WO2008009963A2 - Dérivés de la pyrimidine - Google Patents

Dérivés de la pyrimidine 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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PCT/GB2007/002767
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WO2008009963A3 (fr
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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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Publication of WO2008009963A3 publication Critical patent/WO2008009963A3/fr

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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

Cette invention concerne des dérivés de la pyrimidine, leurs intermédiaires, leurs utilisations, ainsi que des procédés de production associés. Cette invention concerne en particulier l'hormone parathyroïde (PTH) et des ligands du récepteur de la protéine associée à l'hormone parathyroïde (PTHrp) (PTH-1 ou ligands du récepteur de la PTH/PTHrp). Cette invention concerne également des méthodes de préparation de ces ligands ainsi que des composés utilisés comme intermédiaires dans ces méthodes.
PCT/GB2007/002767 2006-07-21 2007-07-20 Dérivés de la pyrimidine WO2008009963A2 (fr)

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US9012462B2 (en) 2008-05-21 2015-04-21 Ariad Pharmaceuticals, Inc. Phosphorous derivatives as kinase inhibitors
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