-20 aryl), NH(C7-20 aralkyl), NH(C7-20 alkaryl), N(Cj-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-20 aralkyl), N(C1-6 alkyl)(C7-20 alkaryl), =N(C-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(C-6 alkyl)C(O)(C6-20 aryl), N(C1-6 alkyl)C(O)(C7-20 aralkyl), N(C-6 alkyl)C(θχC7-20 alkaryl), NO2, CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(C-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, SO2NH(C7-20 aralkyl), SO2NH(C7-20 alkaryl), SO2N(C-6 alkyl)(C6-20 aryl), SO2N(C-6 alkyl)(C7-20 aralkyl), SO2N(C-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(C1-6 alkyl)(C7-20 aralkyl) and C(O)N(C1-6 alkyl)(C7-20 alkaryl) on the backbone; and,
(iii) 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; at least one of R1 and R2 has a structure independently selected from the group consisting of (a), (b) and (C),
Figure imgf000106_0001
n is 0 or 1; m is O, 1, 2, 3, 4, 5 or 6;
R5 and R7 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(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), NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NHC(O)(C1-6 alkyl), NO2, CN, SO2NH2, SO2NH(C-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), 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, Cs-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, C]-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 (iv), (v) and (vi):
(iv) -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(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;
(v) 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,
(vi) groups independently selected from the group consisting Of C1-10 alkyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, C]2-20 aryloxyaryl, C7-20 aryloxyalkyl, C)-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; R6 is selected from the group consisting of -NR9R10, -CONR9R10, -NR9COR10, -OR10, -R11, - NR9C(=NR12)N(R13)2 and -N=C(NR12R9)N(R13)2; wherein:
R9 is selected from the group consisting of H, C1-6 alkyl, C1-6 aminoalkyl, C1-12 alkylaminoalkyl, C1-1S dialkylaminoalkyl, C3-20 cycloalkyl, C3-20 aminocycloalkyl, C4-20 (cycloalkyl)alkyl, C4-20 (aminocycloalkyl)alkyl, C6-20 aryl, C6-20 aminoaryl, C7-20 aralkyl, C7-20 aminoaralkyl, C7-20 alkaryl, C7-20 aminoalkaryl, Cj-2O 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, Cs-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, C]-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, C9-30 heterocyclylalkaryl, C4-30 heterocyclylalkoxyalkyl, C4-30 heterocyclylalkylaminoalkyl, Cs-30 heteroarylalkaryl, C3-30 heteroarylalkoxyalkyl, C3-30 heteroarylalkylaminoalkyl, C7-30 aryloxyalkyl, C7-30 arylaminoalkyl, C7-30 alkylaminoaiyl, Ci-I0 aminoalkyl, C1-I2 alkylaminoalkyl, C]-18 dialkylaminoalkyl, 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-I0 alkyl, C1-20 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(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, N(C-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-20 alkaryl), N(C-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), C(O)(C7-20 alkaryl), guanidinyl and guanidinyl C1-10 alkyl; 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(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(Ci-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;
Ru is selected from the group consisting of H, -C(=NH)NH2, -C(=NH)NHC)-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 aiyl, -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(C,-3o heteroaryl)2, -C(=NCi-20 alkyl)NH2, -C(=NC,-20 alkyl)NHC1-20 alkyl, -C(=NC1-20 alkyl)N(Ci-20 alkyl)2, -C(=NCi.2o alkyl)NHC3-30 cycloalkyl, -C(=NC]-20 alkyl)N(C3-30 cycloalkyl)2, -C(=NC-20 alkyl)NHC6-30 aryl, -C(=NC,-20 alkyl)N(C6-30 aryl)2, -C(=NC,-20 alkyl)NHC6-30 alkaryl, -C(=NCi-20 alkyl)N(C6-30 alkaryl)2, -C(=NCi-20 alkyl)NHC6-30 aralkyl, -C(=NC,-20 alkyl)N(C6-30 aralkyl)2, -C(=NC-2o alkyl)NHC2-30 heterocyclyl, -C(=NC]-20 alkyl)N(C2-30 heterocyclyl)2, -C(=NCi-20 alkyl)NHCi-30 heteroaryl, -C(=NC,-20 alkyl)N(Ci-30 heteroaryl)2, 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, C]-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-I0 aminoalkyl, C7-20 aminoaralkyl, C7-20 aminoalkaryl, C2-20 alkylguanidinylalkyl and ureayl Ci-I0 alkyl; any of the groups defined as R1 1 (except H) being optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from C]-I0 alkyl, Ci-20 haloalkyl, C)-20 perhaloalkyl, Ci-20 hydroxyalkyl, C3-I0 CyClOaIlCyI, 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(Ci-6 alkyl), N(C-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(C-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-20 alkaryl), N(Cj-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 R11 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(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), 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(C1-6 alkyl)SO2, N(C6-20 aryl)SO2, C(O)NHNHC(O), =N-N- and
C(O)NHNH;
R12 is selected from the group consisting of H, Ci-2O 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, C7-3O aralkyl, C7-30 alkaryl, C6-3O aryl, Ci-30 heteroaryl and C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, C]-I0 aminoalkyl, C6-20 aminoaryl, guanidinyl Ci-I0 alkyl, C2-20 alkylguanidinylalkyl, ureayl Ci-I0 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(Ci-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), NH(C1-6 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, NO2, CN, C(O)H and C(O)(C1-6 alkyl); and each R13 is 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 and C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, Ci-I0 aminoalkyl, C6-20 aminoaryl, guanidinyl Ci-I0 alkyl, C2-20 alkylguanidinylalkyl, ureayl 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 halo, OH, OC]-6 alkyl, NH2, COOH, COO(Ci-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(C-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)(C1-6 alkyl), or each R12 is joined to one another to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring; or R12 and one of R13 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R13 not joined to R12 is H or Cj-6 alkyl; and where one of R1 and R2 is not a group (a), (b), and (c), it is independently selected from the same group as R3, as defined above.
2. A compound according to claim 1, wherein -(CH2)m-R6 is located in the para position relative to the -(O)n- group.
3. A compound according to claim 1 , wherein n = 0.
4. A compound according to claim 1, wherein R1 and/or R2 is a group having the structure (ai):
Figure imgf000110_0001
wherein R5 and R7 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)(C1-6 alkyl).
5. A compound according to claim 1, wherein R1 and/or R2 is a group having the structure (a2) or (a3):
Figure imgf000110_0002
6. A compound according to any preceding claim, wherein R5 and R7 are both H.
7. A compound according to any preceding claim, wherein R6 is selected from the group consisting Of-NR9R10, -NR9COR10 and -NR9C(=NR12)N(R13)2.
8. A compound according to any preceding claim, wherein R1 and/or R2 is selected from the group consisting of the following structures:
Figure imgf000111_0001
and
Figure imgf000111_0002
9. A compound according to any preceding claim, wherein R9 is H.
10. A compound according to any preceding claim, wherein R10 is selected from the group consisting of Ci.io heteroaryl, C2-Io heterocyclyl, C3-Io heteroaralkyl, C3-I0 heterocyclylalkyl and CJ.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), N(Ci-4 alkyl)2, guanidinyl and guanidinyl Ci-6 alkyl.
11. A compound according to any preceding claim, wherein R10 is selected from the group consisting of guanidinylethyl, di(Ci_6 alkyl)ammo(Ci-6 alkyl), amino(Ci-6 alkyl), (4,5-dihydro-lH-imidazol-2-yl, 4,5-dihydro-lH-imidazol-2-yl(Ci.6 alkyl) and lH-imidazol-2-yl(C1-6 alkyl) group 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, OH3 NH2, NO2, CN, COOH, C(O)H, C(O)O(C,-6 alkyl), 0(C1-6 alkyl), OC(O)(Ci-6 alkyl) and C(O)(Ci-6 alkyl).
12. A compound according to any preceding claim, wherein R12 and both R13 are H.
13. A compound according to any of claims 1 to 6, wherein R6 is a group -NHCO(C]-6 alkyl)guanidine or -NHCO(Ci-6 alkyl)amine.
14. A compound according to any of claims 1 to 6, wherein R6 is a group -CH2NHCH2CH2N(CH3)2, -CH2NHCH2CH2morpholine, -CH2NHCH2CH2CH2NH2 or -CH2NH2.
15. A compound according to claim 1, wherein R1 is selected from the group consisting of (( 1 H-imidazol-2-yl)methylamino)-phenyl, (( 1 H-imidazol-2-yl)ethylamino)-phenyl, ((lH-imidazol-2-yl)propylamino)-phenyl, (4,5-dihydro-lH-imidazol-2-ylamino)-phenyl,
((4,5-dihydro-lH-imidazol-2-yl)methylamino)-phenyl and guanidinylphenyl and R1 and R2 are different.
16. A compound according to claim 1, wherein when R2 is not selected from the group consisting of (a), (b), (c), (ai), (a2) and (a3) as defined in any preceding claim, R2 is 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)(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(C7-15 aralkyl), C(O)N(C7-15 aralkyl)2, C(O)NH(C7-15 alkaryl), C(O)N(C7-I5 alkaryl)2 and hydrocarbyl or heterocarbyl groups selected from Cj-2O 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, 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 or 4 groups, independently selected from the groups defined in (x), (xi) and (xii):
(x) -CH=CH-, -C≡C-, S, N, -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(C1-6 alkyl), N(Ci-6 alkyl)C(O)O, NHC(O)NH, NHC(O)O, NH, N(C,-6 alkyl), O, CO, SO2, NHSO2 and C(O)NHNH in the backbone; (xi) COOH, COO(Ci-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(Ci-6 alkyl), OC(O)(Ci-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 alkaryl), OC(O)(C7-20 aralkyl), =0, NH2, =NH, NH(Ci-6 alkyl), N(C-6 alkyl)2, =N(Ci-6 alkyl), NHC(O)(Ci-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(C7-15 aralkyl), C(O)N(C7-15 aralkyl)2, C(O)NH(C7-15 alkaryl), C(O)N(C7-15 alkaryl)2, NO2, CN, SO2NH2, C(O)H5 C(O)(C1-6 alkyl) on the backbone; and,
(xii) 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.
17. A compound according to claim 1, wherein when R2 is not selected from the group consisting of (a), (b), (c), (a,), (a2) and (a3), R2 is a group -(CR16RI7)m-X-R18; wherein:
m' is O, 1, 2, 3 or 4; X is a bond, -CH=CH-, -C≡C-, S, N, Si(C1-6 alkyl)2, Si(OH)2, Si(OC1-6 alkyl)2, C(O)NH, C(O)NCi-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(Ci-6 alkyl), NHC(O)NH, NHC(O)O, NH, N(Ci-10 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, Ci-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, Ci-I0 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(Ci-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), P(OH)(O)2, halo, haloCi-6 alkyl, perhaloC1-6 alkyl, OH, 0(C,-6 alkyl), =0, NH2, =NH, NH(Cj-6 alkyl), N(Cj-6 alkyl)2, =N(C,-6 alkyl), NHC(O)(C-6 alkyl), NO2, CN, SO2NH2, C(O)H and C(O)(Ci-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, C]-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 or20-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, Cs-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, Cj-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, Ci-I0 aminoalkyl, Ci-I0 alkylaminoalkyl, C6-20 aminoaryl, guanidine C]-I0 alkyl, C2-20 alkylguanidinylalkyl, urea 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 COOH, COO(Ci-6 alkyl), SH, S(Ci-6 alkyl), SO2H, SO2(Ci-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), P(OH)(O)2, halo, haloC1-6 alkyl, perhaloCi-6 alkyl, OH, 0(Ci-6 alkyl), =0, NH2, =NH, NH(C1-6 alkyl), N(C,-6 alkyl)2, =N(C]-6 alkyl), NHC(O)(C-6 alkyl), C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)2, C(O)NH(C6-12 aryl), C(O)N(C6-I2 aryl)2, C(O)NH(C7-12 aralkyl), C(O)N(C7-I2 aralkyl)2, C(O)NH(C2 alkaryl), C(O)N(C7-J2 alkaryl)2, NO2, CN, SO2, SO2NH2, C(O)H and C(O)(Ci-6 alkyl), CM0 alkyl, C2-10 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.
18. A compound according to claim 17, wherein X is a bond, NH, N(Cj-6 alkyl) or O.
19. A compound according to claim 17 or 18, wherein m' is O.
20. A compound according to any of claims 17 to 19, wherein R18 is selected from the group consisting of H, Ci-10 alkyl, C2-I0 alkoxyalkyl, C7-20 alkoxyaryl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, Cj-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, SH, SO2H, SO2(C1-3 alkyl), SO2(C6-I0 aryl), 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-io cycloalkyl, C4-15 (cycloalkyl)alkyl, C7-I2 aralkyl, C7-I2 alkaryl, Ci-J2 heteroaryl and C6-I2 aryl.
21. A compound according to any preceding claim, wherein R3 and R4 are independently selected from the group consisting of H, COOH, COO(Ci-6 alkyl), CN, SH, S(Ci-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), NH2, NH(C1-6 alkyl), N(Cj-6 alkyl)2, NHC(O)(Ci-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, Ci-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 (xiii), (xiv) and (xv): (xiii) -CH=CH-, -C≡C-, S, -N=, Si(C-6 alkyl)2, Si(OH)2, C(O)NH, C(O)N(Cj-6 alkyl), C(O)O, N(C-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), O, CO, SO2, NHSO2 and C(O)NHNH in the backbone;
(xiv) COOH, COO(C1-6 alkyl), SH, S(C1-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H, SO2(Cj-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, C(O)H and C(O)(C1-6 alkyl) on the backbone; and,
(xv) groups independently selected from the group consisting of C1-10 alkyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, C]2-20 aryloxyaryl, C7-20 aryloxyalkyl, Ci-10 alkoxy, C6-20 aryloxy, C2-10 alkenyl, C2-I0 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl and C6-20 aryl on the backbone.
22. A compound according to any preceding claim, wherein R4 is selected from the group consisting of Cj-6 alkyl, C5-8 cycloalkyl, Cj-4 alkoxy, Cj-8 alkoxyalkyl, C7-J0 aralkyl, C7-J0 alkaryl, C6-10 aryl, C1-10 heteroaryl and C2-10 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, SO2H, P(OH)(O)2, OH, NH2, NO2, CN, SO3H, SO2NH2 and C(O)H.
23. A compound according to any preceding claim, wherein R4 is H.
24. A compound according to any preceding claim, wherein R3 is selected from the group consisting of C]-4 alkyl, C5-!o cycloalkyl, C6-I4 (cycloalkyl)alkyl, Ci-4 alkoxy, C5-I0 cycloalkyloxy, C5-io cycloalkyloxyalkyl, C6-I4 (cycloalkyl)oxyalkyl, C7-i6 aralkyloxy, C8-I6 aralkyloxyalkyl, C7-I6 aryloxyalkyl, C7-I6 aryloxy, C7-I2 aralkyl, C7-I2 alkaryl, C6-I0 aryl, Ci-I0 heteroaryl and C2- io heterocyclyl, any of which are optionally substituted with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from =0, COOH, F, Cl, Br, I, OH, NH2, NH(Ci-6 alkyl), NO2, CN, CH3 and C(O)H;
H, F, Cl, Br, COOH, SH, SO2H, P(OH)(O)2, OH, NH2, NO2, CN, SO3H, SO2NH2 and C(O)H.
25. A compound according to any preceding claim, wherein R3 is selected from the group consisting of H, phenylethyl, phenylpropyl, phenylbutyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclohexyl optionally substituted with 1, 2, 3 or 4 methyl groups, (cyclohexyl)Ci-3 alkyl wherein the cycloalkyl moiety is optionally substituted with 1, 2, 3 or 4 methyl groups, (cyclohexyl)oxy(Ci-3 alkyl) wherein the cycloalkyl moiety is optionally substituted with 1, 2, 3 or 4 methyl groups, (cycloheptyl)oxy C]-3 alkyl, adamantyl, adamantylmethyl, adamantylethyl, adamantylpropyl, adamantylbutyl, naphthyl, phenyl, pyridyl, benzyl, tolyl, benzyloxymethyl, phenylethyloxy, xylyl, pyridinyl, pyranyl, tetrahydropyranyl, dihydropyranyl, furanyl, hydroxyphenyl, phenylamino, acetamido, benzylamido and benzylamino.
26. A pharmaceutical composition comprising a compound, salt, solvate or pro-drug according to any preceding claim and a pharmaceutically acceptable diluent or carrier.
27. A method of making a pharmaceutical composition according to claim 26, comprising mixing said compound, salt, solvate or pro-drug with a pharmaceutically acceptable diluent or carrier.
28. A compound, salt, solvate or pro-drug according to any of claims 1 to 25, for use in therapy.
29. 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 25 or a pharmaceutical composition according to claim 26.
30. 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 25, or a
5 pharmaceutical composition according to claim 26.
31. A method according to any of claims 29 or 30, wherein the disease is cancer.
32. A method according to any of claims 29 or 30, wherein the disease is osteoporosis.
33. A method according to any of claims 29 or 30, wherein the disease is an inflammatory disease.
10 34. A method according to any of claims 29 or 30, wherein the disease is an autoimmune disease.
35. A method according to any of claims 29 or 30, wherein the disease is metastases following a primary tumour.
36. A method according to any of claims 29 or 30, wherein the condition is lack of hair 15 eruption.
37. A method according to any of claims 29 or 30, 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 0 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. 5 38. Use of a compound, salt, solvate or pro-drug according to any of claims 1 to 25, or a pharmaceutical composition according to claim 26, in the manufacture of a medicament for the prophylaxis or treatment of a disease as defined in any of claims 29 to 37.
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