WO2006129120A9 - Benzotriazepinone derivatives - Google Patents

Benzotriazepinone derivatives

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Publication number
WO2006129120A9
WO2006129120A9 PCT/GB2006/002042 GB2006002042W WO2006129120A9 WO 2006129120 A9 WO2006129120 A9 WO 2006129120A9 GB 2006002042 W GB2006002042 W GB 2006002042W WO 2006129120 A9 WO2006129120 A9 WO 2006129120A9
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WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
alkaryl
aralkyl
groups
Prior art date
Application number
PCT/GB2006/002042
Other languages
French (fr)
Other versions
WO2006129120A3 (en
WO2006129120A2 (en
Inventor
Iain Mair Mcdonald
Ildiko Maria Buck
David John Dunstone
Ian Duncan Linney
Michael John Pether
John Spencer
Katherine Isobel Mary Steel
Patrizia Tisselli
Paul Trevor Wright
Robert Anthony David Hull
Carol Austin
Elaine Anne Harper
Eric Griffin
Sarkis Barret Kalindjian
Caroline Minli Rachel Low
Original Assignee
James Black Foundation
Iain Mair Mcdonald
Ildiko Maria Buck
David John Dunstone
Ian Duncan Linney
Michael John Pether
John Spencer
Katherine Isobel Mary Steel
Patrizia Tisselli
Paul Trevor Wright
Robert Anthony David Hull
Carol Austin
Elaine Anne Harper
Eric Griffin
Sarkis Barret Kalindjian
Caroline Minli Rachel Low
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by James Black Foundation, Iain Mair Mcdonald, Ildiko Maria Buck, David John Dunstone, Ian Duncan Linney, Michael John Pether, John Spencer, Katherine Isobel Mary Steel, Patrizia Tisselli, Paul Trevor Wright, Robert Anthony David Hull, Carol Austin, Elaine Anne Harper, Eric Griffin, Sarkis Barret Kalindjian, Caroline Minli Rachel Low filed Critical James Black Foundation
Publication of WO2006129120A2 publication Critical patent/WO2006129120A2/en
Publication of WO2006129120A3 publication Critical patent/WO2006129120A3/en
Publication of WO2006129120A9 publication Critical patent/WO2006129120A9/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
    • C07D255/04—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention is concerned with benzotriazepinone derivatives, their intermediates, uses thereof and processes for their production.
  • the present invention relates to parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrp) receptor ligands, (PTH-I or PTH/PTHrp receptor ligands).
  • PTH parathyroid hormone
  • PTHrp parathyroid hormone related protein
  • the invention also relates to methods of preparing such ligands and to compounds which are useful as intermediates in such methods.
  • PTH is an 84 amino acid peptide circulating hormone produced by the parathyroid glands.
  • the primary function of PTH is to maintain a constant concentration of calcium in the extracellular fluid. It does so by acting directly or indirectly on various peripheral target tissues to mobilise calcium entry into the blood.
  • 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. As such, PTH-I receptor antagonists may be expected to help prevent this condition. In addition elevated PTH and/or
  • PTHrp levels have been associated with lack of hair eruption in transgenic mice, in congestive heart failure and in a number of inflammatory and auotoimmune diseases such as rheumatoid arthritis. These findings suggest a possible role may exist for PTH-I receptor antagonists in helping to treat or prevent these and other conditions either associated with elevated levels of
  • PTH or PTHrp or with over-activation of PTH-I receptors.
  • PTH has an anabolic action on osteoblasts therefore indicating a potential benefit for a PTH-I receptor ligand (such as an agonist or partial agonist) in helping to prevent or treat osteoporosis.
  • 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.
  • WO-A-03/041714 discloses a number of benzotriazepinone derivatives for use in the treatment of gastrin related disorders.
  • EP-A-0645378 describes a class of bicyclic compounds which are said to inhibit squalene synthetase.
  • R 1 , R 4 and R s are independently selected from H, COOH, COO(C, -6 alkyl), COO(C 6-20 aryl), COO(C 7-20 aralkyl), COO(C 7-20 alkaryl), SH, S(C 1-6 alkyl), S(C 6-20 aryl), S(C 7-20 alkaryl), S(C 7-20 aralkyl), SO 2 H, SO 3 H, SO 2 (C 1-6 alkyl), SO 2 (C 6-20 aryl), SO 2 (C 7-20 alkaryl), SO 2 (C 7-20 aralkyl), SO(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 5 0(C 1-6
  • R la and R 5a are independently selected from H, COOH, COOCH 3 , COOCH 2 CH 3 , halo, OH, OCH 3 , OCH 2 CH 3, OCF 3 , CF 3 , CH 3 , OCCl 3 , CCl 3 , OCF 2 CF 3, CF 2 CF 3, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , NHC(O)(CH 3 ), NO 2 , CN, OC(O)CH 3 and C(O)H; or R 1 is joined to R 5 , R 5a or R la to form a 5, 6, 7, 8, 9 or 10-membered saturated, unsaturated or aromatic, heterocyclic or carbocyclic ring which is optionally substituted with one or more of the groups, preferably, 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (b) and (c) above; or R 5 is joined to R 1 , R 5a or R la to form a 5, 6, 7, 8, 9 or 10-member
  • R 3 is selected from H, COOH, COO(Ci -20 alkyl), COO(C 6-20 aryl), COO(C 7-20 aralkyl), COO(C 7-20 alkaryl), SO 3 H, SO 2 (C 1-6 alkyl), SO 2 (C 6-20 aryl), SO 2 (C 7-20 alkaryl), SO 2 (C 7-20 aralkyl), CN, SO 2 NH 2 , SO 2 NH(C 1-6 alkyl), SO 2 N(C 1-6 alkyl) 2 , SO 2 NH(C 6-20 aryl), SO 2 N(C 6-20 aryl) 2 , SO 2 NH(C 7-20 aralkyl), SO 2 NH(C 7-20 alkaryl), SO 2 N(C 1-6 alkyl)(C 6-20 aryl), SO 2 N(C 1-6 alkyl)(C 7-20 aralkyl), SO 2 N(C 1-6 alkyl)(C 7-20 alkaryl), SO 2 N(C 1-6 al
  • R 2 is a group
  • n is an integer of 0, 1, 2, 3, 4 or 5
  • m is an integer of 0, 1, 2, 3, 4 or 5
  • the group -(CH 2 ) m - is optionally substituted by 1 or more -OH groups on the CH 2 backbone, preferably 1 -OH group;
  • R 7 and R 8 are independently selected from the group consisting of H, COOH, COO(C 1-6 alkyl), COO(C 6-20 aryl), COO(C 7-20 aralkyl), COO(C 7-20 alkaryl), SH, S(C 1-6 alkyl), SO 2 H, SO 3 H 3 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), 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 1-6 alkyl
  • R 9 is selected from the group consisting of H and C 1-6 alkyl, C 3-20 cycloalkyl, C 4-20 (cycloalkyl)alkyl, C 6-20 aryl, C 7-20 aralkyl, C 7-20 alkaryl, C 1-20 heteroaryl and C 2-20 heterocyclyl;
  • R 10 is selected from the group consisting of, H, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkoxyalkyl, C 7-30 alkoxyaryl, C 2-20 alkynyl, C 3-30 cycloalkyl, C 4-30 (cycloalkyl)alkyl, C 5-30 cycloalkenyl, C 7-30 cycloalkynyl, C 7-30 aralkyl, C 7-30 alkaryl, C 6-30 aryl, C 1-30 heteroaryl, C 2-30 heterocyclyl, C 2-30 heteroaralkyl, C 3-30 heterocyclylalkyl, C 9-30 heterocyclylalkaryl, C 4-30 heterocyclylalkoxyalkyl, C 4-30 heterocyclylalkylaminoalkyl, C 8-30 heteroarylalkaryl, C 3-30 heteroarylalkoxyalkyl, C 3-30 heteroarylalkylaminoalkyl, C 7-30 aryloxyalkyl, C 7-30
  • each R 14 is independently selected from the group consisting of H, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkoxyalkyl, C 7-30 alkoxyaryl, C 2-20 alkynyl, C 3-30 cycloalkyl, C 4-30 (cycloalkyl)alkyl, C 5-30 cycloalkenyl, C 7-3O cycloalkynyl, C 7-30 aralkyl, C 7-30 alkaryl, C 6-30
  • the group -(CH 2 ) m - is substituted by 1 -OH groups on the CH 2 backbone.
  • the -(CH 2 ) m - group is not substituted by an -OH group.
  • R 2 is a group having the structure:
  • R 7 and R 8 are independently selected from the group consisting of H, alkyl, halo, haloCi -6 alkyl, perhaloCi -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), R 6 is as defined above, n is O or 1 and m is O or 1. Where n is 1 or more, R 7 and/or R 8 are preferably located in the ortho or meta position relative to the -(CH 2 ),,- group, most preferably the meta position. Where n is O, R 7 and/or R 8 are preferably located in the ortho or meta position relative to the N 1 atom, most preferably the meta position.
  • R 7 is H and R 8 is H, Cl, Br, or F, preferably H or Br.
  • R 7 and R 8 are both H.
  • n is O or 1, most preferably O.
  • m is O or 1, most preferably O.
  • R 2 is selected from
  • R 9 is selected from H, methyl, ethyl, propyl, phenyl, phenylethyl, benzyl, tolyl and xylyl, more preferably H or methyl, most preferably H.
  • R 10 is selected from the group consisting of Ci -B heteroaryl, C 2-I s heterocyclyl, C 2- i 5 heteroaralkyl, C 3-15 heterocyclylalkyl, C 1-15 alkyl, C 6-20 aryl, C 7-20 aralkyl, C 3-15 cycloalkyl, and C 4-15 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 6-16 aryl) 2 , NH(C 7-16 aralkyl), N(C 7-16 aralkyl) 2 , NH(C 7-16 alkaryl), N(C 7-I6 alkaryl) 2; N(Cj -4 alkyl)(C 6 .i 6 aryl), N(Cj -4 alkyl)(C 7- i 6 alkaryl), N(C 1-4 alkyl)(C 7-16 aralkyl), N(C 6-16 aryl)(C 7-I6 alkaryl), N(C 6-16 aryl)(C 7- i 6 aralkyl), S(C 1-6 alkyl), NO 2 ,
  • R 10 is selected from the group consisting of C 6-20 aryl, C 7-20 aralkyl, C 3-15 cycloalkyl, C 4-15 cycloalkylalkyl, Ci -15 heteroaryl, C 2-15 heterocyclyl, C 2-15 heteroaralkyl, C 3-15 heterocyclylalkyl and C 1-10 alkyl, any of which are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from NH 2 , NH(Ci -4 alkyl) or N(Cj -4 alkyl) 2 .
  • R 10 is selected from the group consisting Of C 1-10 heteroaryl, C 2-10 heterocyclyl, C 3- io heteroaralkyl, C 3-I o 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(C 1-4 alkyl) or N(Ci -4 alkyl) 2 .
  • R 10 is selected from the group consisting of of Ci -I0 alkyl, C 3-I5 cycloalkyl, C 4-I5 cycloalkylalkyl, C 7-20 aralkyl, furanyl, furanyl(Ci -3 alkyl), pyridyl, pyridyl(C ⁇ 3 alkyl), phthalimido, phthalimido(Ci -3 alkyl), thienyl, thienyl(Ci -3 alkyl), pyrrolyl, pyrrolyl(C 1-3 alkyl), imidazolyl, imidazolyl(Ci -6 alkyl), pyrazolyl, pyrazolyl(Ci -3 alkyl), thiazolyl, thiazolyl(C 1-3 alkyl), isothiazolyl, isothiazolyl(Ci -3 alkyl), thiazolylmethyl, isothiazolylmethyl, oxazolyl,
  • R 10 is selected from the group consisting of pyridyl, pyridyl(C 1-3 alkyl), phthalimido, phthalimido(Ci_ 3 alkyl), pyrrolyl, pyrrolyl(Ci_ 3 alkyl), imidazolyl, alkyl), pyrazolyl, pyrazolyl(Ci -3 alkyl), thiazolyl, thiazolyl(Ci- 3 alkyl), isothiazolyl, isothiazolyl(Ci -3 alkyl), thiazolylmethyl, isothiazolylmethyl, oxazolyl, oxazolyl(Ci -3 alkyl), pyrrolidinyl, pyrrolidinyl(C 1-3 alkyl), pyrrolinyl, pyrrolinyl(Ci -3 alkyl), imidazolidinyl, imidazolidinyl(C 1-3 alkyl), imidazol
  • R 10 is a lH-imidazol-2-yl(C 1-6 alkyl) group which may be substituted with 1 or more groups independently selected from C 1-6 alkyl, halo, haloC ⁇ alkyl, hydroxyC 1-6 alkyl, perhaloC 1-6 alkyl, OH, NH 2 , NO 2 , CN, COOH, C(O)H, C(O)O(C 1-6 alkyl), 0(C 1-6 alkyl), OC(O)(C 1-6 alkyl) and C(O)(C 1-6 alkyl).
  • R ⁇ 0 is a lH-imidazol-2-ylmethyl, lH-imidazol-2-ylethyl or lH-imidazol-2-ylpropyl group.
  • R 10 is a 4,5-dihydro-lH-imidazol-2-ylmethyI, 4,5-dihydro-lH-imidazol-2-ylethyl or 4,5-dihydro-lH-imidazol-2-ylpropyl group.
  • 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 10 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, morpholinyl.
  • R 6 comprises the group OR 10 , preferably m is 0 or 1, most preferably 0.
  • R 6 comprises the group OR 10
  • R 10 is selected from the group consisting of C 1-10 heteroaryl, C 2-10 heterocyclyl, C 3-I0 heteroaralkyl, C 3-10 heterocyclylalkyl, C 1-6 alkylamino Ci -6 alkyl, di(C]. 6 alkyl)amino C 1-6 alkyl and C 1-6 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(C 1-4 alkyl) or N(C 14 alkyl) 2 .
  • R 6 comprises the group OR 10
  • R 10 is selected from the group consisting of lH-imidazol-2-ylmethyl, lH-imidazol-2-ylethyl, lH-imidazol-2-ylpropyl,
  • each R 14 is independently selected from the group consisting of H, C 1 - J o alkyl, C 2-1O alkenyl, C 2-10 alkoxyalkyl, C 7-20 alkoxyaryl, C 2-10 alkynyl, C 3-20 cycloalkyl, C 4-20 (cycloalkyl)alkyl, C 5-2 O cycloalkenyl, C 7-2 O cycloalkynyl, C 7-20 aralkyl, C 7-20 alkaryl, C 6-20 aryl, C 1-20 heteroaryl, C 2-20 heterocyclyl, C 2-20 heteroaralkyl, C 3-2O heterocyclylalkyl, Ci -10 aminoalkyl, C 6-1O aminoaryl, guanidinyl Ci -6 alkyl, C 2-12 alkylguanidinylalkyl, ureayl Ci -6 alkyl and C 2-I2 alkylureaylalkyl, any of which (except H) are optionally substitute
  • R ls is selected from the group consisting of H, CN, Ci -10 alkyl, C 2-10 alkenyl, C 2-10 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, Ci -20 heteroaryl and C 2-2O heterocyclyl, C 2-20 heteroaralkyl, C 3-20 heterocyclylalkyl, C 1-10 aminoalkyl, C 6-10 aminoaryl, guanidinyl Ci -6 alkyl, C 2-I2 alkylguanidinylalkyl, ureayl Ci -6 alkyl and C 2-12 alkylureaylalkyl, any of which (except H) are optionally substituted on
  • each R 14 is independently selected from the group consisting of H and C 1-4 alkyl, or R 15 and one of R 14 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R 14 not joined to R 15 is selected from the group consisting of H and C 1-4 alkyl.
  • R 15 and one of R 14 are joined to form a group selected from imidazole, dihydroimidazole, tetrahydropyrimidinyl, benzimidazole and triazole.
  • each R 14 is independently selected from the group consisting of H and methyl.
  • R 15 and one of R 14 are joined to form a group selected from imidazole, dihydroimidazole and tetrahydropyrimidinyl.
  • R 2 in a particularly preferred embodiment, when n is 1 or more, -(CH 2 ) m -R 6 is located in the meta or para position relative to the -(CH 2 ) n - group, most preferably the para position. In a further particularly preferred embodiment, when n is 0, -(CH 2 ) m -R 6 is located in the para position relative to the to the N 1 atom. Most preferably, n is 0 and R 6 is located in the para position relative to the to the N 1 atom.
  • R 6 comprises a guanidinyl moiety.
  • R 6 is a group
  • R 2 is selected from the group consisting of (( 1 H-imidazol-2-yl)methylamino)-phenyl, (( 1 H-imidazol-2-yl)ethylamino)-phenyl,
  • R 3 is independently selected from the group consisting of H, COOH 3 COO(Ci -6 alkyl), COO(C 6-20 aryl), COO(C 7-20 alkaryl), COO(C 7-20 aralkyl), C(O)H, C(O)(C 1-6 alkyl), C(O)NH 2 , C(O)NH(C 1-6 alkyl), C(O)N(C 1-6 alkyl) 2 , C(O)NH(C 6-15 aryl), C(O)N(C 6-15 aryl) 2 , C(O)NH(C 7-15 aralkyl), C(O)N(C 7-I5 aralkyl) 2 , C(O)NH(C 7-I5 alkaryl), C(O)N(C 7-I5 alkaryl) 2 and hydrocarbyl or heterocarbyl groups selected from C 1-20 alkyl, C 2-20 alkenyl, C 1-20 alkoxy, C 2-20 alkoxyalky
  • R 3 is not H.
  • R 4 is not H.
  • R 18 is selected from the group consisting of H, Ci -20 alkyl, C 2-20 alkenyl, C 2-20 alkoxyalkyl, C 7-30 alkoxyaryl, Ci 2-30 aryloxyaryl, C 2-20 alkynyl, C 3-3O 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, C 6-20 aminoaryl, guanidine Cj -I0 alkyl, C 2-20 alkylguanidinylalkyl, urea C 1-10 alkyl and C 2-20 alkylureaylalkyl, any of which (except H) are optionally substituted
  • (cycloalkyl)alkyl C 7-20 aralkyl, C 7-20 alkaryl, C 1-20 heteroaryl and C 6-20 aryl.
  • m' is 0, 1 or 2, more preferably O or 1.
  • X is a bond, C(O)NH, C(O)N(C 1-6 alkyl) or C(O)N(C 6-20 aryl).
  • R 16 and R 17 are independently selected from the group consisting of H, Ci -I0 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, Ci -20 heteroaryl, C 2-20 heterocyclyl, C 2-20 heteroaralkyl and C 3-20 heterocyclylalkyl.
  • R 16 and R 17 are joined to form a 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14-membered, saturated, unsaturated or aromatic ring.
  • the ring may be a heterocyclic or heteroaromatic ring.
  • the ring formed by R 16 and R 17 is a cycloalkyl, heterocyclyl or heteroaromatic group.
  • the ring is a C 6-I0 cycloalkyl, C 4-J0 heterocyclyl or Ci -]0 heteroaryl group.
  • m' is O 5
  • X is a bond and R 18 is a C 5-I2 cycloalkyl group.
  • X is a bond, C(O)NH or C(O)N(Ci -6 alkyl).
  • X is a bond
  • R 16 and R 17 are both H
  • m' is O or 1
  • X is C(O)NH
  • R 16 and R 17 are both H
  • m' is O or 1
  • R 18 is selected from the group consisting of methyl, ethyl, propyl, butyl, phenyl, benzyl, biphenyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, quinolinyl, naphthyl, tetramethylcyclohexyl, benzocycloheptyl, benzodioxepinyl, bicyclooctyl, tetrahydropyranyl, dihydropyranyl, tetramethyltetrahydropyranyl, cyclohexylmethyL, phenylethylbenzyl, phenoxybenzyl, phenylethynylbenzyl, cyclohexylbenzyl, pyranyl, tolyl, ethylbenzyl, xylyl
  • 6 alkyl N(C 1-6 alkyl), NO 2 , CN, OCH 3 , SO 2 , SO 2 NH 2 and C(O)H, Ci -6 alkyl, C 2-6 alkoxyalkyl, C 7-10 alkoxyaryl, C 3-10 cycloalkyl, C 4-1S (cycloalkyFjalkyl, C 7-12 aralkyl, C 7-12 alkaryl, Ci -12 heteroaryl and Cn -I2 aryl.
  • R 3 comprises a benzyl group, optionally substituted with 1, 2 or 3 groups, independently selected from COO(C 1-6 alkyl), COO(C6 -2 o aryl), COO(C 7-20 aralkyl), COO(C 7-20 alkaryl), halo, trihalomethyl, OH, NH 2 , 0(C 1-6 alkyl), 0(C 6-20 aryl), 0(C 7-20 aralkyl), 0(C 7-20 alkaryl), Ci -6 alkyl, C 6-I2 aryl, C 7-I2 aralkyl, C 7-I2 alkaryl, C 8-12 aralkynyl, C 6-12 aryloxy, Ci -12 heteroaryl, C 5-I2 cycloalkyl and C(O)(C 1-6 alkyl) on the backbone.
  • 1, 2 or 3 groups independently selected from COO(C 1-6 alkyl), COO(C6 -2 o aryl), COO(
  • R 3 comprises a cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, quinolinyl, tetrahydropyranyl, naphthyl, benzocycloheptyl, or benzodioxepinyl group, optionally substituted with 1, 2, 3 or 4 groups independently selected from COO(Ci -6 alkyl), halo, trihalomethyl, OH, NH 2 , 0(C 1-6 alkyl), C ]-6 alkyl, C 6-I2 aryl, C 7-12 aralkyl, C 7- I 2 alkaryl, C 6-I2 aryloxy, Ci -I2 heteroaryl, C 5-I2 cycloalkyl and C(O)(C 1-6 alkyl) on the backbone.
  • R 1 , R 4 and R 5 are independently selected from the group consisting of H, COOH,
  • NHC(O)O NH, N(Ci -6 alkyl), O, CO, SO 2 , NHSO 2 and C(O)NH in the backbone;
  • R 1 is joined to R 5 , R 5a or R la to form a ring, or when R 5 is joined to R 5a or R la to form a ring, preferably it is a 5, 6 or 7-membered ring which is optionally substituted with 1, 2 or 3 of the groups independently selected from the groups defined in (b) and (c) above.
  • R 1 , R la , R 5 or R 5a are joined to one another to form a ring.
  • R 5a , R 5 , R 1 and R la are in the 6, 7, 8 and 9 positions respectively of the compound of formula (I).
  • R 5a , R 5 , R 1 and R la are linked with one another to form a ring, adjacently positioned groups are linked, rather than remotely positioned groups.
  • R 5a and R 5 are preferably joined to one another when they are in the 6 and 7 position respectively.
  • R 1 and R 5 are independently selected from the group consisting of H, COOH, SH, SO 2 H, P(OH)(O) 2 , F, Cl, Br, I, OH, NH 2 , NO 2 , CN, SO 2 NH 2 , C(O)H, and hydrocarbyl or heterocarbyl groups selected from Ci -6 alkyl, Ci -6 alkoxy, C 2-6 alkoxyalkyl, C 7-20 alkoxyaryl, C3- 2 0 cycloalkyl, C 4-2 O (cycloalkyl)alkyl, C 7-2 O aralkyl, C 7-2 O alkaryl, C 6-2 O aryl, C 1-2O heteroaryl and C 2-2O heterocyclyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups, preferably 1, 2, 3 or 4 groups, independently selected from the groups defined in (a), (b) and (c): (a) C(O)NH, C(C(
  • R 1 and R 5 are independently selected from the group consisting of C 1-4 alkyl, C 5-8 cycloalkyl, Ci -4 alkoxy, Cj -4 alkylcarbonylamino, C 1-4 alkylaminocarbonyl, C 3-1O cycloalkylcarbonylamino, C 3-1 O cycloalkylaniinocarbonyl, C 2-I0 heterocyclylcarbonylamino, C 2-1 O heterocyclylaminocarbonyl, C 6-1 O arylcarbonylamino, C 6-1 O arylaminocarbonyl, C 1-1 O heteroarylcarbonylamino, C 1-I o heteroarylaminocarbonyl, C 1-6 alkylamino, di (C 1-4 alkyl)amino, C 7-1 O aralkyl, C 7-1O alkaryl, C 6-1 O aryl, Ci -1 O heteroaryl and C 2-10 heterocyclyl, any of which are optionally substituted with one or
  • R 1 and R 5 are independently selected from the group consisting of H, F, Cl, Br, C 1-4 alkyl, C(O)Ci -6 alkyl, C 5- g cycloalkyl, C 1-4 alkoxy, dimethylamino, tolyl, xylyl, pyridyl, pyridinyl, furanyl, hydroxyphenyl, phenylamino, acetamido, oxopyrrolidinyl, dibenzylamido, piperidinylcarbonyl, benzylamido, benzylamino, OH, NH 2 and N(CH 3 ) 2 .
  • R 1 is H and R 5 is selected from the group consisting of H, F, Cl, Br, methyl, tolyl, xylyl, pyridinyl, pyridiyl, furanyl, hydroxyphenyl, phenylamino, acetamido, oxopyrrolidinyl, dibenzylamido, piperidinylcarbonyl, benzylamido, benzylamino, OH, NH 2 and N(CH 3 ) 2 .
  • R 5 and R 1 are both H.
  • R 1 and R 5 are located in the 8 and 7 positions respectively of the compound of formula (I).
  • R 1 is a methyl group located in the 8-position of the compound of formula (I) as indicated herein.
  • R 4 is selected from the group consisting of H, hydrocarbyl or heterocarbyl groups selected from Ci -1O alkyl, C 2 - 1 0 alkoxyalkyl, Ci 2-2 O aryloxyaryl, C 7-20 aryloxyalkyl, Ci -I0 alkoxy, C 7-2O alkoxyaryl, C 4-2O alkoxycycloalkyl, 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 heteroaralkyl and C 2-20 heterocyclyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups, preferably 1, 2 or 3 groups, independently selected from the groups defined in (a), (b)
  • R 4 is selected from the group consisting of Ci -6 alkyl, C 2-6 alkoxyalkyl, C 12-20 aryloxyaryl, C 7-I2 aryloxyalkyl, C 1-I0 alkoxy, C 7-I2 alkoxyaryl, C 5-I2 alkoxycycloalkyl, C 3-I2 cycloalkyl, C 4-12 (cycloalkyl)alkyl, C 7-I2 aralkyl, C 7-I2 alkaryl, C 6-I2 aryl, CM 2 heteroaryl, C 2-I2 heteroaralkyl and C 2-I2 heterocyclyl, any of which is optionally substituted with one or more of the groups, preferably 1, 2 or 3 groups, independently selected from the groups defined in (a), (b) and (c):
  • R 4 is selected from the group consisting of Ci -6 alkyl, C 3-I2 cycloalkyl, C 6-I2 aryl, C 1-I2 heteroaryl, C 2-12 heterocyclyl, C 2-6 alkoxyalkyl, C 5-I2 alkoxycycloalkyl, C 2-10 alkylthioalkyl, C 4-I2 alkylthiocycloalkyl, C 2-I0 alkylsulfonylalkyl, C 6-I2 alkylsulfonylcycloalkyl and C 6-I2 alkylaminocycloalkyl.
  • R 4 is selected from the group consisting of methyl, cyclohexyl, phenyl, isopropyl, fluorophenyl, cyclohexylmethyl, adamantyl, pyranyl, tetrahydropyranyl, piperidinylmethyl, cyclohexylsulfanylmethyl, cyclohexanesulfonylmethyl, phenoxymethyl, cyclohexylphenoxymethyl, methoxyphenoxymethyl, naphthalenyloxymethyl, ethanoylphenoxymethoxy, aminoacetylaminophenoxymethyl, cyanophenoxymethyl, acetylaminophenoxymethyl, cyclohexylidenemethyl and aminoacetylphenoxymethyl.
  • R 4 is a cyclohexyl group.
  • R la and R 5a are independently selected from H, CH 3 , F, Cl, Br and OH. Most preferably, both R la and R 5a are H. Preferably, R la and R 5a are located in the 9 and 6 positions respectively of the compound of formula (I).
  • the substitution may be in any of the positions designated 6, 7, 8 or 9 in formula (I).
  • the nitrogen atom is unsubstituted.
  • the benzo moiety of the benzotriazepinone ring system is unsubstituted in or on the benzo ring.
  • Certain compounds of the invention exist in various regioisomeric, enantiomeric, tautomeric and diastereomeric forms. It will be understood that the invention comprehends the different regioisomers, enantiomers, tautomers and diastereomers in isolation from each other as well as mixtures.
  • 2-Amino phenyl ketones (III) are either obtained commercially, or prepared by Lewis acid-mediated reaction of an appropriate aniline (P) with a suitable nitrile (R 4 CN) (Sugasawa, T. et al, J. Am. Chem. Soc, (1978), 100, 4842). (Reaction Scheme 1). Alternatively, they may be obtained by reaction of an appropriate 2-amino-benzonitrile (II) with a Grignard reagent (R 4 MgCl) or alkyl lithium (R 4 Li). In the following schemes, R la and R 5a are not shown in the interests of simplicity and clarity. Reaction Scheme 1 (")
  • 1,3,4-benzotriazepinones are prepared by treatment of a suitable 2-araino phenyl ketone (III), with a suitable bifunctional carbonyl reagent, such as phosgene, trichloromethyl chloroformate or bis(trichloromethyl) carbonate and a suitable hydrazine, NH 2 NHP (wherein P represents either a protecting group, R 3 or a suitable precursor R 3' thereof).
  • a suitable 2-araino phenyl ketone (III) with a suitable bifunctional carbonyl reagent, such as phosgene, trichloromethyl chloroformate or bis(trichloromethyl) carbonate and a suitable hydrazine, NH 2 NHP (wherein P represents either a protecting group, R 3 or a suitable precursor R 3' thereof).
  • thiophosgene may be used in place of a suitable bifunctional carbonyl reagent to afford a l,3,4-benzotriazpin-2-thione (IV), followed by basic peroxide-mediated oxidation to obtain the 1,3,4-benzotriazepinone (V) (Reaction Scheme 2).
  • 1,3,4-benzotriazepinones (V) may also be obtained by initial activation of a suitable 2-amino phenyl ketone (III) with a suitable bifunctional carbonyl reagent, such as /? ⁇ r ⁇ -nitrobenzyl chloroformate, bis(trichloromethyl) carbonate or l,r-carbonyldiimidazole, followed by treatment with a suitable urethane-protected hydrazine, PTNKNHR 3' (wherein P' represents a urethane protecting group and R 3' represents R 3 or a suitable precursor thereof) to form a substituted semicarbazide derivative (VI) as an intermediate (Reaction Scheme 3). Removal of the urethane protecting group P', results in concomitant ring closure to form the 1,3,4-benzotriazepinones (V).
  • a suitable bifunctional carbonyl reagent such as /? ⁇ r ⁇ -nitrobenzyl chloroformate, bis(trichloro
  • the 1,3,4-benzotriazepine (V) may also be obtained by starting from a suitable 2-iodo aniline (VII) (Reaction scheme 4). Sonogashira reaction (Tykwinski, R. R. Angew. Int. Ed. (2003), 42, 1566) affords the corresponding acetylide derivative (VIII) which, on reaction with a suitable bifunctional carbonyl reagent and a suitable urethane-protected hydrazine, P'NHNHR 3 , affords the semicarbazide intermediate (IX).
  • Mercuric oxide-mediated oxidation yields the required ketone precursor (VI), suitable for conversion to the 1,3,4-benzotriazepine (V) according to the method outlined in reaction scheme 3.
  • N-I substituted benzotriazepines (X) are obtained from (V) by base catalysed alkylation using sodium hydride and a suitable alkyl halide, R 2 Br or R 2 F, (wherein R 2 represents a suitable precursor of R 2 ) (Reaction scheme 5).
  • arylation may be achieved by copper-mediated arylation reaction with a suitable aryl iodide R 2 I.
  • R 2 groups which are suitable precursors of R 2 will depend on the particular nature of R 2 .
  • a suitable precursor of R 2 is
  • R 6' is a suitable precursor of R 6 .
  • R 6' groups which are suitable precursors of R 6 will depend on the particular nature of R 6 .
  • Suitable R 6 ' substituents include NO 2 , which can be reduced by tin (II) chloride to the corresponding aniline.
  • the aniline substituent can be further modified to the required R 6 group by, amongst others, acylation with amino acid derivatives, reductive amination with an appropriate aldehyde, or guanylation with a suitable guanylating agent.
  • Other suitable R 6 substituents include esters that can be converted to amide derivatives via the corresponding carboxylic acid.
  • Other suitable R 6' substituents include aldehydes that can be converted to ethers via the corresponding alcohols.
  • R 3' substituents which are suitable precursors of R 3 will depend on the particular nature of R 3 .
  • P represents R 3' these can obtained directly by treatment of (III) using the appropriate substituted hydrazine, or indirectly when P represents a protecting group, such as 4-methoxybenzyl or fert-butyloxycarbonyl, by first removal of the protecting group with trifluoroacetic acid or hydrochloric acid, followed by base catalysed reaction using sodium hydride and R 3' Br.
  • the present invention also provides a method of making compounds according to formula (I).
  • Another aspect of the present invention is a pharmaceutical composition
  • 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. Sci., 1977, Jan, 66 (1), pi
  • salts of the acidic or basic compounds of the invention can of course be made by conventional procedures, such as by reacting the free base or acid with at least a stoichiometric amount of the desired salt-forming acid or base.
  • Pharmaceutically acceptable salts of the acidic compounds of the invention include salts with inorganic cations such as sodium, potassium, calcium, magnesium, zinc, and ammonium, and salts with organic bases.
  • Suitable organic bases include N-methyl-D-glucamine, arginine, benzathine, diolamine, olamine, procaine and tromethamine.
  • Pharmaceutically acceptable salts of the basic compounds of the invention include salts derived from organic or inorganic acids. Suitable anions include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, pamoate, phosphate, polygalacturonate, stearate, succinate, sulfate, subsalicylate, 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", Drug Delivery Systems, 1985, pp. 112-176, Drugs, 1985, 29, pp.
  • Pro-drug forms of the pharmacologically-active compounds of the invention will generally be compounds according to formula (T) having an acid group which is esterified or amidated. Included in such esterified acid groups are groups of the form -COOR a , wherein R a is C 1 ⁇ 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 1-5 alkyl, phenyl, substituted phenyl, benzyl, or substituted benzyl, and R c is -OH or one of the groups just recited for R b .
  • compositions of formula (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.
  • Binding agents may include starch and gelatine.
  • the lubricating agent if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
  • Capsules for oral use include hard gelatine capsules in which the active ingredient is mixed with a solid diluent and soft gelatine capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin.
  • suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth
  • 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(C 1-6 alkyl) 2
  • the two alkyl groups may be the same or different.
  • Formulaic representation of apparent orientation of a group within the backbone is not necessarily intended to represent actual orientation.
  • a divalent amide group represented as C(O)NH is also intended to cover NHC(O).
  • linking bonds may be on any suitable ring atom, subject to the normal rules of valency.
  • pyrrolyl substituted on the backbone contemplates all possible isomeric forms.
  • pyrrolyl substituted on the backbone includes all of the following permutations:
  • halogen or halo
  • halogen substituents in the compounds of the invention are chlorine, bromine and fluorine substituents.
  • Groups such as 1IaIo(C 1-6 alkyl) includes mono-, di- or tri-halo substituted Cj -O alkyl groups.
  • 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.
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form or individual enantiomers may be prepared by standard techniques known to those skilled in the art, for example, by enantiospecific synthesis or resolution, formation of diastereomeric pairs by salt formation with an optically active acid, followed by fractional crystallization and regeneration of the free base.
  • 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 1 , R 3 , R 4 , R s , R 7 , R 8 , R 14 , R 15 , R 16 , R 17 and R 18 are unsubstituted, in or on the backbone.
  • the group R 1 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 3 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 3 or 4, more preferably by 1 substituent, as defined herein.
  • the group R 4 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 5 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 7 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 8 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 14 is substituted, in or on the backbone, by I 5 2, 3 or 4 preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 15 is substituted, in or on the backbone, by 1, 2, 3 or 4 preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
  • the group R 16 is substituted, in or on the backbone, by I 5 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.
  • backbone preferably means the carbon backbone of the group being referred to.
  • backbone includes the possibility for substitution on a heteroatom, such as nitrogen, which is located in the carbon backbone.
  • the term “in the backbone” when referring to a substitution means that the backbone is interrupted by one or more of the groups indicated. Where more than one substitution occurs, they may be adjacent to one another or remote, i.e., separated by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more carbon atoms.
  • NHC(O) group links the ethyl group to the rest of the molecule. In the latter, the NHC(O) group interrupts the carbon chain, and the butyl moiety links the methylaminocarbonyl moiety to the rest of the molecule.
  • 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, alkarylatnino, aminoalkyl, aminoaryl, aminoaralkyl, aminoalkaryl, guanidinyl, guanidinylalkyl, alkylguanidinyl, alkylguanidinylalkyl, ureayl, ureaylalkyl, alkylureayl and alkylureaylalkyl, all of which are further defined herein. This list is non-exhaustive, and the skilled person will readily understand other groups and combinations of the above-mentioned groups fall under the
  • 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-0-", 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, acenaplithyl, 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, chlor
  • 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 5 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.
  • aryl and alkyl moieties of such a group may be substituted as defined herein, with regard to the definitions of aryl and alkyl.
  • the alkyl moiety may be straight or branched.
  • Particularly preferred examples of aralkyl include benzyl, methylbenzyl, ethylbenzyl, dimethylbenzyl, diethylbenzyl, methylethylbenzyl, methoxybenzyl, chlorobenzyl, dichlorobenzyl, trichlorobenzyl, phenethyl, phenylpropyl, diphenylpropyl, phenylbutyl, biphenylmethyl, fluorobenzyl, difluorobenzyl, trifluorobenzyl, phenyltolylmethyl, trifluoromethylbenzyl, bis(trifluoromethyl)benzyl, propylbenzyl, tolylmethyl, fluorophenethyl, fluor
  • 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, propylamine, 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.
  • 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.
  • aminoacylkyl refers to an aralkyl group with an amine substituent. Binding is through the aralkyl group. Such groups have the number of carbon atoms as indicated.
  • the aralkyl moiety of such a group may be substituted as defined herein, with regard to the definition of aralkyl.
  • the alkyl moiety may be straight or branched.
  • aminoalkaryl refers to an alkaryl group with an amine substituent. Binding is through the alkaryl group. Such groups have the number of carbon atoms as indicated.
  • the alkaryl moiety of such a group may be substituted as defined herein, with regard to the definition of alkaryl.
  • the alkyl moiety may be straight or branched.
  • guanidinyl refers to a guanidine group that has had one or more hydrogen atoms removed to form a radical.
  • ureayl refers to a urea group that has had one or more hydrogen atoms removed to form a radical.
  • substituents which are referred to as being on the carbon backbone of a group with a compound definition, for example, "alkaryl”
  • the substituent may be on either or both of the component moieties, e.g., on the alkyl and/or aryl moieties.
  • substituents which are referred to as being in the carbon backbone of a group with a compound definition, for example, "heteroaralkyl"
  • the substituent may interrupt either or both of the component moieties, e.g., in the alkyl and/or aryl moieties.
  • cyclic systems e.g., cycloalkyl, aryl, heteroaryl, etc.
  • Such systems comprise fused, non-fused and spiro conformations, such as bicyclooctyl, adamantyl, biphenyl and benzofuran.
  • Step a Subcloning and engineering of IMAGE clones encoding the human PTHlR into a mammalian expression vector
  • NCBI database http://www.ncbi.nlm.nih.gov
  • the NCBI database contained 4 mRNA sequences for the human PTHl receptor, having the accession numbers L04308 (Schipani et al. Endocrinology 132, 2157-2165 (1993)), U17418 (Adams et al. Biochemistry, 34, 10553-10559 (1995)), X68596 (Schneider et al. Eur. J. Pharmacol. 246, 149-155 (1993)) and NM_000316 (Hoey et al. Br J Cancer 2003, 88, 567-573). Alignment of these sequences revealed that all four sequences had 100% amino acid identity.
  • the consensus sequence was taken as the wild type (WT) sequence.
  • IMAGE clones Integrated Molecular Analysis of Genomes and their Expression
  • HGMP Human Genome Mapping Project, Cambridge, U.K.
  • Plasmid DNA was prepared using EndoFreeTM plasmid Maxi-prep columns (Qiagen). The DNA was then sequenced using primers 1-5 (see Table 1).
  • the Maxi-prep plasmid DNAs for clones 5183607 and 5186838 were amplified by PCR (polymerase chain reaction) from the start codon to the stop codon using primers 6 and 7, containing Eco Rl (Promega) and Xba I (Promega) restriction sites, respectively.
  • the PCR was performed in 2OmM Tris-HCl (pH 8.8), 1OmM KCl, 1OmM (NHO 2 SO 4 , 2mM MgCl 2 , 0.2mM dNTP containing 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.
  • PCR products from IMAGE clones 5183607 and 5186838 were purified separately using the MinEluteTM PCR purification kit.
  • 5 ⁇ g of the 1.8kb PCR product generated from IMAGE clone 5183607 (N138S mutation) was restriction-digested with Eco Rl and Kpn I in buffer E (Promega, 6mM Tris-HCl, 6mM MgCl 2 , 10OmM NaCl, pH 7.5, ImM DTT) containing O.l ⁇ g/ ⁇ l BSA at 37 0 C for Ih 40min.
  • Both PCR fragments i.e. 60ng of the 337bp fragment and 280ng of the 1.4kb fragment
  • PCR fragments were ligated together in a single ligation reaction in the presence of lOOng of Eco Kl/Xba I digested and shrimp alkaline phosphatase (Promega) treated mammalian expression vector using the QuickStickTM DNA Ligation kit (Bioline). After 15 min at room temperature, 2.5 ⁇ l of the ligation mix was transformed into lOO ⁇ l XLl -Blue competent cells (Stratagene).
  • DNA from eleven of the resulting transformed colonies was prepared using plasmid Mini prep columns (Qiagen) according to the manufacturer's instructions. Of the ten clones that were positive (as determined by restriction digestion of the miniprep DNA), DNA was prepared from one positive clone using the plasmid Maxi-prep columns. The resulting DNA was then fully sequenced by MWG-Biotech AG (Ebersberg, Germany) on both strands using primers 2 and 8-12 (see Table 1). Sequence analysis revealed 100% amino acid identity within the coding region compared to sequence L04308 (WT human PTHlR).
  • HEK293 cells from the European Collection of Cultures were cultured in Minimal Essential Media (with Earle's Salts) (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 hPTHIR per dish, at a ratio of 1:1 (TransfastTM reagent:DNA).
  • 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.
  • Stable clones with the greatest expression of the human PTH 1 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, MX. & 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 ml ⁇ 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 -70 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 ( ⁇ 3 4) (50 ⁇ l; 1OuM).
  • competition 200pM
  • saturation 2pM-300nM
  • Dissociation constants were determined using the Cheng & Prusoff equation (1973) to correct for the receptor occupancy of the ligand. In practice pIC 5 o values are equivalent to pKi values due to the low occupancy of the radioligand.
  • Step a N-Amino-N-benzyl-N'-ft-cyclohexylcarbonylphenylJ-urea
  • Step c 3-Benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2-d ⁇ hydro-3 ⁇ rl > 3, 4-benzotriazepin-2-one
  • Step d l-(4-Aminophenyl)-3-benzyl-5-cyclohexyl-l ,2-dihydro-3H-l ,3 ,4-benzotriazepin-2-one
  • Step e N 5 N' ' -Bis-(tert-butoxycarbonyl)-W '-[4-(3-benzyl-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3Y ⁇ -l ,3,4-benzotriazepin-l-yl)-phenyl]-guanidine
  • HgCl 2 (176mg, 0.65mmol) was added to a solution of l-(4-aminophenyl) ⁇ 3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l 5 3,4-benzotriazepin-2-one (274mg, O. ⁇ mmol), NEt 3 (269 ⁇ l, 2mmol), and l,3-bis-(t ⁇ rt-butoxycarbonyl)-2 ⁇ methyl-2-thiopseudourea (176mg, 0.7mmol) in DCM (1OmL) at ambient temperature. The mixture was stirred overnight and the insoluble salts removed by filtration through a pad of celite.
  • Step f A solution of N,N-bis-(fert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro ⁇ 3H-l,3 5 4-benzotriazepm-l-yl)-phenyl]-guanidine (324mg, 0.5mmol) in 4M ⁇ C1- dioxan (4mL) was stirred at ambient temperature for 16h. The solvent was removed at reduced pressure and the residue was re-evaporated from Et 2 O (3 x 5mL). Trituration of the residue with Et 2 O afforded the hydrochloride salt of the title compound, which was isolated by filtration and dried (200mg, 77%).
  • Step a 3-Cyclohexylmethyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3 ⁇ .-l,3,4- benzotriazepin-2-one was obtained using steps a-c of the method of preparation of example 1, except that cyclohexylmethyl hydrazine was used in step a in place of benzylhydrazine.
  • Step b The title compound was obtained using steps d-f of the method of preparation of example 1 except that 3-cyclohexylmethyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one was used in step d in place of 3 ⁇ benzyl-5-cyclohexyl-l-(4- nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one.
  • Step b The title compound was prepared by the method of preparation of example 1 except that l-(2-amino-phenyl)-2-methyl-propan-l-one was used in step a in place of (2- aminophenyl)-cyclohexyl-methanone.
  • Step d (2-Amino-5-fluoro-phenyl)-cyclohexyl-methanone was obtained by the method of preparation of example 5 step a, except that cyclohexylmagnesium chloride and 2-amino-5- fluorobenzonitrile were used in place of isopropylmagnesium chloride and 2-aminobenzonitrile respectively.
  • 1 H NMR (CDCl 3 ) 7.43 (IH, m), 7.03 (IH, m), 6.62 (IH, m), 6.11 (2H, br s), 3.16 (IH, m), 1.89-1.24 (1OH, m).
  • Step e The title compound was obtained by the method of preparation of example 1 except that (2-amino-5-fluoro-phenyl)-cyclohexyl-methanone was used in step a in place of (2- aminophenyl)-cyclohexyl-methanone.
  • 1 H NMR (DMSOd 6 ) 10.08 (IH, bs), 7.70-6.70 (15H, m), 5.00-4.30 (2H, bd), 2.97 (IH, m), 1.90-1.00 (1OH, m).
  • Example 8 N- ⁇ 4-[3-Benzyl-5-(2-fluoro-phenyl)-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l- ylj-phenyl ⁇ -guanidine
  • (2- amino-phenyl)-(2-fluoro-phenyl)-methanone (Frye, S. V., Johnson, M. C; Valvano, N. L. J. Org. Chem., (1991), 56, 3750) was used in step a in place of (2-aminophenyl)-cyclohexyl- methanone.
  • Step a l-(2-Amino-phenyl)-2-cyclohexyl-ethanone
  • Step b N-Amino-N-benzyl-W-P-t ⁇ -cyclohexyl-acetyty-phenylJthiourea
  • Step e The title compound was obtained as the hydrochloride salt using steps c-f of the method of preparation of example 1, except that 3-benzyl-5-cyclohexylmethyl-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one in step c.
  • N-Bromosuccinimide (12.5g, 0.07mol) was added in portions to a solution of anthranilonitrile (7.5g, 0.06mol) in DCM at O 0 C. The mixture was stirred at O 0 C for 2h and allowed to warm to ambient temperature. The precipitate formed was removed by filtration and the filtrate washed with saturated NaHCO 3 , brine and dried (MgSO 4 ). Filtration and evaporation of solvent afforded the title compound (11.3g, 62%).
  • 1 H NMR (CDCl 3 ) 7.49 (IH, s), 7.40 (IH, d), 6.65 (IH, d), 4.39 (2H, br s).
  • Step b (2-Amino-5-bromophenyl) cyclohexyl methanone was obtained by the method of preparation of example 5 step a, except that cyclohexylmagnesium chloride and 5-bromo-2- aminobenzonitrile were used in place of isopropylmagnesium chloride and 2- aminobenzonitrile respectively.
  • 1 H NMR (CDCl 3 ) 7.82 (IH, s), 7.31 (IH, d), 6.58 (IH, d), 6.29 (2H, d), 3.19 (IH, m), 1.86 (4H, d), 1.74 (IH, d), 1.36 (5H, m).
  • Step c 3-Benzyl-7-bromo-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using steps a-c of the method of preparation of example 1 except that (2-amino-5-bromophenyl) cyclohexyl methanone was used in step a in place of (2- aminophenyl)-cyclohexyl-methanone.
  • Step d 3-Benzyl-7-bromo-5-cyclohexyl-l-(4-aminophenyl)-l,2-dihydro-3 ⁇ -l,3,4- benzotriazepin-2-one was obtained using step d of the method of preparation of example 1, except that 3-benzyl-7-bromo-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one.
  • Step e N,N'-Bis-(tevt-butoxycar'bonyl)- ⁇ N"-[4-(3-benzyl-7-bromo-5-cyclohexyl-2-oxo- l,2-dihydro-3 ⁇ .-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine was obtained using step e of the method of preparation of example 1, except that 3-benzyl-7-bromo-5-cyclohexyl-l-(4- aminophenyl)-l,2-dihydro ⁇ 3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5- cyclohexyl- 1 -(4-aminophenyl)- l,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one.
  • Step f The title compound was obtained as the hydrochloride salt using step f of the method of preparation of example 1, except that N,N'-bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-7- bromo-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3 ⁇ - 1 ,3 ,4-benzotriazepin- 1 -yl)-phenyl]-guanidine was used in place of N,N'-bis-(fert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine.
  • Step a (2-Amino-4-methyl-phenyl)-cyclohexyl-methanone was obtained by the method of preparation of example 5 step a, except that cyclohexylmagnesium chloride and 4-methyl-2- aminobenzonitrile were used in place of isopropylmagnesium chloride and 2- aminobenzonitrile respectively.
  • Step b The title compound was prepared by the method used in the: preparation of example 1 except that (2-amino-4-methyl-phenyl)-cyclohexyl-methanone was used in step a in place of (2-aminophenyl)-cyclohexyl-methanone.
  • 1 H NMR (DMSO-d 6 ) 10.20 (IH, s), 7.60 (4H 5 br s), 7.48 (IH, m), 7.37-7.08 (1OH, m), 6.62 (IH, s), 5.00-4.25 (2H 5 d), 2.90 (IH 5 m), 2.19 (3H 5 s), 1.72-1.13 (10H 5 m).
  • Example 13 N-Benzhydryl-2-[5-cyclohexyl- 1 -(4-guanidino-phenyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-3 -y] -acetamide
  • Step a [5 -Cyclohexyl-1 -(4-nitro-phenyl)-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-3-yl]- acetic acid ethyl ester
  • Step b [l-(4-Amino-phenyl)-5-cyclohexyl-2-oxo-l ,2-dihydro-3H-l , 3, 4-benzotriazepin-3-ylJ- acetic acid ethyl ester was obtained using step d of the method of preparation of example 1, except that [5-cyclohexyl- 1 -(4-nitro-phenyl)-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-3-yl] ⁇ acetic acid ethyl ester was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyI)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one.
  • Step c [5-Cyclohexyl-l-(4-(N,N'-bis-(tert-butoxycarbonyl)-guanidino)-phenyl)-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester was obtained using step e of the method of preparation of example 1, except that [l-(4-amino-phenyl)-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester was used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one.
  • Step d [5-Cyclohexyl- 1 -(4-(N,N'-bis-(tert-butoxycarbonyl)-guanidino)-phenyl)-2-oxo- 1 ,2- dihydro-SH-ljS ⁇ -benzotriazephv ⁇ -yrj-acetic acid
  • Step e [5-Cyclohexyl-l-(4-(N 5 N'-bis-(tert-butoxycarbonyl)-guanidino)-phenyl)-2-oxo-l,2- dihydro-3H-l,3 5 4-benzotriazepin-3-yl]-acetic acid N-hydroxysuccinimide ester
  • Step f N-Benzhydryl ⁇ -fS-cyclohexyl-l- ⁇ -bis-ftert-butoxycarbonyty-guanidino-phenyl ⁇ -oxo- 1 ,2-dihydro-SH-l ,3,4-benzotriazepin-yl-]-acetamide
  • Step g The title compound was obtained as the hydrochloride salt using step f of the method of preparation of example 1, except that ⁇ -benzhydryl ⁇ 2-[5-cyclohexyl-l-(4-bis-(f ⁇ rt- butoxycarbonyl)-guanidino-phenyl-2-oxo-l 5 2-dihydro-3H-l,3 5 4-benzotriazepin-yl-]-acetamide was used in place of N,N'-bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine.
  • Example 15 2-[5-Cyclohexyl-l-(4-guanidinophenyl)-2-oxo-l,2-dihydro-3H-l, 3,4- benzotriazepin-3-yl]- ' N-phenethyl-acetamide.
  • the title compound was obtained using steps d-f of the method of preparation of example 13 except that phenethylamine was used in step f in place of diphenylmethylamine.
  • Example 16 2-[5-Cyclohexyl-l-(4-guanidinophenyl)-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-3-yl] ⁇ H-pyridin-2-ylmethyl-acetamide.
  • Example 17 2-[5-Cyclohexyl-l-(4-guanidinophenyl)-2-oxo-l ,2-dihydro-3H-l , 3, 4- benzotriazepin-3-yl]- ' N-(4-methoxy-benzyl)-acetamide
  • the title compound was obtained using steps d-f of the method of preparation of example 13 except that 4-methoxybenzylamine was used in step f in place of diphenylmethylamine.
  • Example 19 2-[5-Cyclohexyl-l-(4-guanidinophenyl)-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepm-3-yl]- ' N-quinolin-8-yl-acetamide
  • the title compound was obtained using steps d-f of the method of preparation of example 13 except that 8-aminoquinoline was used in step f in place of diphenylmethylamine.
  • Example 20 ⁇ N-[4-(5-Cyclohexyl-2 ⁇ oxo-3-(3-phenyl-allyl)-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-1-yl) -phenyl] -guanidine
  • Step a 5-Cyclohexyl-3-(4-methoxy-benzyl)-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using steps a-c of the method of preparation of example 1, except that 4-methoxybenzylhydrazine was used in step a in place of benzylhydrazine.
  • Step b 5-Cyclohexyl-l-(4-nitrophenyl)-l ,2-dihydro-3H-l ,3 ,4-benzotriazepin-2-one
  • a solution 5-cyclohexyl-3-(4-methoxy-benzyl)-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (3.1Og, 6.4mmol) in trifluoroacetic acid (15mL) was heated under reflux for 2h. The solution was evaporated to dryness and the residue partitioned between EtOAc and saturated NaHCO 3 . The organic layer was separated and dried (MgSO4).
  • Step c S-CyclohexylA ⁇ -nitrophenyl ⁇ -phenyl-allyiyi ⁇ -d ⁇ hydro ⁇ H-l ⁇ -benzotriazepin- 2-one
  • Step d l-(4-Aminophenyl)-5-cyclohexyl-3-(3-phenyl-allyl)-l,2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step d of the method of preparation of example 1, except that 5-cyclohexyl-l -(4-nitrophenyl-3 -(3 -phenyl-allyl)- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-2-one was used in place of 3-ben2yl-5-eyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one.
  • Step e Bis-ftert-butoxycarbonylJ-ft- ⁇ -cyclohexyl- ⁇ -oxo-S- ⁇ henyl-allylJ-l ⁇ -dihydro-SH- l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyi)-5-cyclohexyl-3-(3-phenyl-allyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of l-(4-aminophenyl)-3-benzyl-5- cyclohexyI-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one.
  • Step f The title compound was obtained using step f of the method of preparation of example 1, except that bis-(fert-butoxycarbonyl)-[4-(5-cyclohexyl-2-oxo-3-(3-phenyl-allyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine was used in place of N,N-bi$-(tert- butoxycarbonyl)-N' -[4-(3 -benzyl-5 -cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 , 3 ,4-benzotriazepin- 1 - yl)-phenyl]-guanidine.
  • Example 22 ⁇ -[4-(5-Cyclohexyl-3-naphthalen-2-ylmethyl-2-oxo-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-1-yl) -phenyl] '-guanidine
  • the title compound was obtained using steps c-f of the method of preparation of example 20, except that 2-bromomethylnaphthalene was used in step c in place of (3-bromopropenyl)- benzene.
  • Example 23 N-ft- ⁇ -ft-tert-Butyl-ben ⁇ yty-S-cyclohexyte-oxo-lJ-dihydro-SH-l ⁇ J- benzotriazepin-1-ylJ-phenylj-guanidine.
  • the title compound was obtained using steps c-f of the method of preparation of example 20, except that 4-tert-butyl-benzyl bromide was used in step c in place of (3-bromopropenyl)- benzene.
  • Example 25 ⁇ -[4- ⁇ -Biphenyl-2-ylmethyl-5- ( ⁇ dohexyl-2-oxo-l,2-dihydro-3Y ⁇ .-l,3,4- benzotriazepin-1-yl) -phenyl] '-guanidine
  • Step a l-(4-Aminophenyl)-5-cyclohexyl-3-biphenyl-2-ylmethyl-l,2-dihydro-3Yi-l,3,4- benzotriazepin-2-one was obtained using steps c and d of the method preparation of example 20, except that 2-bromomethyl-biphenyl was used in place of (3-bromopropenyl)-benzene in step c.
  • Step b The title compound was obtained using steps e and f of the method of preparation of example 20, except that l-(4-aminophenyl)-5-cyclohexyl-3-biphenyl-2 ⁇ ylmethyl-l,2-dihydro-
  • Step a 4-(l-Adamantyl) benzyl bromide
  • benzoyl peroxide (lOmg) and N- bromosuccinimide (940mg, 5.25mmol) in CCU (3OmL) were heated at reflux for 2h. On cooling, the mixture was filtered and the filtrate evaporated to afford the product (1.18g, 74%).
  • 1 HNMR (CDCl 3 ) 7.35 (4H, s), 4.50 (2H, s), 2.11 (3H, m), 1.91 (6H, m), 1.78 (6H, m).
  • Step b The title compound was obtained using steps c-f of the method of preparation of example 20 except that 4-adamantylbenzyl bromide was used in step c in place of (3- bromopropenyO-benzene.
  • 1 HNMR (DMSO-d 6 /D 2 O) 7.62 (IH, d), 7.43-7.17 (8H, m) 7.07 (2H, m), 6.79 (IH, d), 4.78 (IH, m), 4.40 (IH, m), 2.96 (IH, m), 2.00 (3H, m) 1.78-1.69 (18H, m), 1.35-1.21 (4H, m).
  • IC 4 H 8 O 2 requires: C 64.93, H 6.71, N 11.95%.
  • Example 27 ⁇ -[4-(5-Cyclohexyl-3-naphthalen-l-ylmethyl-2-oxo-l,2-dihydro ⁇ 3H-l, 3, 4- benzotriazepin-l-yl)-phenyl]-guanidine
  • Example 28 Y ⁇ - ⁇ 4-[5-Cyclohexyl-2-oxo-3-(l-phenyl-ethyl)-l,2-dihydro-3H-l, 3, 4- benzotriazepin-l-yl]-phenyl ⁇ -guanidine
  • Example 29 Yi-(4- ⁇ 5-Cyclohexyl-3-[2-(l-methyl-cyclohexyl)-2-oxo-ethyl]-2-oxo-l,2-dihydro- SH-1, 3, 4-benzotriazepin-l-yl ⁇ -phenyl)-guanidine
  • Example 31 ⁇ -[4-(3-Biphenyl-3-ylmethyl-5-cyclohexyl-2-oxo ⁇ l ,2-dihydro-3H-l ,3 ,4- benzotriazepin-l-yl)-phenyl]-guanidine
  • the title compound was obtained using steps c-f of the method of preparation of example 20, except that 3-bromomethyl-biphenyl was used in step c in place of (3-bromopropenyl)- benzene.
  • Example 34 N- ⁇ 4-[5-Cyclohexyl-2-oxo-3-(2,4,6-trimethyl-benzyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl]-phenyl ⁇ -guanidine
  • the title compound was obtained using steps c-f of the method of preparation of example 20, except that 2,4,6-trimethylbenzyl bromide was used in step c in place of (3-bromopropenyl)- benzene.
  • Example 35 N- ⁇ 4-[5-Cyclohexyl-2-oxo-3-(3-phenoxy-benzyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl]-phenyl ⁇ -guanidine
  • the title compound was obtained using steps c-f of the method of preparation of example 20, except that 3-phenoxybenzyl bromide was used in step c in place of (3-bromopropenyl)- benzene.
  • Example 36 ⁇ k- ⁇ 4-[5-Cyclohexyl-3-(2-methyl-biphenyl-3-ylmethyl)-2-oxoA,2-d ⁇ hydro-3H- l,3,4-benzotriazepin-l-yl]-phenyl ⁇ -guanidine
  • Example 37 ⁇ - ⁇ 4-[5-Cyclohexyl-3-(3, 3-diphenyl-propyl)-2-oxo-l,2-dihydro-3H-l, 3, 4- benzotriazepin-l-yl]-phenyl ⁇ -guanidine
  • Step a 2-[4-(3-Benzyl-5-cyclohexyl-2-oxo-l,2-dihyd ⁇ -o-3H-l,3,4-benzotriazepin-l-yl)- phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester was obtained using step e of the method of preparation of example 1 except that 2-thioxoimidazolidine-l,3- dicarboxylate was used in place of bis-(ter/-butoxycarbonyl)-2-methyl-2-thiopseudourea.
  • Step b 3-Benzyl-5-cyclohexyl-l-[4-(4,5-dihihydro-lH-imidazol-2-ylamino)-phenyl]-l,2- dihydro-3H-l, 3, 4-ben ⁇ otriazepin-2-one
  • Example 41 3-Benzyl-5-cyclohexyl-l-[4-(l,4,5,6-tetrahydro-pyrirnidin-2-ylamino)-phenyl]- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one.
  • Example 43 3-(3-Chloro-biphenyl-2-ylmethyl)-5-cyclohexyl-l-[4-(4, 5-dihydro-lH-imidazol-2- ylamino)-phenyl]-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
  • Step a l-(4-Aminophenyl)-5-cyclohexyl-3-(3-chloro-biphenyl-2-ylmethyl)-l,2-dihydro-3H ⁇ l,3,4-benzotr ⁇ azepin-2-one was obtained using step c of the method of preparation of example 20, except that 2-bromomethyl-3-chloro-biphenyl was used in place of (3-bromopropenyl)- benzene, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4- nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step d of the method of preparation of example 1.
  • Step b The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyl)-5-cyclohexyl-3-(3-chloro-biphenyl-2-ylmethyl)-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one and di-tert-butyl 2-thioxoimidazolidine-l,3-dicarboxylate were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and bis-(fe/Y-butoxycarbonyl)-2-methyl-2-thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3
  • Step a l-(4-Aminophenyl)-5-cyclohexyl-3-(2-phenethyl ⁇ benzyl)-l ,2-dihydro-3H-l ,3 ,4- benzotriazepin-2-one was obtained using step c of the method of preparation of example 20, except that l-(2-bromophenethyl)benzene was used in place of (3-bromopropenyl)-benzene followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4- nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step d of the method of preparation of example 1.
  • Step b The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyl)-5-cyclohexyl-3-(2-phenethyl-benzyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and di-tert-butyl 2-thioxoimidazolidine-l,3-dicarboxylate were used in place of 1 -(4-aminophenyl)-3 -benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and bis-(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotria
  • Example 45 2'- ⁇ 5-Cyclohexyl-l-[4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl]-2-oxo-l,2 ⁇ dihydro-3H-l,3,4-benzotriazepin-3-ylmethyl ⁇ -biphenyl-2-carboxylic acid methyl ester
  • Step a 2'-Bromomethyl-biphenyl-2-carboxylic acid methyl ester was obtained using step a of the method of preparation of Example 26, except that 2'-methyl-biphenyl-2-carboxylic acid methyl ester (Badone, D. et al. J. Org. Chem. (1997), 62, 170-173) was used in place of 4-(l- adamantyl)toluene.
  • Step b 2'- ⁇ 5-Cyclohexyl-l-[4-aminophenyl)-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-3- ylmethyl ⁇ -biphenyI-2-carboxylic acid methyl ester was obtained using step c of the method of preparation of example 20, except that 2'-bromomethyl-biphenyl-2-carboxylic acid methyl ester was used in place of (3-bromopropenyl)-benzene, followed by treatment of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step d of the method of preparation of example 1.
  • Step c The title compound was obtained using step e of the method of preparation of example 1, except that 2'- ⁇ 5-cyclohexyl-l-[4-aminophenyl)-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-3-ylmethyl ⁇ -biphenyl-2-carboxylic acid methyl ester and di-tert-butyl 2- thioxoimidazolidine-l,3-dicarboxylate were used in place of l-(4-aminophenyl)-3-benzyl-5- cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and bis-(tert-butoxycarbonyl)-2- methyl-2-thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5 ⁇ cyclohexyl-2-oxo- 1
  • Step a l-(4-Aminophenyl)-5-cyclohexyl-3-naphthalen-2-ylmethyl-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step c of the method of preparation of example 20, except that 2-bromomethylnaphthalene was used in place of (3-bromopropenyl)-benzene followed by treatment of the product, in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2 ⁇ dihydro-3H-l,3,4-benzotriazepin-2-one, according to step d of the method of preparation of example 1.
  • Step b The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyl)-5-cyclohexyl-3-naphthalen-2-ylmethyl-l,2-dihydro-3H- l,3,4-benzotriaze ⁇ in-2-one and di-tert-butyl 2-thioxoimidazolidine-l,3-dicarboxylate were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and bis-(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl ⁇ 2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin
  • Step a l ⁇ -AmmophenylJ-S-cyclohexyl-S-fS' ⁇ '-bis-trifluoromethyl-biphenyl ⁇ -ylmethyl)-! ⁇ - dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step c of the method of preparation of example 20, except that 2'-bromomethyl-3,5-bis-trifluoromethyl-biphenyl was used in place of (3-bromopropenyl)-benzene followed by treatment of the product, in place of 3-benzyl-5- cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step d of the method of preparation of example 1.
  • Step b The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyl)-5-cyclohexyl-3-(3',5'-bis-trifluoromethyl-biphenyl-2- ylmethyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and di-tert-butyl 2-thioxoimidazolidine- 1,3-dicarboxylate were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l ,3,4-benzotriazepin-2-one and bis-(/ert-butoxycarbonyl)-2-methyl-2- thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4-(3- benzyl-5-cyclohexyl-2-oxo- 1 ,2-dihydr
  • Example 48 ⁇ -Cyclohexyl-l-ft-ft.S-dihydro-lH-imidazol ⁇ -ylaminoJ-phenylJ-S- ⁇ '-methyl- biphenyl-2-ylmethyl)-l,2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
  • Step a l- ⁇ -Aminophenylj-S-cyclohexyl-S-t ⁇ '-methyl-biphenyl ⁇ -ylmethylJ-l ⁇ -dihydro-SH- l,3,4-benzotriazepin-2 ⁇ one was obtained using step c of the method of preparation of example 20, except that 2-bromomethyl-2'-methyl-biphenyl was used in place of (3-bromopropenyl)- benzene followed by treatment of the product, in place of 3-benzyl-5-cyclohexyl-l-(4- nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step d of the method of preparation of example 1.
  • Step b The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyl)-5-cyclohexyl-3-(2'-methyl-biphenyl-2-ylmethyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one and di-ter/-butyl 2-thioxoimidazolidine-l,3- dicarboxylate were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one and bis-(t ⁇ rt-butoxycarbonyl)-2-methyl-2-thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5- cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3,4
  • Step a l-(4-Aminophenyl)-5-cyclohexyl-3-(l-naphthalen-l-yl-ethyl)-l,2-dihydro-3H-l,3,4- henzotriazepin-2-one was obtained using step c of the method of preparation of example 20, except that l-(l ⁇ bromo-ethyi)-naphthalene was used in place of (3-bromopropenyl)-benzene followed by treatment of the product, in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one, according to step d of the method of preparation of example 1.
  • Step b The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyl)-5-cyclohexyl-3-(l-naphthalen-l-yl-ethyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one and di-tert-butyl 2-thioxoimidazolidine-l,3-dicarboxylate were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and bis-(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,
  • Step a l-(4-Aminophenyl)-5-cyclohexyl-3-(2-phenylethynyl-benzyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using step c of the method of preparation of example 20, except that l-(2-(2-(bromomethyl)phenyl)ethynyl)benzene (Saishida H. et ah, J. Chem. Soc. Perkin Trans.
  • Step b The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyl)-5-cyclohexyl-3-(2-phenylethynyl-benzyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one and di-tert-butyl 2-thioxoimidazolidine-l,3-dicarboxylate were used in place of l-(4-amino ⁇ henyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and bis-(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4-(3 ⁇ benzyl-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3,4-benzo
  • Step a l-(4-Aminophenyl)-5-cyclohexyl-3-(2-cyclohexyl-benzyl)-l ,2-dihydro-3H-l ,3 ,4- benzotriazepin-2-one was obtained using step c of the method of preparation of example 20, except that l-bromomethyl-2-cyclohexyl-benzene was used in place of (3-bromopropenyl)- benzene followed by treatment of the product, in place of 3-benzyl ⁇ 5-cyclohexyl ⁇ l-(4- nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step d of the method of preparation of example 1.
  • Step b The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyl)-5-cyclohexyl-3-(2-cyclohexyl-benzyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and di-tert-butyl 2-thioxoimidazolidine-l,3-dicarboxylate were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and bis-(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4 ⁇ (3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepm-l
  • Example 52 ⁇ N-[4-(3-Cycloheptyl-5-cyclohexyl-2-oxo-l, 2-dihydro-3H-l, 3, 4-benzotriazepin-l - yl) -phenyl] -guanidine
  • Step a W-Cycloheptyl-hydrazinecarboxylic acid t&ft-butyl ester
  • Step c l-(4-Amino-phenyl)-3-cycloheptyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin ⁇ 2-one was obtained using steps c and d of the method of preparation of example 1, except that 3-cycloheptyl-5-cyclohexyl-l,2 ⁇ dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c.
  • Step d The title compound was obtained using steps e and f of the method of preparation of example 1, except that l ⁇ (4-ammo ⁇ phenyl)-3-cycloheptyl ⁇ 5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l ,3,4-benzotriazepin-2-one in step e.
  • Step a 3,5-Dicyclohexyl-l ,2-dihydro-3 ⁇ L-l ,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation example 52, except that cyclohexanone was used in place of cycloheptanone in step a.
  • 1 H NMR (CDCl 3 ) 7.34-7.27 (2H, m), 7.11-7.06 (IH, m), 6.81-6.78 (IH, m), 6.27 (IH, br s), 3.93-3.88 (IH, m), 2.75-2.66 (IH, m), 1.85-1.21 (2OH, m).
  • Step b The title compound was obtained using steps c-f of the method of preparation of example 1, except that 3,5-dicyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c.
  • 1 H NMR (CD 3 COOD) 7.61-7.25 (7H, m), 6.88-6.86 (IH, m), 3.85 (IH, br m), 2.98 (IH, m), 1.90- 1.10 (2OH, m).
  • Example 54 ⁇ N-[4-(5-Cyclohexyl-3-dicyclohexylmethyl-2-oxo-l,2-dihydro-3H-l,3,4- benzoti"iazepin-l-yl)-phenyl]-guanidine
  • Step a 5-Cyclohexyl-3-dicyclohexylmethyl-l,2-dihydro-3 ⁇ .-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that dicyclohexylketone was used in place of cycloheptanone in step a.
  • Step b The title compound was obtained using steps c-f of the method of preparation of example 1, except that 5-cyclohexyl-3-dicyclohexylmethyl- -l,2-dihydro-3H- 1,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c.
  • Example 55 ⁇ - ⁇ 4-[5-Cyclohexyl-3-(2,2-diphenyl-ethyl)-2-oxo-J,2-dihydro-3H-l,3,4 ⁇ benzotriazepin-l-yl]-phenyl ⁇ -guanidine
  • Step a 5-Cyclohexyl-3-(diphenyl-ethyl)-l,2-dihydro-3Y ⁇ -l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that dicyclohexylketone was used in place of cycloheptanone in step a.
  • 1 H NMR (CDCI 3 ) 7.27-7.26 (IH, m), 7.12-6.99 (12H, m), 6.68 (IH, m), 5.99 (IH, s), 4.33-4.22 (3H, m), 2.61-2.54 (IH, m), 1.80-1.72 (5H, m), 1.50-1.21 (5H, m).
  • Step b The title compound was obtained using steps c-f of the method of preparation of example I 5 except that 5-cyclohexyl-3-(diphenyl-ethyl)-l,2-dihydro-3H-l,3,4-benzotriazepin- 2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c.
  • Example 56 l ⁇ - ⁇ 4-[5-Cyclohexyl-3-(2,2-dimethyl-propyl)-2-oxo-l,2-dihydro-3H-l, 3, 4- benzotriazepin-l-yl]-phenyl ⁇ -guanidine
  • Step a 5-Cyclohexyl-3-(2,2-dimethyl-propyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 2,2- dimethylpropanone was used in place of cycloheptanone in step a.
  • Step b The title compound was obtained using steps c-f of the method of preparation of example 1, except that 5-cyclohexyl-3-(2,2-dimethyl-propyl)-l,2-dihydro-3H-l,3,4 ⁇ benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c.
  • Example 57 ⁇ - ⁇ 4-[5-Cyclohexyl-2-oxo-3-(c ⁇ %-4-phenyl-cyclohexyl)-l,2-d ⁇ hydi'o-3H ⁇ l,3,4 ⁇ benzotriazepin-l-yl]-phenyl ⁇ -guanidine
  • Step a W-(cis-4-Phenyl-cyclohexyl)-hydrazinecarboxylic acid text-butyl ester and W-(trans-4- phenyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester were prepared using step a of method of preparation of example 52, except that 4-phenyl-cyclohexanone was used in place of cycloheptanone. The products were separated by by chromatography on silica gel with hexane- EtOAc (2:1) as eluant.
  • the high R f compound was assigned as N ! -(cis ⁇ 4-phenyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester.
  • 1 HNMR (CDCl 3 ) 7.32-7.15 (5H, m), 6.02 (IH, br s), 3.80 (IH, br s), 3.24 (IH, br s), 2.59-2.51 (IH, m), 1.91-1.82 (4H, m), 1.68-1.54 (13H, m).
  • the low R f derivative was assigned as N l -(trans-4-phenyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester.
  • 1 H ⁇ MR (CDCl 3 ) 7.32-7.16 (5H, m), 6.06 (IH, br s), 4.02 (IH, br s), 2.94-2.87 (IH, m), 2.54-2.45 (IH, m), 2.03-1.92 (4H, m), 1.59-1.45 (HH, m), 1.32-1.20 (2H. m).
  • Step b 5-Cyclohexyl-3-(c ⁇ s-4-phenyl-cyclohexyl)-l,2-dihydro-3H-l,3,4-ben ⁇ otriazepin-2-one was obtained using step b of the method of preparation of example 52, except that JV-(cis-4- phenyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester was used in place of JV ⁇ trans 4- cyano-cis-4-phenyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester .
  • Step c The title compound was obtained using steps c-f of the method of preparation of example 1, except that 5-cyclohexyl-3-(cis-4-phenyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c.
  • Step a 5-Cyclohexyl-3-(tvans-4-phenyl-cyclohexyl)-l,2-dihydro-3H-l, 3, 4-benzotri ⁇ zepin-2-one was obtained using step b of the method of preparation of example 52, except that iV-(trans-4- phenyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester (example 57, step a) was used in place of N'-cycloheptyl-hydrazinecarboxylic acid tert-butyl ester.
  • Step b The title compound was obtained using steps c-f of the method of preparation of example 1, except that 5-cyclohexyl-3-(fr ⁇ r ⁇ -4-phenyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H ⁇ l,3,4- benzotriazepin-2-one in step c.
  • Example 59 ⁇ - ⁇ 4-[3-( ⁇ -Benzoyl-piperidin-4-yl)-5-cyclohexyl-2-oxo-l,2-d ⁇ hydro-3 ⁇ -l,3,4- benzotriazepin-l-yl]-phenyl ⁇ guanidine
  • Step a 3-(l -BenzoyI ⁇ iperidin-4-yl)-5-cyclohexyl-l ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 1- benzoyl piperidin-4-one was used in place of cycloheptanone in step a.
  • Step b The title compound was obtained using steps c-e of the method of preparation of example 1, except that 3-(l-benzoyl-piperidm-4-yl)-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c, followed by reaction of the product obtained, in place of 2-[4- (S-benzyl-S-cyclohexyl ⁇ -oxo-l ⁇ -dihydro-SH-l ⁇ -benzotriazepin-l-yO-phenylimino]- imidazolidine-l,3-dicarboxylic acid di-fert-butyl ester, according to step b of the method of preparation of example 39.
  • Example 60 ⁇ N- ⁇ 4-[5-Cyclohexyl-2-oxo-3-(trans-2-phenyl-cyclohexyl)-l,2-dihydro-3H ⁇ l,3,4- benzotri ⁇ zepin-l ⁇ yl]-phenyl ⁇ -gu ⁇ nidine
  • Step a 5-CycIohexyl-3-(trans-2-phenyl-cyclohexyl)-l,2-dihydro-3H-l,3,4-benzotri ⁇ zepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 2- phenyl-cyclohexanone was used in place of cycloheptanone in step a.
  • Step b The title compound was obtained using steps c-f of the method of preparation of example 1, except that 5-cyclohexyl-3-(tr ⁇ ns-2-phenyl-cyclohexyl)-l,2-dihydro-3H-l,3,4 ⁇ benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c.
  • Step a 5-Cyclohexyl-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that tetrahydro-pyran-4-one was used in place of cycloheptanone in step a.
  • Step b The title compound was obtained using steps c-f of the method of preparation of example 1, except that 5-cyclohexyl-3-(tetrahydropyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl ⁇ l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c.
  • Step a 3-(l-Benzyl-piperidin-4-yl)-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 1- benzyl-piperidin-4-one was used in place of cycloheptanone in step a.
  • Step b The title compound was obtained using steps c-e of the method of preparation of example 1, except that 3 ⁇ (l-benzyl-piperidin-4-yl)-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c, followed by reaction of the product obtained, in place of 2-[4- (3 -benzyl-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 -yl)-phenylimino]- imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39.
  • Example 63 ⁇ -[4-(3-Adamantan-2-yl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine
  • Step a 3-Adamantan-2-yl-5-cyclohexyl-l,2-d ⁇ hydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 2- adamantanone was used in place of cycloheptanone in step a.
  • 1 H NMR (CDCl 3 ) 7.40-7.33 (2H, m), 7.15-7.13 (IH, m), 6.85-6.82 (IH, m), 6.44 (IH, br s), 4.15 (IH, s), 2.74-2.65 (IH, m), 2.42 (2H, br s), 1.89-1.21 (22H, m).
  • Step b The title compound was obtained using steps c-f of the method of preparation of example 1, except that 3-adamantan-2-yl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c.
  • Example 64 ⁇ -[4-(5-Cyclohexyl-3-cyclooctyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l- yl) -phenyl] -guanidine.
  • Step a 5-Cyclohexyl-3-cyclooctyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that cyclooctanone was used in place of cycloheptanone in step a.
  • Step b l-(4-Amino-phenyl)-3-cyclooctyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one was obtained by using steps c and d of the method of preparation of example 1, except that 5-cyclohexyl-3-cyclooctyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c.
  • Step c The title compound was obtained using steps e and f of the method of preparation of example 1, except that l-(4-amino-phenyl)-3-cycloctyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one in step e.
  • Example 65 ⁇ N-[4-(3-Cyclodecyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l- yl) -phenyl] -guanidine.
  • Step a 3-Cyclodecyl-5-cyclohexyl ⁇ l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that cyclodecanone was used in place of cycloheptanone in step a.
  • Step b l-(4-Amino-phenyl)-3-cyclodecyl-5-cyclohexyl-l ,2-dihydro-3H-l ,3 ,4-benzotriazepin-2- one was obtained by using steps c and d of the method preparation of example 1, except that 3- cyclodecyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c.
  • Step c The title compound was obtained using steps e and f of the method of preparation of example 1, except that l ⁇ (4-amino-phenyl)-3-cyclodecyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one in step e.
  • Example 66 ⁇ N- ⁇ 4-[5-Cyclohexyl-2-oxo-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl] ⁇ phenyl ⁇ -guanidine
  • Step a 5-Cyclohexyl-3-(3, 3, 5, 5-tetramethyl-cyclohexyl)-l ,2-dihydro-3H-l , 3, 4-benzotriazepin- 2-one was obtained using steps a and b of the method of preparation of example 52, except that 3,3,5,5-tetramethyl-cyclohexanone was used in place of cycloheptanone in step a.
  • Step b The title compound was obtained using steps c-e of the method of preparation of example 1, except that 5-cyclohexyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c, followed by reaction of the product obtained, in place of 2-[4- (3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenylimino]- imidazolidine-l,3-dicarboxylic acid di-tert-buty ⁇ ester, according to step b of the method of preparation of example 39.
  • Example 67 ⁇ N-(4- ⁇ 5-Cyclohexyl-3-[4-cis-(2-methoxy-phenyl)-cyc ⁇ ohexyl]-2-oxo-l,2-dihydro- 3H-l,3,4-benzotriazep ⁇ n ⁇ l-yl ⁇ -phenyl)-guanidine
  • Step a 5-Cyclohexyl-3-[4-cis-(2-methoxy-phenyl)-cyclohexylJ-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 4-(2-methoxy-phenyl)-cyclohexanone was used in place of cycloheptanone in step a.
  • Step b l-(4-Amino-phenyl)-3-[4-cis-(2-methoxy-phenyl)-cyclohexylJ-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained by using steps c and d of the method of preparation of example I 5 except that 5-cyclohexyl-3-[4-cis-(2-methoxy-phenyl)-cyclohexyl]- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one in step c.
  • Step c The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-amino-phenyl)-3-[4-cis-(2-methoxy-phenyl)-cyclohexyl]-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of l-(4-amino-phenyl)-3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin- l-yl)-phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step
  • Example 68 N- ⁇ 4-[3-(4-trms-Cyano-4-cis-phenyl-cyclohexyI)-5-cyclohexyl-2-oxo-l,2-dihydro- 3H-l,3,4-henzotriazepin-l-yl]-phenyl ⁇ -guanidine
  • Step a W-(trans-4-Cyano-cis-4-pnenyl-cyclohexyl)-hydrazinecarboxylic acid text-butyl ester andW-(cis-4-Cyano-trans-4-phenyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester- were prepared using step a of method of preparation of example 52, except that 4-phenyl 4-cyano cyclohexanone was used in place of cycloheptanone.
  • the low R f derivative was assigned as iV-(cis-4-cyano-trans-4-phenyl-cyclohexyl)- hydrazinecarboxylic acid tert-butyl ester.
  • 1 H NMR (CDCl 3 ) 7.50-7.47 (2H, m), 7.42-7.32 (3H, m), 6.09 (IH, s), 4.05 (IH, s), 3.00-2.93 (IH, m), 2.24-2.19 (2H, m), 2.08-2.04 (2H, m), 1.78- 1.70 (4H, m), 1.48 (9H, s).
  • Step b 4-(5-Cyclohexyl-2-oxo-l,2-dihydro-3H-l, 3, 4-benzotriazepin-3-yl)-l-cis-phenyl- cyclohexanecarbonitrile was obtained using step b of the method of preparation of example 52, except that N"-(trans 4-cyano-cis-4-phenyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester was used in place of N'-cycloheptyl-hydrazinecarboxylic acid tert-butyl ester ⁇ H ⁇ MR (CDCl 3 ) 7.40-7.27 (7H, m), 7.17-7.12 (IH, m), 6.87 (IH, d), 6.55 (IH, br s), 4.26-4.18 (IH, m), 2.63 (IH, m), 2.32-2.17 (4H, m), 2.04-1.89 (4H, m
  • Step c 4-[l-(4-Amino ⁇ phenyl)-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-3-yl] ⁇ 1-cis-phenyl-cyclohexanecarbonitrile was obtained by using steps c and d of the method of preparation of example 1, except that 4-(5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-3-yl)-l-cis-phenyl-cyclohexanecarbonitrile was used in place of 3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c.
  • Step d The title compound was obtained using steps e and f of the method of preparation of example 1, except that 4-[l-(4-amino-phenyl)-5-cyclohexyl-2 ⁇ oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-3-yl]-l-cis-phenyl-cyclohexanecarbonitrile was used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step e.
  • Example 69 ⁇ - ⁇ 4-[5-Cyclohexyl-3-(4, 4-diphenyl-cyclohexyl)-2-oxo-l,2-dihydro-3H-l, 3, 4- benzotriazepin-l ⁇ yl]-phenyl ⁇ -guanidine
  • Step a 5-Cyclohexyl-3-(4,4-diphenyl-cyclohexyl)-l,2 ⁇ dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 4,4- diphenyl cyclohexanone was used in place of cycloheptanone in step a.
  • Step b l-(4-Amino-phenyl)-5-cyclohexyl-3-(4, 4-diphenyl-cyclohexyl)-l,2-dihydro-3H ⁇ l,3,4- benzotriazepin-2-one was obtained by using steps c and d of the method of preparation of example 1, except that 5-cyclohexyl-3-(4,4-diphenyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c.
  • Step c The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-amino-phenyl)-5-cyclohexyl-3-(4,4-diphenyl-cyclohexyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one was used in place of l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one followed by reaction of the product obtained, in place of 2-[4-(3 -benzyl-S-cyclohexyl ⁇ -oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 -yl)- phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step
  • Example 70 ⁇ [4-(5-Cyclohexyl-2-oxo-3-spiro[5.5]undec-3-yl-l,2-dihydro-3H-l, 3, 4- benzotriazepin-l-yl)-phenyl]-guanidine
  • Step a S-Cyclohexyl ⁇ -spiro ⁇ .SJundecS-yl-J ⁇ -dihydro-SH-lJ ⁇ -benzotriazepm ⁇ -one was obtained using steps a and b of the method of preparation of example 52, except that spiro[5.5]undec-3-one was used in place of cycloheptanone in step a.
  • 1 H NMR (CDCl 3 ) 7.35- 7.27 (2H, m), 7.11-7.07 (IH, m), 6.79 (IH, d), 6.05 (IH, br s), 3.96-3.85 (IH, m), 2.76-2.69 (IH, m), 1.97-1.09 (28H, m).
  • Step b l-(4-Amino-phenyl)-5-cyclohexyl-3-spiro[5.5]undec-3-yl-l, 2 ⁇ dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained by using steps c and d of the method of preparation of example I 5 except that 5-cyclohexyl-3-spiro[5.5]undec-3-yl-l,2-dihydro-3H-l 5 3 5 4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c.
  • Step c The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-amino-phenyl)-5-cyclohexyl-3-spiro[5.5]undec-3-yl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of l ⁇ (4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 -yl)- phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of
  • Step a ⁇ [4-(3-Benzyl-5-cyclohexyl-2-oxo-l,2 ⁇ dihydro-3H-l,3,4-benzotriazepin-l-yl)- phenylcarbamoyl]-methyl ⁇ -carbamic acid tert-butyl ester
  • a solution of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin- 2-one (example 1, step d) (212mg, 0.5mmol), tert-butoxycarbonyl glycine (105mg, 0.60mmol), EDC (115mg, 0.60mmol), and N-hydroxybenzotriazole hydrate (81mg, 0.60mmol) in DCM (5mL) was stirred at ambient temperature for 16hr.
  • Step b The title compound was obtained using step f of the method used in the preparation of example 1, except that ⁇ [4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-y ⁇ -phenylcarbamoylj-methylj-carbamic acid tert-butyl ester was used in place of N,N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l J 2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine.
  • Example 76 2-Amino- ⁇ N-[4- (3-benzyl-5-cyclohexyl-2-oxo-l , 2-dihydro-3H-l , 3, 4- benzotriazepin-1-yl) -phenyl] -3 -phenyl-propionamide
  • the title compound was obtained using step a of the method of preparation of example 71, except that tert-butoxycarbonyl (D/L)-phenylalanine was used in place of tert-butoxycarbonyl glycine, followed by reaction of the product obtained, in place of N,N-bis-(tert- butoxycarbonyl)-N / -[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l- yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1.
  • Example 77 2-Amino- ⁇ N-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-1-yl) -phenyl] -2-phenyl-acetamide
  • the title compound was obtained using step a of the method of preparation of example 71, except that tert-butoxycarbonyl (D/L)-phenylglycine was used in place of tert-butoxycarbonyl glycine, followed by reaction of the product obtained, in place of N,N-bis-(tert- butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 - yl)- ⁇ henyl]-guanidine, according to step f of the method of preparation of example 1.
  • Example 78 Pyrrolidine-2-carboxylic acid [4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H ⁇ 1, 3, 4-benzotriazepin-l-yl)-phenyl]-amide
  • the title compound was obtained using step a of the method of preparation of example 71, except that tert-butoxycarbonyl (D/L)-proline was used in place of fert-butoxycarbonyl glycine, followed by reaction of the product obtained, in place of N,N-bis-(tert- butoxycarbony ⁇ -iV'- ⁇ S-benzyl-S-cyclohexyl ⁇ -oxo-l ⁇ -dihydro-SH-l ⁇ -benzotriazepin-l- yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1.
  • step a of the method of preparation of example 71 except that N-tert-butoxycarbonyl-O-tert-butyl (L)-serine was used in place of tert- butoxycarbonyl glycine, followed by reaction of the product obtained, in place of 2-[4-(3- benzyl-5 -cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 , 3 ,4-benzotriazepin- 1 -yl)-phenylimino] - imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39.
  • Example 80 2-Amino- ⁇ N-[4-(3-benzyl-5-cyclohexyl-2-oxo-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-l-yl)-phenyl]-2-methyl-propionamide
  • Example 81 (S)-2-Amino- ⁇ N-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-3 -yl) -phenyl] -3 -methoxy-propionamide
  • the title compound was obtained using step a of the method of preparation of example 71, except that tert-butoxycarbonyl (L)-serine methyl ether was used in place of tert- butoxycarbonyl glycine, followed by reaction of the product obtained, in place of N,N -bis- (tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-3-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1.
  • step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-biphenyl-2-ylmethyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 25, step a) and fert-butoxycarbonyl Z-valine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and ter/-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N / -[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-3-
  • step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-biphenyl-2-ylmethyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 25, step a) and fert-butoxycarbonyl Z- ⁇ -leucine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-3
  • Example 90 (S)-3-Amino-5-methyl-hexanoic acid [4-(3-biphenyl-2-ylmethyl-5-cyclohexyl-2- oxo-l,2-dihydro-3H-l,3, 4-benzotriazepin-l -yl)-phenyl] -amide
  • the title compound was obtained using step a of the method of preparation of example 71, except that 1 -(4-amino-phenyl)-3-bi ⁇ henyl-2-ylmethyl-5-cyclohexyl- 1 ,2-dihydro-3H-l ,3,4- benzotriazepin-2-one (example 25, step a) and tert-butoxycarbonyl Z- ⁇ -homo-leucine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2
  • Step a 5-Cyclohexyl-3-(cis-4-naphthalen-2-yl-cyclohexyl)-l,2-dihydro-3H-l, 3, 4- benzotfiazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 4-(naphthalen-2-yl)-cyclohexanone was used in place of cycloheptanone in step a.
  • Step b l-(4-Amino-phenyl)-5-cyclohexyl-3-(cis-4-naphthalen-2 ⁇ yl-cyclohexyl)-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one was obtained by using steps c and d of the method of preparation of example 1, except that 5-cyclohexyl-3-(cw-4-naphthalen-2-yl-cyclohexyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5 ⁇ cyclohexyl-l,2- dihydro-3H-l,3,4-benzot ⁇ azepin-2-one in step c.
  • Step c The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-5-cyclohexyl-3-(cis-4-naphthalen-2-yl-cyclohexyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one and fert-butoxycarbonyl L-valine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriaze
  • step a of the method of preparation of example 71 except that l-(4-amino-phenyl)-3-[4-cw-(2-methoxy-phenyl)-cyclohexyl]-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one (example 67, step b) and tert-butoxycarbonyl X-valine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N ) iV-bis-(/ert-butoxycarbonyl)-iV / -[4-(3-benzyl-5-cyclohexyl-2- oxo-l,
  • Step a 3-Bicyclo[3.3. l]non-9-yl-5-cyclohexyl-l, 2-dihydro-3H-l , 3, 4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that bicyclo[3.3.1]non-9-one was used in place of cycloheptanone in step a.
  • Step b l-(4-Amino-phenyl)-3-bicyclo[3.3.1]non-9-yl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained by using steps c and d of the method of preparation of example 1, except that 3-bicyclo[3.3.1]non-9-yl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5 ⁇ cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c.
  • Step c The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-bicyclo[3.3.1]non-9-yl-5-cyclohexyl-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl I-valine were used in place of l-(4- aminophenyl)-3 -benzyl-5 -cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l
  • Step a 4-(5-Cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotri ⁇ zepin-3-yl)-l-tr ⁇ ns-phenyl- cyclohex ⁇ nec ⁇ rbonitrile was obtained using step b of the method of preparation of example 52, except that iV-(cis-4-cyano-trans-4-phenyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester (example 68, step a) was used in place of N'-cycloheptyl-hydrazinecarboxylic acid tert- butyl ester. ⁇ ⁇ MR (CDCl 3 ) 7.53-7.50 (2H, m), 7.42-7.27 (5H, m), 7.16-7.14 (IH, m), 6.84 (IH, d), 6.35 (IH, br s), 4.12-4.03 (IH, m
  • Step b 4-[l-(4-Amino-phenyl)-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotri ⁇ zepin-3-yl]- l-tv&ns-phenyl-cyclohex ⁇ nec ⁇ rbonitrile was obtained by using steps c and d of the method of preparation of example 1, except that 4-(5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepm-S-y ⁇ -l-trans-phenyl-cyclohexanecarbonitrile was used in place of 3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c.
  • Step c The title compound was obtained using step a of the method of preparation of example 71, except that 4-[l-(4-amino-phenyl)-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-S-ylJI-l-trans-phenyl-cyclohexanecarbonitrile and /er/-butoxycarbonyl i-valine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3 5 4- benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(ter/-butoxycarbonyl)-N / -[4-(3-benzyl-5-cyclohexyl-2 ⁇ oxo-l,2-dihydro-3H-
  • Example 100 (S)-2-Amino-N- ⁇ 4-[3-(cis-4-tert-butyl-cyclohexyl)-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotri ⁇ zepin-l-yl]-phenyl ⁇ -3-methyl-butyr ⁇ mide
  • Step a 3-(Cis-4-tert-butyl ⁇ cyclohexyl)-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one was obtained using steps a and b of the method of preparation of example 52, except that 4-tert-butyl-cyclohexanone was used in place of cycloheptanone in step a.
  • Step b l-(4-Amino-phenyl)-3-(cis-4-t& ⁇ -butyl ⁇ cyclohexyl)-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using steps c and d of the method of preparation of example 1, except that 3-(cis-4-tert-butyl-cyclohexyl)-5-cyclohexyl l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c.
  • Step c The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-(cis-4-tert-butyl-cycIohexyl)-5-cyclohexyl-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl i-valine were used in place of l-(4- aminophenyl)-3 -benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N // -[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-
  • Example 101 ⁇ S>)-2-Amino- ⁇ -(4- ⁇ 5-cyclohexyl-3-[cis-4-(4-methoxy-phenyl)-cyclohexyl]-2- oxo-1, 2-dihydro-3H-l, 3, 4-benzotriazepin-l -yl ⁇ -phenyl)-3-methyl-butyramide
  • Step a 5-Cyclohexyl-3-[cis,-4-(4-methoxy-phenyl)-cyclohexyl]-l,2-dihydro-3H-l,3,4 ⁇ benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 4-(4-methoxy-phenyl)-cyclohexanone was used in place of cycloheptanone in step a.
  • Step b l-(4-Amino-phenyl)-5-cyclohexyl-3-[cis-4-(4-methoxy-phenyl)-cyclohexyl]-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained by using steps c and d of the method of preparation of example 1, except that 5-cyclohexyl-3-[cis-4 ⁇ (4-methoxy-phenyl)-cyclohexyl]- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one in step c.
  • Step c The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-5-cyclohexyl-3-[cis-4-(4-methoxy-phenyl)-cyclohexyl]- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and ter ⁇ -butoxycarbonyl L-valine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and fert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N ) N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4
  • Step a 5-Cyclohexyl-3-cyclododecyl-l,2-dihydro ⁇ 3H-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that cyclododecanone was used in place of cycloheptanone in step a.
  • Step b l-(4-Arnino-phenyl)-3-cyclododecyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained by using steps c and d of the method of preparation of example 1, except that 5-cyclohexyl-3-cyclododecyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c.
  • Step c The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-cyclododecyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and tert-butoxycarbonyl Z-valine were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N // -[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-gu
  • Example 104 2-Amino- ⁇ N-[4-(5-cyclohexyl-2-oxo-3-spiro[5.5]undec-3-yl-l,2-dihydro-3H- 1, 3, 4-benzotriazepin-3-yl)-phenyl]-3-methyl-butyramide
  • Example 105 (S)-2-Amino-N-[4-(3-cyclodecyl-5-cyclohexyl-8-methyl-2-oxo-l,2-dihydro-3H- 1, 3, 4-benzotriazepin-l-yl) -phenyl] -3 -methyl-butyr amide
  • Step a 3-Cyclodecyl-5-cyclohexyl-8-methyl-l,2-d ⁇ hydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that cyclododecanone was used in place of cycloheptanone in step a and (2-amino-4-methyl- phenyl)-cyclohexyl-methanone (example 11, step a) was used in place of (2-aminophenyl)- cyclohexyl-methanone in step b.
  • Step b /- (4-Amino-phenyl)-3-cyclodecyl-5-cyclohexyl-8-methyl-l, 2-d ⁇ hydro-3H-l, 3, 4- benzotriazepin-2-one was obtained by using steps c and d of the method of preparation of example 1, except that 3-cyclodecyl-5-cyclohexyl-8-methyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H- 1,3,4- benzotriazepin-2-one in step c.
  • Step c The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-cyclodecyl-5-cyclohexyl-8-methyl-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl Z-valine were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(fert-butoxycarbonyl)-N / -[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl
  • Example 106 ⁇ S)-2-Amino- ⁇ - ⁇ 4-[5-cyclohexyl-8-methyl-2-oxo-3-(3,3,5,5-tetramethyl- cyclohexyl)-l,2-dihydro-3H-l,3A-benzotriazepin-l-yl]-phenyl ⁇ -3-methyl-butyramide
  • Step a 5-Cyclohexyl-8-methyl-3-(3, 3, 5, 5-tetramethyl-cyclohexyl)-l , 2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 3,3,5,5-tetramethyl-cyclohexanone was used in place of cycloheptanone in step a and (2-amino-4-methyl- ⁇ henyl)-cyclohexyl-methanone (example 11, step a) was used in place of (2-aminophenyI)-cyclohexyl-methanone in step b.
  • Step b l-(4-Amino-phenyl)-5-cyclohexyl-8-methyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained by using steps c and d of the method of preparation of example 1, except that 5-cyclohexyl-8-methyl-3-(3,3,5,5-tetramethyl- cyclohexyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c.
  • Step c The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-5-cyclohexyl-8-methyl-3-(3,3,5,5-tetramethyl-cyclohexyl)- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl Z-valine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and ter ⁇ -butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(te?”t-butoxycarbonyl)-N / -[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4
  • Step a NJ$'-Bis-(tert ⁇ butoxycarbonyI)-N''-[4-(3-N-te ⁇ -butoxycarbonyl-aminomethyl-5- cyclohexyl-2-oxo-l ,2-dihydro-3H-l , 3, 4-benzotriazepin-3-yl)-phenyl]-guanidine
  • Step b The title compound was obtained using step f of the method of preparation of example 1, except that N,N'-bis-(tert-butoxycarbonyl)-N"-[4-(3-N-tert-butoxycarbonyl-aminomethyl-5- cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine was used in place of N,N -bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyI-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine.
  • Example 109 N-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H ⁇ l,3,4-benzotriazepin-l-yl)- phenyl]-3-guanidino-propionamide.
  • step a of the method of preparation of example 71 except that N,N-bis-(tert-butoxycarbonyl)guanidino-propionic acid was used in place of tert- butoxycarbonyl glycine, followed by reaction of the product obtained, in place of 2-[4-(3- benzyl-5 -cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 -yl)-phenylimino]- imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39.
  • Example 110 N-[3-(3-Benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H ⁇ l,3,4-benzotriazepin-l-yl)- phenylj-guanidine
  • Step a 3-Benzyl-5-cyclohexyl-l-(4-nitro-benzyl)-l ,2-dihydro-3H-l ,3 ,4-benzotriazepine-2-one was obtained using step c of the method of preparation of example 20, except that 3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 1, step b) and 4-nitrobenzyl bromide were used in place of 5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and (3-bromopropenyl)-benzene.
  • Step b The title compound was obtained using steps d-f of the method of preparation of example 1, except that 3-benzyl-5-cyclohexyl-l-(4-nitro-benzyl)-l,2-dihydro-3H-l,3,4- benzotriazepine-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one in step d.
  • Example 112 N-[4-(3-Benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)- phenyl] ⁇ N',N"-dimethyl-guanidine
  • Step a l- ⁇ - ⁇ -Benzyl-S-cyclohexyl-l-oxo-l ⁇ -dihydro-SH-l ⁇ A-benzotriazepin-l-yty-phenyl]- 3-methyl-thiourea
  • Step b The title compound was obtained using step e of the method of preparation of example 1, except that methylamine and l-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro- 3H-l,3,4-benzotriazepin-l-yl)-phenyl]-3-methyl-thiourea were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and 1,3- ⁇ «-(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea respectively.
  • Example 113 N-[4-(3-Benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l- yl)-2-bromo-phenyl]-guanidine.
  • Step a l-(4-Amino-3-bromo-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one
  • Step b The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-amino-3-bromo-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin ⁇ l-yl)- phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39.
  • Example 114 (S)-2-Amino- ' N-[4-(3-benzyl-5-cycIohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-3-methyl-butyramide
  • Step a (6-Fluoro-2-aminophenyl) cyclohexyl methanone was obtained by the method of preparation of example 5 step a, except that cyclohexylmagnesium chloride and 6-fluoro-2- aminobenzonitrile were used in place of isopropylmagnesium chloride and 2- aminobenzonitrile respectively.
  • Step b 1 -(4-Aminophenyl)-3-benzyl-5-cyclohexyl-6-fluoro-l ,2-dihydro-3 ⁇ ⁇ -l ,3,4- benzotriazepin-2-one was obtained using steps a-d of the method of preparation of example 1, except that (6-fluoro-2-aminophenyl)-cyclohexyl-methanone was used in step a in place of (2- aminophenyl)-cyclohexyl-methanone.
  • Step c The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-6 ⁇ fluoro-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and fert-butoxycarbonyl i-valine were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guan
  • Example 115 (S)-2-Amino-N- ⁇ 4- [3-(2-cyclohexyl-benzyl)-5-cyclohexyl-2-oxo-l,2-dihydro- 3H-l,3,4-benzotriazepin-l-yl)-phenyl]-3-methyl-butyramide
  • the title compound was obtained using step a of the method of preparation of example 71, except that l-(4-aminophenyl)-5-cyclohexyl-3-(2-cyclohexyl ⁇ benzyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 51, step a) and fert-butoxycarbonyl /.--valine were used in place of 1 -(4-aminophenyl)-3-benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotria
  • Step a l-(4-Aminophenyl)-5-cyclohexyl-3-octyl-l ,2-dihydro-3H-l ,3 ,4-benzotriazepin-2-one was obtained using steps c and d of the method of preparation of example 20, except that 1- octyl bromide was used in place of (3-bromopropenyl)-benzene in step c.
  • Step b The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-aminophenyl)-5-cyclohexyl-3-octyl-l,2-dihydro-3H-l,3,4-benzotriazepin- 2-one and fert-butoxycarbonyl L- valine were used in place of l-(4-aminophenyl)-3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert- butoxycarbonyl)-N // -[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l- yl)-phenyl]-gu
  • Step a l-(4-Aminophe ⁇ l)-5-cyclohexyl-3-(l-phenyl-ethyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using steps c and d of the method preparation of example 20, except that (l-bromo-ethyl)-benzene was used in place of (3-bromopropenyl)-benzene in step c.
  • Step b The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl-5-cyclohexyl-(l-phenyl-ethyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 118, step a) and tert-butoxycarbonyl Z-valine were used in place of 1 -(4-aminophenyl)-3-benzyl-5 -cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4
  • Example 120 2-Amino-N- ⁇ 4-[5-cyclohexyl-3-(3,3-diphenyl-propyl)-2-oxo-l,2 ⁇ dihydro-3H- 1, 3, 4-benzotriazepin-l-yl]-phenyl ⁇ -3-methyl-butyramide
  • Step a l-(4-Aminophenyl)-5-cyclohexyl-3-(3,3-diphenyl-propyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using steps c and d of the method of example 20, except that 3,3-diphenylpropyl bromide was used in place of (3-bromopro ⁇ enyl)-benzene in step c.
  • Step b The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl-5-cyclohexyl-(3,3-diphenyl-propyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and tert-butoxycarbonyl Z-valine were used in place of l-(4- ammophenyty-S-benzyl-S-cyclohexyl-l ⁇ -dihydro-SH-l ⁇ -benzotriazepin ⁇ -one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of ⁇ N-bis- ⁇ ert-butoxycarbonyO-N'- ⁇ -CS-benzyl-S-cyclohexyl ⁇ -oxo-l ⁇ -dihydro-SH-l ⁇ - benzotriazepin-l-yl)-phenyl]-gu
  • Step a l-(4-Amino-phenyl)-5-cyclohexyl-3-naphtalen-2-ylmethyl-l ,2-dihydro-3H-l ,3 ,4- benzotriazepin-2-one was obtained using steps c and d of the method of preparation of example 20, except that 2-bromomethyl-naphthalene was used in place of (3-bromopro ⁇ enyl)- benzene in step c.
  • Step b The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-5-cyclohexyl-3-naphthalen-2-ylmethyl-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl i-valine were used in place of l-(4- aminophenyl)-3 -benzyl-5 -cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N / -bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l
  • the title compound was obtained using steps a-e of the method of preparation of example 1 except that cyclohexylmethyl hydrazine was used in place of benzylhydrazine in step a and 2- chloro-l-iodo-4-nitrobenzene replaced 4-iodo-nitrobenzene in step d, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39.
  • step a (500mg, l.Ommol) and NEt 3 (0.2ImL, l.lmmol) in DCM (1OmL) was added bromoacetyl bromide (O.lmL, l.lmmol) and the reaction mixture was stirred at ambient temperature for 2h.
  • reaction mixture was diluted with DCM (1OmL), washed with saturated aqueous NaHCO 3 /20mL), brine (2OmL) and dried (MgSO 4 ). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with EtOAc-hexane (3:7) as eluant (470mg, 75%).
  • Step b To a solution of N-[4-(3-biphenyl-2-ylmethyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-3-yl)-phenyl]-2-bromo-acetamide (230mg, 0.37mmol) in DCM (5mL) was added pyrrolidine (310 ⁇ l, 3.7mmol) and the reaction mixture was stirred at ambient temperature for 2h, diluted with DCM (1OmL), washed with saturated aqueous NaHCO 3 (IOmL), brine (1OmL) and dried (MgSO 4 ).
  • Example 125 N-[4-(3-Benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yI) ⁇ phenyl]-N,N'-dimethyl-guanidine
  • Step a N ⁇ '-Bis-ft&n-butoxycarbonyl ⁇ '- ⁇ -fS-benzyl-S-cyclohexyl ⁇ -oxo-lJ-difydw-SH- l,3,4-benzotriazepin-3 ⁇ yl)-phenyl]-N,N"-dimethyl-guanidine
  • Step b The title compound was obtained using step f of the method of preparation of example 1, except that N,N'-bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-N,N"-dimethyl-guanidine was used in place of N,N-bis-(tert-butoxycarbonyl)-N / -[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepm-l-yl)-phenyl]-guanidine.
  • Step a l- ⁇ - ⁇ -Benzyl-S-cyclohexyl ⁇ -oxo-l ⁇ -dihydro-SH-lJ ⁇ -benzotriazepin-l-yty-phenyl]- 3-cyclohexyl-thiourea was obtained using step a of the method of preparation of example 112, except that cyclohexyl isothiocyanate was used in place of methyl isothiocyanate.
  • Step b The title compound was obtained using step e of the method of preparation of example 1, except that l-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)- phenyl]-3-cyclohexyl-thiourea and methylamine were used in place of l-(4-aminophenyl)-3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and ⁇ ,3-bis-(tert- butoxycarbonyl)-2-methyl-2-thiopseudourea respectively.
  • step e of the method of preparation of example 1, except that l-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)- phenyl]-3-methyl-thiourea (example 112, step a) and pyrrolidine were used in place of l-(4- aminophenyl)-3 -benzyl-5 -cyclohexyl-1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one and 1 ,3-bis-
  • Step a 3-Benzyl-5-cyclohexyl-l-(4-methylamino-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin- 2-one
  • l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 1, step d) (420mg, l.Ommol), 37% formalin (80 ⁇ l, l.lmmol) and HOAc (0.1 l ⁇ l, 2.0mmol) in DCE (5mL) was added sodium triacetoxy borohydride (360mg, 1.7mmol) in small portions.
  • Step b ( ⁇ [3-Benzyl-5-cyclohexyl-2-oxo)-l ,2-dihydro-3H-l , 3, 4-benzotriazepin-l-yl)-phenylJ- methyl-carbamoyl ⁇ -metyl)-carbamic acid tert-butyl ester
  • the reaction mixture was diluted with DCM (1OmL), washed with 5% KHSO 4 (1OmL), saturated aqueous NaHCO 3 (1OmL), brine (1OmL), dried, filtered and the solvent was evaporated.
  • the crude product was purified by chromatography on silica gel using hexane-EtOAc (8:2) as eluant to afford the product as a colourless foam (70mg, 39%).
  • Step c The title compound was obtained using step f of the method of preparation of example 1 except that ( ⁇ [3-benzyl-5-cyclohexyl-2-oxo)-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)- phenyl]-methyl-carbamoyl ⁇ -methyl)-carbamic acid tert-butyl ester was used in place of N,N- bis-(tert-butoxycarbonyl)-N / -[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine.
  • Example 129 N-[4-(3-Benzyl-5-cyclohexyl-2 ⁇ oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)- phenyl]-2-cyclohexylamino-acetamide
  • Step a N-[4-(3-Benzyl ⁇ 5-cyclohexyl-2-oxo-l ,2 ⁇ dihydro-3H-l , 3, 4-benzotriazepin-l -yl) -phenyl] - 2-bromo-acetamide was obtained using step a of the method of preparation of example 123 except that l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l ; ,3,4-benzotriazepin-2- one (example 1, step d) was used in place of l-(4-amino-phenyl)-3-biphenyl-2-ylmethyl-5-cyclohexyl-l,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one .
  • Step b The title compound was prepared using step b of the method of preparation of example 123 except that N-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l- yl)-phenyl]-2-bromo-acetamide and cyclohexylamine were used in in place of N-[4-(3- biphenyl-2-ylmethyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]- 2-bromo-acetamide and pyrrolidine respectively.
  • Example 130 N-(2-Amino-ethyl)-4-(3-benzyl-5-cyclohexyl-2-oxo-l, 2-d ⁇ hydro-SH-l , 3, 4- benzotriazepin-l-yl)-benzamide
  • Step a 4-(3-Ben ⁇ yl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-benzoic acid methyl ester was prepared using step c of the method of preparation of example 1, except that methyl-4-iodobenzoate was used instead of 4-iodo-nitrobenzene.
  • Step b 4-(3-Benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-benzoic acid was prepared using step d of the method of preparation of example 13, except that 4-(3- benzyl-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin- 1 -yl)-benzoic acid methyl ester was used instead of [5-cyclohexyl-l-(4-(N,N'- ⁇ -(tert-butoxycarbonyl)-guanidino)- phenyl)-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl]-acetic acid ethyl ester.
  • Step c The title compound was obtained using step a of the method of preparation of example 71, except that 2-(amino-ethyl)-carbamic acid tert-butyl ester and 4-(3-benzyl-5-cyclohexyl-2- oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-benzoic acid were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l 5 3,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N / -bis-(tert-butoxycarbonyl)-N / -[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3 ; 4- benzotriaze
  • Example 131 N- [3- (3-Benzyl ⁇ 5-cyclohexyl-2-oxo-l , 2-dihydro-3H-l, 3, 4-benzotriazepin-l - ylmethyl)-phenyl]-guanidine
  • Step a 3-Benzyl-5-cyclohexyl-l-(3-nitro-benzyl)-l ,2-dihydro-3H-l ,3 ' ,4-benzotriazepine-2-one was obtained using step c of the method of preparation of example 20, except that 3-benzyl-5- cyclohexyl ⁇ l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 1, step b) and 3-nitrobenzyl bromide were used in place of 5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and (3-bromo
  • Step b The title compound was obtained using steps d-f of the method of preparation of example 1, except that 3-benzyl-5-cyclohexyl-l-(3-nitro-benzyl)-l,2-dihydro-3H-l,3,4- benzotriazepine-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one in step d.
  • Example 132 4-[5-Cyclohexyl-l ⁇ (4-guanidino-phenyl)-2-oxo-l ,2-dihydro-3H-l ,3 ,4- benzotriazepm-3-ylmethylJ-benzoic acid methyl ester
  • the title compound was obtained using steps c-f of the method of preparation of example 20, except that 4-methoxycarbonylbenzyl bromide was used in step c in place of (3- bromopropenyl)-benzene.
  • Step b 5-Cyclohexyl-3-phenyl-l ,2-dihydro-3H-l , 3, 4-benzotriazepin-2-one
  • Step c 5-Cyclohexyl-l-(4-nitrobenzyl)-3-phenyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step c of the method of preparation of example 20, except that 5- cyclohexyl-3 -phenyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and 4-nitrobenzylbromide were used in place of 5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one and (3-bromopropenyl)-benzene respectively.
  • Step d The title compound was obtained as the di-hydrochloride salt using step d-f of the method of preparation of example 1, except that 5 -cyclohexyl-l-(4-nitrobenzyl)-3 -phenyl- 1,2- dihydro-3H-l,3,4-benzotriazepin-2-one was used step d in place of 3-benzyl-5-cyclohexyl-l- (4-nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one.
  • step a The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-biphenyl-2-ylmethyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 25, step a) was used in place of l-(4-aminophenyl)-3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N / -[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example
  • Example 135 3-Biphenyl-2-ylmethyl-5-cyclohexyl-l- ⁇ 4-[(lH-imidazol-2-ylmethyl)-amino]- phenyl ⁇ -l ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one
  • the title compound was obtained using step a of the method of preparation of example 128, except that 1 -(4-amino-phenyl)-3 -biphenyl-2-ylmethyl-5 -cyclohexyl- 1 ,2-dihydro-3 H- 1 ,3 ,4- benzotriazepin-2-one (example 25, step a) and l-H-imidazol-2-carbaldehyde were used in place of 1 -(4-aminophenyl)-3-benzyl-5-cyclohexyl- 1 ,2-dihydro-3 ⁇ - 1 ,3,4-benzotriazepin-2-one and
  • Example 136 3-Biphenyl-2-ylmethyl-5-cyclohexyl-l- ⁇ 4-[(lH-imidazol-4-ylmethyl)-amino]- phenyl ⁇ -l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
  • the title compound was obtained using step a of the method of preparation of example 128, except that 1 ⁇ (4-amino-phenyl)-3 -biphenyl-2-ylmethyl-5 -cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4- benzotriazepin-2-one (example 25, step a) and l-H-imidazol-4-carbaldehyde were used in place of 1 -(4-aminophenyl)-3 -benzyl-5 -cyclohexyl- 1 ,2-dihydro-3 ⁇ - 1 ,3 ,4-benzotriazepin-2
  • Example 137 l-[4-(2-Amino-3-methyl-butylamino)-phenyl]-3-hiphenyl-2-ylmethyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
  • Example 138 3-Biphenyl-2-ylmethyl-5-cyclohexyl-l-[4-[(lH-imidazol-2-ylamino)-phenyl]- 1 ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one
  • Step a ⁇ - ⁇ -Biphenyl ⁇ -ylmethyl-S-cyclohexyl ⁇ -oxo-lJ-dihydro-SH-l.S ⁇ -benzotriazepin-l- y ⁇ ) -phenyl] -thiourea
  • step a (500mg, lmmol) in toluene (5mL) was added thiophosgene (92 ⁇ l, 1.2mmol) and the solution was heated at reflux for 1.5h. The solution was cooled, THF (5mL) was added and NH 3 gas was bubbled into the solution for 5min. The reaction mixture was stirred at ambient temperature for 30min then the solvent was evaporated.
  • Step b ft- ⁇ -Biphenyl ⁇ -ylmethylS-cyclohexyl ⁇ -oxo-l ⁇ -dihydroSH-l ⁇ -benzotriazepin-l- yl)-phenyl]-N'-(2,2-dimethoxy-ethyl)-guanidine
  • Step c A solution of [4 ⁇ (3-biphenyl-2-ylmethyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-N'-(2,2-dimethoxy-ethyl)-guanidine (540mg, 0.86mmol) in 6N HCl (5mL) was stirred at ambient temperature for 4h. The solution was basified to pH8 by the addition of 2N NaOH and extracted with DCM (2 x 15mL) and the extracts dried (MgSO 4 ).
  • Example 139 3-Biphenyl-2-ylmethyl-5-cyclohexyl-l- ⁇ 4-[(thiazole-2-yhnethyl)-amino]- phenylj-l ,2-dihydro-3H-l , 3, 4-benzotriazepin-2-one
  • the title compound was obtained using step a of the method of preparation of example 128, except that 1 -(4-amino-phenyl)-3 -biphenyl-2-ylmethyl-5 -cyclohexyl- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-2-one (example 25, step a) and thiazol-2-carbaldehyde were used in place of 1- (4-aminophenyl)-3-benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and formalin respectively.
  • Example 140 3-Benzyl-5-cyclohexyl ⁇ l-[4-(4, 5-dihydro-lH-imidazol-2-ylamino)-phenyl]-8- inethyl-1, 2-dihydro-3H-l, 3, 4-henzotriazepin-2-one
  • the title compound was prepared by the method used in the: preparation of example 1 except that (2-amino-4-methyl-phenyl)-cyclohexyl-methanone was used in step a in place of (2- aminophenyl)-cyclohexyl-methanone and di-tert-butyl 2-thioxoimidazolidine-l,3- dicarboxylate replaced bis-(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea in step e.
  • Step a l-(4-Aminophenyl)-3-benzyl-5-cyclohexyl-8-methyl-l,2-dihydro-3H-l, 3, 4- bemotriazepin-2-one was prepared by the method used in steps a-d in the preparation of example 1 except that (2-amino-4-methyl-phenyl)-cyclohexyl-methanone was used in step a in place of (2-aminophenyl)-cyclohexyl-methanone.
  • Step b The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl-8-methyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and fert-butoxycarbonyl i-valine were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of ⁇ N-bis- ⁇ ert-butoxycarbony ⁇ -N'- ⁇ -CS-benzyl-S-cyclohexyl ⁇ -oxo-l ⁇ -dihydro-SH-l ⁇ - benzotriazepin-l-yl)-phenyl]-guanidine, according to step
  • Example 142 N ⁇ - ⁇ -tert-Butyl-thiazol- ⁇ -ylmethylJS-cyclohexyl ⁇ -oxo-lJ-dihydro-SH- l,3,4-benzotriazepin-l-yl]-phenyl ⁇ -guanidine
  • Step a [S-Cyclohexyl-l-ft-nitro-phenylJ ⁇ -oxo-l ⁇ -dihydroSH-l.S ⁇ -benzotriazepinS-yl]- acetic acid N-hydroxysuccinimide ester was prepared using step d of the method of preparation of example 13 except that [5-cyclohexyl-l-(4-nitro-phenyl)-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-3-yl]-acetic acid ethyl ester (example 13, step a) was used in place of [5- cyclohexyl-l
  • Step b 2 ⁇ [5-Cyclohexyl-l-(4-nitro-phenyl)-2-oxo-l ,2-dihydro-3H-l ,3 ,4-benzotriazepin-3-yl]- acetamide was prepared using step f of the method of preparation of example 13 except that [5- cyclohexyl-l-(4-nitro-phenyl)-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl]-acetic acid ⁇ - hydroxysuccinimide ester and ammonia were used in place of [5-cyclohexyl-l-(4-(N,N'-6w- (tert-butoxycarbonyl)-guanidino)-phenyl)-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-3-yl]- acetic acid N-hydroxysuccinimide este
  • Step c 2-[5-Cyclohexyl-l-(4-nitro-phenyl)-2-oxo-l, 2-dihydro-3H-l, 3, 4-henzotriazepin-3-yl]- thioacetamide
  • Step d 3-(4-tQxt-Butyl-thiazol-2-ylmethyl)'5-cyclohexyl-l-(4-nitro-phenyl)-l,2-dihydro-3H- 1, 3, 4-benzotriazepin-2-one
  • 2-[5-cyclohexyl-l-(4-nitro-phenyl)-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin- 3-yl]-thioacetamide (lOOmg, 0.23mmol) and 1-bromopinacolone (40 ⁇ l, 0.29mmol) in EtOH (5mL) was heated under reflux for 2 Ih.
  • Step e The title compound was obtained using steps d-f of the method of preparation of example 1 except that 3-(4-tert-butyl-thiazol-2-ylmethyl)-5-cyclohexyl-l-(4-nitro-phenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was used in step d in place of 3 ⁇ benzyl-5-cyclohexyl- l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one.
  • step a of the method of preparation of example 128, except that l-(4-amino-phenyl)-3-cyclodecyl-5-cyclohexyl-8-methyl-l,2-dihydro ⁇ 3H-l,3,4- benzotriazepin-2-one (example 105, step b): and l-H-imidazol-2-carbaldehyde were used in place of 1 -(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3 ⁇ -l,3,4-benzotriazepin-2-one and formalin respectively.
  • step a of the method of preparation of example 128, except that 1 -(4-amino-phenyl)-5-cyclohexyl-8-methyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one (example 106, step b) and l-H-imidazol-2- carbaldehyde were used in place of l-(4-aminophenyl) ⁇ 3-benzyl-5-cyclohexyl-l,2-dihydro-3 ⁇ - l,3,4-benzotriazepin-2-one and formalin respectively.
  • Example 145 2-Amino-N-[4-(3-benzyl-5-cyclohexylmethyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-1-yl) -phenyl] -acetamide
  • Step a l-(4-Amino-phenyl)-3-benzyl-5-cyclohexylmethyl-l,2-dihydro-3H-l,3,4-benzotriazepin- 2-one was obtained using steps c and d of the preparation of example 1, except that 3-benzyl-5- cyclohexylmethyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one: (example 9, step d) was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c.
  • Step b The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-benzyl-5-cyclohexylmethyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1.
  • Step c 3-Benzyl-5-methyl-l'(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step c of the method of preparation of example 1, except that 3-benzyl-5- methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one.
  • Step f l-(4-Amino-phenyl)-3-benzyl-5-piperidin-l-ylmethyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using step d of the method of preparation of example 1, except that 3 -benzyl- 1 -(4-nitro-phenyl)-5 -piperidin- 1 -ylmethyl- 1 ,2-dihydro-3H- 1 ,3 ,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one.
  • Step g The title compound was obtained using steps e and f of the method of preparation of example 1, except that l-(4-amino-phenyl)-3-benzyl-5-piperidin-l-ylmethyl-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one was used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl- l,2-dihydro-3H-l,3 5 4-benzotriazepin-2-one in step e.
  • Example 147 2-Amino-N-[4-(3-ben ⁇ yl-2-oxo-5-piperidin-l-ylmethyl-l,2-dihydro-3H-l,3,4- bemotriazepin-1-yl) -phenyl] -acetamide
  • the title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-benzyl-5-piperidin-l-ylmethyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 146, step f) was used in place of l ⁇ (4-aminophenyl) ⁇ 3-benzyl- 5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one followed by reaction of the product obtained, in place of N,N-bis-(fcr/-butoxycarbonyl)-N'
  • Step a 3-Benzyl-5-cyclohexylsulfanyhnethyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one Sodium (16mg, 0.70mmol) was added to MeOH (ImL) to give a solution, to which was added cyclohexanethiol (173uL, 1.41mmol).
  • Step b l-(4 ⁇ Amino-phenyl)-3-benzyl-5 ⁇ cyclohexylsulfanylmethyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using step d of the method of preparation of example 1, except that 3 -benzyl-5 -cyclohexylsulfanylmethyl- 1 -(4-nitro-phenyl)- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one.
  • Step c ⁇ -(S-BenzylS-cyclohexylsulfanylmethyl ⁇ -oxo-l ⁇ -dihydroSH-l ⁇ -benzotriazepin- l-ylj-phenylcarbamoylj-methylj-carbamic acid tevt-butyl ester was obtained using step a of the method of preparation of example 71, except that l-(4-amino- phenyl)-3-benzyl-5-cyclohexylsulfanylmethyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one.
  • Step d The title compound was obtained using step f of the method of preparation of example 1 except that ⁇ [4-(3-benzyl-5-cyclohexylsulfanylmethyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepm-l-yl)-phenylcarbamoyl]-methyl ⁇ -carbamic acid tert-butyl ester was used in place of in place of ⁇ N-bis-(tert-butoxycarbonyl)-N / -[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine.
  • Step a ⁇ [4-(3-Benzyl-5-(yclohexanesulfor ⁇ lmet ⁇ l-2 ⁇ oxo-l,2-dihydro-3H-l,3 t 4-benzotriazepm- l-yl)-phenylcarbamoyl]-methyl ⁇ -carbamic acid tert-butyl ester 3-Chloroperoxybenzoic acid (70mg, 0.31mmol) was added to an ice-cooled solution of ⁇ [4-(3- benzyl-S-cyclohexylsulfanylmethyl ⁇ -oxo-l ⁇ -dihydro-SH-ljS ⁇ -benzotriazepin-S-yl)- phenylcarbamoyl]-methyl ⁇ -carbamic acid tert-butyl ester (example 148, step c) (200mg, 0.32mmol) in DCM (5mL).
  • Step b The title compound was obtained using step f of the method of preparation of example 1 except that ⁇ [4-(3-benzyl-5-cyclohexanesulfonylmethyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenylcarbamoyl]-methyl ⁇ -carbamic acid tert-bxxtyl ester was used in place of in place of N ) N-bis-(fert-butoxycarbonyl)-N / -[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro ⁇ 3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine.
  • Step a 3-Benzyl-l-(4-nitro-phenyl)-5-phenoxymethyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one
  • Step b l-(4-Amino-phenyl)-3-benzyl-5-phenoxymethyl-l ,2-dihydro-3H-l ,3 ,4-benzotriazepin-2- one was obtained using step d of the method of preparation of example 1, except that 3-benzyl- l-(4-nitro-phenyl)-5-phenoxymethyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3 -benzyl-5 -cyclohexyl- 1 -(4-nitrophenyl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one .
  • Step c The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-benzyl-5-phenoxymethyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of l-(4-aminophenyl)-3 -benzyl-5 -cyclohexyl- 1,2- dihydro-3H-l,3,4-benzotriazepin-2-one, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1.
  • Example 156 4- ⁇ l-[4-(2-A ⁇ nino-acetylamino)-phenyl]-3-benzyl-2 ⁇ oxo-l,2-dih.ydro-3H-l,3,4- benzotriazepin-5-ylmethoxy ⁇ -benzoic acid methyl ester
  • Example 159 N- ⁇ 4-[5-(4-Acetylamino-phenoxymethyl)-3-benzyl-2 ⁇ oxo-l,2-dihydro-3H ⁇ l,3,4 ⁇ benzotriazepin-l-yl]-phenyl ⁇ -2-amino-acetamide
  • the title compound was prepared by a similar method to that used in the preparation of example 150 except that N-(4-hydroxy-phenyl)-acetamide was used in step a in place of phenol.
  • Example 160 4- ⁇ l-[4-(2-Amino-acetylamino)-phenyl]-3-benzyl-2-oxo-l, 2-d ⁇ hydro-SH-l, 3, 4- benzotriazepin-5 ⁇ yl]methoxy ⁇ -benz ⁇ nide
  • the title compound was prepared by a similar method to that used in the preparation of example 150 except that 4-hydroxy-benzamide was used in step a in place of phenol.
  • Example 161 N- ⁇ 4-[5-Cyclohexyl-2-oxo-3-(5-phenyl-[l,3,4]oxadiazol-2-ylmethyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl]-phenyl ⁇ -guanidine
  • Step a Benzoic acid ((N,N' ' -bis-(tert-butoxycarbonyl)-N f -3-[l-(4-guanidino-phenyl)-5- cyclohexyl ⁇ -oxo-l ⁇ -dihydro-SH-l ⁇ -benzotriazepin-l-ylJJ-acetylJ-hydrazide was prepared using step f of the method of preparation of example 13 except that benzoic hydrazide was used in place of diphenylmethylamine.
  • Step b N,N'-bis-(tert-butoxycarbonyl)-N"-l-(4-guanidino-phenyl)-5-cyclohexyl-3-(5-phenyl- [1 ,3,4]oxadiazol-2-ylmethyl)-l ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one
  • Step a N-[3-Benzyl-5-cyclohexyl-l -(4-nitro-phenyl)-2-oxo-l ,2-dihydro-3H-l ,3,4- benzotriazep ⁇ n-7-ylJ-acetamide
  • Step b N 5 N' ' -Bis-(tevt-butoxycarbonyl)- ' N" ' -[4-(7-acetamido-3-benzyl-5-cyclohexyl-2-oxo-l ,2- dihydro-3H-l ,3,4-benzotriazepin-l -yl) -phenyl] -guanidine was obtained using steps d and e of the method of preparation of example 1 except that N-[3-benzyl-5-cyclohexyl-l-(4- nitrophenyl)-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-7-yl]-acetamide was used in step d in place of 3 -benzyl-5-cyclohexyl- 1 -(4-nitro-phenyl)- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one.
  • Step c The title compound was obtained using step b of the method of preparation of example 39 except that N,N'-Bis-(tert-butoxycarbonyl)-N"-[4-(7-acetamido-3-benzyl-5-cyclohexyl-2- oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine was used in place of 2-[4- (3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenylimino]- imidazolidine-l,3 ⁇ dicarboxylic acid di-fert-butyl ester.
  • step f of the method of preparation of example 1 except that N,N'-bis-(tert-butoxycarbonyl)-N"-[4-(7-acetamido-3-benzyl-5-cyclohexyl-2-oxo- l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine (example 162, step b) was used in place of N,N-bis-(ter/-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-
  • Example 165 3-Benzyl-5-cyclohexyl-l-(4-guanidino-phenyl)-2-oxo-l,2-dihydro-3H-l, 3, 4- benzotriazepine-7-carboxylic acid dibenzylamide
  • Step a l ⁇ (4-Aminophenyl)-3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepine-7-carboxylic acid dibenzylamide
  • step e of the method of preparation of example 1 except that l-(4-ammophenyI)-3-benzyl-5-cyclohexyI-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepine-7-carboxylic acid dibenzylamide was used in place of l-(4-aminophenyl)-3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo-l 5 2-dihydro-3H-l,3 5 4 ⁇ benzotriazepin-l-yl)-phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester according to step b of the method of preparation of example 39.
  • Example 166 N-ft- ⁇ -Benzyl-S-cyclohexyl ⁇ -oxo ⁇ -fpiperidine-I-carbonylJ-l ⁇ -dihydroSH- 1, 3, 4-benzotriazepin-l-ylJ-phenyl ⁇ -guanidine
  • Step a 3-Benzyl-7-amino-5-cyclohexyl-l-(4-nitro-phenyl)-l,2-dihydro-3H ⁇ l,3,4- benzotriazepin-2-one was obtained using step f of the method of preparation of example 1 except that N-[3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-2-oxo-l 5 2-dihydro-3H-l,3,4- benzotriazepin-7-yl]-acetamide (example 162, step a) was used in place of N,N ⁇ bis-(tert ⁇ butoxycarbonyl)-N"-[4-(3 -benzyl-S-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 - yl)-phenyl]-guanidine.
  • Step b 3-Benzyl-7-benzylamino ⁇ 5-cyclohexyl-l-(4-nitrophenyl)-l,2-d ⁇ hydt'o-3H-l,3,4- benzotriazepin-2-one was obtained using step a of the method of preparation of example 128, except that 3-benzyl-7-amino-5-cyclohexyl-l -(4-nitrophenyl)-l,2-dihydro-3H-l,3 5 4- benzotriazepin-2-one and benzaldehyde were used in place of l-(4-aminophenyl)-3-benzyl-5- cyclohexyl-l 5 2-dihydro-3H-l 5 3,4-benzotriazepin-2-one and formalin respectively.
  • Step c The title compound was obtained using steps d and e of the method of preparation of example 1, except that 3-benzyl-7-benzylamino-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one was used in step d in place of 3-benzyl-5-cyclohexyl-l-(4- nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3 ⁇ -l,3,4-benzotriazepin- l-yl)-phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester according to step b of the method of preparation of example 39.
  • Example 169 N-[4-(3-Benzyl-5-cyclohexyl-7-dimethylamino-2-oxo-l ,2-dihydro-3H-l ,3 ,4- benzotriazepin-1-yl) -phenyl] -guanidine
  • Step a 3-Benzyl-5-cyclohexyl-7-dimethylamino-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one

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Abstract

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

Description

BENZOTRIAZEPINONE DERIVATIVES Field of the Invention
The present invention is concerned with benzotriazepinone derivatives, their intermediates, uses thereof and processes for their production. In particular, the present invention relates to parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrp) receptor ligands, (PTH-I or PTH/PTHrp receptor ligands). The invention also relates to methods of preparing such ligands and to compounds which are useful as intermediates in such methods.
Background of the Invention
PTH is an 84 amino acid peptide circulating hormone produced by the parathyroid glands. The primary function of PTH is to maintain a constant concentration of calcium in the extracellular fluid. It does so by acting directly or indirectly on various peripheral target tissues to mobilise calcium entry into the blood. In turn, PTH synthesis and release are controlled principally by the level of serum calcium. When the concentration of calcium is low, PTH secretion increases but is decreased when the calcium concentration is high. PTH enhances the distal tubular reabsorption of calcium in the kidney (Marcus, R. in The Pharmacological Basis of Therapeutics, 9th Ed. (1996), ppl525-1529, Hardman, J. G.; Goodman Gilman, A. and Limbard, L. E. Ed. (McGraw-Hill)). At the same time, it inhibits the reabsorption of phosphate and stimulates the conversion of vitamin D to 1,25-dihydroxyvitamin D or calcitriol. Calcitriol is secreted into the circulation and interacts with specific receptors in the intestine that contribute to a rise in the plasma calcium concentration by improving the efficiency of gut calcium absorption. PTH also increases the delivery of calcium to the extracellular fluid by increasing overall bone resorption during bone remodelling. In bone remodeling osteoclast precursor cells are recruited to sites on the bone surface in response to physical or biochemical signals (such as the release of soluble cytokines by osteoblasts, or the expression of membrane-bound signalling proteins on the osteoblast cell surface). Once located at the bone surface these cells are transformed into multinucleated osteoblasts that cause bone lysis by secretion of acid and enzymes thereby generating resorption pits in the bone. Bone remodeling is completed by ingress of preosteoblasts into theses cavities which on progression into osteoblasts deposit bone matrix constituents such as collagen and osteocalcin, amongst other proteins.
Parathyroid hormone related peptide (PTHrp) shares some of the actions of PTH (Clemens, T. L. et al, Br. J. Pharmacol, (2001), 134, 1113-1116). PTHrp is found in three forms of 173, 141 and 139 amino acids and shares significant N-terminal amino acid sequence homology with PTH, particularly within the first 13 residues. Unlike PTH, PTHrp is not normally present in the circulation but is thought to act as a paracrine or autocrine factor. PTHrp regulates chondrocyte growth, differentiation in the growth plates of developing long bones, and branching morphogenesis of the mammary gland. It is also produced by the lactating breast, atria, brain, bone osteoblasts, uterus, bladder, stomach and by a number of tumour cell types including those responsible for prostate, breast, lung, ovarian, bladder and squamous carcinomas and in Leydig tumour cells and other cancers of the kidney.
PTH interacts with two distinct G-protein coupled receptors (Gensure, R. C. et al, Biochem. Biophys. Res Comm., (2005), 328, 666-678). PTH-I or PTH/PTHrp receptors, hereinafter termed PTH-I receptors, are located predominantly in the kidney and on bone osteoblasts and are responsible for the effects of PTH on calcium homeostasis (Gardella, T. J. and Juppner, H. Trends in Endocrinology and Metabolism, (2001), 12(5), 210-217). They are also found on cancer cells, most particularly in prostate, breast, gastric, ovarian, bladder and Leydig tumours, where they are responsible for the involvement of PTH and/or PTHrp on the primary tumours as well as in the initiation of and progression to bone metastases. In contrast to PTH, PTHrp is a selective stimulant of PTH-I receptors. PTH-2 receptors are predominantly located in the brain suggesting a distinct physiological role to PTH-I receptors. The N-terminal 39 residues of tuberoinfundibular peptide (TIP39) is a selective stimulant of PTH-2 receptors (Usdin, T. B. et al., Trends in Endocrinology and Metabolism, (2003), 14(1), 14-19).
Compounds which interact with PTH-I receptors are important because of their potential pharmaceutical use as antagonists, partial inverse agonists, inverse agonists, agonists or partial agonists of the endogenous peptides PTH or PTHrp. Such compounds are described herein as ligands. Thus, the term ligand, as used herein, can mean that the compound is an antagonist, partial inverse agonist, inverse agonist, agonist or partial agonist.
Disruption of calcium homeostasis, resulting from conditions that produce an alteration in the level of PTH, may produce clinical impairment of bone such as osteoporosis, as well as other clinical disorders including, anaemia, renal impairment, ulcers, myopathy and neuropathy.
Hypercalcemia is a condition characterised by elevation of serum calcium and is often associated with primary hyperparathyroidism in which an excess of PTH production occurs.
This is often the result of parathyroid gland adenoma, hyperplasia or carcinoma. On the other hand, humoral hypercalcaemia of malignancy (HHM) results in most instances from
PTHrp-producing squamous, renal, breast, ovarian or bladder carcinomas. Both forms of hypercalcemia may be expected to benefit from a PTH-I receptor antagonist. Cell lines originating from tumours in kidney, breast, prostate, lung and from osteosarcomas have been shown to be capable of growing in response to either PTH or PTHrp. Thus a PTH-I antagonist may have a role in the treatment or prevention of primary tumours, most especially osteosarcoma, clear cell renal carcinoma, and prostate, breast, gastric, ovarian, and bladder cancers, tissue from each of which has been shown to contain both PTH-I receptors and to secrete PTHrp. Furthermore, cancers of the lung, prostate and breast have a propensity for metastasis to bone, a process underpinned by PTH and PTHrp (Guise, T. A. et al, J. Clin. Invest., (1996), 98(7), 1544-1549). PTH-I receptors are present on bone osteoblasts and control the activation of osteoclasts. Osteoclasts act on bone, providing sites for bone metastases to form and resulting in number of factors to be released, including PTHrp, which act to stimulate growth of both the primary tumour and of the bone metastases. These actions release more PTHrp leading to a vicious cycle of tumour growth. Thus, in addition to their actions on the primary tumour, PTH-I antagonists may be expected to help treat or prevent bone metastases resulting from these primary cancers. As such, these compounds might be expected to alleviate the clinical sequelae, such as fracture, severe bone pain, spinal cord compression and hypercalcaemia often associated with bone metastases.
PTHrp is also considered to contribute to cachexia, the condition of malnutrition, muscle wasting and net protein loss often associated with cancer patients. As such, PTH-I receptor antagonists may be expected to help prevent this condition. In addition elevated PTH and/or
PTHrp levels have been associated with lack of hair eruption in transgenic mice, in congestive heart failure and in a number of inflammatory and auotoimmune diseases such as rheumatoid arthritis. These findings suggest a possible role may exist for PTH-I receptor antagonists in helping to treat or prevent these and other conditions either associated with elevated levels of
PTH or PTHrp, or with over-activation of PTH-I receptors.
PTH has an anabolic action on osteoblasts therefore indicating a potential benefit for a PTH-I receptor ligand (such as an agonist or partial agonist) in helping to prevent or treat osteoporosis. Other conditions where such compounds may be considered to have a potential role are, for example, in the treatment of diabetes, in wound healing and other conditions either associated with lowered levels of PTH or PTHrp, or with under-activation of PTH-I receptors.
Various peptide-based ligands for PTH-I receptors have been obtained by modification of the hormones for PTH receptors. Synthetic PTH(I -34) retains the full activity displayed by larger fragments of PTH. Truncation of this fragment from the C-terminal end has in general resulted in less potent agonists. The potency of these ligands, containing the native amino acid sequence, has also been enhanced by incorporating amino acid substitutions (inter alia Aib for Ala at positions 1 and 3) at the N-terminus. For example, compounds of this type of 21 and 19 (Gensure, R. C. et al, MoI. Endocrinology, (2003), 17(12), 2647-2658) and of 14 amino acid residues in length (Shimuzu, N. et al., J. Biol. Chem., (2001), 276(52), 49003-49012) display agonism in cell based assays. In contrast, based on the behaviour of compounds obtained by truncation of PTH(I -34) from the N-tercninal, including amongst others, PTH(7-34) (Nutt, R. F. et al, Endocrinology, (1990), 127(1), 491-493) and PTH/PTHrp(14-34) (Caulfield, M. P. et al, Endocrinology, (1990), 127(1), 83-87 and Abou-Samra, A. B. et al, Endocrinology, (1989), 125(4), 2215-2217), changes of this type have generally afforded partial agonists or antagonists. PTH-I receptor antagonists have been described based on the bovine sequence of PTH (([NIe8-18, £>-Trp12, Tyr34]bPTH(7-34)NH2, (BIM-44002)), (Rosen, H. N. et al, Calcif. Tissue Int. (1997), 61, 455-459)) and on the bovine and mouse sequences of TIP, bTIP(7-39) (Hoare, S. R. J. et al, J. Biol Chem., (2000), 275(35), 27274-27283) and mTIP(7-39) (Hoare, S. R. J. and Usdin, T. B. Peptides, (2002), 23(5), 989-998) respectively. Octapeptides containing D-amino acids are reported to be PTH-I receptor antagonists based on their effects on PTH(l-34) stimulated cAMP in rat osteosarcoma cells (US 2004/ 0235749).
WO-A-03/041714 discloses a number of benzotriazepinone derivatives for use in the treatment of gastrin related disorders.
US Patent No. 5,091,381 describes benzotriazepines which are said to bind to peripheral benzodiazepine receptors.
EP-A-0645378 describes a class of bicyclic compounds which are said to inhibit squalene synthetase.
Summary of the Invention
In a first aspect of the present invention, there is provided a compound of formula (I):
Figure imgf000005_0001
or a salt, solvate or pro-drug thereof; wherein: one of the carbon atoms labelled 6, 7, 8 or 9 may be replaced by a nitrogen atom; R1, R4 and Rs are independently selected from H, COOH, COO(C,-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH, S(C1-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(C1-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH5 0(C1-6 alkyl), 0(C6-20 aryl), 0(C7-20 alkaryl), 0(C7-20 aralkyl), NH2, NH(C1-6 alkyl), N(Cj-6 alkyl)2, NH(C6-20 aryl), NH(C7-20 alkaryl), NH(C7-20 aralkyl), N(C1-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-20 alkaryl), N(C1-6 alkyl)(C7_20 aralkyl), N(C6-20 aryl)2j N(C6-20 aryl)(C7-20 alkaryl), N(C6-20 aryl)(C7-20 aralkyl), NHC(O)(C1-6 alkyl), NHC(O)(C6-20 aryl), NHC(O)(C7-20 alkaryl), NHC(O)(C7-20 aralkyl), N(C1-6 alkyl)C(0)(C6-2o aryl), N(C1-6 alkyl)C(O)(C7-20 alkaryl), N(C1-6 alkyl)C(O)(C7-20 aralkyl), C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)2, C(O)NH(C6-20 aryl), C(O)N(C6-20 aryl)2, C(O)NH(C7-20 aralkyl), C(O)N(C7-20 aralkyl)2, C(O)NH(C7-20 alkaryl), C(O)N(C7-20 alkaryl)2, C(O)N(C1-6 alkyl)(C6-20 aryl), C(O)N(C1-6 alkyl)(C7-20 alkaryl), C(O)N(C1-6 alkyl)(C7-20 aralkyl), C(O)N(C6-20 aryl)(C7-20 alkaryl), C(O)N(C6-20 aryl)(C7-20 aralkyl), NO2, CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(Ci-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, SO2N(C1-6 alkyl)(C6-20 aryl), SO2N(C1-6 alkyl)(C7-20 alkaryl), SO2N(C1-6 alkyl)(C7-20 aralkyl), SO2N(C6-20 aryl)(C7-20 alkaryl), SO2N(C6-20 aryl)(C7-2o aralkyl), C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl), C(O)(C7-20 aralkyl), OC(O)(C1-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 aralkyl), OC(O)(C7-20 alkaryl) and Cj-30 hydrocarbyl or Cj-30 heterocarbyl groups, wherein any of the Ci-30 hydrocarbyl or C1-30 heterocarbyl groups are optionally substituted with one or more of the groups, preferably 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (a), (b) and (c):
(a) -CH=CH-, -C≡C-, S, N, -N=, Si(C1-6 alkyl)2, Si(OH)2, Si(OC,-6 alkyl)2, C(O)NH, C(O)N(Ci-6 alkyl), C(O)O, N(Ci-6 alkyl)C(O)N(C1-6 alkyl), NHC(O)N(C1-6 alkyl), N(C1-6 alkyl)C(O)O, NHC(O)NH, NHC(O)O, NH, N(C1-6 alkyl), N(C6-20 aryl), N(C7-20 alkaryl), N(C7-20 aralkyl), O, CO, SO2, NHSO2, NHSO2NH, N(Ci-6 alkyl)SO2NH, N(C1-6 alkyl)SO2N(C1-6 alkyl), N(C6-20 aryl)SO2NH, SO, C(O)N(C6-20 aryl), N(Ci-6 alkyl)SO2, N(C6-20 aryl)SO2, C(O)NHNHC(O), =N-N- and C(O)NHNH in the backbone; (b) COOH, COO(Ci-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH, S(C1-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(C1-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(C1-6 alkyl), 0(C6-20 aryl), 0(C7-20 alkaryl), 0(C7-20 aralkyl), =0, NH2, =NH, NH(Q-6 alkyl), N(Ci-6 alkyl)2, NH(C6-20 aryl), NH(C7-20 aralkyl), NH(C7-20 alkaryl), N(Ci-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-2o aralkyl), N(C1-6 alkyl)(C7-20 alkaryl), =N(C1-6 alkyl), =N(C6-20 aryl), =N(C7-20 aralkyl), =N(C7-20 alkaryl), NHC(O)(Ci-6 alkyl), NHC(O)(C6-20 aryl), NHC(O)(C7-20 aralkyl), NHC(O)(C7-20 alkaryl), N(Ci-6 alkyl)C(O)(C6-20 aryl), N(C1-6 alkyl)C(O)(C7-20 aralkyl), N(Ci-6 alkyl)C(O)(C7-20 alkaryl), NO2, CN, SO2NH2, SO2NH(Ci-6 alkyl), SO2N(Ci-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, SO2NH(C7-20 aralkyl), SO2NH(C7-20 alkaryl), SO2N(Ci-6 alkyl)(C6-2o aryl), SO2N(C1-6 alkyl)(C7-20 aralkyl), SO2N(Ci-6 alkyl)(C7-20 alkaryl), NHSO2(C1-6 alkyl), NHSO2(C6-20 aryl), NHSO2(C7-20 aralkyl), NHSO2(C7-20 alkaryl), N(C1-6 alkyl)SO2(C1-6 alkyl), N(C1-6 alkyl)SO2(C6-20 aryl), N(C1-6 alkyl)SO2(C7-20 aralkyl), N(C1-6 alkyl)SO2(C7-20 alkaryl), C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl), C(O)(C7-20 aralkyl), OC(O)(C1-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 aralkyl), OC(O)(C7-20 alkaryl), C(O)NH(C1-6 alkyl), C(O)NH(C6-20 aryl), C(O)NH(C7-20 aralkyl), C(O)NH(C7-20 alkaryl), C(O)N(C1-6 alkyl)2, C(O)N(C1-6 alkyl)(C6-20 aryl), C(O)N(C1-6 alkyl)(C7-2o aralkyl) and C(O)N(C1-6 alkyl)(C7-2o alkaryl) on the backbone; and,
(c) groups independently selected from the group consisting of C1-10 alkyl, C2-I0 alkoxyalkyl, C7-20 alkoxyaryl, C12-20 aryloxyaryl, C7-20 aryloxyalkyl, C1-10 alkoxy, C6-20 aryloxy, C2-10 alkenyl, C2-10 alkynyl, C3-2o cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl and C6-20 aryl on the backbone;
Rla and R5a are independently selected from H, COOH, COOCH3, COOCH2CH3, halo, OH, OCH3, OCH2CH3, OCF3, CF3, CH3, OCCl3, CCl3, OCF2CF3, CF2CF3, NH2, NH(CH3), N(CH3)2, NHC(O)(CH3), NO2, CN, OC(O)CH3 and C(O)H; or R1 is joined to R5, R5a or Rla to form a 5, 6, 7, 8, 9 or 10-membered saturated, unsaturated or aromatic, heterocyclic or carbocyclic ring which is optionally substituted with one or more of the groups, preferably, 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (b) and (c) above; or R5 is joined to R1, R5a or Rla to form a 5, 6, 7, 8, 9 or 10-membered saturated, unsaturated or aromatic, heterocyclic or carbocyclic ring which is optionally substituted with one or more of the groups, preferably, 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (b) and (c) above;
R3 is selected from H, COOH, COO(Ci-20 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(C1-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, SO2NH(C7-20 aralkyl), SO2NH(C7-20 alkaryl), SO2N(C1-6 alkyl)(C6-20 aryl), SO2N(C1-6 alkyl)(C7-20 aralkyl), SO2N(C1-6 alkyl)(C7-20 alkaryl), SO2N(C6-20 aryl)2, SO2N(C6-20 aryl)(C7-20 aralkyl), SO2N(C6-20 aryl)(C7-20 alkaryl), C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl), C(O)(C7-20 aralkyl), C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)2, C(O)NH(C6-20 aryl), C(O)N(C6-20 aryl)2, C(O)NH(C7-20 aralkyl), C(O)N(C7-20 aralkyl)2, C(O)NH(C7-20 alkaryl), C(O)N(C7-20 alkaryl)2, C(O)N(C1-6 alkyl)(C6-20 aryl), C(O)N(C1-6 alkyl)(C7-20 aralkyl), C(O)N(C1-6 alkyl)(C7-20 alkaryl), C(O)N(C6-20 aryl)(C7-2o aralkyl), C(O)N(C6-20 aryl)(C7-20 alkaryl) and C1-30 hydrocarbyl or C1-30 heterocarbyl groups, wherein any of the Ci-30 hydrocarbyl or C1-3O heterocarbyl groups are optionally substituted with one or more of the groups, preferably 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (dX (e) and (f):
(d) -CH=CH-, -C≡C-, S, N, -N=, Si(C1-6 alkyl)2, Si(OH)2, Si(OC1-6 alkyl)2, C(O)NH5 C(O)N(C1-6 alkyl), C(O)O, N(C1-6 alkyl)C(O)N(C1-6 alkyl), NHC(O)N(C1-6 alkyl), N(Cj-6 alkyl)C(O)O, NHC(O)NH, NHC(O)O, NH, N(C1-6 alkyl), N(C6-20 aryl), N(C7-20 alkaryl), N(C7-20 aralkyl), O, CO, SO2, NHSO2, NHSO2NH, N(C1-6 alkyl)SO2NH, N(C1-6 alkyl)SO2N(C1-6 alkyl), N(C6-20 aryl)SO2NH, SO, C(O)N(C6-20 aryl), N(C1-6 alkyl)SO2s N(C6-20 aryl)SO2, C(O)NHNHC(O), =N-N- and C(O)NHNH in the backbone; (e) COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH, S(C1-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(C1-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(C1-6 alkyl), 0(C6-20 aryl), 0(C7-20 alkaryl), 0(C7-20 aralkyl), =O, NH2, =NH, NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), NH(C7-20 aralkyl), NH(C7-20 alkaryl), N(C1-6 alkyl)(C6-2o aryl), N(C1-6 alkyl)(C7-20 aralkyl), N(C1-6 alkyl)(C7-2o alkaryl), =N(C1-6 alkyl), =N(C6-20 aryl), =N(C7-20 aralkyl), =N(C7-20 alkaryl), NHC(O)(C1-6 alkyl), NHC(O)(C6-20 aryl), NHC(O)(C7-20 aralkyl), NHC(O)(C7-20 alkaryl), N(C1-6 alkyl)C(O)(C6-20 aryl), N(Ci-6 alkyl)C(O)(C7-20 aralkyl), N(C1-6 alkyl)C(θχC7-20 alkaryl), NO2, CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(Ci-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, SO2NH(C7-20 aralkyl), SO2NH(C7-20 alkaryl), SO2N(Ci-6 alkyl)(C6-2o aryl), SO2N(Ci-6 alkyl)(C7-20 aralkyl), SO2N(C1-6 alkyl)(C7-20 alkaryl), NHSO2(C1-6 alkyl), NHSO2(C6-20 aryl), NHSO2(C7-20 aralkyl), NHSO2(C7-20 alkaryl), N(C1-6 alkyl)SO2(Ci-6 alkyl), N(C]-6 alkyl)SO2(C6-20 aryl), N(Ci-6 alkyl)SO2(C7-20 aralkyl), N(C1-6 alkyl) SO2(C7-20 alkaryl), C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl), C(O)(C7-20 aralkyl), OC(O)(C1-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 aralkyl), OC(O)(C7-20 alkaryl), C(O)NH(C1-6 alkyl), C(O)NH(C6-20 aryl), C(O)NH(C7-20 aralkyl), C(O)NH(C7-20 alkaryl), C(O)N(C1-6 alkyl)2, C(O)N(C1-6 alkyl)(C6-20 aryl), C(O)N(C1-6 alkyl)(C7-20 aralkyl) and C(O)N(Ci-6 alkyl)(C7-2o alkaryl) on the backbone; and, (f) groups independently selected from the group consisting of Ci-I0 alkyl, C2-I0 alkoxyalkyl, C7-20 alkoxyaryl, Ci2-20 aryloxyaryl, C7-20 aryloxyalkyl, Ci-10 alkoxy, C6-20 aryloxy, C2-10 alkenyl, C2-10 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl and C6-20 aryl on the backbone;
R2 is a group
Figure imgf000009_0001
wherein: n is an integer of 0, 1, 2, 3, 4 or 5; m is an integer of 0, 1, 2, 3, 4 or 5; wherein the group -(CH2)m- is optionally substituted by 1 or more -OH groups on the CH2 backbone, preferably 1 -OH group;
R7 and R8 are independently selected from the group consisting of H, COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH, S(C1-6 alkyl), SO2H, SO3H3 SO2(Ci-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(C1-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(C1-6 alkyl), NH2, NH(Ci-6 alkyl), N(C1-6 alkyl)2, NHC(O)(C1-6 alkyl), NO2, CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(C1-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl) and C(O)(C7-20 aralkyl), and hydrocarbyl or heterocarbyl groups selected from Ci-20 alkyl, C2-20 alkenyl, C1-20 alkoxy, C2-20 alkoxyalkyl, C6-30 aryloxy, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, Ci-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl and C3-30 heterocyclylalkyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups, preferably 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (g), (h) and (i): (g) -CH=CH-, -C≡C-, S, N, -N=, Si(Ci-6 alkyl)2, Si(OH)2, Si(OCj-6 alkyl)2, C(O)NH, C(O)N(C1-6 alkyl), C(O)O, N(Ci-6 alkyl)C(O)N(Ci-6 alkyl), NHC(O)N(Ci-6 alkyl), N(Ci-6 alkyl)C(O)O, NHC(O)NH, NHC(O)O, NH, N(C3-6 alkyl), N(C6-20 aryl), N(C7-20 alkaryl), N(C7-20 aralkyl), O, CO, SO2, NHSO2 and C(O)NHNH in the backbone;
(h) COOH, COO(Ci-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH, S(Ci-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H, SO2(Ci-6 alkyl),
SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(Ci-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(C1-6 alkyl), 0(C6-20 aryl), 0(C7-20 alkaryl), 0(C7-20 aralkyl), =0, NH2, =NH, NH(Cj-6 alkyl), N(Ci-6 alkyl)2, =N(CW alkyl), NHC(O)(C1-6 alkyl), NO2, CN, SO2NH2, SO2NH(Ci-6 alkyl), SO2N(Ci-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl) and C(O)(C7-20 aralkyl) on the backbone; and,
(i) groups independently selected from the group consisting of C1-10 alkyl, C2-I0 alkoxyalkyl, C7-20 alkoxyaryl, C12-20 aryloxyaryl, C7-20 aryloxyalkyl, C1-10 alkoxy, C6-20 aryloxy, C2-10 alkenyl, C2-io alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl and C6-20 aryl on the backbone; when n is 1 or more, -(CH2)m-R6 is located in the ortho, meta or para position relative to the -(CH2)n- group; when n is O, ~(CH2)m-R6 is located in the meta or para position relative to the to the N1 atom (the N1 atom being shown in the representative structure of compound of formula (I) above);
R6 is selected from the group consisting of NR9R10, CONR9R10, NR9COR10, OR10, NR9C(=NR15)N(R14)2 and N=C(NR15 R9)N(Rl4)2; wherein:
R9 is selected from the group consisting of H and C1-6 alkyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C6-20 aryl, C7-20 aralkyl, C7-20 alkaryl, C1-20 heteroaryl and C2-20 heterocyclyl;
R10 is selected from the group consisting of, H, C1-20 alkyl, C2-20 alkenyl, C2-20 alkoxyalkyl, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, C1-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, C9-30 heterocyclylalkaryl, C4-30 heterocyclylalkoxyalkyl, C4-30 heterocyclylalkylaminoalkyl, C8-30 heteroarylalkaryl, C3-30 heteroarylalkoxyalkyl, C3-30 heteroarylalkylaminoalkyl, C7-30 aryloxyalkyl, C7-30 arylaminoalkyl, C7-30 alkylaminoaryl, C1-10 aminoalkyl, C7-20 aminoaralkyl, C7-20 aminoalkaryl, C2-20 alkylguanidinylalkyl and ureayl C1-10 alkyl; or, in the groups NR9R10 and CONR9R10, R9 and R10 may be joined to form a 3, 4, 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring; any of the groups defined as R10 (except H) being optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from C1-10 alkyl, C1-20 haloalkyl, C1-20 perhaloalkyl, C1-20 hydroxyalkyl, C3-10 cycloalkyl, halo, OH, OC1-6 alkyl, NH2, OC(Ci-6 alkyl), OC(C6-20 aryl), OC(C7-20 aralkyl), OC(C7-20 alkaryl), OCO(C1-6 alkyl), OCO(C6-20 aryl), OCO(C7-20 aralkyl), OCO(C7-20 alkaryl), COOH, COO(Ci-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), NH(C]-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), N(C6-20 aryl)2, NH(C7-20 aralkyl), N(C7-20 aralkyl)2, NH(C7-20 alkaryl), N(C7-20 alkaryl)2, N(C1-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-20 alkaryl), N(Ci-6 alkyl)(C7-20 aralkyl), N(C6-20 aryl)(C6-2o aryl), N(C6-20 aryl)(C7-20 alkaryl), N(C6-20 aryl)(C7-20 aralkyl), NO2, CN, C(O)H, C(O)(Ci-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 aralkyl) and C(O)(C7-20 alkaryl); any of the groups defined as R10 (except H) being optionally substituted in the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from -CH=CH-, -C=C-, S, N, -N=, Si(C1-6 alkyl)2, Si(OH)2, Si(OCi-6 alkyl)2, C(O)NH, C(O)N(C1-6 alkyl),
C(O)O, N(C1-6 alkyl)C(O)N(C1-6 alkyl), NHC(O)N(Ci-6 alkyl), N(C1-6 alkyl)C(O)O,
NHC(O)NH, NHC(O)O, NH, N(C1-6 alkyl), N(C6-20 aryl), N(C7-20 alkaryl), N(C7-20 aralkyl), O,
CO, SO2, NHSO2, NHSO2NH, N(C]-6 alkyl)SO2NH, N(Ci-6 alkyl)SO2N(C1-6 alkyl), N(C6-20 aryl)SO2NH, SO, C(O)N(C6-20 aryl), N(C1-6 alkyl)SO2, N(C6-20 aryl)SO2, C(O)NHNHC(O), =N-N- and C(O)NHNH; each R14 is independently selected from the group consisting of H, C1-20 alkyl, C2-20 alkenyl, C2-20 alkoxyalkyl, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-3O cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, C1-30 heteroaryl and C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, C1-10 aminoalkyl, C6-20 aminoaryl, guanidinyl C1-10 alkyl, C2-20 alkylguanidinylalkyl, ureayl C1-10 alkyl and C2-20 alkylureaylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, OH, OCi-6 alkyl, NH2, COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), OC(O)(Ci-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 aralkyl), OC(O)(C7-20 alkaryl), NH(Cj-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), N(C6-20 aryl)2, NH(C7-20 aralkyl), N(C7-20 aralkyl)2, NH(C7-20 alkaryl), N(C7-20 alkaryl)2, N(C1-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-20 aralkyl), N(Ci-6 alkyl)(C7-20 alkaryl), N(C6-20 aryl)(C7-20 aralkyl), N(C6-20 aryl)(C7-20 alkaryl), NO2, CN, C(O)H and C(O)(Ci-6 alkyl), or each R14 is joined to one another to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring; and, R15 is selected from the group consisting of H, CN, Ci-20 alkyl, C2-20 alkenyl, C2-2O alkoxyalkyl, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, C1-30 heteroaryl and C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, C1-I0 aminoalkyl, C6-20 aminoaryl, guanidinyl Ci-I0 alkyl, C2-20 alkylguanidinylalkyl, ureayl Ci-10 alkyl and C2-20 alkylureaylalkyl, any of which (except H) are optionally on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, OH, OCi-6 alkyl, NH2, COOH, COO(Ci-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), NH(C1-6 alkyl), N(Ci-6 alkyl)2, NH(C6-20 aryl), N(C6-20 aryl)2, NH(C7-20 aralkyl), N(C7-20 aralkyl)2, NH(C7-20 alkaryl), N(C7-20 alkaryl)2, NO2, CN, C(O)H and C(O)(Cj-6 alkyl); or R15 and one of R14 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R14 not joined to R15 is H or Ci-6 alkyl.
Preferably, the group -(CH2)m- is substituted by 1 -OH groups on the CH2 backbone. In a preferred embodiment, the -(CH2)m- group is not substituted by an -OH group.
Preferably R2 is a group having the structure:
Figure imgf000012_0001
wherein R7 and R8 are independently selected from the group consisting of H,
Figure imgf000012_0002
alkyl, halo, haloCi-6 alkyl, perhaloCi-6 alkyl, OH, NH2, NO2, CN, COOH, C(O)H, C(O)O(C1-6 alkyl) and C(O)(C1-6 alkyl), R6 is as defined above, n is O or 1 and m is O or 1. Where n is 1 or more, R7 and/or R8 are preferably located in the ortho or meta position relative to the -(CH2),,- group, most preferably the meta position. Where n is O, R7 and/or R8 are preferably located in the ortho or meta position relative to the N1 atom, most preferably the meta position.
Preferably, R7 is H and R8 is H, Cl, Br, or F, preferably H or Br. Preferably, R7 and R8 are both H.
Preferably n is O or 1, most preferably O. Preferably m is O or 1, most preferably O. Preferably, R2 is selected from
Figure imgf000012_0003
and
Figure imgf000013_0001
Preferably R9 is selected from H, methyl, ethyl, propyl, phenyl, phenylethyl, benzyl, tolyl and xylyl, more preferably H or methyl, most preferably H.
Preferably R10 is selected from the group consisting of Ci-B heteroaryl, C2-Is heterocyclyl, C2-i5 heteroaralkyl, C3-15 heterocyclylalkyl, C1-15 alkyl, C6-20 aryl, C7-20 aralkyl, C3-15 cycloalkyl, and C4-15 cycloalkylalkyl, any of which are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from NH2, NH(Ci-4 alkyl),
N(C1-4 alkyl)2, NH(C6-16 aryl), N(C6-16 aryl)2, NH(C7-16 aralkyl), N(C7-16 aralkyl)2, NH(C7-16 alkaryl), N(C7-I6 alkaryl)2; N(Cj-4 alkyl)(C6.i6 aryl), N(Cj-4 alkyl)(C7-i6 alkaryl), N(C1-4 alkyl)(C7-16 aralkyl), N(C6-16 aryl)(C7-I6 alkaryl), N(C6-16 aryl)(C7-i6 aralkyl), S(C1-6 alkyl), NO2,
CN, OH, SH, OC1-6 alkyl, C(O)H and C(O)(Ci-6 alkyl).
Preferably R10 is selected from the group consisting of C6-20 aryl, C7-20 aralkyl, C3-15 cycloalkyl, C4-15 cycloalkylalkyl, Ci-15 heteroaryl, C2-15 heterocyclyl, C2-15 heteroaralkyl, C3-15 heterocyclylalkyl and C1-10 alkyl, any of which are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from NH2, NH(Ci-4 alkyl) or N(Cj-4 alkyl)2.
Preferably R10 is selected from the group consisting Of C1-10 heteroaryl, C2-10 heterocyclyl, C3-io heteroaralkyl, C3-Io heterocyclylalkyl and Ci-6 alkyl, any of which are optionally substituted on the backbone with one or more groups, preferably 1, 2 or 3 groups, independently selected from NH2, NH(C1-4 alkyl) or N(Ci-4 alkyl)2.
Preferably R10 is selected from the group consisting of of Ci-I0 alkyl, C3-I5 cycloalkyl, C4-I5 cycloalkylalkyl, C7-20 aralkyl, furanyl, furanyl(Ci-3 alkyl), pyridyl, pyridyl(Cμ3 alkyl), phthalimido, phthalimido(Ci-3 alkyl), thienyl, thienyl(Ci-3 alkyl), pyrrolyl, pyrrolyl(C1-3 alkyl), imidazolyl, imidazolyl(Ci-6 alkyl), pyrazolyl, pyrazolyl(Ci-3 alkyl), thiazolyl, thiazolyl(C1-3 alkyl), isothiazolyl, isothiazolyl(Ci-3 alkyl), thiazolylmethyl, isothiazolylmethyl, oxazolyl, OXaZoIyI(Ci-3 alkyl), pyrrolidinyl, pyrrolidinyl(Ci-3 alkyl), pyrrolinyl, pyrrolinyl(Ci-3 alkyl), imidazolidinyl, imidazolidinyl(C1-3 alkyl), imidazolinyl, imidazolinyl(Ci-3 alkyl), imidazolemethyl, dihydroimidazolyl, dihydroimidazolyl(C1-3 alkyl), dihydroimidazolylmethyl, tetrahydropyrimidinyl, tetrahydroρyrimidinyl(C1-3 alkyl), benzimidazolyl, benzimidazolyl(Ci-3 alkyl), tetrahydroisoquinolinyl, tetrahydroisoquinolyl(C1-3 alkyl), pyrazolidinyl, pyrazolidinyl(Ci-3 alkyl), tetrahydro&ranyl, tetrahyrdofuranyl(Ci-3 alkyl), pyranyl, pyranyl(Ci-3 alkyl), pyridonyl, pyridonyl(Ci-3 alkyl), pyronyl, pyronyl(C1-3 alkyl), pyrazinyl, pyrazinyl(C1-3 alkyl), pyridazinyl, pyridazinyl(Ci-3 alkyl), piperidinyl, piperidinyl(Ci-3 alkyl), piperazinyl, piperazinyl(Ci-3 alkyl), morpholinyl, morpholinyl(Ci-3 alkyl), thionaphthyl,
Figure imgf000014_0001
alkyl), benzofuranyl, benzofuranyl(Ci.3 alkyl), isobenzofuryl, isobenzofUryl(Ci-3 alkyl), indolyl, UIdOIyI(C1-3 alkyl), oxyindolyl, OXyUIdOnIyI(C1-3 alkyl), isoindolyl, isoindolyl(Ci_3 alkyl), indazolyl, indazolyl(Ci_3 alkyl), indolinyl, indolinyl(C1-3 alkyl), isoindolinyl, isoindoliny^C^ alkyl), isoindazolyl, isoindazolyl(Ci-3 alkyl), benzopyranyl, benopyranyl(C1-3 alkyl), coumarinyl, coumarinyl(C1-3 alkyl), isocoumarinyl, isocoumarinyl(Ci.3 alkyl), quinolyl, quinolyl(Ci-3 alkyl), isoquinolyl, isoquinolyl(C1-3 alkyl), napthridinyl, naphthridinyl(C1-3 alkyl), cinnolinyl, cinnolinyl(Ci-3 alkyl), quinazolinyl, quinazolinyl(C1-3 alkyl), pyridopyridyl, pyridopyridy^C^ alkyl), benzoxazinyl, benzoxazinyl(Ci_3 alkyl), quinoxadinyl, qumoxadinyl(Ci..3 alkyl), chromenyl, chromeny^Cμs alkyl), chromanyl, chromanyl(Ci-3 alkyl), isochromanyl, isochromanyl(Ci.3 alkyl), carbolinyl, carboliny^Ci-a alkyl), thiophenyl, thiophenyI(C1-3 alkyl), thiazolyl, thiazolinyl(C1-3 alkyl), isoxazolyl, isooxazolyl(C].3 alkyl), isoxazolonyl, isoxazolonyl(Ci.3 alkyl), isothiazolyl, isothiazolyl(Ci.3 alkyl), triazolyl, triazolyl(Ci.3 alkyl), oxadiazolyl, oxadiazolyl(Ci-3 alkyl), thiadiazolyl, thiadiazolyl(C1-3 alkyl), pyridazyl, pyridazyl(C1-3 alkyl), any of which are optionally substituted on the backbone with one or more groups independently selected from =0, COOH, SH, SO2H, P(OH)(O)2, halo, trihalomethyl, OH, NH2, =NH, NH(C1-6 alkyl), =N(Ci-6 alkyl), NO2, CN, OCH3, SO2NH2 and C(O)H, C1-6 alkyl, C2-6 alkoxyalkyl, C7-J0 alkoxyaryl, C3-10 cycloalkyl, C4-15 (cycloalkyl)alkyl, C7-12 aralkyl, C7-12 alkaryl, Ci-12 heteroaryl and C6-I2 aryl, most preferably optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, CH3, OH, OCH3, OCH2CH3 and NH2.
Preferably R10 is selected from the group consisting of pyridyl, pyridyl(C1-3 alkyl), phthalimido, phthalimido(Ci_3 alkyl), pyrrolyl, pyrrolyl(Ci_3 alkyl), imidazolyl,
Figure imgf000014_0002
alkyl), pyrazolyl, pyrazolyl(Ci-3 alkyl), thiazolyl, thiazolyl(Ci-3 alkyl), isothiazolyl, isothiazolyl(Ci-3 alkyl), thiazolylmethyl, isothiazolylmethyl, oxazolyl, oxazolyl(Ci-3 alkyl), pyrrolidinyl, pyrrolidinyl(C1-3 alkyl), pyrrolinyl, pyrrolinyl(Ci-3 alkyl), imidazolidinyl, imidazolidinyl(C1-3 alkyl), imidazolinyl, imidazolinyl(C].3 alkyl), imidazolemethyl, dihydroimidazolyl, dihydroimidazolyl(C1-3 alkyl), dihydroimidazolylmethyl, tetrahydropyrimidinyl, tetrahydroρyrimidinyl(Ci-3 alkyl), benzimidazolyl, benzimidazolyl(C1-3 alkyl), tetrahydroisoquinolinyl, tetrahydroisoquinolyl(C1-3 alkyl), pyrazolidinyl, pyrazolidiny^C^ alkyl), pyridonyl, pyridonyl(C1-3 alkyl), pyrazinyl, pyrazinyl(Ci-3 alkyl), pyridazinyl, pyridazmyl(Ci-3 alkyl), piperidinyl, piperidinyl(C1-3 alkyl), piperazinyl, piperazinyl(Ci-3 alkyl), morpholinyl, morpholinyl(C1-3 alkyl), indolyl, indolyl(Ci-3 alkyl), oxyindolyl, oxyindonlyl(C1-3 alkyl), isoindolyl, isoindolyl(C1-3 alkyl), indazolyl, indazolyl(Ci.3 alkyl), indolinyl, UIdOlUIyI(C1-3 alkyl), isoindolinyl, isoindolinyl(C1-3 alkyl), isoindazolyl, isoindazoly^C^ alkyl), quinolyl, quinolyl(C!_3 alkyl), isoquinolyl, isoquinolyl(Ci-3 alkyl), quinazolinyl,
Figure imgf000015_0001
alkyl), pyridopyridyl, pyridopyridyl(C1-3 alkyl), benzoxazinyl, benzoxazinyl(C1-3 alkyl), quinoxadinyl, quinoxadmyl(C1-3 alkyl), carbolinyl, carbolinyl(C1-3 alkyl), thiophenyl, thiophenyl(Ci_3 alkyl), thiazolyl, thiazolinyl(Ci.3 alkyl), isoxazolyl, isooxazolyl(C1-3 alkyl), isoxazolonyl, isoxazolonyl(C1-3 alkyl), isothiazolyl, isothiazolyl(Ci,3 alkyl), triazolyl, triazolyl(C1-3 alkyl), oxadiazolyl, oxadiazolylCCi.3 alkyl), thiadiazolyl, thiadiazolyl(Ci.3 alkyl), pyridazyl, pyridazyl(C].3 alkyl), any of which are optionally substituted on the backbone with one or more groups independently selected from =0, COOH, SH, SO2H, P(OH)(O)2, halo, trihalomethyl, OH, NH2, =NH, NH(C1-6 alkyl), =N(C1-6 alkyl), NO2, CN, OCH3, SO2NH2 and C(O)H, C1-6 alkyl, C2-6 alkoxyalkyl, C7-10 alkoxyaryl, C3-10 cycloalkyl, C4-1S (cycloalkyl)alkyl, C7-12 aralkyl, C7-I2 alkaryl, Ci-I2 heteroaryl and Ce-I2 aryl, most preferably optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, CH3, OH, OCH3, OCH2CH3 and NH2.
In a particularly preferred embodiment, R10 is a lH-imidazol-2-yl(C1-6 alkyl) group which may be substituted with 1 or more groups independently selected from C1-6 alkyl, halo, haloCμβ alkyl, hydroxyC1-6 alkyl, perhaloC1-6 alkyl, OH, NH2, NO2, CN, COOH, C(O)H, C(O)O(C1-6 alkyl), 0(C1-6 alkyl), OC(O)(C1-6 alkyl) and C(O)(C1-6 alkyl).
In a particularly preferred embodiment, Rϊ0 is a lH-imidazol-2-ylmethyl, lH-imidazol-2-ylethyl or lH-imidazol-2-ylpropyl group. In a particularly preferred embodiment, R10 is a 4,5-dihydro-lH-imidazol-2-ylmethyI, 4,5-dihydro-lH-imidazol-2-ylethyl or 4,5-dihydro-lH-imidazol-2-ylpropyl group.
In a preferred embodiment, R10 represents a natural or synthetic amino acid residue. The amino acid may be an α- or β-amino acid. Particularly preferably, R10 represents the residue of a natural amino acid corresponding to an amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, lysine, arginine, histidine, aspartic acid, glutamic acid, asparagine, glutamine, cysteine and methionine. For the sake of clarity, where R10 represents an amino acid residue corresponding to glycine, NR9R10 has the structure:
Figure imgf000015_0002
In the embodiment where R9 and R10 may be joined to form a 3, 4, 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, 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, morpholinyl.
When R6 comprises the group OR10, preferably m is 0 or 1, most preferably 0.
When R6 comprises the group OR10, preferably R10 is selected from the group consisting of C1-10 heteroaryl, C2-10 heterocyclyl, C3-I0 heteroaralkyl, C3-10 heterocyclylalkyl, C1-6 alkylamino Ci-6 alkyl, di(C].6 alkyl)amino C1-6 alkyl and C1-6 alkyl, any of which are optionally substituted on the backbone with one or more groups, preferably 1, 2 or 3 groups, independently selected from NH2, NH(C1-4 alkyl) or N(C14 alkyl)2.
When R6 comprises the group OR10, preferably R10 is selected from the group consisting of lH-imidazol-2-ylmethyl, lH-imidazol-2-ylethyl, lH-imidazol-2-ylpropyl,
4,5-dihydro-lH-imidazol-2-ylmethyl, 4,5-dihydro-lH-imidazol-2-ylethyl, 4,5-dihydro-lH-imidazol-2-ylpropyl, dimethylaminoethyl, methylaminoethyl, methylaminomethyl, diethylaminoethyl, ethylaminoethyl, diethylaminomethyl, ethylaminomethyl, piperidinylethyl, pyrrolidinylmethyl, morpholinylmethyl, pyrrolidinylethyl, morpholinylethyl, piperidinylmethyl, pyrrolidinylpropyl, morpholinylpropyl and piperidinylpropyl. Preferably each R14 is independently selected from the group consisting of H, C1-Jo alkyl, C2-1O alkenyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, C2-10 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C5-2O cycloalkenyl, C7-2O cycloalkynyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, C1-20 heteroaryl, C2-20 heterocyclyl, C2-20 heteroaralkyl, C3-2O heterocyclylalkyl, Ci-10 aminoalkyl, C6-1O aminoaryl, guanidinyl Ci-6 alkyl, C2-12 alkylguanidinylalkyl, ureayl Ci-6 alkyl and C2-I2 alkylureaylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, OH, OCH3, OCH2CH3 and NH2, or each R14 is joined to one another to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring; and,
Preferably Rls is selected from the group consisting of H, CN, Ci-10 alkyl, C2-10 alkenyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, C2-I0 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C5-20 cycloalkenyl, C7-20 cycloalkynyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, Ci-20 heteroaryl and C2-2O heterocyclyl, C2-20 heteroaralkyl, C3-20 heterocyclylalkyl, C1-10 aminoalkyl, C6-10 aminoaryl, guanidinyl Ci-6 alkyl, C2-I2 alkylguanidinylalkyl, ureayl Ci-6 alkyl and C2-12 alkylureaylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, OH, OCH3, OCH2CH3 and NH2; or R15 and one of R14 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R14 not joined to R15 is H or C1-6 alkyl. Preferably each R14 is independently selected from the group consisting of H and C1-4 alkyl, or R15 and one of R14 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R14 not joined to R15 is selected from the group consisting of H and C1-4 alkyl. Preferably R15 and one of R14 are joined to form a group selected from imidazole, dihydroimidazole, tetrahydropyrimidinyl, benzimidazole and triazole. Preferably each R14 is independently selected from the group consisting of H and methyl.
Preferably R15 and one of R14 are joined to form a group selected from imidazole, dihydroimidazole and tetrahydropyrimidinyl.
With regard to R2, in a particularly preferred embodiment, when n is 1 or more, -(CH2)m-R6 is located in the meta or para position relative to the -(CH2)n- group, most preferably the para position. In a further particularly preferred embodiment, when n is 0, -(CH2)m-R6 is located in the para position relative to the to the N1 atom. Most preferably, n is 0 and R6 is located in the para position relative to the to the N1 atom.
Preferably R6 comprises a guanidinyl moiety. Preferably R6 is a group
Figure imgf000017_0001
where each R14 and R15 are H.
In a preferred embodiment, R2 is selected from the group consisting of (( 1 H-imidazol-2-yl)methylamino)-phenyl, (( 1 H-imidazol-2-yl)ethylamino)-phenyl,
((lH-imidazol-2-yl)propylamino)-phenyl and (4,5-dihydro-lH-imidazol-2-ylamino)-phenyl. In the above groups, preferably the phenyl moiety of the R2 group is substituted with the named substituents in the para position relative to the point of attachment of the R2 group to the rest of the compound of formula (I).
Preferably R3 is independently selected from the group consisting of H, COOH3 COO(Ci-6 alkyl), COO(C6-20 aryl), COO(C7-20 alkaryl), COO(C7-20 aralkyl), C(O)H, C(O)(C1-6 alkyl), C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)2, C(O)NH(C6-15 aryl), C(O)N(C6-15 aryl)2, C(O)NH(C7-15 aralkyl), C(O)N(C7-I5 aralkyl)2, C(O)NH(C7-I5 alkaryl), C(O)N(C7-I5 alkaryl)2 and hydrocarbyl or heterocarbyl groups selected from C1-20 alkyl, C2-20 alkenyl, C1-20 alkoxy, C2-20 alkoxyalkyl, C6-3o aryloxy, C7-30 alkoxyaryl, C2-2O alkynyl, C3-30 cycloalkyL C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, C i .30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl and C3-30 heterocyclylalkyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups, preferably 1, 2, 3 or 4 groups, independently selected from the groups defined in (d), (e) and (f): (d) -CH=CH-, -C≡C-, S, N, -N=, Si(Ci-6 alkyl)2, Si(OH)2, C(O)NH, C(O)N(C1-6 alkyl), C(O)O, N(C1-6 alkyl)C(O)N(C1-6 alkyl), NHC(O)N(C1-6 alkyl), N(C1-6 alkyl)C(O)O, NHC(O)NH, NHC(O)O, NH, N(Cj-6 alkyl), O, CO, SO2, NHSO2 and C(O)NHNH in the backbone;
(e) COOH, COO(C1-6 alkyl), SH, S(Ci-6 alkyl), SO2H, SO3H5 SO2(Ci-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(C1-6 alkyl), OC(O)(C1-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 alkaryl), OC(O)(C7-20 aralkyl), =0, NH2, =NH, NH(C1-6 alkyl), N(C1-6 alkyl)2, =N(C1-6 alkyl), NHC(O)(C1-6 alkyl), C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)2, C(O)NH(C6-15 aryl), C(O)N(C6-15 aryl)2, C(O)NH(C7-15 aralkyl), C(O)N(C7-15 aralkyl)2, C(O)NH(C7-15 alkaryl), C(O)N(C7-15 alkaryl)2, NO2, CN, SO2NH2, C(O)H, C(O)(Cj-6 alkyl) on the backbone; and,
(f) groups independently selected from the group consisting of C1-]O alkyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, C12-20 aryloxyaryl, C7-20 aryloxyalkyl, C1-10 alkoxy, C6-20 aryloxy, C2-J0 alkenyl, C2-10 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl and C6-2O aryl on the backbone. Preferably R3 is not H. Preferably R4 is not H. Preferably R3 is -(CR16R17)m>-X-R18; wherein: m' is O, 1, 2, 3 or 4; X is a bond, -CH=CH-, -C≡C-, S, N, Si(Cj-6 alkyl)2, Si(OH)2, Si(OCj-6 alkyl)2, C(O)NH, C(O)NCj-6 alkyl, C(O)NC6-20 aryl, C(O)NC7-20 aralkyl, C(O)NC7-20 alkaryl, C(O)O, N(Cj-6 alkyl)C(O)N(C1-6 alkyl), NHC(O)N(Cj-6 alkyl), OC(O)N(Cj-6 alkyl), NHC(O)NH, NHC(O)O, NH, N(C1-6 alkyl), O, CO, SO2, SO2NH, NHSO2, and C(O)NHNH; R16 and R17 are independently selected from the group consisting of H, Ci-2O alkyl, C2-20 alkenyl, C2-20 alkoxyalkyl, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, Cs-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-3Q aryl, Ci-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyL Ci-I0 aminoalkyl and C6-20 aminoaryl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from COOH, COO(C1-6 alkyl), SH, S(C1-6 alkyl), SO2H, SO2(Ci-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), P(OH)(O)2, halo, haloCμe alkyl, perhaloCi-6 alkyl, OH, 0(C1-6 alkyl), =0, NH2, =NH, NH(Cj-6 alkyl), N(C1-6 alkyl)2, =N(d-6 alkyl), NHC(O)(C1-6 alkyl), NO2, CN, SO2NH2, C(O)H and C(O)(Ci-6 alkyl), Ci-I0 alkyl, C2-J0 alkoxyalkyl, C7-20 alkoxyaryl, C2-I0 alkynyl, C3-20 cycloalkyl, C4-2Q (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, Ci-20 heteroaryl and C6-20 aryl; or R16 and R17 are joined to form a 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20-membered, saturated, unsaturated or aromatic, heterocyclic or carbocyclic ring; and,
R18 is selected from the group consisting of H, Ci-20 alkyl, C2-20 alkenyl, C2-20 alkoxyalkyl, C7-30 alkoxyaryl, Ci2-30 aryloxyaryl, C2-20 alkynyl, C3-3O cycloalkyl, C4-30 (cycloalkyl)alkyl, Cs-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, Ci-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, Ci-I0 aminoalkyl, C6-20 aminoaryl, guanidine Cj-I0 alkyl, C2-20 alkylguanidinylalkyl, urea C1-10 alkyl and C2-20 alkylureaylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from COOH, COO(C1-6 alkyl), SH,
S(Cj-6 alkyl), SO2H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), P(OH)(O)2, halo, haloCi-6 alkyl, perhaloC1-6 alkyl, OH, 0(C1-6 alkyl), =O, NH2, =NH, NH(Cj-6 alkyl), N(C1-6 alkyl)2, ^N(C1-6 alkyl), NHC(O)(C1-6 alkyl), C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(Ci-6 alkyl)2,
C(O)NH(C6-I2 aryl), C(O)N(C6-I2 aryl)2, C(O)NH(C7-12 aralkyl), C(O)N(C7-12 aralkyl)2, C(O)NH(C7-J2 alkaryl), C(O)N(C7-12 alkaryl)2, NO2, CN, SO2, SO2NH2, C(O)H and C(O)(C1-6 alkyl), C1-10 alkyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, C2-10 alkynyl, C3-20 cycloalkyl, C4-20
(cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C1-20 heteroaryl and C6-20 aryl.
Preferably m' is 0, 1 or 2, more preferably O or 1.
Preferably X is a bond, C(O)NH, C(O)N(C1-6 alkyl) or C(O)N(C6-20 aryl). Preferably R16 and R17 are independently selected from the group consisting of H, Ci-I0 alkyl, C2-20 alkoxyalkyl, C7-20 alkoxyaryl, Ci2-20 aryloxyaryl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, Ci-20 heteroaryl, C2-20 heterocyclyl, C2-20 heteroaralkyl and C3-20 heterocyclylalkyl. Preferably R18 is selected from the group consisting of H, C]-I0 alkyl, C2-io alkoxyalkyl, C7-20 alkoxyaryl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, Ci-20 heteroaryl, C2-20 heterocyclyl, C2-20 heteroaralkyl and C3-2O heterocyclylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2 or 3 groups, independently selected from =0, COOH, SH, SO2H, P(OH)(O)2, halo, trihalomethyl, OH, NH2, =NH, NH(Ci-6 alkyl), =N(d-6 alkyl), NO2, CN, OCH3, SO2NH2 and C(O)H, Ci_6 alkyl, C2-6 alkoxyalkyl, C7-I0 alkoxyaryl, C3-I0 cycloalkyl, C4-I5 (cycloalkyl)alkyl, C7-12 aralkyl, C7-I2 alkaryl, Ci-I2 heteroaryl and C6-I2 aryl.
Preferably, R16 and R17 are joined to form a 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14-membered, saturated, unsaturated or aromatic ring. The ring may be a heterocyclic or heteroaromatic ring. Preferably, the ring formed by R16 and R17 is a cycloalkyl, heterocyclyl or heteroaromatic group. Preferably, the ring is a C6-I0 cycloalkyl, C4-J0 heterocyclyl or Ci-]0 heteroaryl group.
In a particularly preferred embodiment, m' is O5 X is a bond and R18 is a C5-I2 cycloalkyl group. In another preferred embodiment, X is a bond, C(O)NH or C(O)N(Ci-6 alkyl). In another preferred embodiment, X is a bond, R16 and R17 are both H, m' is O or 1 and R18 is selected from the group consisting of C1-10 alkyl, C2-20 alkoxyalkyl, C7-20 alkoxyaryl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, Ci-20 heteroaryl, C2-20 heterocyclyl, C2-20 heteroaralkyl and C4-20 heterocyclylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2 or 3 groups, independently selected from =0, COOH5 SH, SO2H, P(OH)(O)2, halo, trihalomethyl, OH, NH2, =NH, NH(Ci-6 alkyl), =N(CW alkyl), NO2, CN, OCH3, SO2NH2 and C(O)H.
Preferably X is C(O)NH, R16 and R17 are both H, m' is O or 1 and R18 is selected from the group consisting of Ci-I0 alkyl, C2-20 alkoxyalkyl, C7-20 alkoxyaryl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, Ci-20 heteroaryl, C2-20 heterocyclyl, C2-20 heteroaralkyl and C3-20 heterocyclylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2 or 3 groups, independently selected from =0, COOH, halo, trihalomethyl, OH, NH2, NO2, CN, OCH3, Ci-6 alkyl, C2-6 alkoxyalkyl, C3-I0 cycloalkyl, C4-I5 (cycloalkyl)alkyl, C7-12 aralkyl, C7-I2 alkaryl and C6-I2 aryl.
Preferably R18 is selected from the group consisting of methyl, ethyl, propyl, butyl, phenyl, benzyl, biphenyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, quinolinyl, naphthyl, tetramethylcyclohexyl, benzocycloheptyl, benzodioxepinyl, bicyclooctyl, tetrahydropyranyl, dihydropyranyl, tetramethyltetrahydropyranyl, cyclohexylmethyL, phenylethylbenzyl, phenoxybenzyl, phenylethynylbenzyl, cyclohexylbenzyl, pyranyl, tolyl, ethylbenzyl, xylyl isopropylbenzyl, cyclohexylmethyl, methoxyphenyl, diphenylmethyl, phenethyl, pyridylmethyl, butylphenyl, binaphthyl, adamantyl, propylbenzyl, mesitylyl, ethyltolyl, butylbenzyl, indanyl, diethylbenzyl, methylindanyl, dimethylethylbenzyl, phenylpentyl, tetramethylbenzyl, phenylhexyl, dipropylbenzyl, triethylbenzyl, tetrahydronaphthyl, cyclohexylbenzyl, methylnaphthyl, naphthylmethyl, methyltetrahydronaphthyl, ethylnaphthyl, dimethylnaphthyl, diphenylethyl, diphenylmethyl, propylnaphthyl, butylnaphthyl, phenanthryl, fluoryl, stilbyl, methylfluoryl, benzphenanthryl, triphenylmethyl, acenaphthyl, azulenyl, phenylnaphthyl, methylchrysyl, benzfluoryl, pyrenyl, hexamethylbenzyl, perylenyl, picenyl, dihydroisoxazolyl, furanyl, pyridyl, phthalimido, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofUranyl, pyranyl, pyronyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, moφholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, carbolinyl, thiophenyl, thiazolyl, isoxazolyl, isoxazolonyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridazyl, tetrahydrobenzoannulenyl, phenylcyclohexyl, benzoylpiperidinyl, benzylpiperidinyl, cyclopropylmethyl and tetrahydrothiopyranyl, any of which are optionally substituted with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from =0, COOH, SH, SO2H, P(OH)(O)2, halo, trihalomethyl, OH, NH2, =NH, NH(d.6 alkyl), =N(C1-6 alkyl), NO2, CN, OCH3, SO2, SO2NH2 and C(O)H, Ci-6 alkyl, C2-6 alkoxyalkyl, C7-10 alkoxyaryl, C3-10 cycloalkyl, C4-1S (cycloalkyFjalkyl, C7-12 aralkyl, C7-12 alkaryl, Ci-12 heteroaryl and Cn-I2 aryl.
In a particularly preferred embodiment, R3 comprises a benzyl group, optionally substituted with 1, 2 or 3 groups, independently selected from COO(C1-6 alkyl), COO(C6-2o aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), halo, trihalomethyl, OH, NH2, 0(C1-6 alkyl), 0(C6-20 aryl), 0(C7-20 aralkyl), 0(C7-20 alkaryl), Ci-6 alkyl, C6-I2 aryl, C7-I2 aralkyl, C7-I2 alkaryl, C8-12 aralkynyl, C6-12 aryloxy, Ci-12 heteroaryl, C5-I2 cycloalkyl and C(O)(C1-6 alkyl) on the backbone.
In a particularly preferred embodiment, R3 comprises a cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, quinolinyl, tetrahydropyranyl, naphthyl, benzocycloheptyl, or benzodioxepinyl group, optionally substituted with 1, 2, 3 or 4 groups independently selected from COO(Ci-6 alkyl), halo, trihalomethyl, OH, NH2, 0(C1-6 alkyl), C]-6 alkyl, C6-I2 aryl, C7-12 aralkyl, C7-I2 alkaryl, C6-I2 aryloxy, Ci-I2 heteroaryl, C5-I2 cycloalkyl and C(O)(C1-6 alkyl) on the backbone.
Preferably R1, R4 and R5 are independently selected from the group consisting of H, COOH,
COO(C1-6 alkyl), CN, SH, S(C1-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(C1-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(C1-6 alkyl), NH2, NH(C1-6 alkyl), N(Ci-6 alkyl)2, NHC(O)(C1-6 alkyl), NO2, CN, SO2NH2, C(O)H and C(O)(Ci-6 alkyl), and hydrocarbyl or heterocarbyl groups selected from Ci-20 alkyl, C2-20 alkenyl, C1-20 alkoxy, C2-20 alkoxyalkyl, C6-3O aryloxy, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, Cs-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-3O aryl, C1-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl and C2-30 heterocyclylalkyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups independently selected from the groups defined in (a), (b) and (c):
(a) -CH=CH-, -C≡C-, S, -N=, Si(C1-6 alkyl)2, Si(OH)2, C(O)NH, C(O)N(C1-6 alkyl), C(O)O, N(C1-6 alkyl)C(O)N(Ci-6 alkyl), NHC(O)N(Ci-6 alkyl), N(Ci-6 alkyl)C(O)O, NHC(O)NH,
NHC(O)O, NH, N(Ci-6 alkyl), O, CO, SO2, NHSO2 and C(O)NHNH in the backbone;
(b) COOH, COO(C1-6 alkyl), SH, S(C1-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(Ci-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(Ci-6 alkyl), 0(C6-20 aryl), 0(C7-20 alkaryl), 0(C7-20 aralkyl), =O, NH2, =NH, NH(Cj-6 alkyl), N(C1-6 alkyl)2, =N(C1-6 alkyl), NHC(O)(C1-6 alkyl), NO2, CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(C1-6 alkyl)2, C(O)H and C(O)(C1-6 alkyl) on the backbone; and,
(c) groups independently selected from the group consisting of C1-I0 alkyl, C2-I0 alkoxyalkyl, C7-20 alkoxyaryl, C12-20 aryloxyaryl, C7-20 aryloxyalkyl, Ci-10 alkoxy, C6-20 aryloxy, C2-io alkenyl, C2-10 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl and C6-20 aryl on the backbone.
When R1 is joined to R5, R5a or Rla to form a ring, or when R5 is joined to R5a or Rla to form a ring, preferably it is a 5, 6 or 7-membered ring which is optionally substituted with 1, 2 or 3 of the groups independently selected from the groups defined in (b) and (c) above. Preferably, none of R1, Rla, R5 or R5a are joined to one another to form a ring.
Preferably, R5a, R5, R1 and Rla are in the 6, 7, 8 and 9 positions respectively of the compound of formula (I). Preferably, where any of R5a, R5, R1 and Rla are linked with one another to form a ring, adjacently positioned groups are linked, rather than remotely positioned groups. For example, R5aand R5 are preferably joined to one another when they are in the 6 and 7 position respectively.
Preferably R1 and R5 are independently selected from the group consisting of H, COOH, SH, SO2H, P(OH)(O)2, F, Cl, Br, I, OH, NH2, NO2, CN, SO2NH2, C(O)H, and hydrocarbyl or heterocarbyl groups selected from Ci-6 alkyl, Ci-6 alkoxy, C2-6 alkoxyalkyl, C7-20 alkoxyaryl, C3-20 cycloalkyl, C4-2O (cycloalkyl)alkyl, C7-2O aralkyl, C7-2O alkaryl, C6-2O aryl, C1-2O heteroaryl and C2-2O heterocyclyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups, preferably 1, 2, 3 or 4 groups, independently selected from the groups defined in (a), (b) and (c): (a) C(O)NH, C(O)NMe, C(O)O, NHC(O)NH, NHC(O)O, NH, O, CO, SO2, NHSO2, and C(O)NHNH in the backbone;
(b) =O, COOH, SH, SO2H, SO3H, P(OH)(O)2, F, Cl, Br, I, OH, NH2, =NH, NH(C1-6 alkyl), =N(C w alkyl), NO2, CN, SO2NH2, and C(O)H on the backbone; and,
(c) groups independently selected from the group consisting of C 1.6 alkyl, C2-6 alkoxyalkyl, C7-I0 alkoxyaryl, C3-1O cycloalkyl, C4-12 (cycloalkyl)alkyl, C7-12 aralkyl, C7-12 alkaryl, C1-12 heteroaryl and C6-12 aryl on the backbone.
Preferably R1 and R5 are independently selected from the group consisting of C1-4 alkyl, C5-8 cycloalkyl, Ci-4 alkoxy, Cj-4 alkylcarbonylamino, C1-4 alkylaminocarbonyl, C3-1O cycloalkylcarbonylamino, C3-1O cycloalkylaniinocarbonyl, C2-I0 heterocyclylcarbonylamino, C2-1O heterocyclylaminocarbonyl, C6-1O arylcarbonylamino, C6-1O arylaminocarbonyl, C1-1O heteroarylcarbonylamino, C1-Io heteroarylaminocarbonyl, C1-6 alkylamino, di (C1-4 alkyl)amino, C7-1O aralkyl, C7-1O alkaryl, C6-1O aryl, Ci-1O heteroaryl and C2-10 heterocyclyl, any of which are optionally substituted with one or more groups, preferably 1, 2 or 3 groups, independently selected from =0, COOH, F, Cl, Br, I, OH, NH2, NH(C1-6 alkyl), NO2, CN and C(O)H; H, F, Cl, Br, COOH, SH, SO2H, P(OH)(O)2, OH, NH2, NO2, CN, SO3H, SO2NH2 and C(O)H.
Preferably R1 and R5 are independently selected from the group consisting of H, F, Cl, Br, C1-4 alkyl, C(O)Ci-6 alkyl, C5-g cycloalkyl, C1-4 alkoxy, dimethylamino, tolyl, xylyl, pyridyl, pyridinyl, furanyl, hydroxyphenyl, phenylamino, acetamido, oxopyrrolidinyl, dibenzylamido, piperidinylcarbonyl, benzylamido, benzylamino, OH, NH2 and N(CH3)2. Preferably R1 is H and R5 is selected from the group consisting of H, F, Cl, Br, methyl, tolyl, xylyl, pyridinyl, pyridiyl, furanyl, hydroxyphenyl, phenylamino, acetamido, oxopyrrolidinyl, dibenzylamido, piperidinylcarbonyl, benzylamido, benzylamino, OH, NH2 and N(CH3)2.
In a particularly preferred embodiment, R5 and R1 are both H.
Preferably, R1 and R5 are located in the 8 and 7 positions respectively of the compound of formula (I).
In an alternative particularly preferred embodiment, R1 is a methyl group located in the 8-position of the compound of formula (I) as indicated herein. Preferably R4 is selected from the group consisting of H, hydrocarbyl or heterocarbyl groups selected from Ci-1O alkyl, C2-10 alkoxyalkyl, Ci2-2O aryloxyaryl, C7-20 aryloxyalkyl, Ci-I0 alkoxy, C7-2O alkoxyaryl, C4-2O alkoxycycloalkyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, Ci-20 heteroaryl, C2-20 heteroaralkyl and C2-20 heterocyclyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups, preferably 1, 2 or 3 groups, independently selected from the groups defined in (a), (b) and (c):
(a) S, C(O)NH, C(O)NMe, C(O)O, NHC(O)NH, NHC(O)O, NH, N, O, CO, SO2, SO2NH, NHSO2 and C(O)NHNH in the backbone; (b) =O, COOH, SH, SO2H, P(OH)(O)2, F, Cl, Br5 1, OH, NH2, =NH, NH(C1-6 alkyl), =N(Ci-6 alkyl), NO2, CN, SO3H, SO2NH2, C(O)(CL6 alkyl) and C(O)H on the backbone; and,
(c) groups independently selected from the group consisting of Ci-6 alkyl, C2-6 alkoxyalkyl, C7-Io alkoxyaryl, C3-I0 cycloalkyl, C4-I2 (cycloalkyl)alkyl, C7-I2 aralkyl, C7-I2 alkaryl and C6-I2 aryl on the backbone. Preferably R4 is selected from the group consisting of Ci-6 alkyl, C2-6 alkoxyalkyl, C12-20 aryloxyaryl, C7-I2 aryloxyalkyl, C1-I0 alkoxy, C7-I2 alkoxyaryl, C5-I2 alkoxycycloalkyl, C3-I2 cycloalkyl, C4-12 (cycloalkyl)alkyl, C7-I2 aralkyl, C7-I2 alkaryl, C6-I2 aryl, CM2 heteroaryl, C2-I2 heteroaralkyl and C2-I2 heterocyclyl, any of which is optionally substituted with one or more of the groups, preferably 1, 2 or 3 groups, independently selected from the groups defined in (a), (b) and (c):
(a) S, C(O)NH, NHC(O), C(O)NMe, NMeC(O), C(O)O, NHC(O)NH5 NHC(O)O, OC(O)NH, NH5 O, CO, SO2, SO2NH, NHSO2, and C(O)NHNH in the backbone;
(b) COOH, SH, SO2H, P(OH)(O)2, F, Cl5 Br, I, OH, NH2, =NH, NH(C1-6 alkyl), =N(Ci-6 alkyl), NO2, CN, SO3H5 SO2NH2, C(O)(Ci-6 alkyl), C(O)(Ci-6 aminoalkyl), C(O)NH2, and C(O)H on the backbone;
(c) groups independently selected from the group consisting of Ci-4 alkyl, Ci-4 alkoxy, C2-4 alkoxyalkyl, C7-I0 alkoxyaryl, C5-I0 cycloalkyl, C4-J0 (cycloalkyl)alkyl, C7-I0 aralkyl, C7-I0 alkaryl, C1-I2 heteroaryl and C6-10 aryl on the backbone.
Preferably R4 is selected from the group consisting of Ci-6 alkyl, C3-I2 cycloalkyl, C6-I2 aryl, C1-I2 heteroaryl, C2-12 heterocyclyl, C2-6 alkoxyalkyl, C5-I2 alkoxycycloalkyl, C2-10 alkylthioalkyl, C4-I2 alkylthiocycloalkyl, C2-I0 alkylsulfonylalkyl, C6-I2 alkylsulfonylcycloalkyl and C6-I2 alkylaminocycloalkyl. Preferably R4 is selected from the group consisting of methyl, cyclohexyl, phenyl, isopropyl, fluorophenyl, cyclohexylmethyl, adamantyl, pyranyl, tetrahydropyranyl, piperidinylmethyl, cyclohexylsulfanylmethyl, cyclohexanesulfonylmethyl, phenoxymethyl, cyclohexylphenoxymethyl, methoxyphenoxymethyl, naphthalenyloxymethyl, ethanoylphenoxymethoxy, aminoacetylaminophenoxymethyl, cyanophenoxymethyl, acetylaminophenoxymethyl, cyclohexylidenemethyl and aminoacetylphenoxymethyl.
In a particularly preferred embodiment, R4 is a cyclohexyl group.
Preferably, Rla and R5a are independently selected from H, CH3, F, Cl, Br and OH. Most preferably, both Rla and R5a are H. Preferably, Rla and R5a are located in the 9 and 6 positions respectively of the compound of formula (I).
Where the benzo moiety of the benzotriazepinone ring system is substituted in the benzo ring by a nitrogen atom, the substitution may be in any of the positions designated 6, 7, 8 or 9 in formula (I). Preferably, the nitrogen atom is unsubstituted. In one embodiment, the benzo moiety of the benzotriazepinone ring system is unsubstituted in or on the benzo ring.
Certain compounds of the invention exist in various regioisomeric, enantiomeric, tautomeric and diastereomeric forms. It will be understood that the invention comprehends the different regioisomers, enantiomers, tautomers and diastereomers in isolation from each other as well as mixtures.
Compounds of the present invention are optionally prepared by the representative procedures shown in reaction schemes 1-7, or the general methods disclosed in WO-A-03/041714, or combinations thereof.
2-Amino phenyl ketones (III) are either obtained commercially, or prepared by Lewis acid-mediated reaction of an appropriate aniline (P) with a suitable nitrile (R4CN) (Sugasawa, T. et al, J. Am. Chem. Soc, (1978), 100, 4842). (Reaction Scheme 1). Alternatively, they may be obtained by reaction of an appropriate 2-amino-benzonitrile (II) with a Grignard reagent (R4MgCl) or alkyl lithium (R4Li). In the following schemes, Rla and R5a are not shown in the interests of simplicity and clarity. Reaction Scheme 1 (")
Figure imgf000026_0001
(I1)
Figure imgf000026_0002
1,3,4-benzotriazepinones (V) are prepared by treatment of a suitable 2-araino phenyl ketone (III), with a suitable bifunctional carbonyl reagent, such as phosgene, trichloromethyl chloroformate or bis(trichloromethyl) carbonate and a suitable hydrazine, NH2NHP (wherein P represents either a protecting group, R3 or a suitable precursor R3' thereof). Alternatively, thiophosgene may be used in place of a suitable bifunctional carbonyl reagent to afford a l,3,4-benzotriazpin-2-thione (IV), followed by basic peroxide-mediated oxidation to obtain the 1,3,4-benzotriazepinone (V) (Reaction Scheme 2).
Reaction Scheme 2
Figure imgf000026_0003
1,3,4-benzotriazepinones (V) may also be obtained by initial activation of a suitable 2-amino phenyl ketone (III) with a suitable bifunctional carbonyl reagent, such as /?αrα-nitrobenzyl chloroformate, bis(trichloromethyl) carbonate or l,r-carbonyldiimidazole, followed by treatment with a suitable urethane-protected hydrazine, PTNKNHR3' (wherein P' represents a urethane protecting group and R3' represents R3 or a suitable precursor thereof) to form a substituted semicarbazide derivative (VI) as an intermediate (Reaction Scheme 3). Removal of the urethane protecting group P', results in concomitant ring closure to form the 1,3,4-benzotriazepinones (V).
Reaction Scheme 3
Figure imgf000027_0001
When R4 is a methyl substituent, the 1,3,4-benzotriazepine (V) may also be obtained by starting from a suitable 2-iodo aniline (VII) (Reaction scheme 4). Sonogashira reaction (Tykwinski, R. R. Angew. Int. Ed. (2003), 42, 1566) affords the corresponding acetylide derivative (VIII) which, on reaction with a suitable bifunctional carbonyl reagent and a suitable urethane-protected hydrazine, P'NHNHR3, affords the semicarbazide intermediate (IX). Mercuric oxide-mediated oxidation yields the required ketone precursor (VI), suitable for conversion to the 1,3,4-benzotriazepine (V) according to the method outlined in reaction scheme 3.
Reaction Scheme 4
Figure imgf000027_0002
N-I substituted benzotriazepines (X) are obtained from (V) by base catalysed alkylation using sodium hydride and a suitable alkyl halide, R2Br or R2F, (wherein R2 represents a suitable precursor of R2) (Reaction scheme 5). Alternatively arylation may be achieved by copper-mediated arylation reaction with a suitable aryl iodide R2I.
Reaction Scheme 5
Figure imgf000027_0003
(V) (X) Certain compounds of the invention in which the R4 substituent is modified are obtained by bromination of (X), wherein R4 is a methyl substituent, using bromine in acetic acid. The corresponding bromide (XI) can then be displaced by a suitable nucleophile (Nu), affording 1,3,4-benzotriazepinones (XII) containing modification in the R4 substituent (Reaction scheme 6).
Reaction scheme 6
Figure imgf000028_0001
Modification of R2 and/or R3' groups affords the desired benzotriazepinones (XIII) (Reaction scheme 7). Reaction scheme 7
Figure imgf000028_0002
R2 groups which are suitable precursors of R2, will depend on the particular nature of R2. A suitable precursor of R2 is
Figure imgf000028_0003
wherein R6' is a suitable precursor of R6. R6' groups which are suitable precursors of R6, will depend on the particular nature of R6. Suitable R6' substituents include NO2, which can be reduced by tin (II) chloride to the corresponding aniline. The aniline substituent can be further modified to the required R6 group by, amongst others, acylation with amino acid derivatives, reductive amination with an appropriate aldehyde, or guanylation with a suitable guanylating agent. Other suitable R6 substituents include esters that can be converted to amide derivatives via the corresponding carboxylic acid. Other suitable R6' substituents include aldehydes that can be converted to ethers via the corresponding alcohols.
R3' substituents which are suitable precursors of R3 will depend on the particular nature of R3. When P represents R3' these can obtained directly by treatment of (III) using the appropriate substituted hydrazine, or indirectly when P represents a protecting group, such as 4-methoxybenzyl or fert-butyloxycarbonyl, by first removal of the protecting group with trifluoroacetic acid or hydrochloric acid, followed by base catalysed reaction using sodium hydride and R3'Br.
Hence, the present invention also provides a method of making compounds according to formula (I).
Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I), substantially as described herein before, with a pharmaceutically acceptable diluent or carrier.
Yet another aspect of the present invention is a method of making a pharmaceutical composition comprising a compound of formula (I) substantially as described herein before, comprising mixing said compound with a pharmaceutically acceptable diluent or carrier.
The present invention provides a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described herein before, for use in therapy.
Some diseases that may be treated according to the present invention include, cardiovascular diseases, disorders of the peripheral and central nervous system, inflammation, urological diseases, developmental disorders, cancer, metabolic diseases, endocrinological diseases and disorders of the gastroenterology system in a mammal.
The present invention provides a method for the treatment of a disease mediated by PTH-I receptors, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described herein before.
In particular, the present invention provides a method for the prophylaxis or treatment of cancer, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described herein before.
In particular, the present invention provides a method for the prophylaxis or treatment of osteoporosis, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described herein before. In particular, the present invention provides a method for the prophylaxis or treatment of an inflammatory disease, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described herein before.
In particular, the present invention provides a method for the prophylaxis or treatment of an autoimmune disease, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described herein before.
In particular, the present invention provides a method for the prophylaxis or treatment of metastases, particularly bone metastases, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described herein before. In particular, the present invention provides a method for the treatment of lack of hair eruption, by administration to a subject of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described herein before.
Specific diseases that may be treated or prevented according to the present invention include osteoporosis, anaemia, renal impairment, ulcers, myopathy, neuropathy, hypercalcemia, hyperparathyroidism, parathyroid gland adenoma, parathyroid gland hyperplasia, parathyroid gland carcinoma, squamous carcinoma, renal carcinoma, breast carcinoma, prostate carcinoma, lung carcinomas, osteosarcomas, clear cell renal carcinoma, prostate cancer, lung cancer, breast cancer, gastric cancer, ovarian cancer, bladder cancer, bone fracture, severe bone pain, spinal cord compression, cachexia, malnutrition, muscle wasting, net protein loss, arthritis, rheumatoid arthritis, diabetes, congestive heart failure and wound healing.
The present invention also provides the use of a compound of formula (I), or a salt, solvate or pro-drug thereof, substantially as described herein before, in the manufacture of a medicament for the prophylaxis or treatment of any of the diseases described herein before.
The compounds of the present invention may also be present in the form of pharmaceutical acceptable salts. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." FDA approved pharmaceutical acceptable salt forms (International J. Pharm. 1986, 33,201-217; J. Pharm. Sci., 1977, Jan, 66 (1), pi) include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
Pharmaceutically acceptable salts of the acidic or basic compounds of the invention can of course be made by conventional procedures, such as by reacting the free base or acid with at least a stoichiometric amount of the desired salt-forming acid or base.
Pharmaceutically acceptable salts of the acidic compounds of the invention include salts with inorganic cations such as sodium, potassium, calcium, magnesium, zinc, and ammonium, and salts with organic bases. Suitable organic bases include N-methyl-D-glucamine, arginine, benzathine, diolamine, olamine, procaine and tromethamine.
Pharmaceutically acceptable salts of the basic compounds of the invention include salts derived from organic or inorganic acids. Suitable anions include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, pamoate, phosphate, polygalacturonate, stearate, succinate, sulfate, subsalicylate, 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", Drug Delivery Systems, 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 (T) having an acid group which is esterified or amidated. Included in such esterified acid groups are groups of the form -COORa, wherein Ra is C1^ alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, or one of the following:
Figure imgf000031_0001
Amidated acid groups include groups of the formula -CONRbRc, wherein Rb is H, C1-5 alkyl, phenyl, substituted phenyl, benzyl, or substituted benzyl, and Rc is -OH or one of the groups just recited for Rb.
Compounds of formula (I) having an amino group may be derivatised with a ketone or an aldehyde such as formaldehyde to form a Mannich base. This will hydrolyse with first order kinetics in aqueous solution. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject. Pharmaceutically acceptable ester derivatives in which one or more free hydroxy groups are esterified in the form of a pharmaceutically acceptable ester are particularly pro-drug esters that may be convertible by solvolysis under physiological conditions to the compounds of the present invention having free hydroxy groups.
It is anticipated that the compounds of the invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration, and inhalation.
For oral administration, the compounds of the invention will generally be provided in the form of tablets or capsules or as an aqueous solution or suspension.
Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate and lactose.
Corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatine. The lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
Capsules for oral use include hard gelatine capsules in which the active ingredient is mixed with a solid diluent and soft gelatine capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil. For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
Effective doses of the compounds of the present invention may be ascertained be conventional methods. The specific dosage level required for any particular patient will depend on a number of factors, including severity of the condition being treated, the route of administration and the weight of the patient. In general, however, it is anticipated that the daily dose (whether administered as a single dose or as divided doses) will be in the range 0.001 to 5000 mg per day, more usually from 1 to 1000 mg per day, and most usually from 10 to 200 mg per day. Expressed as dosage per unit body weight, a typical dose will be expected to be between 0.01 μg/kg and 50 mg/kg, especially between 10 μg/kg and 10 mg/kg, between 100 μg/kg and 2 mg/kg.
Where reference is made to dialkyl groups [e.g. N(C1-6 alkyl)2], it is understood that the two alkyl groups may be the same or different.
Formulaic representation of apparent orientation of a group within the backbone is not necessarily intended to represent actual orientation. Thus, a divalent amide group represented as C(O)NH is also intended to cover NHC(O).
In the interests of simplicity, terms which are normally used to refer to monovalent groups (such as "alkyl" or "phenyl") are also used herein to refer to divalent bridging groups which are formed from the corresponding monovalent group by the loss of one hydrogen atom. Whether such a term refers to a monovalent group or to a divalent group will be clear from the context. For example, when R3 is -(CR16R17)m-X-R18, it is clear that X must be a divalent group. Thus, when X is defined as NC1-6 alkylC(O), for example, this refers to a divalent group having the structure:
Chalky I
O Where a divalent bridging group is formed from a cyclic moiety, the linking bonds may be on any suitable ring atom, subject to the normal rules of valency.
Where any particular moiety is substituted, for example a pyrrolyl group comprising a substituent on the heteroaryl ring, unless specified otherwise, the term "substituted on the backbone" contemplates all possible isomeric forms. For example, pyrrolyl substituted on the backbone includes all of the following permutations:
Figure imgf000034_0001
Figure imgf000034_0002
where one of the bonds shown is to the rest of the molecule or another moiety, and the other bond is to the defined substituent. This applies correspondingly to groups having a plurality of substituents. The term "halogen" or "halo" is used herein to refer to any of fluorine, chlorine, bromine and iodine. Most usually, however, halogen substituents in the compounds of the invention are chlorine, bromine and fluorine substituents. Groups such as 1IaIo(C1-6 alkyl) includes mono-, di- or tri-halo substituted Cj-O alkyl groups. Moreover, the halo substitution may be at any position in the alkyl chain. "Perhalo" means completely halogenated, e.g., trihalomethyl and pentachloroethyl.
The terms "comprising" and "comprises" means "including" as well as "consisting" e.g. a composition "comprising" X may consist exclusively of X or may include something additional e.g. X + Y.
The word "substantially" does not exclude "completely" e.g. a composition which is "substantially free" from Y may be completely free from Y. Where necessary, the word "substantially" may be omitted from the definition of the invention.
"Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. "May" means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form or individual enantiomers may be prepared by standard techniques known to those skilled in the art, for example, by enantiospecific synthesis or resolution, formation of diastereomeric pairs by salt formation with an optically active acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
The term "solvate" means a compound of as defined herein, or a pharmaceutically acceptable salt of a compound of structure (I), wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a hydrate.
As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds. In one preferred embodiment, preferably the groups R1, R3, R4, Rs, R7, R8, R14, R15, R16, R17 and R18 are unsubstituted, in or on the backbone.
In one preferred embodiment, preferably the group R1 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
In one preferred embodiment, preferably the group R3 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 3 or 4, more preferably by 1 substituent, as defined herein.
In one preferred embodiment, preferably the group R4 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein. In one preferred embodiment, preferably the group R5 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
In one preferred embodiment, preferably the group R7 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein. In one preferred embodiment, preferably the group R8 is substituted, in or on the backbone, by 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
In one preferred embodiment, preferably the group R14 is substituted, in or on the backbone, by I5 2, 3 or 4 preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
In one preferred embodiment, preferably the group R15 is substituted, in or on the backbone, by 1, 2, 3 or 4 preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
In one preferred embodiment, preferably the group R16 is substituted, in or on the backbone, by I5 2, 3 or 4 preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
In one preferred embodiment, preferably the group R17 is substituted, in or on the backbone, by 1, 2, 3 or 4 preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein. In one preferred embodiment, preferably the group R18 is substituted, in or on the backbone, by 1, 2, 3 or 4 preferably 1, 2 or 3, more preferably by 1 substituent, as defined herein.
Reference to the "backbone" preferably means the carbon backbone of the group being referred to. However, the term "backbone" includes the possibility for substitution on a heteroatom, such as nitrogen, which is located in the carbon backbone. As used herein, the term "in the backbone" when referring to a substitution, means that the backbone is interrupted by one or more of the groups indicated. Where more than one substitution occurs, they may be adjacent to one another or remote, i.e., separated by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more carbon atoms.
Furthermore, "in the backbone" comprehends a substitution that may be adjacent or remote to the point of attachment of the group being substituted to the rest of the molecule. It also comprehends the group being the point of attachment to the rest of the molecule. For the sake of clarity, both "ethylaminocarbonyl" and "methylaminocarbonylbutyl" fall under the scope of the definition "Ci-β alkyl group substituted with an NHC(O) group". In the former, the
NHC(O) group links the ethyl group to the rest of the molecule. In the latter, the NHC(O) group interrupts the carbon chain, and the butyl moiety links the methylaminocarbonyl moiety to the rest of the molecule. As used herein, the term "on the backbone" when referring to a substitution, means that one or more hydrogen atoms on the backbone is replaced by one or more of the groups indicated. Where more than one substitution occurs, they may be on the same, adjacent or remote carbon atoms, i.e., located on carbon atoms that are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more carbon atoms apart.
Where a group comprises two or more moieties defined by a single carbon atom number, for example, C2-20 alkoxyalkyl, the carbon atom number indicates the total number of carbon atoms in the group.
As used herein, the term "heteroatom" includes N, O, S, P, Si and halogen (including F, Cl, Br and I).
As used herein, the term "hydrocarbyl group" refers to a monovalent hydrocarbon radical, having the number of carbon atoms as indicated, which contains a carbon backbone comprising one or more hydrogen atoms. The term "hydrocarbyl group" is intended to cover alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, cycloalkynyl, aralkyl, alkaryl, aryl, all of which are further defined herein. This list is non-exhaustive, and the skilled person will readily understand other groups and combinations of the above-mentioned groups fall under the scope of the term "hydrocarbyl group".
As used herein, the term "heterocarbyl group" refers to a monovalent hydrocarbon radical, having the number of carbon atoms as indicated, which contains a carbon backbone comprising one or more heteroatoms in or on the carbon backbone, and optionally containing one or more hydrogen atoms. The term "heterocarbyl group" is intended to cover alkoxyalkyl, alkoxyaryl, heteroaryl, heterocyclyl, heteroaralkyl, heterocyclylalkyl, aryloxyalkyl, alkoxy, cycloalkyloxy, aryloxy, alkylamino, cycloalkylamino, arylamino, alkylaminoalkyl, aralkylamino, alkarylatnino, aminoalkyl, aminoaryl, aminoaralkyl, aminoalkaryl, guanidinyl, guanidinylalkyl, alkylguanidinyl, alkylguanidinylalkyl, ureayl, ureaylalkyl, alkylureayl and alkylureaylalkyl, all of which are further defined herein. This list is non-exhaustive, and the skilled person will readily understand other groups and combinations of the above-mentioned groups fall under the scope of the term "heterocarbyl group".
As used herein, the term "alkyl" refers to a straight or branched saturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated. By way of non-limiting example, suitable alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, dodecyl and eicosyl.
As used herein, the term "alkenyl" refers to a straight or branched unsaturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated, and the distinguishing feature of a carbon-carbon double bond. By way of non-limiting example, suitable alkenyl groups include ethenyl, propenyl, butenyl, penentyl, hexenyl, octenyl, nonenyl, dodecenyl and eicosenyl, wherein the double bond may be located any where in the carbon backbone.
As used herein, the term "alkynyl" refers to a straight or branched unsaturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated, and the distinguishing feature of a carbon-carbon triple bond. By way of non-limiting example, suitable alkynyl groups include ethynyl, propynyl, butynyl, penynyl, hexynyl, octynyl, nonynyl, dodycenyl and eicosynyl, wherein the triple bond may be located any where in the carbon backbone.
As used herein, the term "cycloalkyl" refers to a cyclic saturated monovalent hydrocarbon radical, having the number of carbon atoms as indicated. By way of non-limiting example, suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl, trimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, spiroundecyl, bicyclooctyl and adamantyl.
As used herein, the term "(cycloalkyl)alkyl" refers to an alkyl group with a cycloalkyl substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated. By way of non-limiting example, suitable (cycloalkyl)alkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, methylcyclohexylmethyl, dimethylcyclohexylmethyl, trimethylcyclohexylmethyl, cycloheptylmethyl, cycloheptylethyl, cycloheptylpropyl, cycloheptylbutyl and adamantylmethyl.
As used herein, the terms "cycloalkenyl" and "cycloalkynyl" refer to cyclic unsaturated monovalent hydrocarbon radicals. A "cycloalkenyl" is characterized by a carbon-carbon double bond and a "cycloalkynyl" is characterized by a carbon-carbon triple bond. Such groups have the number of carbon atoms as indicated. By way of non-limiting example, suitable cycloalkenyl groups include cyclohexene and cyclohexadiene.
Alkoxy refers to the group "alkyl-O-", where alkyl is as defined above. By way of non-limiting example, suitable alkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy. Aryloxy refers to the group "aryl-0-", where aryl is as defined herein. By way of non-limiting example, suitable aryloxy groups include phenoxy, tolyloxy and xylyloxy.
As used herein, the term "alkoxyalkyl" refers to an alkyl group having an alkoxy substituent. Binding is through the alkyl group. The alkyl group and/or the alkoxy group has the number of carbon atoms as indicated. The alkyl moiety may be straight or branched. The alk and alkyl moieties of such a group may be substituted as defined above, with regard to the definition of alkyl. By way of non-limiting example, suitable alkoxyalkyl groups include methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxypropyl and ethoxypropyl. As used herein, the term "alkoxyaryl" refers to an aryl group having an alkoxy substituent. Binding is through the aryl group. The aryl group and/or the alkoxy group have the number of carbon atoms as indicated. The alkoxy and aryl moieties of such a group may be substituted as defined herein, with regard to the definitions of alkoxy and aryl. The alkyl moiety may be straight or branched. By way of non-limiting example, suitable alkoxyaryl groups include methoxyphenyl, ethoxyphenyl, dimethoxyphenyl and trimethoxyphenyl.
As used herein, the term "aryl" refers to monovalent unsaturated aromatic carbocyclic radical having one, two, three, four, five or six rings, preferably one, two or three rings, which may be fused or bicyclic. Preferably, the term "aryl" refers to an aromatic monocyclic ring containing 6 carbon atoms, which may be substituted on the ring with 1, 2, 3, 4 or 5 substituents as defined herein; an aromatic bicyclic or fused ring system containing 7, 8, 9 or 10 carbon atoms, which may be substituted on the ring with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents as defined herein; or an aromatic tricyclic ring system containing 10, 11, 12, 13 or 14 carbon atoms, which may be substituted on the ring with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 substituents as defined herein. By way of non-limiting example, suitable aryl groups include phenyl, biphenyl, binaphthyl, indanyl, phenanthryl, fluoryl, flourenyl, stilbyl, benzphenanthryl, acenaplithyl, azulenyl, phenylnaphthyl, benzfluoryl, tetrahydronaphthyl, perylenyl, picenyl, chrysyl, pyrenyl, tolyl, chlorophenyl, dichlorophenyl, trichlorophenyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, fluorophenyl, difluorophenyl, trifluorophenyl, nitrophenyl, dinitrophenyl, trinitrophenyl, aminophenyl, diaminophenyl, triaminophenyl, cyanophenyl, chloromethylphenyl, tolylphenyl, xylylphenyl, chloroethylphenyl, trichloromethylphenyl, dihydroindenyl, benzocycloheptyl and trifluoromethylphenyl.
The term "heteroaryl" refers to a monovalent unsaturated aromatic heterocyclic radical having one, two, three, four, five or six rings, preferably one, two or three rings, which may be fused or bicyclic. Preferably, "heteroaryl" refers to an aromatic monocyclic ring system containing five members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms, an aromatic monocyclic ring having six members of which one, two or three members are a N atom, an aromatic bicyclic or fused ring having nine members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms or an aromatic bicyclic ring having ten members of which one, two or three members are a N atom. By way of non-limiting example, suitable heteroaryl groups include furanyl, pyranyl, pyridyl, phthalimido, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, pyronyl, pyrazinyl, tetrazolyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxadinyl, chromenyl, chromanyL isochromanyl, carbolinyl, thiazolyl, isoxazolyl, isoxazolonyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, benzodioxepinyl and pyridazyl.
The term "heterocyclyl" refers to a saturated or partially unsaturated ring having three members of which at least one member is a N5 O or S atom and which optionally contains one additional O atom or additional N atom; a saturated or partially unsaturated ring having four members of which at least one member is a N, O or S atom and which optionally contains one additional O atom or one or two additional N atoms; a saturated or partially unsaturated ring having five members of which at least one member is a N, O or S atom and which optionally contains one additional O atom or one, two or three additional N atoms; a saturated or partially unsaturated ring having six members of which one, two or three members are an N, O or S atom and which optionally contains one additional O atom or one, two or three additional N atoms; a saturated or partially unsaturated ring having seven members of which one, two or three members are an N, O or S atom and which optionally contains one additional O atom or one, two or three additional N atoms; a saturated or partially unsaturated ring having eight members of which one, two or three members are an N, O or S atom and which optionally contains one additional O atom or one, two or three additional N atoms; a saturated or partially unsaturated bicyclic ring having nine members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms; or a saturated or partially unsaturated bicyclic ring having ten members of which one, two or three members are an N, O or S atom and which optionally contains one additional O atom or one, two or three additional N atoms. Preferably, heterocycles comprising peroxide groups are excluded from the definition of hetercyclyl. By way of non-limiting example, suitable heterocyclyl groups include pyrrolinyl, pyrrolidinyl, dioxolanyl, tetrahydrofuranyl, morpholinyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrothiopyranyl and piperazinyl.
The term "heterocyclylalkyl" refers to an alkyl group with a heterocyclyl substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated. The heterocyclyl and alkyl moieties of such a group may be substituted as defined herein, with regard to the definitions of heterocyclyl and alkyl. The alkyl moiety may be straight or branched. By way of non-limiting example, suitable heterocyclylalkyl groups include methyl, ethyl, propyl, butyl, pentyl and hexyl substituted with one or more of the heterocyclyl groups indicated immediately above.
As used herein, the term "alkaryl" refers to an aryl group with an alkyl substituent. Binding is through the aryl group. Such groups have the number of carbon atoms as indicated. The alkyl and aryl moieties of such a group may be substituted as defined herein, with regard to the definitions of alkyl and aryl. The alkyl moiety may be straight or branched. Particularly preferred examples of alkaryl include tolyl, xylyl, butylphenyl, mesityl, ethyltolyl, methylindanyl, methylnaphthyl, methyltetrahydronaphthyl, ethylnaphthyl, dimethylnaphthyl, propylnaphthyl, butylnaphthyl, methylfluoryl and methylchrysyl. As used herein, the term "aralkyl" refers to an alkyl group with an aryl substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated. The aryl and alkyl moieties of such a group may be substituted as defined herein, with regard to the definitions of aryl and alkyl. The alkyl moiety may be straight or branched. Particularly preferred examples of aralkyl include benzyl, methylbenzyl, ethylbenzyl, dimethylbenzyl, diethylbenzyl, methylethylbenzyl, methoxybenzyl, chlorobenzyl, dichlorobenzyl, trichlorobenzyl, phenethyl, phenylpropyl, diphenylpropyl, phenylbutyl, biphenylmethyl, fluorobenzyl, difluorobenzyl, trifluorobenzyl, phenyltolylmethyl, trifluoromethylbenzyl, bis(trifluoromethyl)benzyl, propylbenzyl, tolylmethyl, fluorophenethyl, fluorenylmethyl, methoxyphenethyl, dimethoxybenzyl, dichlorophenethyl, phenylethylbenzyl, isopropylbenzyl, diphenylmethyl, propylbenzyl, butylbenzyl, dimethylethylbenzyl, phenylpentyl, tetramethylbenzyl, phenylhexyl, dipropylbenzyl, triethylbenzyl, cyclohexylbenzyl, naphthylmethyl, diphenylethyl, triphenylmethyl and hexamethylbenzyl.
The term "heteroaralkyl" refers to an alkyl group with a heteroaryl substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated. The heteroaryl and alkyl moieties of such a group may be substituted as defined herein, with regard to the definitions of heteroaryl and alkyl. The alkyl moiety may be straight or branched. By way of non-limiting example, suitable heteroaralkyl groups include methyl, ethyl, propyl, butyl, pentyl and hexyl substituted with one or more of the specific heteroaryl groups indicated above. The term "alkylamino" refers to an amine group with an alkyl substituent. Binding is through the amine group. Such groups have the number of carbon atoms as indicated. The alkyl moiety of such a group may be substituted as defined herein, with regard to the definition of alkyl. The alkyl moiety may be straight or branched. By way of non-limiting example, suitable alkylamino groups include methylamino, ethylamino, propylamine, butylamino, pentylamino and hexylamino. The term "cycloalkylamino" refers to an amine group with a cycloalkyl substituent. Binding is through the amine group. Such groups have the number of carbon atoms as indicated. The cycloalkyl moiety of such a group may be substituted as defined herein, with regard to the definition of cycloalkyl. The alkyl moiety may be straight or branched. By way of non-limiting example, suitable cycloalkylamino groups include cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino, cyclononylamino and cyclododecylamino.
The term "aminoalkyl" refers to an alkyl group with an amine substituent. Binding is through the alkyl group. Such groups have the number of carbon atoms as indicated. The alkyl moiety of such a group may be substituted as defined herein, with regard to the definition of alkyl. By way of non-limiting example, suitable aminoalkyl groups include aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl and aminohexyl.
The term "arylamino" refers to an amine group with an aryl substituent. Binding is through the amine group. Such groups have the number of carbon atoms as indicated. The aryl moiety of such a group may be substituted as defined herein, with regard to the definition of aryl. By way of non-limiting example, suitable arylamino groups include phenylamino, biphenylamino, methylphenylamino, methoxyphenylamino, tolylamino and chlorophenylamino.
The term "alkarylamino" refers to an amine group with an alkaryl substituent. Binding is through the amine group. Such groups have the number of carbon atoms as indicated. The alkaryl moiety of such a group may be substituted as defined herein, with regard to the definition of alkaryl. The alkyl moiety may be straight or branched.
The term "aminoaralkyl" refers to an aralkyl group with an amine substituent. Binding is through the aralkyl group. Such groups have the number of carbon atoms as indicated. The aralkyl moiety of such a group may be substituted as defined herein, with regard to the definition of aralkyl. The alkyl moiety may be straight or branched.
The term "aminoalkaryl" refers to an alkaryl group with an amine substituent. Binding is through the alkaryl group. Such groups have the number of carbon atoms as indicated. The alkaryl moiety of such a group may be substituted as defined herein, with regard to the definition of alkaryl. The alkyl moiety may be straight or branched. The term "guanidinyl" refers to a guanidine group that has had one or more hydrogen atoms removed to form a radical.
The term "ureayl" refers to a urea group that has had one or more hydrogen atoms removed to form a radical. With regard to one or more substituents which are referred to as being on the carbon backbone of a group with a compound definition, for example, "alkaryl", the substituent may be on either or both of the component moieties, e.g., on the alkyl and/or aryl moieties.
With regard to one or more substituents which are referred to as being in the carbon backbone of a group with a compound definition, for example, "heteroaralkyl", the substituent may interrupt either or both of the component moieties, e.g., in the alkyl and/or aryl moieties.
Other 'compound' group definitions will be readily understandable by the skilled person based on the previous definitions and the usual conventions of nomenclature.
Reference to cyclic systems, e.g., cycloalkyl, aryl, heteroaryl, etc., contemplates monocyclic and polycyclic systems. Such systems comprise fused, non-fused and spiro conformations, such as bicyclooctyl, adamantyl, biphenyl and benzofuran.
Compounds were tested at human PTHl receptors which have been cloned into an HEK293 cell line as follows:
Step a: Subcloning and engineering of IMAGE clones encoding the human PTHlR into a mammalian expression vector
The NCBI database (http://www.ncbi.nlm.nih.gov) contained 4 mRNA sequences for the human PTHl receptor, having the accession numbers L04308 (Schipani et al. Endocrinology 132, 2157-2165 (1993)), U17418 (Adams et al. Biochemistry, 34, 10553-10559 (1995)), X68596 (Schneider et al. Eur. J. Pharmacol. 246, 149-155 (1993)) and NM_000316 (Hoey et al. Br J Cancer 2003, 88, 567-573). Alignment of these sequences revealed that all four sequences had 100% amino acid identity. The consensus sequence, as represented by L04308, was taken as the wild type (WT) sequence. IMAGE clones (Integrated Molecular Analysis of Genomes and their Expression) (Lennon et al. Genomics 33, 151-152 (1996)), 5183607 and 5186838, were purchased from the HGMP (Human Genome Mapping Project, Cambridge, U.K.). Plasmid DNA was prepared using EndoFree™ plasmid Maxi-prep columns (Qiagen). The DNA was then sequenced using primers 1-5 (see Table 1). The Maxi-prep plasmid DNAs for clones 5183607 and 5186838 were amplified by PCR (polymerase chain reaction) from the start codon to the stop codon using primers 6 and 7, containing Eco Rl (Promega) and Xba I (Promega) restriction sites, respectively. The PCR was performed in 2OmM Tris-HCl (pH 8.8), 1OmM KCl, 1OmM (NHO2SO4, 2mM MgCl2, 0.2mM dNTP containing O.lμM of each primer and Ing of the template DNA. A hot start PCR was used: the reactions were denatured for 2min at 950C, cooled to 750C, then IU of Taq Polymerase (Invitrogen) was added and the reactions were cycled 30 times at 950C for lmin, 550C for 30sec and 720C for 3min. After a final extension at 720C for 5min, the samples were cooled to 40C and analysed by electrophoresis.
The PCR products from IMAGE clones 5183607 and 5186838 were purified separately using the MinElute™ PCR purification kit. 5μg of the 1.8kb PCR product generated from IMAGE clone 5183607 (N138S mutation) was restriction-digested with Eco Rl and Kpn I in buffer E (Promega, 6mM Tris-HCl, 6mM MgCl2, 10OmM NaCl, pH 7.5, ImM DTT) containing O.lμg/μl BSA at 370C for Ih 40min. The products were separated using an ethidium bromide stained 1% agarose/TBE gel and the 337bp fragment was isolated and purified using the MinElute™ gel extraction kit. Similarly, 5μg of the 1.8kb from PCR product generated from IMAGE clone 5186838 (E49G mutation) was restriction digested with Xba I and Kpn I in mulitcore buffer (Promega, 25mM Tris -acetate pH 7.5, 10OmM potassium acetate, 1OmM magnesium acetate, ImM DTT) containing O.lμg/μl BSA at 370C for Ih 40min. The 1.4kb fragment was isolated as above.
Both PCR fragments (i.e. 60ng of the 337bp fragment and 280ng of the 1.4kb fragment) were ligated together in a single ligation reaction in the presence of lOOng of Eco Kl/Xba I digested and shrimp alkaline phosphatase (Promega) treated mammalian expression vector using the QuickStick™ DNA Ligation kit (Bioline). After 15 min at room temperature, 2.5μl of the ligation mix was transformed into lOOμl XLl -Blue competent cells (Stratagene).
DNA from eleven of the resulting transformed colonies was prepared using plasmid Mini prep columns (Qiagen) according to the manufacturer's instructions. Of the ten clones that were positive (as determined by restriction digestion of the miniprep DNA), DNA was prepared from one positive clone using the plasmid Maxi-prep columns. The resulting DNA was then fully sequenced by MWG-Biotech AG (Ebersberg, Germany) on both strands using primers 2 and 8-12 (see Table 1). Sequence analysis revealed 100% amino acid identity within the coding region compared to sequence L04308 (WT human PTHlR).
Table 1 : Oligonucleotides used for Sequence or PCR analysis
Figure imgf000045_0001
Restriction sites are in bold. Start codon is underlined. Stop codon is in italics and underlined. Step b: Generation of Stable Cell Line
HEK293 cells from the European Collection of Cultures (ECACC) were cultured in Minimal Essential Media (with Earle's Salts) (Invitrogen), containing 2mM Glutamaxl (Invitrogen), 10% heat-inactivated foetal bovine serum (Invitrogen), Ix non-essential amino acids (Invitrogen). Cells (2.1 x 106) were seeded into 100mm x 20mm dishes (Corning) and transfected the following day using the Transfast™ reagent (Promega), using either 13, 26 or 31μg of the plasmid DNA containing the engineered hPTHIR per dish, at a ratio of 1:1 (Transfast™ reagent:DNA). After 48h the cells were trypsinised (Culture of Animal Cells, a Manual of Basic Techniques; 4th ed.; Freshney, R. Wiley Press) and seeded in duplicate 35mm x 10mm dishes at low densities (10,000, 2,500 or 500 cells/dish) in media containing 800μg/ml G-418. The remainder of the cells were kept for whole cell radioligand binding analyses. The plated cells were selected for 20 days, with media changes every 3-4 days, using 10% conditioned media from untransfected HEK293 cells, until individual colonies appeared visible to the naked eye. Cloning rings were used to isolate individual, well-separated colonies and trypsinisation was used to transfer the cells in each colony to a suitable vessel for expansion. The cells were expanded and analysed by RT-PCR and radioligand binding analysis. Media, containing 400μg/ml G-418, was used for routine culture of the HEK293/hPTHlR cell lines. Cells were trypsinised and used straight away for whole cell radioligand binding assays or frozen as a pellet on dry ice then stored at -8O0C for membrane-based radioligand binding assays. Step c: Clonal selection
Stable clones, with the greatest expression of the human PTH1 receptor, were selected by establishing the specific binding of [125I]-[NIe8'18, Tyr34]-hPTH(l-34) at a range of cell concentrations (2.5 x 104 - 7.5 x 105 cell ml"1) using assay conditions previously described (ORLOFF, J.G., WU, T.L., HEATH, H. W., BRADY, T.G., BRINES, MX. & STEWART, A.F. J. Biol. Chem., (1989), 264, 6097-6103). Of the clones examined, clone 9B3 was selected because it gave the highest amount of specific binding (74% and 4911cpm) at an added cell concentration of 1 x 105 cell ml^and [125I]-[NIe8'18, Tyr34]-hPTH(l-34) concentration of 2OpM. In addition, there was a linear relationship between cell concentration and specific binding.
Step d: Membrane preparation Harvested clone 9B3 cells were stored as pellets at -700C. When required, aliquots were thawed, by mixing with ice-cold buffer A. (5OmM Tris-HCl, pH7.2 at 210C; 3mM MgCl2, 3mM CaCl2, 3mM KCl and 3mg ml"1 bacitracin). The cell/membrane suspension was centrifuged (20min, 20,00Og @ 40C; Hettich microfuge) and the final cell pellet resuspended by homogenisation (Polytron PTlO, setting 7, 1 x Is), to a membrane concentration equivalent to 3 x 104 cells ml"1 added, in buffer A (210C; containing lOμM chymostatin and lμM 1 , 10-phenanthroline) .
Step e: Incubation conditions
For competition, saturation and kinetic studies, membranes were prepared as described in step d and used at a concentration of 3 x 104 cells ml"1. Non-specific binding was defined with PTH(μ34) (50μl; 1OuM). For competition and saturation studies, membranes were incubated for 210min at 210C, in final volume of 0.5ml, [125I]-[NIe8'18, Tyr34]-hPTH(l-34) (50μl; competition =200pM; saturation =2pM-300nM). To establish that the binding of [125I]-[NIe8'18, Tyr34]-hPTH(l-34) reached equilibrium, kinetic studies were performed. Membranes were incubated with [125I]-[NIe8'18, Tyr34]-hPTH(l-34) (50μl; 20OpM) for increasing time intervals (l-1200min). To establish the time-course of the dissociation, specific binding was determined at increasing time intervals times (2-1200min) after addition of lμM PTH(l-34). The assays were terminated by rapid filtration through Whatman GF/B filter mats or GF/B Unifilters (0.3% polyethyleneimme). Filters were washed with ice-cold 5OmM Tris-HCl (pH7.4) and counted on a Wallac gamma counter (lmin) or TopCount (3min). Step f: Saturation and kinetic analysis
The binding of [125I]-[NIe8'18, Tyr34]-hPTH(l-34) to the human PTHi receptor reached equilibrium after 70min at 21°C (n=3) and was saturable (pKD=8.84 ; nH=1.35; n=l). The binding was dissociated by IuM PTH. Step g: Competition studies
A number of reference compounds and compounds of the invention were tested for their ability to compete for human PTHi receptors labelled with [125I]-[NIe8'18, Tyr34]-hPTH(l-34). Compounds were diluted and added to 96 well plates together with radioligand and membranes using a Beckman Biomek. The ability of compounds to inhibit specific binding was determined in at least two experiments, in triplicate and over a range of concentrations at half-log unit intervals. Compound affinity values (pICso; mid-point curve location) and mid-point slope parameter (nπ) were derived through fitting competition data to the Hill equation (Graph-Pad Prism). Dissociation constants (K;) were determined using the Cheng & Prusoff equation (1973) to correct for the receptor occupancy of the ligand. In practice pIC5o values are equivalent to pKi values due to the low occupancy of the radioligand.
The pKi values for reference compounds are shown in the table below.
Figure imgf000047_0001
* error is standard deviation
The following compounds have been synthesised in accordance with the present invention.
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
6.98±0.04(3) 191 6.98(2)
6.51(2) 192 7.77±0.07(3)
6.88±0.03(3) 193 8.03±0.04(3)
Figure imgf000056_0001
6.86±0.08(3) 194 6.92(2)
6.95±0.02(4) 195 6.29(2)
Figure imgf000056_0002
Figure imgf000056_0003
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Experimental Commercially available dichloromethane (DCM), tetrahydrofuran (THF) and N,N- dimethylformamide (DMF) were used. Column chromatography was performed on Merck silica gel 60(40-63 μm) using the reported solvent systems. 1H NMR spectra were recorded on a Bruker DRX-300 instrument at 300MHz and the chemical shifts (δπ) were recorded relative to an internal standard.
Example 1 : N-[4-(3-Benzyl-5-cyclohexyl-2-oxo-l ,2-dihydro-3H-l ,3,4-benzotriazepin-l -yl)- phenylj-guanidine
Step a: N-Amino-N-benzyl-N'-ft-cyclohexylcarbonylphenylJ-urea
A solution of (2-aminophenyl)-cyclohexyl-methanone (10.2g, 50mmol) and NEt3 (13.8mL, lOOmmol) in DCM (75mL) was added drop-wise over 30 mins. to a stirred solution of bis- (trichloromethyl)carbonate (4.95g, 16.7mmol) in DCM (75mL) under argon maintained at - 400C. The mixture was stirred at -4O0C for 20 mins. and then a solution of benzylhydrazine (6.12g, 50mmol) in DCM (5OmL) was added over 20 min. The reaction mixture was allowed to warm to ambient temperature and stirred for 16h. The solution was washed with H2O (2 x 20OmL), dried with MgSO4, filtered and the solvent removed at reduced pressure. The residue was purified by chromatography on silica gel with EtOAc-DCM (1:19) as eluant to afford the title compound (11.3g, 65%). 1H NMR (CDCl3) 12.32 (IH, br s), 8.76 (IH, d), 7.90 (IH, d), 7.52 (IH, t), 7.37-7.27 (5H, m), 7.02 (IH, t), 4.81 (2H, s), 3.71 (2H, s), 3.33 (IH, m), 1.90-1.30 (1OH, m). Step b: 3-Benzyl-5-cyclohexyl-l ,2-dihydro-3ΕL-l ,3 ,4-benzotriazepin-2-one
A solution of N-amino-N-benzyl-N-(2-cyclohexylcarbonylphenyl)-urea (11.3Og, 32mmol) and />-TSA.H2O (0.5g) in /-PrOH (10OmL) was heated under reflux for Ih. H2O (2OmL) was added, and the solvent was removed at reduced pressure whereupon a white solid crystallised. The solid was isolated by filtration washed with MeOH and dried to afford the product (9.5Og, 87%). 1H ΝMR (CDCl3) 7.35-7.23 (8H, m), 7.12 (IH, t), 6.86 (IH, d), 4.81 (2H, s), 2.62 (IH, m), 1.78-1.25 (1OH, m).
Step c: 3-Benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dϊhydro-3Εrl> 3, 4-benzotriazepin-2-one
A mixture of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (8.5Og, 26mmol), 4-iodo-nitrobenzene (7.4Og, 28 mmol), Cu powder (1.79g, 28 mmol), Cu(OAc)2 (4.64g, 26mmol), and anhydrous K2CO3 (3.52g, 26mmol) in DMF (75mL) was heated at 1500C for Ih. On cooling, the reaction mixture was partitioned between EtOAc (20OmL) and 2M NH4OH (30OmL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (10OmL) and the combined extracts were washed successively with 2M NH4OH (20OmL), H2O (2 x 20OmL) and dried (MgSO4). Filtration and evaporation of the solvent afforded the product as a yellow foam (11.58g, 94%). 1H NMR (CDCl3) 8.16 (2H, d), 7.52 (2H, d), 7.43 (2H,m), 7.37 (IH, d), 7.23-7.13 (5H, m), 6.99 (IH, d), 5.00 (IH, br s), 4.70 (IH, br s), 2.80 (IH, m), 1.78-1.17 (10H5 m).
Step d: l-(4-Aminophenyl)-3-benzyl-5-cyclohexyl-l ,2-dihydro-3H-l ,3 ,4-benzotriazepin-2-one
A solution of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one (11.6g, 26mmol) and SnCl2-H2O (34.6g, 150mmol) in EtOAc (20OmL) was heated under reflux for 5h. On cooling, the reaction mixture was diluted with EtOAc (20OmL), washed with saturated NaHCO3 solution (50OmL), brine (20OmL)5 and dried (MgSO4). Filtration and evaporation of the solvent afforded the crude product which was purified by chromatography on silica gel with EtOAc-DCM (15:85) as eluant (7.17g, 66%). 1H NMR (CDCl3) 7.30-7.14 (10H5 m), 6.82 (IH, d), 6.66 (2H, d), 4.75 (2H, br s), 3.70 (2H, br s), 2.75 (IH, m), 1.82-1.25 (1OH, m). Step e: N5N' ' -Bis-(tert-butoxycarbonyl)-W '-[4-(3-benzyl-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3Y{-l ,3,4-benzotriazepin-l-yl)-phenyl]-guanidine
HgCl2 (176mg, 0.65mmol) was added to a solution of l-(4-aminophenyl)~3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l53,4-benzotriazepin-2-one (274mg, O.όmmol), NEt3 (269μl, 2mmol), and l,3-bis-(tørt-butoxycarbonyl)-2~methyl-2-thiopseudourea (176mg, 0.7mmol) in DCM (1OmL) at ambient temperature. The mixture was stirred overnight and the insoluble salts removed by filtration through a pad of celite. The solvent was evaporated from the filtrate and the product was obtained by chromatography of the residue on silica gel with EtOAc- DCM-Ηexane (2:9:9) as eluant (324mg, 75%). 1H NMR (CDCl3) 11.62 (IH, s), 10.37 (IH5 s), 7.61 (2H, d), 7.37 (2H,d), 7.30-7.16 (8H5 m), 6.75 (IH, d), 5.00 (IH, br s), 4.60 (IH5 br s ), 2.75 (IH, m), 1.83-1.27 (10, m), 1.55 (9H, s), 1.50 (9H5 s).
Step f: A solution of N,N-bis-(fert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro~3H-l,354-benzotriazepm-l-yl)-phenyl]-guanidine (324mg, 0.5mmol) in 4M ΗC1- dioxan (4mL) was stirred at ambient temperature for 16h. The solvent was removed at reduced pressure and the residue was re-evaporated from Et2O (3 x 5mL). Trituration of the residue with Et2O afforded the hydrochloride salt of the title compound, which was isolated by filtration and dried (200mg, 77%). 1H NMR (DMSO-d6) 10.01 (IH5 s) 7.60 (IH, d), 7.52 (4H5 br s), 7.41-7.14 (1 IH5 m), 6.81 (IH5 d)5 4.75 (IH, br s), 4.40 (IH, br s)5 2.95 (IH5 m)5 1.73-1.00 (1OH, m). Found: C 61.94, H 6.08, N 16.34%; C28H30N6O-2HCl requires: C 62.34, H 5.98, N 15.58%. Example 2: N-[4-(3-Benzyl-2-oxo-5-phenyl-l,2-dihydro-3Η.-l,3,4-benzotriazepin-l-yl)- phenylj-guanidine
The title compound was prepared by the method of preparation of example 1 except that (2- aminophenyl)-phenyl-methanone was used in step a in place of (2-aminophenyl)-cyclohexyl- methanone. 1H NMR (DMSO-d6) 9.94 (IH, s), 7.54-7.46 (12H, m), 7.29-7.21 (8H, m), 7.11 (lH,d), 6.93 (IH, d), 5.85 (IH, br s), 5.60 (IH, br s). Found: C 63.08, H, 4.99, N 15.78%; C28H24N6O-2HC1 requires: C 63.04, H 5.10, N 15.75%.
Example 3 : N-[4-(5-Cyclohexyl-3-methyl-2-oxo-l,2-dihydro-3Y{-l,3,4-benzotriazepin-l-yl)- phenyl-guanidine
The title compound was prepared by the method of preparation of example 1 except that methyl hydrazine was used in step a in place of benzylhydrazine. 1H NMR (DMSO-d6) 10.02 (IH, s), 7.63 (IH, d), 7.55 (4H, br s), 7.41-7.24 (6H, m), 6.76 (IH, d), 2.29 (IH, m), 2.93 (3H, s) 2.00-1.00 (1OH, m). Found: C 55.77, H, 6.23, N 17.62%; C22H26N6O-2HCl-0.5H2O requires: C 55.93, H 6.19, N 17.79%
Example 4: N-[4-(5-Cyclohexyl-3-cyclohexylmethyl-2-oxo-l,2-dihydro-3Ε{-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine
Step a: 3-Cyclohexylmethyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3Η.-l,3,4- benzotriazepin-2-one was obtained using steps a-c of the method of preparation of example 1, except that cyclohexylmethyl hydrazine was used in step a in place of benzylhydrazine.
Step b: The title compound was obtained using steps d-f of the method of preparation of example 1 except that 3-cyclohexylmethyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one was used in step d in place of 3~benzyl-5-cyclohexyl-l-(4- nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (DMSOd6) 10.07 (IH, s), 7.63 (IH, d), 7.54 (4H, br s), 7.42-7.22 (6H, m), 6.77 (IH, d), 3.47 (2H, m) 2.99 (IH, m), 2.00- 0.50 (21H, m). Found: C 61.76, H 6.68, N 15.43%; C28H36N6O^HCl requires: C 61.65, H 7.02, N 15.41%.
Example 5 : N-[4-(3-Benzyl-5-isopropyl-2-oxo-l ,2-dihydro-3H-l ,3, 4-benzotriazepin-l -yl)- phenylj-guanidine Step a: l-(2-Amino-phenyl)-2-methyl-propan-l-one
A solution of isopropylmagnesium chloride (2M in Et2O; 100 mL,) was added to a solution of 2-aminobenzonitrile (11.8g, O.lmol) in Et2O (100 mL) at O0C. After stirring overnight at ambient temperature, the reaction mixture was cooled to -6O0C and 5N HCl added drop-wise. After warming to ambient temperature, the aqueous layer was separated and basified to pH 4 by the addition of KOH followed by extraction with EtOAc. The extract was washed with brine and dried (MgSO4). Filtration and evaporation of the solvent afforded a yellow solid (11.1 g, 96%). 1H NMR (CDCl3) 7.79 (IH5 d), 7.27 (IH, m), 6.65 (2H, m), 6.29 (2H, bs), 3.60 (IH, sept), 1.23 (6H, d). Step b: The title compound was prepared by the method of preparation of example 1 except that l-(2-amino-phenyl)-2-methyl-propan-l-one was used in step a in place of (2- aminophenyl)-cyclohexyl-methanone. 1H NMR (DMSO-d6) 7.61 (IH5 m), 7.5-7.36 (7H, m), 7.25-7.12 (8H, m), 6.80 (IH, d), 4.49 (2H, m) 3.22 (IH, m), 1.16-1.01 (6H, m). Example 6: N-ft-fS-Cyclohexyl-S-ft-methoxy-benzyl^-oxo-l^-dihydroSll-lJJ- benzotriazepin-l-yl]-phenyl}-guanidine
The title compound was prepared by the method of preparation of example 1 except that 4- methoxybenzylhydrazine was used in step a in place of benzylhydrazine and trifluoroacetic acid was used in step f in place of HCl-dioxan. 1H NMR (DMSO-d6) 9.67 (IH, m), 7.60-7.27 (HH, m), 7.10 (2H, d), 6.78 (3H, m), 4.53 (IH, m), 4.37 (IH, m), 3.68 (3H, s), 2.95 (IH, m), 1.75-1.15 (1OH, m). Found: C 58.57, H 5.17, N 12.54%; C29H32N6O2-LS CF3CO2H-0.3 C4H4O2 requires: C 58.69, H 5.36, N 12.51%.
Example 7: N-ft-ft-Benzyl-S-tyclohexyl-V-fluoro-l-oxo-l^-dihydro-Sii-l^^-benzotriazepin- 1 -yl)-phenyl]-guanidine Step a: 5-Fluoro-2-nitrobenzamide
5-Fluoro 2-nitrobenzoic acid (24.93g, 0.14mol) was dissolved in dry DCM (20OmL) and oxalyl chloride (24mL, 0.27mol) added followed by DMF (2 drops). The mixture was stirred at ambient temperature for 2h and evaporated from DCM (3 x 10OmL), dissolved in acetone (10OmL) and added slowly to 27% aqueous ammonia (50OmL) at O0C over 15min. The mixture was concentrated (-100 mL) and neutralised with 2N HCl. The yellow precipitate was filtered, washed with H2O and dried under vacuum at 5O0C for 2 days to afford the product as a yellow solid (15.04g, 61%). 1R NMR (DMSO-d6) 8.16 (IH, m), 7.28 (2H, m), 5.89 (2H, br s).
Step b: 5-Fluoro-2-nitrobenzonitrile
To dry DMF (70mL)cooled to -1O0C was added thionyl chloride (6mL, 82mmol) dropwise over 10 min. 5-fluoro 2-nitrobenzoic acid (15.04g ,82mmol) was added in small portions over 1 h. The mixture was allowed to warm to ambient temperature and poured into H2O (20OmL). The precipitate formed was isolated by filtration, washed with H2O and dried to afford the product as a colourless solid (10.7Og, 79%). 1H NMR (CDCl3) 8.41 (IH, m), 7.62 (IH, m), 7.52 (IH, m). Step c: 2-Amino-5-fluorobenzonitrile
A mixture of 5-fluoro-2-nitrobenzonitrile (9.7Og, 58mmol) and 10% palladium on charcoal (Ig) in MeOH (20OmL) was stirred under an atmosphere of hydrogen for 5h. The mixture was filtered through a pad of celite and evaporated. The residue was triturated with Et2O-hexane (4OmL / 1:3) and filtered. Evaporation of the filtrate afforded the product as a pale yellow solid (4.65g, 58%). 1H NMR (CDCl3) 7.09 (2H, m), 6.71 (IH5 m), 4.29 (2H, bs).
Step d: (2-Amino-5-fluoro-phenyl)-cyclohexyl-methanone was obtained by the method of preparation of example 5 step a, except that cyclohexylmagnesium chloride and 2-amino-5- fluorobenzonitrile were used in place of isopropylmagnesium chloride and 2-aminobenzonitrile respectively. 1H NMR (CDCl3) 7.43 (IH, m), 7.03 (IH, m), 6.62 (IH, m), 6.11 (2H, br s), 3.16 (IH, m), 1.89-1.24 (1OH, m).
Step e: The title compound was obtained by the method of preparation of example 1 except that (2-amino-5-fluoro-phenyl)-cyclohexyl-methanone was used in step a in place of (2- aminophenyl)-cyclohexyl-methanone. 1H NMR (DMSOd6) 10.08 (IH, bs), 7.70-6.70 (15H, m), 5.00-4.30 (2H, bd), 2.97 (IH, m), 1.90-1.00 (1OH, m). Found: C 60.70, H 5.65, N 14.87%; C28H29FN6O^HCl requires: C 60.32, H 5.61, N 15.07%.
Example 8: N-{4-[3-Benzyl-5-(2-fluoro-phenyl)-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l- ylj-phenyl}-guanidine The title compound was obtained by the method of preparation of example 1 except that (2- amino-phenyl)-(2-fluoro-phenyl)-methanone (Frye, S. V., Johnson, M. C; Valvano, N. L. J. Org. Chem., (1991), 56, 3750) was used in step a in place of (2-aminophenyl)-cyclohexyl- methanone. 1H NMR (DMSOd6-D2O) 7.53 (IH, m), 7.42 (2H, d), 7.33-7.17 (12H, m), 6.97 (IH, d), 6.90 (IH, d), 4.72 (2H, bs). Found: C 62.97, H 5.00, N 14.24%; C28H23FN6O- 1.3HC1- 0.7C4H8O2 requires: C 62.96, H 5.13, N 14.3%.
Example 9: N-ft-β-Benzyl-S-cyclohexylmethyl^-oxo-l^-dihydro-SH-lJ^-benzotriazepin-l- yl)-phenyl]-guanidine
Step a: l-(2-Amino-phenyl)-2-cyclohexyl-ethanone
A solution of bromomethyl-cyclohexane (84.Og, 0.47mol) in Et2O (35OmL) was added to a suspension of Mg turnings (12.68g, 0.52mol) in Et2O (35OmL). The mixture was heated under reflux until most of the Mg had reacted, and on cooling to ambient temperature was added to a solution of 2-aminobenzonitrile (20.Og, 0.17mol) in Et2O (20OmL) at O0C. The reaction mixture was allowed to warm to ambient temperature, heated under reflux for 6 h and stirred at ambient temperature for 16 h. The mixture was cooled to 00C and 5M HCl (32OmL) added. The aqueous layer was separated and basified to pH 9 by the addition of Na2CO3, extracted with EtOAc (2 x 50OmL) and the extracts dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with EtOAc-hexane (0:100-1:10) as eluant to afford the title compound (10.44g, 28%). 1H NMR (CDCl3) 7.74 (IH, dd), 7.27 (IH, m), 6.67-6.62 (2H, m), 6.27 (2H, m), 2.79 (2H, d), 1.96 (IH, m), 1.79-1.54 (4H, m), 1.32-0.87 (6H, m).
Step b: N-Amino-N-benzyl-W-P-tø-cyclohexyl-acetyty-phenylJthiourea
A solution of l-(2-amino-phenyl)-2-cyclohexyl-ethanone (6.09g, 28mmol) and NEt3 (7.8ImL, 56mmol) in DCM (2OmL) was added dropwise to an ice-cooled solution of thiophosgene (2.14mL, 28mmol) in DCM (5OmL). The ice bath was removed and the mixture was stirred at ambient temperature for 30 min, re-cooled in ice whereupon a solution of benzyl hydrazine (4.11g, 34mmol) in DCM (2OmL) was added dropwise. The mixture was stirred at ambient temperature for 16 h, diluted with DCM (10OmL), washed with H2O (3 x 10OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was recrystallised from EtOH to afford the title compound (4.58g, 51%). 1H NMR (CDCl3) 12.51 (IH, s), 9.01 (IH, d), 7.81 (IH, dd), 7.55 (IH, t), 7.40-7.33 (5H, m), 7.17 (IH, t), 5.51 (2H, s), 3.85 (2H, s), 2.83 (2H, d), 1.95 (IH, m), 1.76-1.53 (5H, m), 1.30-0.99 (5H, m).
Step c 3-Benzyl-5-cyclohexylmethyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2- thione
A mixture of N-amino-N-benzyl-iV-[2-(2-cyclohexyl-acetyl)-phenyl]thiourea (4.57g, 12mmol) and/?~TSA.H2θ (228mg, 1.2mmol) in 2-propanol (4OmL) was heated under reflux for 1 h. The mixture was allowed to reach ambient temperature and concentrated (~20mL). The resulting precipitate was isolated by filtration, washed with cold 2-propanol and dried to afford the product (3.87g, 89%). 1H ΝMR (CDCl3) 7.38 (IH5 1), 7.24-7.11 (8H, m), 6.85 (IH, d), 5.28 (2H, s), 2.44 (2H, d), 1.65-1.55 (5H, m), 1.41 (IH, m), 1.10-0.80 (5H, m).
Step d S-Benzyl-5-cyclohexylmethyl-l, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
A solution of sodium methoxide in MeOH (1.5M; 2.75mL, 4mmol) was added to a suspension of 3 -benzyl-5-cyclohexylmethyl- 1 -(4-nitrophenyl)- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-2- thione (1.5Og, 4mmol) in MeOH-THF(1 :1 / 34mL). 30% Hydrogen peroxide (3.4OmL, 30mmol) was added dropwise and the solution was stirred at ambient temperature for Ih. The mixture was diluted with H2O (10OmL), and extracted with EtOAc (2 x 10OmL). The extracts were washed with H2O (10OmL), brine (5OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with EtOAc-hexane (3:10) as eluant followed by recrystallisation from EtOH to afford the title compound (793mg, 55%). 1H ΝMR (CDCl3) 7.39-7.12 (8H, m), 6.84 (IH, d), 6.64 (IH, s), 4.84 (2H, s), 2.52 (2H, d), 1.63-1.55 (5H, m), 1.44 (IH, m), 1.10-1.00 (3H, m), 0.96-0.86 (2H, m). Step e: The title compound was obtained as the hydrochloride salt using steps c-f of the method of preparation of example 1, except that 3-benzyl-5-cyclohexylmethyl-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one in step c. 1H NMR (DMSOd6) 9.96 (IH, s), 7.63 (IH, d), 7.51 (4H, bs), 7.43 (IH5 1), 7.36-7.16 (8H, m), 7.10 (2H, d), 6.81 (IH, d), 4.75 (IH, br s), 4.50 (IH, br s), 2.90 (2H, m), 1.70-1.35 (6H, m), 1.20-0.80 (5H, m). Found: C 65.36, H 6.44, N 15.01%; C29H32N6O-1.3HC1-0.3 C4H8O2 requires: C 65.42, H 6.49, N 15.16%.
Example 10: N-[4-(3-Benzyl-7-bromo-5-cydohexyl-2-oxo-l ,2-dihydro-3K-l ,3 ,4- benzotiia∑epin-3 -yl) -phenyl] -guanidine Step a: 2-Amino-5-bromo-benzonitrile
N-Bromosuccinimide (12.5g, 0.07mol) was added in portions to a solution of anthranilonitrile (7.5g, 0.06mol) in DCM at O0C. The mixture was stirred at O0C for 2h and allowed to warm to ambient temperature. The precipitate formed was removed by filtration and the filtrate washed with saturated NaHCO3, brine and dried (MgSO4). Filtration and evaporation of solvent afforded the title compound (11.3g, 62%). 1H NMR (CDCl3) 7.49 (IH, s), 7.40 (IH, d), 6.65 (IH, d), 4.39 (2H, br s).
Step b. (2-Amino-5-bromophenyl) cyclohexyl methanone was obtained by the method of preparation of example 5 step a, except that cyclohexylmagnesium chloride and 5-bromo-2- aminobenzonitrile were used in place of isopropylmagnesium chloride and 2- aminobenzonitrile respectively. 1H NMR (CDCl3) 7.82 (IH, s), 7.31 (IH, d), 6.58 (IH, d), 6.29 (2H, d), 3.19 (IH, m), 1.86 (4H, d), 1.74 (IH, d), 1.36 (5H, m).
Step c. 3-Benzyl-7-bromo-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using steps a-c of the method of preparation of example 1 except that (2-amino-5-bromophenyl) cyclohexyl methanone was used in step a in place of (2- aminophenyl)-cyclohexyl-methanone.
Step d: 3-Benzyl-7-bromo-5-cyclohexyl-l-(4-aminophenyl)-l,2-dihydro-3Η-l,3,4- benzotriazepin-2-one was obtained using step d of the method of preparation of example 1, except that 3-benzyl-7-bromo-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one.
Step e: N,N'-Bis-(tevt-butoxycar'bonyl)-~N"-[4-(3-benzyl-7-bromo-5-cyclohexyl-2-oxo- l,2-dihydro-3Η.-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine was obtained using step e of the method of preparation of example 1, except that 3-benzyl-7-bromo-5-cyclohexyl-l-(4- aminophenyl)-l,2-dihydro~3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5- cyclohexyl- 1 -(4-aminophenyl)- l,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one.
Step f: The title compound was obtained as the hydrochloride salt using step f of the method of preparation of example 1, except that N,N'-bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-7- bromo-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3Η- 1 ,3 ,4-benzotriazepin- 1 -yl)-phenyl]-guanidine was used in place of N,N'-bis-(fert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine. 1H NMR (CD3OD): 7.67 (IH, s),
7.50 (3H, m), 7.36 (2H, d), 7.18 (5H, m), 6.80 (IH, d), 4.70 (2H, br s), 2.85 (IH, m), 1.80 (5H, m), 1.30 (5H, m). Found: C 55.15, H 5.19, N 12.51%;
Figure imgf000083_0001
requires: C 59.79, H 5.71, N 16.83%.
Example 11 : N-[4-(3-Benzyl-5-cyclohexyl-8-methyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-1-yl) -phenyl] -guanidine
Step a: (2-Amino-4-methyl-phenyl)-cyclohexyl-methanone was obtained by the method of preparation of example 5 step a, except that cyclohexylmagnesium chloride and 4-methyl-2- aminobenzonitrile were used in place of isopropylmagnesium chloride and 2- aminobenzonitrile respectively. 1HNMR (CDCl3) 7.66-6.46 (3H5 m), 6.25 (2H, br s), 3.25 (IH, m), 2.27 (3H, s), 1.87-1.28 (1OH, m).
Step b: The title compound was prepared by the method used in the: preparation of example 1 except that (2-amino-4-methyl-phenyl)-cyclohexyl-methanone was used in step a in place of (2-aminophenyl)-cyclohexyl-methanone. 1H NMR (DMSO-d6) 10.20 (IH, s), 7.60 (4H5 br s), 7.48 (IH, m), 7.37-7.08 (1OH, m), 6.62 (IH, s), 5.00-4.25 (2H5 d), 2.90 (IH5 m), 2.19 (3H5 s), 1.72-1.13 (10H5 m). Found C 62.60, H 6.48, N, 15.19%; C29H33N6O^HCl requires: C 62.93, H 6.19, N 15.18.
Example 12: N-[4-(5-Adamantan-lyl-3-benzyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l- yl)-phenyl] -guanidine
The title compound was prepared by the method used in the preparation of example 1 except that adamantan-l-yl-(2-amino-phenyl)-methanone (Cappelii, A et al, J. Med. C hem, (1999), 42, 1556) was used in step a in place of (2-amino-phenyl)-cyclohexyl-methanone. 1H NMR (DMSO-d6), 9.83 (IH, s), 7.63 (IH5 d), 7.44-7.06 (HH, m), 7.40 (4H, br s), 6.85 (IH, d), 4.80 (IH, d), 4.40 (IH, d), 2.00-1.67 (15H, m). Found: C 65.10, H 6.21, N 14.35%; C32H34N6O- 2HCl requires: C 64.98, H 6.09, N 14.21%.
Example 13 : N-Benzhydryl-2-[5-cyclohexyl- 1 -(4-guanidino-phenyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-3 -y] -acetamide Step a: [5 -Cyclohexyl-1 -(4-nitro-phenyl)-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-3-yl]- acetic acid ethyl ester
A mixture of (5-cyclohexyl-2-oxo-l,2-dihydro-3H-l53,4-benzotriazepin-3-yl)-acetic acid ethyl ester (WO 03041714) (6.5Og, 20mmol), 4-iodo-nitrobenzene (5.48g, 22mmol), Cu powder (1.4Og, 22mmol), and anhydrous NaOAc, (4.1Og 50mmol) in dry DMF (5OmL) were stirred at 15O0C for 4h. The reaction mixture was cooled, diluted with EtOAc-H2O (1:1 /40OmL) and filtered through a plug of celite. The organic layer was separated, washed with brine (3 x 10OmL) and dried (MgSO4). The solvent was removed at reduced pressure and the residue purified by chromatography on silica gel with EtOAc-DCM-Hexane (1 :4:5) as eluant to afford the title compound (4.0Og, 44%). 1H NMR (CDCl3) 8.15 (2H, d), 7.53 (2H, d), 7.50-7.38 (3H, m), 6.97 (IH, d), 4.30 (2H, d), 4.21-4.14 (2H, q), 2.80 (IH, m), 2.00-1.20 (1OH, m), 1.23 (3H, t).
Step b: [l-(4-Amino-phenyl)-5-cyclohexyl-2-oxo-l ,2-dihydro-3H-l , 3, 4-benzotriazepin-3-ylJ- acetic acid ethyl ester was obtained using step d of the method of preparation of example 1, except that [5-cyclohexyl- 1 -(4-nitro-phenyl)-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-3-yl]~ acetic acid ethyl ester was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyI)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (CDCl3) 7.38 (IH, d), 7.25 (IH, t), 7.13 (3H, m), 6.81 (IH, d), 6.65 (2H, d), 4.32 (2H, br s), 4.14 (2H, q), 3.80 (2H, br s)5 2.81 (IH, m), 1.87-1.20 (1OH, m), 1.22 (3H, t). Step c: [5-Cyclohexyl-l-(4-(N,N'-bis-(tert-butoxycarbonyl)-guanidino)-phenyl)-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester was obtained using step e of the method of preparation of example 1, except that [l-(4-amino-phenyl)-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester was used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (CDCl3) 11.62 (IH, s), 10.38 (IH, s), 7.60 (2H, d), 7.42-7.25 (5H, m), 6.77 (IH, d), 4.25 (2H, bs), 4.14 (2H, q), 2.80 (IH, m), 1.88-1.20 (1OH, m), 1.53 (9H, s), 1.50 (9H, s), 1.22 (3H, t).
Step d: [5-Cyclohexyl- 1 -(4-(N,N'-bis-(tert-butoxycarbonyl)-guanidino)-phenyl)-2-oxo- 1 ,2- dihydro-SH-ljS^-benzotriazephvθ-yrj-acetic acid
A solution of [5 -cyclohexyl-1 -(4-(N,N'-bis-(tert-butoxycarbonyl)-guanidino)-phenyl)-2-oxo- l,2-dihydro-3H-l,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (5.15g, 7.94mmol) in THF (10OmL) was treated with IM LiOH (16mL, 16mmol) and the resultant reaction mixture was stirred at ambient temperature for 16hr. The pH of the solution was adjusted to pH 4 with IM HCl, and the solvent reduced to half volume at reduced pressure. The mixture was diluted with DCM (10OmL) and washed with H2O (10OmL), brine (10OmL), and dried (MgSO4). Filtration and evaporation of the solvent afford the title compound (4.26g, 85%). 1H NMR (CDCl3) 11.60 (IH, br ), 10.41 (IH, s), 7.63 (2H, d), 7.43 (2H, d), 7.32-7.22 (4H, m), 6.80 (IH5 d), 4.10 (2H, br d) 2.86 (IH, m), 2.00-1.00 (10H5 m), 1.53 (9H5 s), 1.50 (9H5 s).
Step e: [5-Cyclohexyl-l-(4-(N5N'-bis-(tert-butoxycarbonyl)-guanidino)-phenyl)-2-oxo-l,2- dihydro-3H-l,354-benzotriazepin-3-yl]-acetic acid N-hydroxysuccinimide ester
A solution of [5-cyclohexyl-l-(4-(N,N'-bis-(tert-butoxycarbonyl)-guanidino)-phenyl)-2-oxo- l,2-dihydro-3H-l,3,4-benzotriazepin-3-yl]-aceiiic acid (2.54g, 4mmol), N-hydroxysuccinimide (522mg, 4.8mmol), and EDC (922mg5 4.8mmol) in DCM (4OmL) was stirred at ambient temperature for 16h. The solution was washed with saturated NaHCO3(40mL), brine (4OmL) and dried (MgSO4). Filtration and evaporation of the solvent afforded the title compound (2.68g, 92%). 1H NMR (CDCl3) 11.62 (lH,s), 10.39 (IH, s), 7.62 (2H, d), 7.42-7.17 (5H5 m), 6.77 (IH5 d), 4.85-4.25 (2H5 br d), 2.85 (IH5 m), 2.80 (4H5 s), 2.00-1.20 (10H5 m), 1.54 (9H,s), 1.51 (9H, s).
Step f: N-Benzhydryl^-fS-cyclohexyl-l-ø-bis-ftert-butoxycarbonyty-guanidino-phenyl^-oxo- 1 ,2-dihydro-SH-l ,3,4-benzotriazepin-yl-]-acetamide
A solution of [5-cyclohexyl-l-(4-(N,N'-έw-(tert-butoxycarbonyl)-guanidino)-phenyl)-2-oxo- l,2-dihydro-3H-l,3,4-benzotriazepin-3-yl]-acetic acid N-hydroxysuccinimide ester (146mg, 0.2mmol), and diphenylmethylamine (46mg, 0.25mmol) in DCM (ImL) was stirred at ambient temperature for 16hr. The solvent was evaporated and the residue was chromatographed on silica gel with EtOAc-DCM (1 :9) to afford the product (71mg, 53%).
Step g: The title compound was obtained as the hydrochloride salt using step f of the method of preparation of example 1, except that Ν-benzhydryl~2-[5-cyclohexyl-l-(4-bis-(ført- butoxycarbonyl)-guanidino-phenyl-2-oxo-l52-dihydro-3H-l,354-benzotriazepin-yl-]-acetamide was used in place of N,N'-bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine. 1NMR (DMSOd6) 9.89 (IH5 br s), 8.38 (IH, d), 7.60 (IH, d), 7.50 (4H, br s), 7.50-7.19 (16H5 m), 6.78 (IH, d), 6.01 (IH, d), 4.25-3.75 (2H, br d), 2.96 (2H, m), 1.73-1.05 (1OH, m). Found: C 64.21, H 6.11, N 13.89%; C36H37N7O2-2HCl-0.5 C4H8O2 requires: C 63.97, H 5.95, N 14.11%.
Example 14: N-Benzyl-2-[5-cyclohexyl-l-(4-guanidinophenyl)-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-3-yl]-acetamide
The title compound was obtained using steps d-f of the method of preparation of example 13 except that benzylamine was used in step f in place of diphenylmethylamine. 1H NMR (DMSO-d6) 9.88 (IH, s), 8.17 (IH5 1), 7.61 (IH5 d), 7.49 (4H5 br s)5 7.43-7.17 (HH5 m), 6.77 (2H, d), 4.22 (2H, d), 4.20-3.75 (2H5 d), 2.96 (IH, m), 1.90-1.00 (1OH, m). Found: C 57.02, H 5.95, N 15.12%; C30H33N7O2-2HCl-2H2O requires: C 56.96, H 6.21, N 15.49%.
Example 15 : 2-[5-Cyclohexyl-l-(4-guanidinophenyl)-2-oxo-l,2-dihydro-3H-l, 3,4- benzotriazepin-3-yl]-'N-phenethyl-acetamide. The title compound was obtained using steps d-f of the method of preparation of example 13 except that phenethylamine was used in step f in place of diphenylmethylamine. 1H NMR (DMSO-d6) 10.00 (IH, s), 7.69 (IH, t), 7.62 (IH, d), 7.53 (4H, br s), 7.41-7.13 (HH, m), 6.78 (IH, d), 4.20-3.75 (2H, d), 3.23 (2H, q), 2.93 (IH, m), 2.64 (2H, t), 2.00-1.00 (1OH, m). Found: C 61.27, H 6.11, N 15.73%; C31H35N7O2-2HCI requires: C 60.98, H 6.11, N 16.05%. Example 16: 2-[5-Cyclohexyl-l-(4-guanidinophenyl)-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-3-yl]^H-pyridin-2-ylmethyl-acetamide.
The title compound was obtained using steps d-f of the method of preparation of example 13 except that 2-pyridinemethylamine was used in step f in place of diphenylmethylamine. 1H NMR (DMSO-d6) 10.13 (IH, s), 8.70 (IH, d), 8.63 (IH, t), 8.30 (IH, t), 7.73 (IH, t), 7.64 (2H, m), 7.58 (4H, br s), 7.43-7.25 (7H, m), 6.78 (2H, d), 4.55 (2H, d), 4.25-3.75 (2H, d), 2.99 (IH, m), 1.76-1.00 (1OH, m). Found: C 52.00, H 5.76, N 16.49%; C29H33N8O2-3HC1-2H2O requires: C 51.98, H 5.86, N 16.72%.
Example 17: 2-[5-Cyclohexyl-l-(4-guanidinophenyl)-2-oxo-l ,2-dihydro-3H-l , 3, 4- benzotriazepin-3-yl]-'N-(4-methoxy-benzyl)-acetamide The title compound was obtained using steps d-f of the method of preparation of example 13 except that 4-methoxybenzylamine was used in step f in place of diphenylmethylamine. 1H NMR (DMSO-d6) 10.07 (IH, s), 8.06 (IH, t), 7.61-6.77 (16H, m), 4.15 (2H, d), 4.20-3.80 (2H, d), 3.72 (3H, s), 2.95 (IH, m), 1.90-1.00 (1OH, m). Found: C 57.97, H 6.29, N 14.96%; C31H35N7O3-2HC1-H2O requires: C 57.76, H 6.10, n 15.21%. Example 18: 2-[5-Cyclohexyl-l-(4-guanidinophenyl)-2-oxo-l,2~dihydro-3H-l,3,4- benzotriazepin-3-yl]-Η-phenyl)-acetamide
The title compound was obtained using steps d-f of the method of preparation of example 13 except that aniline was used in step f in place of diphenylmethylamine. 1H NMR (DMSO-d6) 9.94 (2H, s), 7.70 (IH, d), 7.43 (4H, br s), 7.40-7.24 (1OH, m), 7.00 (IH, t), 6.75 (IH, d), 4.25- 3.80 (2H, d), 3.00 (IH, m), 1.90-1.00 (1OH, m). Found: C 59.64, H 5.93, N 16.86%; C29H3iN7O2-2HCl requires: C 59.79, H 5.71, N 16.83%.
Example 19: 2-[5-Cyclohexyl-l-(4-guanidinophenyl)-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepm-3-yl]-'N-quinolin-8-yl-acetamide The title compound was obtained using steps d-f of the method of preparation of example 13 except that 8-aminoquinoline was used in step f in place of diphenylmethylamine. 1H NMR (DMSO-d6) 10.34 (IH, s), 9.91 (IH, s), 8.63 (2H, m), 8.35 (IH, d), 7.71 (IH, d), 7.62- 7.52 (5H, m), 7.50 (4H, br s), 7.39 (2H, d), 7.35 (2H, d), 6.87 (IH, d), 4.47 (IH5 d), 4.14 (IH, d), 3.06 (IH, m), 1.83-1.00 (1OH, m). Found: C 55.99, H 5.60, N 15.95%; C32H32N8O2-SHCl-H2O requires: C 55.86, H 5.42, N 16.20%.
Example 20 : ~N-[4-(5-Cyclohexyl-2~oxo-3-(3-phenyl-allyl)-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-1-yl) -phenyl] -guanidine
Step a: 5-Cyclohexyl-3-(4-methoxy-benzyl)-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using steps a-c of the method of preparation of example 1, except that 4-methoxybenzylhydrazine was used in step a in place of benzylhydrazine. 1H NMR (CDCl3): 8.13 (2H, d), 7.51 (2H, d), 7.49-7.35 (3H, m), 7.15 (2H, d), 6.98 (IH, d), 6.77 (2H5 d), 4.90 (IH5 br s), 4.55 (IH5 br s), 3.78 (3H, s), 2.75 (IH5 m), 1.83-1.12 (1OH, m).
Step b: 5-Cyclohexyl-l-(4-nitrophenyl)-l ,2-dihydro-3H-l ,3 ,4-benzotriazepin-2-one A solution 5-cyclohexyl-3-(4-methoxy-benzyl)-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (3.1Og, 6.4mmol) in trifluoroacetic acid (15mL) was heated under reflux for 2h. The solution was evaporated to dryness and the residue partitioned between EtOAc and saturated NaHCO3. The organic layer was separated and dried (MgSO4). Filtration and evaporation of the solvent was followed by trituration of the residue with hexane to afford the product. 1H NMR (CDCl3) 8.21 (2H, d), 7.60 (2H, d), 7.50-7.33 (4H5 m), 6.80 (IH5 d), 2.89 (IH, m), 1.96-1.25 (10H5 m).
Step c: S-CyclohexylA^-nitrophenyl^^-phenyl-allyiyi^-dϊhydro^H-l^^-benzotriazepin- 2-one
Sodium hydride (60% dispersion in oil/ 50mg, 1.25mmol) was added to a solution of 5- cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (364mg, lmmol) in dry DMF (4mL) at ambient temperature. The resultant mixture was stirred for lOmin. and (3- bromopropenyl)-benzene (216mg, 1. lmmol) was added. The reaction mixture was heated at
1000C for lhr and on cooling the mixture was diluted with EtOAc (3OmL), washed with brine
(4 x 3OmL) and dried (MgSO4); Filtration and evaporation of the solvent afforded the product (480mg, 100%). 1H NMR (CDCl3) 8.15 (2H5 d), 7.55 (2H, d), 7.53-7.26 (8H, m), 6.98 (IH, d),
6.49 (IH, d), 6.20 (IH, m), 4.50 (IH, br s), 4.25 (IH, br s), 2.86 (IH, m), 2.00-1.10 (1OH, m).
Step d: l-(4-Aminophenyl)-5-cyclohexyl-3-(3-phenyl-allyl)-l,2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step d of the method of preparation of example 1, except that 5-cyclohexyl-l -(4-nitrophenyl-3 -(3 -phenyl-allyl)- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-2-one was used in place of 3-ben2yl-5-eyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (CDCl3) 7.52-7.22 (8H, m), 7.15 (2H, d), 6.81 (IH, d), 6.65 (2H, d), 6.47 (IH, d), 6.30 (IH, m), 4.5-4.00 (2H5 br d), 3.71 (2H, br s), 2.77 (IH, m), 2.00-1.24 (10, m).
Step e: Bis-ftert-butoxycarbonylJ-ft-β-cyclohexyl-Σ-oxo-S-βψhenyl-allylJ-l^-dihydro-SH- l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyi)-5-cyclohexyl-3-(3-phenyl-allyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of l-(4-aminophenyl)-3-benzyl-5- cyclohexyI-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (CDCl3) 11.63 (IH, s), 10.38 (IH, s), 7.60 (2H, d), 7.38-7.17 (1OH, m), 6.81 (IH, d), 6.50 (IH, d), 6.30 (IH, m), 4.50-4.00 (2H, br d), 2.80 (IH, m), 2.00-1.26 (1OH, m), 1.54 (9H, s), 1.50 (9H, s).
Step f: The title compound was obtained using step f of the method of preparation of example 1, except that bis-(fert-butoxycarbonyl)-[4-(5-cyclohexyl-2-oxo-3-(3-phenyl-allyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine was used in place of N,N-bi$-(tert- butoxycarbonyl)-N' -[4-(3 -benzyl-5 -cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 , 3 ,4-benzotriazepin- 1 - yl)-phenyl]-guanidine. 1H ΝMR (DMSO-d6) 9.93 (IH, s), 7.66 (IH, d), 7.51 (4H, br s), 7.41- 7.20 (HH, m), 6.79 (IH, d), 6.43 (IH, d), 6.20 (IH, m), 4.40-3.90 (2H, br d), 3.00 (IH, m), 2.00-1.25 (1OH, m). Found: C 63.01, H 6.13, Ν 14.00%; C30H32N6O^HCl requires: C 63.05, H 6.28, N 13.79%.
Example 21 : N-^-p-Benzhydryl-S-cyclohexyW-oxo-l^-dihydro-SH-ljS^-benzotriazepin-l- yl)-phenyl]-guanidine
The title compound was obtained using steps c-f of the method of preparation of example 20, except that bromodiphenylmethane was used in step c in place of (3-bromopropenyl)-benzene. 1H NMR (DMSO-de) 9.97 (IH, s), 7.66 (IH, d), 7.51 (4H, br s), 7.46-7.07 (16H, m), 6.84 (IH, d), 6.15 (IH, s), 3.90 (IH, m), 1.67-1.00 (1OH, m). Found: C 66.18, H 6.16, N 13.80%; C34H34N6O^HCl requires: C 66.34, H 5.89, N13.65%.
Example 22 : Η-[4-(5-Cyclohexyl-3-naphthalen-2-ylmethyl-2-oxo-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-1-yl) -phenyl] '-guanidine The title compound was obtained using steps c-f of the method of preparation of example 20, except that 2-bromomethylnaphthalene was used in step c in place of (3-bromopropenyl)- benzene. 1H NMR (DMSO-d6) 10.14 (IH, s), 7.91-7.76 (3H, m) 7.73 (IH, s), 7.65 (4H, br s), 7.60-7.51 (6H, m), 7.44-7.38 (4H, m), 6.95 (IH, d) 5.25-4.50 (2H, d), 3.07 (IH, m), 1.86-1.20 (1OH, m). Found: C 65.45, H 6.05, N 14.01%; C32H32N6O-IHCl requires: C 65.19, H 5.81, N 14.25%.
Example 23: N-ft-β-ft-tert-Butyl-ben∑yty-S-cyclohexyte-oxo-lJ-dihydro-SH-lΛJ- benzotriazepin-1-ylJ-phenylj-guanidine. The title compound was obtained using steps c-f of the method of preparation of example 20, except that 4-tert-butyl-benzyl bromide was used in step c in place of (3-bromopropenyl)- benzene. 1H NMR (DMSO-d6) 7.63 (IH, d), 7.60-7.21 (8H, m) 7.05 (2H, m), 6.79 (IH, d), 4.75 (IH, m), 4.23 (IH, m), 2.96 (IH, m), 1.74-1.07 (19H, m). Found: C 59.04, H 6.37, N 12.29%; C32H38N6O-S .6HCl -0.3 Et2O requires: C 58.97, H 6.65, N 12.43%. Example 24: Η-[4-(5-Cyclohexyl-2-oxo-3-quinolin-8-ylmethyl-l,2-dihydro-3H-l,3,4- benzotriazepin-1-yl) -phenyl] -guanidine
The title compound was obtained using steps c-f of the method of preparation of example 20, except that 8-bromomethyl-quinoline was used in step c in place of (3-bromopropenyl)- benzene. 1H NMR (DMSO-d6) 8.90 (IH, d), 8.57 (IH, m), 7.95 (IH, d), 7.69 (IH, m), 7.58- 7.51 (6H, m) 7.43-7.23 (3H, m), 6.85 (IH, m), 5.48 (IH, m), 5.12 (IH5 m), 2.85 (IH, m), 1.66- 1.57 (6H, m), 1.27-1.19 (4H, m). Found: C 54.35, H 5.68, N 13.84%; C31H31N7O-3.7HC1- 2H2O requires: C 54.07, H 5.66, N 14.23%.
Example 25: Υ^-[4-β-Biphenyl-2-ylmethyl-5-(^dohexyl-2-oxo-l,2-dihydro-3Y{.-l,3,4- benzotriazepin-1-yl) -phenyl] '-guanidine Step a: l-(4-Aminophenyl)-5-cyclohexyl-3-biphenyl-2-ylmethyl-l,2-dihydro-3Yi-l,3,4- benzotriazepin-2-one was obtained using steps c and d of the method preparation of example 20, except that 2-bromomethyl-biphenyl was used in place of (3-bromopropenyl)-benzene in step c.
Step b: The title compound was obtained using steps e and f of the method of preparation of example 20, except that l-(4-aminophenyl)-5-cyclohexyl-3-biphenyl-2~ylmethyl-l,2-dihydro-
3H-l,3,4-benzotriazepin-2-one was used in place of 5-cyclohexyl-l-(4-nitrophenyl-3-(3- phenyl-allyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (DMSO-d6) 9.92
(IH, s), 7.56-7.26 (6H, m), 7.25-7.21 (12H, m), 7.10-7.04 (3H, m), 6.75 (IH, d), 4.81 (IH, d),
4.22 (IH, d), 2.89 (IH, m), 1.72-1.18 (1OH, m). Found: C 66.07, H 6.06, N 13.10%; C34H34N6O-2HCl-0.25 C4H8O2 requires: C 65.92, H 6.00, N 13.18%.
Example 26: N-^-P-ft-Adamantan-l-yl-benzylJ-S-cyclohexyl^-oxo-lJ-dihydro-SH-l^J- benzotriazepin-l-yl]-phenyl}-guanidine
Step a: 4-(l-Adamantyl) benzyl bromide A mixture of 4-(l-adamantyl)toluene (1.18g, 5mmol), benzoyl peroxide (lOmg), and N- bromosuccinimide (940mg, 5.25mmol) in CCU (3OmL) were heated at reflux for 2h. On cooling, the mixture was filtered and the filtrate evaporated to afford the product (1.18g, 74%). 1HNMR (CDCl3) 7.35 (4H, s), 4.50 (2H, s), 2.11 (3H, m), 1.91 (6H, m), 1.78 (6H, m). Step b: The title compound was obtained using steps c-f of the method of preparation of example 20 except that 4-adamantylbenzyl bromide was used in step c in place of (3- bromopropenyO-benzene. 1HNMR (DMSO-d6/D2O) 7.62 (IH, d), 7.43-7.17 (8H, m) 7.07 (2H, m), 6.79 (IH, d), 4.78 (IH, m), 4.40 (IH, m), 2.96 (IH, m), 2.00 (3H, m) 1.78-1.69 (18H, m), 1.35-1.21 (4H, m). Found: C 64.86, H 6.66, N 11.90%; C38H44N6O~2.8HCl-0. IC4H8O2 requires: C 64.93, H 6.71, N 11.95%.
Example 27: ^-[4-(5-Cyclohexyl-3-naphthalen-l-ylmethyl-2-oxo-l,2-dihydro~3H-l, 3, 4- benzotriazepin-l-yl)-phenyl]-guanidine
The title compound was obtained using steps c-f of the method of preparation of example 20, except that 1-bromomethyl naphthalene was used in step c in place of (3-bromopropenyl)- benzene. 1H NMR (DMSO-d6/D2O) 7.87 (2H, m), 7.76 (IH, d), 7.49-7.21 (12H, m) 6.79 (IH, d), 5.38 (IH, m), 4.82 (IH, m), 2.89 (IH, m), 1.72-1.61 (6H, m), 1.31-1.14 (4H, m). Found: C 62.80, H 5.73, N 12.80%; C32H32N6O-2.5HCI-0.5 C4H8O2 requires: C 62.64, H 5.95, N 12.89%.
Example 28 : Y{-{4-[5-Cyclohexyl-2-oxo-3-(l-phenyl-ethyl)-l,2-dihydro-3H-l, 3, 4- benzotriazepin-l-yl]-phenyl}-guanidine
The title compound was obtained using steps c-f of the method of preparation of example 20, except that (l-bromo-ethyl)-benzene was used in step c in place of (3-bromopropenyl)- benzene. 1H NMR (DMSO-d6/D2O) 7.49-7.23 (12H, m) 6.77 (IH, d), 5.12 (IH, m), 2.97 (IH, m), 1.75-1.06 (13H, m). Found: C 63.45, H 6.42, N 14.93%; C29H32N6O-LSHCMU C4H8O2 requires: C 63.48, H 6.33, N 14.90%.
Example 29: Yi-(4-{5-Cyclohexyl-3-[2-(l-methyl-cyclohexyl)-2-oxo-ethyl]-2-oxo-l,2-dihydro- SH-1, 3, 4-benzotriazepin-l-yl}-phenyl)-guanidine
The title compound was obtained using steps c-f of the method of preparation of example 20, except that 2-bromo-l-(l-methyl-cyclohexyl)-ethanone (WO 03041714) was used in step c in place of (3-bromopropenyl)-benzene. 1H NMR (DMSO-d6) 7.63 (IH, d), 7.41-7.11 (1OH, m) 6.79 (IH, d), 4.42 (2H, m), 2.98 (IH, m), 1.88-1.04 (23H, m). Found: C 56.16, H 6.53, N 11.87%; C3oH38N602-3.5HCl-0.6 C4H8O2 requires: C 55.98, H 6.71, N 12.09%. Example 30 : ~N-[4-(3-Biphenyl-4-ylmethyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l, 3, 4- benzotriazepin-1 -yl) -phenyl] '-guanidine
The title compound was obtained using steps c-f of the method of preparation of example 20, except that 4-bromomethyl-biphenyl was used in step c in place of (3-bromopropenyl)- benzene. 1H NMR (DMSO-d6/D2O) 7.62-7.22 (18H, m), 6.81 (IH, d), 4.81 (IH, m), 4.48 (IH, m), 2.96 (IH, m), 1.76-1.49 (5H, m), 1.33-1.22 (5H, m). Found: C 64.59, H 5.88, N 12.56%; C34H34N6O-2.3HC1 -0.4 C4H8O2 requires: C 64.61, H 6.02, N 12.77%.
Example 31: Η-[4-(3-Biphenyl-3-ylmethyl-5-cyclohexyl-2-oxo~l ,2-dihydro-3H-l ,3 ,4- benzotriazepin-l-yl)-phenyl]-guanidine The title compound was obtained using steps c-f of the method of preparation of example 20, except that 3-bromomethyl-biphenyl was used in step c in place of (3-bromopropenyl)- benzene. 1H NMR (DMSO-d6/D2O) 7.69-7.09 (17H, m), 6.81 (IH, d), 4.89 (IH, m), 4.38 (IH, m), 2.97 (IH, m), 1.74-1.61 (5H, m), 1.37-1.07 (5H, m). Found: C 64.69, H 5.89, N 12.77%; C34H34N6O-2.3HCI-O.4 C4H8O2 requires: C 64.61, H 6.02, N 12.70%. Example 32: N-tf-fS-Cyclohexyl^-oxo-S-ft-trifluoromethyl-benzylj-lJ-dihydro-SH-l.SJ- benzotriazepin-l-yl]-phenyl}-guanidine
The title compound was obtained using steps c-f of the method of preparation of example 20, except that l-bromomethyl-2-trifluoromethyl-benzene was used in step c in place of (3- bromopropenyl)-benzene. 1H NMR (DMSO-d6/D2O) 7.60-7.21 (1OH, m), 7.04 (IH m), 6.80 (IH, m), 5.09 (IH, m), 4.53 (IH, m), 2.89 (IH, m), 1.68-1.05 (10 H, m).
Example 33 : N-{4-[3-(3, 5-Bis-trifluoromethyl-benzyl)-5-cyclohexyl-2-oxo-l, 2-dihydro-3H- l,3,4-benzotriazepin-l-yl]-phenyl}-guanidine
The title compound was obtained using steps c-f of the method of preparation of example 20, except that l-bromomethyl-3,5-bis-trifluoromethyl-benzene was used in step c in place of (3- bromopropenyl)-benzene. 1H NMR (DMSO-d6/D2O) 7.91-7.82 (3H, m), 7.56-7.12 (7H, m), 4.80 (2H, m), 2.94 (IH, m), 1.70-1.15 (10 H, m). Found: C 43.34, H 4.76, N 11.03%; C3oH3oN6OF6-2HCl-2.8C3H7NO-2CHCl3 requires: C 43.29, H 4.82, N 10.99%.
Example 34: N-{4-[5-Cyclohexyl-2-oxo-3-(2,4,6-trimethyl-benzyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl]-phenyl}-guanidine The title compound was obtained using steps c-f of the method of preparation of example 20, except that 2,4,6-trimethylbenzyl bromide was used in step c in place of (3-bromopropenyl)- benzene. 1H NMR (DMSO-d6/D2O) 7.48-7.20 (7H, m), 6.78 (IH, m), 6.67 (2H, s), 4.72 (IH, d), 4.43 (IH, d), 2.85 (IH, m), 2.11-2.06 (9H, m), 1.64-1.48 (5H, m), 1.26-1.03 (5H, m). Found: C 60.72, H 6.64, N 13.26%; C3iH36N6O-2.8 HCl-0.3 C4H8O2 requires: C 60.69, H 6.52, N 13.19%.
Example 35: 'N-{4-[5-Cyclohexyl-2-oxo-3-(3-phenoxy-benzyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl]-phenyl}-guanidine The title compound was obtained using steps c-f of the method of preparation of example 20, except that 3-phenoxybenzyl bromide was used in step c in place of (3-bromopropenyl)- benzene. 1H NMR (DMSO-d6) 7.42-7.10 (15H, m), 6.96-6.67 (6H, m), 4.75 (IH, m), 4.42 (IH, m), 2.85 (IH, m), 1.70-1.12 (10 H, m). Found: C 58.70, H 5.03, N 10.77%; C34H34N6O2- 1.8 CF3CO2H-0.4 C4H8O2 requires: C 58.91, H 4.92, N 10.52%. Example 36: Υk-{4-[5-Cyclohexyl-3-(2-methyl-biphenyl-3-ylmethyl)-2-oxoA,2-dϊhydro-3H- l,3,4-benzotriazepin-l-yl]-phenyl}-guanidine
The title compound was obtained using steps c-f of the method of preparation of example 20, except that 3-bromomethyl-2-methyl-biphenyl was used in step c in place of (3- bromopropenyl)-benzene. 1H NMR (DMSO-d6/D2O) 7.56-6.78 (16H, m), 4.95 (IH, m), 4.41 (IH, m), 2.90 (IH, m), 1.88 (3H, s), 1.70-1.05 (1OH, m).
Example 37 : Η-{4-[5-Cyclohexyl-3-(3, 3-diphenyl-propyl)-2-oxo-l,2-dihydro-3H-l, 3, 4- benzotriazepin-l-yl]-phenyl}-guanidine
The title compound was obtained using steps c-f of the method of preparation of example 20, except that 3,3-diphenylpropyl bromide was used in step c in place of (3-bromopropenyl)- benzene. 1H NMR (DMSO-d6/D2O) 7.68 (IH, d), 7.44-7.04 (16H, m), 6.80 (IH, d), 3.67 (IH, t), 3.21 (2H, d), 2.96 (IH, m), 2.14 (2H, d), 1.89-1.03 (1OH, m). Found: C 68.09, H 6.41, N 12.81%; C36H38N6O-LOHCl-0.3 C4H8O2 requires: C 68.16, H 6.46, N 12.82%.
Example 38 : N-[4-(5-Cyclohexyl-3-octyl-2-oxo-l, 2-dihydro-3H-l, 3, 4-benzotriazepin-l-yl)- phenylj-guanidine
The title compound was obtained using steps c-f of the method of preparation of example 20, except that 1-octyl bromide was used in place of (3-bromopropenyl)-benzene in step c. 1H NMR (DMSOd6) 7.62-7.10 (7H, m), 6.76 (IH, m), 3.46 (IH, m), 2.98 (IH, m), 1.92-1.12 (22H, m), 0.81 (3H, m). Found: C 57.25, H 7.29, N 13.70%; C29H4ON6O-S-SHCl-O-IC4H8O2 requires: C 57.16, H 7.19, N 13.60%.
Example 39: 3-Benzyl-5-cyclohexyl-l-[4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl]-l,2- dihydro-3H-l , 3, 4-benzotriazepin-2-one
Step a: 2-[4-(3-Benzyl-5-cyclohexyl-2-oxo-l,2-dihydι-o-3H-l,3,4-benzotriazepin-l-yl)- phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester was obtained using step e of the method of preparation of example 1 except that
Figure imgf000093_0001
2-thioxoimidazolidine-l,3- dicarboxylate was used in place of bis-(ter/-butoxycarbonyl)-2-methyl-2-thiopseudourea.
Step b: 3-Benzyl-5-cyclohexyl-l-[4-(4,5-dihihydro-lH-imidazol-2-ylamino)-phenyl]-l,2- dihydro-3H-l, 3, 4-ben∑otriazepin-2-one
A solution of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)- phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester (60mg, 0.09mmol) in trifluoroacetic acid (ImL) was stirred at ambient temperature for 16h. The solvent was removed at reduced pressure and the residue was re-evaporated from Et2O (3 x 5mL).
Trituration of the residue with Et2O afforded the trifluoroacetate salt of the title compound, which was isolated by filtration and dried (40mg, 90%). 1H NMR (CD3OD) 7.49-7.13 (12H, m), 6.83 (IH, d), 5.00-4.25 (2H, d), 3.78 (4H, s), 2.85 (IH, m), 1.83-1.25 (1OH, m). Found: C
60.96, H 5.61, N 13.18%; C3OH32N6O-CF3COOH-LSH2O requires: C 60.66, H 5.72, N13.26%.
Example 40 : 3-Biphenyl-2-ylmethyl-5-cyclohexyl-l -[4-(4, 5-dihydro-lH-imidazol-2-ylamino)- phenylj-l ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one
The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyl)-5-cyclohexyl-3-biphenyl-2-ylmethyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 25, step a) and di-tert-butyl 2-thioxoimidazolidine-l,3- dicarboxylate were used in place of l-(4-aminophenyl)-3~benzyl~5-cyclohexyl-l,2-dihydro- 3Η-l,3,4-benzotriazepin-2-one and bis-(tert-butoxycarbonyl)-2-methyl-2-thioρseudourea respectively, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5- cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 -yl)-phenylimino]-imidazolidine- 1,3- dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39. 1H NMR (CDCl3) 12.40 (IH, bs), 7.38-6.63 (17H, m), 5.20-4.00 (4H, m), 3.81 (4H, s), 2.70 (IH, m), 1.90-1.20 (1OH, m). Found: C 62.87, H 5.23, N 10.98%; C36H36N6O.CF3CO2H-0.7 DCM requires: C 62.63, H 5.22, N 11.32%. Example 41: 3-Benzyl-5-cyclohexyl-l-[4-(l,4,5,6-tetrahydro-pyrirnidin-2-ylamino)-phenyl]- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one.
The title compound was obtained using step e of the method of preparation of example 1, except that di-tert-butyl 2-thioxopyrimidine-l,3-(2H,4H)-dicarboxylate was used in place of bis-(fert~butoxycarbonyl)-2-methyl-2-thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3Η~l,3,4- benzotriazepin-l-yl)-phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39. 1H NMR (DMSO-d6) 9.75
(IH, s), 8.23 (2H, br s), 7.61 (IH, d), 7.41-7.14 (HH, m), 6.80 (IH, d), 5.00-4.25 (2H, d), 3.28 (4H, br s), 2.94 (IH, m), 1.88 (2H, m), 1.85-1.15 (1OH, m). FoundrC 62.20, H 5.95, N 13.03%;
C3IH34N6O-CF3COOH-H2O requires: C 62.07, H 5.80, N 13 17%.
Example 42: 3-Biphenyl-2-ylmethyl-5-cyclohexyl-l~[4-(l,4,5, 6-tetrahydro-pyrimidin-2- ylamino) -phenyl] -1, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyl)-5-cyclohexyl-3-biphenyl-2-ylmethyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 25, step a) and di-tert-butyl 2-thioxopyrimidine-l,3-(2H,4H)- dicarboxylate were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro- 3Η-l,3,4-benzotriazeρin-2-one and bis-(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5- cyclohexyl-2-oxo-l ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 -yl)-phenylimino]-imidazolidine- 1,3- dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39.
1H NMR (CDCl3) 11.58 (IH, bs), 8.10-5.50 (2OH, m), 5.20-4.30 (2H, d), 3.81 (4H, s), 3.42 (4H, m), 2.70 (IH, m), 2.06-1.26 (12H, m). Found: C 62.01, H 5.39, N 10.81%; C37H38N6O- 1.5 CF3CO2H-1.2 H2O requires: C 61.96, H 5.45, N 10.84%.
Example 43 : 3-(3-Chloro-biphenyl-2-ylmethyl)-5-cyclohexyl-l-[4-(4, 5-dihydro-lH-imidazol-2- ylamino)-phenyl]-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
Step a: l-(4-Aminophenyl)-5-cyclohexyl-3-(3-chloro-biphenyl-2-ylmethyl)-l,2-dihydro-3H~ l,3,4-benzotrιazepin-2-one was obtained using step c of the method of preparation of example 20, except that 2-bromomethyl-3-chloro-biphenyl was used in place of (3-bromopropenyl)- benzene, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4- nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step d of the method of preparation of example 1. Step b: The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyl)-5-cyclohexyl-3-(3-chloro-biphenyl-2-ylmethyl)-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one and di-tert-butyl 2-thioxoimidazolidine-l,3-dicarboxylate were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and bis-(fe/Y-butoxycarbonyl)-2-methyl-2-thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 -yl)-phenylimino]-imidazolidine- 1 ,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39. 1H NMR (DMSOd6) 7.50-6.96 (15H, m), 6.65 (IH, d), 4.71 (2H, m), 3.64 (4H, s), 2.77 (IH, m), 1.62- 1.11 (1OH, m). Found: C 60.49, H 4.88, N 10.61%; C36H35ClN6O-LS CF3CO2H-0.3 C4H8O2 requires: C 60.31, H 4.90, N 10.50%.
Example 44: 5-Cyclohexyl-l-[4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl]-3-(2-phenethyl- benzyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
Step a: l-(4-Aminophenyl)-5-cyclohexyl-3-(2-phenethyl~benzyl)-l ,2-dihydro-3H-l ,3 ,4- benzotriazepin-2-one was obtained using step c of the method of preparation of example 20, except that l-(2-bromophenethyl)benzene was used in place of (3-bromopropenyl)-benzene followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4- nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step d of the method of preparation of example 1. Step b: The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyl)-5-cyclohexyl-3-(2-phenethyl-benzyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and di-tert-butyl 2-thioxoimidazolidine-l,3-dicarboxylate were used in place of 1 -(4-aminophenyl)-3 -benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and bis-(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39. 1H NMR (DMSO-d6/D2O) 8.37-6.99 (16H, m), 6.68 (IH, d), 5.01 (IH, d), 4.35 (IH, d), 3.65 (4H, s), 2.91 (2H, m), 2.71 (2H, m), 2.56 (IH, m), 1.71-1.19 (1OH, m). Found: C 63.31, H 5.57, N 10.57%; C38H40N6O-LO CF3CO2H-0.2 C4H8O2 requires: C 63.31, H 5.47, N 10.55%.
Example 45: 2'-{5-Cyclohexyl-l-[4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl]-2-oxo-l,2~ dihydro-3H-l,3,4-benzotriazepin-3-ylmethyl}-biphenyl-2-carboxylic acid methyl ester
Step a: 2'-Bromomethyl-biphenyl-2-carboxylic acid methyl ester was obtained using step a of the method of preparation of Example 26, except that 2'-methyl-biphenyl-2-carboxylic acid methyl ester (Badone, D. et al. J. Org. Chem. (1997), 62, 170-173) was used in place of 4-(l- adamantyl)toluene.
Step b: 2'-{5-Cyclohexyl-l-[4-aminophenyl)-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-3- ylmethyl}-biphenyI-2-carboxylic acid methyl ester was obtained using step c of the method of preparation of example 20, except that 2'-bromomethyl-biphenyl-2-carboxylic acid methyl ester was used in place of (3-bromopropenyl)-benzene, followed by treatment of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step d of the method of preparation of example 1.
Step c: The title compound was obtained using step e of the method of preparation of example 1, except that 2'-{5-cyclohexyl-l-[4-aminophenyl)-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-3-ylmethyl}-biphenyl-2-carboxylic acid methyl ester and di-tert-butyl 2- thioxoimidazolidine-l,3-dicarboxylate were used in place of l-(4-aminophenyl)-3-benzyl-5- cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and bis-(tert-butoxycarbonyl)-2- methyl-2-thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5~cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 -yl)-phenylimino]- imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation example 39. 1H NMR (DMSO-d6/D2O) 7.75 (IH5 m), 7.42-7.19 (12H, m), 6.85
(IH, m), 6.58 (IH, m), 4.76 (IH, m), 4.10 (IH, m), 3.64 (4H, s), 3.49 (3H5 s),: 2.84 (IH, m),
1.65-1.11 (1OH, m). Found: C 58.62, H 4.81, N 9.83%; C38H38N6O3^l CF3CO2H requires: C 58.51, H 4.67, N 9.70%.
Example 46: 5-Cyclohexyl-l-[4-(4,5-dihydw-lH-imidazol-2-ylamino)-phenyl]-3-naphthalen- 2-ylmethyl-l, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
Step a: l-(4-Aminophenyl)-5-cyclohexyl-3-naphthalen-2-ylmethyl-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step c of the method of preparation of example 20, except that 2-bromomethylnaphthalene was used in place of (3-bromopropenyl)-benzene followed by treatment of the product, in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2~ dihydro-3H-l,3,4-benzotriazepin-2-one, according to step d of the method of preparation of example 1. 1H NMR (CDCI3) 7.67 (IH, m), 7.65 (3H, m), 7.42 (2H, m), 7.29 (3H, m), 7.14 (3H5 m), 6.83 (IH, d), 6.67 (2H5 d), 5.20-4.65 (2H, br s), 3.80 (2H, br s), 2.70 (IH, m), 1.81- 1.24 (10, m).
Step b: The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyl)-5-cyclohexyl-3-naphthalen-2-ylmethyl-l,2-dihydro-3H- l,3,4-benzotriazeρin-2-one and di-tert-butyl 2-thioxoimidazolidine-l,3-dicarboxylate were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and bis-(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl~2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 -yl)-phenylimino]-imidazolidine- 1 ,3 -dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation example 39. 1H NMR (DMSOd6ZD2O) 7.81-7.67 (3H, m), 7.58 (2H5 m), 7.45-7.24 (9H, m), 6.79 (IH, d), 4.92 (IH, br s), 4.58 (IH5 br s), 3.64 (4H5 s), 2.89 (IH, m), 1.68-1.13 (1OH5 m). Found: C 62.40, H 5.42, N 11.80%; C34H34N6O-I^ CF3CO2H-0.3 C4H8O2 requires: C 62.63, H 5.23, N 11.53%.
Example 47 : 3-(3 ' 5 '-Bis-trifluoromethyl-biphenyl^-ylmethyfyS-cyclohexyl-l-ft-^, S-dihydro- lH-imidazol-2-ylamino)-phenyl]-l!2-dihydro-3H-l,3,4-benzotriazepin-2-one Step a: l^-AmmophenylJ-S-cyclohexyl-S-fS'^'-bis-trifluoromethyl-biphenyl^-ylmethyl)-!^- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step c of the method of preparation of example 20, except that 2'-bromomethyl-3,5-bis-trifluoromethyl-biphenyl was used in place of (3-bromopropenyl)-benzene followed by treatment of the product, in place of 3-benzyl-5- cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step d of the method of preparation of example 1. 1H NMR (CDCl3) 7.76 (3H, s), 7.33-7.08 (9H5 m), 6.78 (IH, d), 6.63 (2H5 m), 4.86 (IH, m), 4.45 (IH, m), 3.47 (2H. m), 2.69 (IH, m), 1.85-1.22 (10H5 m).
Step b: The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyl)-5-cyclohexyl-3-(3',5'-bis-trifluoromethyl-biphenyl-2- ylmethyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and di-tert-butyl 2-thioxoimidazolidine- 1,3-dicarboxylate were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l ,3,4-benzotriazepin-2-one and bis-(/ert-butoxycarbonyl)-2-methyl-2- thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4-(3- benzyl-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 -yl)-phenylimino]- imidazolidine- 1,3 -dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39. 1H NMR (DMSO-d6) 7.97 (IH, s), 7.87 (2H, s), 7.38-7.14 (12H5 m)5 6.89 (IH5 m), 6.63 (2H5 m), 4.84 (IH, m), 4.33 (IH, m), 3.65 (4H, s), 2.84 (IH, m), 1.66- 1.51 (5H, m), 1.27-1.12 (5H, m). Found: C 55.82, H 4.33, N 9.26%; C38H34F6N6O-LO CF3CO2H-0.3 C4H8O2 requires: C 55.74, H 4.19, N 9.20%. Example 48: δ-Cyclohexyl-l-ft-ft.S-dihydro-lH-imidazol^-ylaminoJ-phenylJ-S-β'-methyl- biphenyl-2-ylmethyl)-l,2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
Step a: l-ø-Aminophenylj-S-cyclohexyl-S-tø'-methyl-biphenyl^-ylmethylJ-l^-dihydro-SH- l,3,4-benzotriazepin-2~one was obtained using step c of the method of preparation of example 20, except that 2-bromomethyl-2'-methyl-biphenyl was used in place of (3-bromopropenyl)- benzene followed by treatment of the product, in place of 3-benzyl-5-cyclohexyl-l-(4- nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step d of the method of preparation of example 1.
Step b: The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyl)-5-cyclohexyl-3-(2'-methyl-biphenyl-2-ylmethyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one and di-ter/-butyl 2-thioxoimidazolidine-l,3- dicarboxylate were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one and bis-(tørt-butoxycarbonyl)-2-methyl-2-thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5- cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin- 1 -yl)-phenylimino]-imidazolidine- 1,3- dicarboxylic acid di-fert-butyl ester, according to step b of the method of preparation of example 39. 1H NMR (DMSO-d6/D2O) 7.57 (IH, d), 7.29 (IH, m), 7.22 (1OH, m), 6.99 (2H, m), 6.68 (2H, m), 4.74 (IH, d), 4.01 (IH, m), 3.64 (4H, s), 2.87 (IH, m), 1.85-1.05 (13H, m). Found: C 58.67, H 4.91, N 9.82%; C37H38N6O-2.4 CF3CO2H-0.1 C4H8O2 requires: C 58.58, H 4.80, N 9.71%.
Example 49: 5-CydohexylA-[4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl]-3-(l- naphthalen-l-yl-ethyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
Step a: l-(4-Aminophenyl)-5-cyclohexyl-3-(l-naphthalen-l-yl-ethyl)-l,2-dihydro-3H-l,3,4- henzotriazepin-2-one was obtained using step c of the method of preparation of example 20, except that l-(l~bromo-ethyi)-naphthalene was used in place of (3-bromopropenyl)-benzene followed by treatment of the product, in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one, according to step d of the method of preparation of example 1.
Step b: The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyl)-5-cyclohexyl-3-(l-naphthalen-l-yl-ethyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one and di-tert-butyl 2-thioxoimidazolidine-l,3-dicarboxylate were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and bis-(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 -yl)-phenylimino]-imidazolidine- 1 ,3 -dicarboxylic acid di-fert-butyl ester, according to step b of the method of preparation example 39. 1H NMR (CD3OD) 7.94-6.81 (16H, m), 6.01 (IH, m), 3.81 (4H, s), 2.78 (IH, m), 1.87-1.33 (13H, m). Found: C 62.59, H 5.37, N 10.38%; C35H36N6O-1.4 CF3CO2H-0.9 C4H8O2 requires: C 62.50, H 5.65, N 10.56%. Example 50: 5-Cyclohexyl-l~[4-(4,5-dihydro-lH-imidazol-2-ylmnino)-phenyl]-3-(2- phenylethynyl-benzyl)-! , 2-dihydro-3H-l, 3, 4-benzotria∑epin-2-one
Step a: l-(4-Aminophenyl)-5-cyclohexyl-3-(2-phenylethynyl-benzyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using step c of the method of preparation of example 20, except that l-(2-(2-(bromomethyl)phenyl)ethynyl)benzene (Saishida H. et ah, J. Chem. Soc. Perkin Trans. 1, (2002), 606) was used in place of (3-bromopropenyl)-benzene followed by treatment of the product, in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one, according to step d of the method of preparation of example 1.
Step b: The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyl)-5-cyclohexyl-3-(2-phenylethynyl-benzyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one and di-tert-butyl 2-thioxoimidazolidine-l,3-dicarboxylate were used in place of l-(4-aminoρhenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and bis-(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4-(3~benzyl-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin- 1 -yl)-phenylimino]-imidazolidine-l ,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39. 1H NMR (DMSOd6ZD2O) 7.42-7.18 (14H, m), 6.99 (IH, m), 6.80 (IH, m), 6.58 (IH, m), 5.14 (IH, m), 4.50 (IH, m), 3.73 (4H, s), 2.82 (IH, m), 1.87-1.16 (1OH, m).
Example 51 : 5-Cyclohexyl-3-(2-cyclohexyl-benzyl)-l-[4-(4,5-dihydro-lH-imidazol-2-ylamino)- phenyl]-! ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one
Step a: l-(4-Aminophenyl)-5-cyclohexyl-3-(2-cyclohexyl-benzyl)-l ,2-dihydro-3H-l ,3 ,4- benzotriazepin-2-one was obtained using step c of the method of preparation of example 20, except that l-bromomethyl-2-cyclohexyl-benzene was used in place of (3-bromopropenyl)- benzene followed by treatment of the product, in place of 3-benzyl~5-cyclohexyl~l-(4- nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step d of the method of preparation of example 1.
Step b: The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-aminophenyl)-5-cyclohexyl-3-(2-cyclohexyl-benzyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and di-tert-butyl 2-thioxoimidazolidine-l,3-dicarboxylate were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and bis-(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea respectively, followed by reaction of the product obtained, in place of 2-[4~(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepm-l-yl)-phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39. 1H NMR (DMSO-d6/D2O) 7.53-7.13 (1OH, m), 6.71 (2H, m), 5.06 (IH, m), 4.26 (IH, m), 3.55 (4H, s), 2.87 (IH, m), 2.49 (IH, m), 1.71-1.02 (2OH, m). Found: C 56.96, H 5.59, N 10.35%; C36H42N6O-I^ CF3CO2H- 2.5C4H10O requires: C 57.15, H 5.89, N 10.05%.
Example 52 : ~N-[4-(3-Cycloheptyl-5-cyclohexyl-2-oxo-l, 2-dihydro-3H-l, 3, 4-benzotriazepin-l - yl) -phenyl] -guanidine
Step a: W-Cycloheptyl-hydrazinecarboxylic acid t&ft-butyl ester
To a stirred solution of the cycloheptanone (2.48mL, 21.0mmol) and tert-butylcarbazate (2.64g, 20.0mmol) in DCE (10OmL) was added sequentially NaBH(OAc)3 (6.36g, 40mmol) and HOAc (2.29mL, 40mmol). The resultant mixture was stirred at ambient temperature until the reaction was complete by TLC. The mixture was treated with 10% K2CO3 (20OmL) and extracted with EtOAc (20OmL). The extract was washed with brine (20OmL) and dried (MgSO4). Filtration and evaporation of the solvent followed by purification of the residue by chromatography on silica gel with as eluant afforded the product (3.5Og, 77%). 1H NMR (CDCl3) 6.02 (IH, br s), 3.82 (IH, br s), 3.02-2.96 (IH, m), 1.80-1.26 (21H, m). Step b: 3-Cycloheptyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
4-Nitrophenylchloroformate (15mmol) was added to an ice-cooled solution of (2- aminophenyl)-cyclohexyl-methanone (15mmol) and NEt3 (15mmol) in DCM (4OmL) and the resultant mixture stirred at this temperature for 2.5h. The mixture was diluted with DCM (3OmL), washed successively with 10% KHSO4 (6OmL), 10% K2CO3 (6OmL), brine (6OmL) and dried (MgSO4). On filtration and evaporation of the solvent the residue was dissolved in toluene (4OmL) and N'-cycloheptyl-hydrazinecarboxylic acid tert-butyl ester (lOmmol) added. The mixture was heated at reflux for 18h and on cooling and the solvent removed under reduced pressure. The residue was dissolved in EtOAc (10OmL), washed with 10% K2CO3 (10OmL), brine (10OmL) and dried (MgSO4). On filtration and evaporation of the solvent the residue was dissolved in Z-PrOH (4OmL), />TSA.H2O (30mmol) was added and the mixture heated at reflux for 2h. On cooling the mixture the solvent was removed under reduced pressure and the residue partitioned between EtOAc-10% K2CO3 (1:1 / 20OmL). The organic layer was separated, washed with brine (10OmL) and dried (MgSO4). Filtration and evaporation of the solvent was followed by addition of Et2O and the resultant solid was isolated by filtration and dried to afford the product. 1H ΝMR (CDCl3) 7.35-7.27 (2H, m), 7.11-7.06 (IH, m), 6.79-6.76 (IH, m), 6.08 (IH, br s), 4.16-4.07 (IH, m), 2.75-2.67 (IH, m), 1.89-1.27 (22H, m).
Step c: l-(4-Amino-phenyl)-3-cycloheptyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin~ 2-one was obtained using steps c and d of the method of preparation of example 1, except that 3-cycloheptyl-5-cyclohexyl-l,2~dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCI3) 7.55-7.08 (5H, m), 6.76-6.64 (3H, m), 4.01-3.92 (IH, m), 3.67 (2H, bs), 2.86-2.78 (IH, m), 2.17-1.16 (22H, m). Step d: The title compound was obtained using steps e and f of the method of preparation of example 1, except that l~(4-ammo~phenyl)-3-cycloheptyl~5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l ,3,4-benzotriazepin-2-one in step e. 1H NMR (DMSO-d6) 9.85 (IH, s), 1.62-1 $9 (HH, m), 6.75-6.71 (IH, m), 3.88-3.80 (IH, m), 3.06-2.99 (IH, m), 1.96-1.10 (22H, m). Found: C 61.49, H 7.16, N 14.23%; C28H36N6O-1.9HC1-0.6 C4H8O2 requires: C 61.39, H 7.24, N 14.13%.
Example 53 : ^-[4-(3,5-Dicyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)- phenylj-guanidine
Step a: 3,5-Dicyclohexyl-l ,2-dihydro-3¥L-l ,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation example 52, except that cyclohexanone was used in place of cycloheptanone in step a. 1H NMR (CDCl3) 7.34-7.27 (2H, m), 7.11-7.06 (IH, m), 6.81-6.78 (IH, m), 6.27 (IH, br s), 3.93-3.88 (IH, m), 2.75-2.66 (IH, m), 1.85-1.21 (2OH, m).
Step b The title compound was obtained using steps c-f of the method of preparation of example 1, except that 3,5-dicyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CD3COOD) 7.61-7.25 (7H, m), 6.88-6.86 (IH, m), 3.85 (IH, br m), 2.98 (IH, m), 1.90- 1.10 (2OH, m). Found: C 61.25, H 6.98, N 14.05%; C27H34N6O-LSHCl requires: C 60.99, H 7.15, N 14.13%.
Example 54: ~N-[4-(5-Cyclohexyl-3-dicyclohexylmethyl-2-oxo-l,2-dihydro-3H-l,3,4- benzoti"iazepin-l-yl)-phenyl]-guanidine
Step a: 5-Cyclohexyl-3-dicyclohexylmethyl-l,2-dihydro-3Η.-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that dicyclohexylketone was used in place of cycloheptanone in step a. 1H NMR (CDCl3) 7.35-7.27 (2H, m), 7.12-7.07 (IH, m), 6.81-6.78 (IH, m), 5.95 (IH, br s), 4.13-4.07 (IH, m), 2.75-2.67 (IH, m), 1.89-0.95 (32H, m).
Step b: The title compound was obtained using steps c-f of the method of preparation of example 1, except that 5-cyclohexyl-3-dicyclohexylmethyl- -l,2-dihydro-3H- 1,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c. 1H NMR (CD3COOD) 7.59-7.45 (4H, m), 7.38-7.28 (3H, m), 7.04 (IH, d), 4.16-4.12b (IH, m), 2.99 (IH, m), 2.02-0.60 (32H, m). Found: C 61.79, H 7.58, N 11.65%; C34H46N6O-2.7HCl-0.8 C4H8O2 requires: C 61.74, H 7.67, N 11.61%.
Example 55 : ^-{4-[5-Cyclohexyl-3-(2,2-diphenyl-ethyl)-2-oxo-J,2-dihydro-3H-l,3,4~ benzotriazepin-l-yl]-phenyl}-guanidine
Step a: 5-Cyclohexyl-3-(diphenyl-ethyl)-l,2-dihydro-3Y{-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that dicyclohexylketone was used in place of cycloheptanone in step a. 1H NMR (CDCI3) 7.27-7.26 (IH, m), 7.12-6.99 (12H, m), 6.68 (IH, m), 5.99 (IH, s), 4.33-4.22 (3H, m), 2.61-2.54 (IH, m), 1.80-1.72 (5H, m), 1.50-1.21 (5H, m).
Step b: The title compound was obtained using steps c-f of the method of preparation of example I5 except that 5-cyclohexyl-3-(diphenyl-ethyl)-l,2-dihydro-3H-l,3,4-benzotriazepin- 2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CD3COOD) 7.47-7.10 (17H, m), 6.74 (IH, d), 4.60 (IH, br s), 4.27-4.22 (IH, m), 3.98 (IH, br s), 2.04-1.72 (5H, m), 1.39-1.30 (5H3 m). Found: C 66.14, H 6.30, N 12.91%; C35H36N6O-2HCl-0.2 C4H8O2 requires: C 66.43, H 6.17, N 12.98%.
Example 56: l^-{4-[5-Cyclohexyl-3-(2,2-dimethyl-propyl)-2-oxo-l,2-dihydro-3H-l, 3, 4- benzotriazepin-l-yl]-phenyl}-guanidine
Step a: 5-Cyclohexyl-3-(2,2-dimethyl-propyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 2,2- dimethylpropanone was used in place of cycloheptanone in step a. 1H NMR (CDCl3): 7.37- 7.33 (2H, m), 7.15-7.10 (IH, m), 6.84 (IH, m), 6.19 (IH, br s), 3.66 (2H, s), 2.70-2.61 (IH, m), 1.84-1.72 (5H, m), 1.54-1.21 (5H, m), 0.76 (9H, s).
Step b: The title compound was obtained using steps c-f of the method of preparation of example 1, except that 5-cyclohexyl-3-(2,2-dimethyl-propyl)-l,2-dihydro-3H-l,3,4~ benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c. 1H NMR (DMSO-d6) 9.73 (IH, s), 7.65-7.62 (IH, d), 7.50-7.22
(1OH, m), 6.84 (IH, d), 4.06 (IH, br d), 2.98-2.89 (2H, m), 1.94-1.70 (6H, m), 1.37-1.10 (4H, m), 0.64 (9H, s). Found: C 58.25, H 6.90, N 14.94%; C26H34N6O-2.4HCl-0.3 C4H8O2 requires: C 58.28, H 6.98, N 14.99%.
Example 57 Υ^-{4-[5-Cyclohexyl-2-oxo-3-(c\%-4-phenyl-cyclohexyl)-l,2-dϊhydi'o-3H~l,3,4~ benzotriazepin-l-yl]-phenyl}-guanidine Step a W-(cis-4-Phenyl-cyclohexyl)-hydrazinecarboxylic acid text-butyl ester and W-(trans-4- phenyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester were prepared using step a of method of preparation of example 52, except that 4-phenyl-cyclohexanone was used in place of cycloheptanone. The products were separated by by chromatography on silica gel with hexane- EtOAc (2:1) as eluant.
The high Rf compound was assigned as N!-(cis~4-phenyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester. 1HNMR (CDCl3) 7.32-7.15 (5H, m), 6.02 (IH, br s), 3.80 (IH, br s), 3.24 (IH, br s), 2.59-2.51 (IH, m), 1.91-1.82 (4H, m), 1.68-1.54 (13H, m).
The low Rf derivative was assigned as Nl-(trans-4-phenyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester. 1H ΝMR (CDCl3) 7.32-7.16 (5H, m), 6.06 (IH, br s), 4.02 (IH, br s), 2.94-2.87 (IH, m), 2.54-2.45 (IH, m), 2.03-1.92 (4H, m), 1.59-1.45 (HH, m), 1.32-1.20 (2H. m).
Step b: 5-Cyclohexyl-3-(c\s-4-phenyl-cyclohexyl)-l,2-dihydro-3H-l,3,4-ben∑otriazepin-2-one was obtained using step b of the method of preparation of example 52, except that JV-(cis-4- phenyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester was used in place of JV^trans 4- cyano-cis-4-phenyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester . 1H ΝMR (CDCl3) 7.37-7.08 (8H, m), 6.82 (IH, d), 6.18 (IH, s), 4.10-4.03 (IH, m), 2.78-2.71 (IH, m), 2.58-2.50 (IH, m), 1.99-1.30 (18H, m).
Step c: The title compound was obtained using steps c-f of the method of preparation of example 1, except that 5-cyclohexyl-3-(cis-4-phenyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c. 1H NMR (DMSOd6) 9.98 (IH, br s), 7.64-7.12 (16H, m), 6.80 (IH, d), 3.80 (IH, br s), 3.04 (IH, m), 2.49 (IH, m), 2.05-1.19 (18H, m). Found: C 65.04, H 6.79, N 13.61%; C33H38N6O-2HCl-0.1 C4H8O2 requires: C 65.08, H 6.67, N 13.63%. Example 58: N-{4-[5-Cyclohexyl-2-oxo-3-(trans-4-phenyI-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriαzepin-l-yl]-phenyl}-guαnidine
Step a: 5-Cyclohexyl-3-(tvans-4-phenyl-cyclohexyl)-l,2-dihydro-3H-l, 3, 4-benzotriαzepin-2-one was obtained using step b of the method of preparation of example 52, except that iV-(trans-4- phenyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester (example 57, step a) was used in place of N'-cycloheptyl-hydrazinecarboxylic acid tert-butyl ester. 1H ΝMR (CDCl3) 7.37-7.35 (2H, m), 7.27-7.13 (6H, m), 6.84-6.81 (IH, m), 6.29 (IH, s), 4.22-4.19 (IH, m), 2.77-2.64 (2H, m), 2.23-2.19 (2H, m), 1.87-1.55 (HH, m), 1.43-1.23 (5H, m) Step b: The title compound was obtained using steps c-f of the method of preparation of example 1, except that 5-cyclohexyl-3-(frαrø-4-phenyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H~l,3,4- benzotriazepin-2-one in step c. 1H NMR (DMSOd6) 9.92 (IH, s), 7.73 (IH, d), 7.48-7.23 (1OH, m), 7.13-7.04 (3H, m), 6.88 (IH, d), 6.68-6.65 (2H, m), 3.97 (IH, br s), 3.06-3.02 (IH, m), 2.49 (IH, m), 2.19-2.14 (2H, m), 1.90-1.16 (16H, m). Found: C 65.55, H 6.77, N 13.60%; C33H38N6O-1.9HC1-0.1 C4H8O2 requires: C 65.47, H 6.69, N 13.71%.
Example 59: Υ\-{4-[3-(ϊ-Benzoyl-piperidin-4-yl)-5-cyclohexyl-2-oxo-l,2-dϊhydro-3Η-l,3,4- benzotriazepin-l-yl]-phenyl}~guanidine Step a: 3-(l -BenzoyIψiperidin-4-yl)-5-cyclohexyl-l ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 1- benzoyl piperidin-4-one was used in place of cycloheptanone in step a. 1H NMR (CDCl3) 7.41- 7.32 (7H, m), 7.15-7.10 (IH, m), 6.82-6.79 (IH, m), 6.29 (IH, br s), 4.81 (IH, br s), 4.24-4.15 (IH, m), 3.81 (IH, br s), 3.09-2.70 (3H, m), 2.05-1.75 (9H, m). Step b: The title compound was obtained using steps c-e of the method of preparation of example 1, except that 3-(l-benzoyl-piperidm-4-yl)-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c, followed by reaction of the product obtained, in place of 2-[4- (S-benzyl-S-cyclohexyl^-oxo-l^-dihydro-SH-l^^-benzotriazepin-l-yO-phenylimino]- imidazolidine-l,3-dicarboxylic acid di-fert-butyl ester, according to step b of the method of preparation of example 39. 1H NMR (DMSO-d6) 7.59-7.29 (12H, m), 6.89 (IH, m), 4.72-4.68 (IH, m), 4.25-4.19 (IH, m), 3.80 (IH, br s), 3.26 (IH, m), 3.04 (2H, br s), 2.82-1.36 (14H, m). Found: C 59.57, H 5.58, N 13.26%; C33H37N7O2- 1.42CF3COOH requires: C 59.32, H 5.34, N 13.51%. Example 60: ~N-{4-[5-Cyclohexyl-2-oxo-3-(trans-2-phenyl-cyclohexyl)-l,2-dihydro-3H~l,3,4- benzotriαzepin-l~yl]-phenyl}-guαnidine
Step a: 5-CycIohexyl-3-(trans-2-phenyl-cyclohexyl)-l,2-dihydro-3H-l,3,4-benzotriαzepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 2- phenyl-cyclohexanone was used in place of cycloheptanone in step a. 1H NMR (CDCl3) 7.27- 7.18 (2H, m), 7.07-6.90 (6H, m), 6.58 (IH, d), 5.78 (IH, s), 4.74-4.69 (IH, m), 3.04-2.97 (IH, m), 2.62-2.61 (IH, m), 2.25-2.05 (3H, m), 1.95-1.87 (4H, m), 1.71-1.53 (8H, m), 1.29-1.19 (3H, m).
Step b: The title compound was obtained using steps c-f of the method of preparation of example 1, except that 5-cyclohexyl-3-(trαns-2-phenyl-cyclohexyl)-l,2-dihydro-3H-l,3,4~ benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c. 1H NMR (DMSOd6) 10.0 (IH, br s), 7.62-6.79 (16H, m), 6.54- 6.51 (IH, m), 4.51 (IH, s), 3.04 (IH, m), 2.87-2.83 (IH, m), 2.29-2.07 (IH, m), 2.06-1.06 (17H, m). Found C 63.10, H 6.76, N 12.45%; C33H38N6O-2.3HCl-0.7 C4H8O2 requires: C 63.21, H 6.80, N 12.35%.
Example 61 Η-{4-[5-Cyclohexyl-2-oxo-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3Η.-l, 3, 4- benzotriazepin-l-yl]-phenyl}-guanidine
Step a: 5-Cyclohexyl-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that tetrahydro-pyran-4-one was used in place of cycloheptanone in step a. 1H NMR (CDCl3) 7.37- 7.31 (2H, m), 7.14-7.09 (IH, m), 6.81 (IH, d), 6.13 (IH, br s), 4.17-4.12 (IH, m), 4.05-4.00 (2H, m), 3.52-3.44 (2H, m), 2.74-2.69 (IH, m), 2.14-2.05 (2H, m), 1.87-1.69 (7H, m), 1.55- 1.19 (7H, m).
Step b: The title compound was obtained using steps c-f of the method of preparation of example 1, except that 5-cyclohexyl-3-(tetrahydropyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl~l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c. 1H NMR (DMSO-d6) 10.12 (IH, s) 7.64-7.54 (5H, m), 7.40-
7.21 (6H, m), 6.78-6.75 (IH, m), 3.95-3.82 (3H, m), 3.41-3.33 (2H, m), 3.04-3.01 (IH, m),
2.01-1.20 (14H, m). Found C 53.30, H 6.42, N 13.57%; C26H32N6O2-2.5HCl-0.4 C4H8O2 requires: C 53.17, H 6.26, N 13.48%.
Example 62 'N-fø-β-fl-Benzyl-piperidin^-ylJS-cyclohexyl^-oxo-l^-dihydro-SH-l^^- benzotriazepin-l-yl]-phenyl}-guanidine
Step a: 3-(l-Benzyl-piperidin-4-yl)-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 1- benzyl-piperidin-4-one was used in place of cycloheptanone in step a. 1H NMR (CDCl3) 7.35- 7.27 (7H, m), 7.12-7.07 (IH, m), 6.79 (IH, d), 6.05 (IH, br s), 3.95-3.92 (IH, m), 3.53 (2H, s), 2.94-2.88 (2H, m), 2.75-2.67 (IH, m), 2.13-2.04 (4H, m), 1.87-1.73 (7H, m), 1.54-1.24 (5H, m).
Step b: The title compound was obtained using steps c-e of the method of preparation of example 1, except that 3~(l-benzyl-piperidin-4-yl)-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c, followed by reaction of the product obtained, in place of 2-[4- (3 -benzyl-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 -yl)-phenylimino]- imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39. 1H NMR (CD3CO2D) 7.56-7.26 (12H, m), 6.84 (IH, d), 4.35 (2H, s), 4.13 (IH, m), 3.74 (2H, m), 3.01-2.98 (3H, m), 2.61 (IH, m), 2.32-1.77 (13H, m), 1.44-1.22 (4H5 m). Found C 54.70, H 5.23, N 11.53%; C33H39N7O-LSCF3CO2H requires: C 54.67, H 5.01, N 11.75%. Example 63: ^-[4-(3-Adamantan-2-yl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine
Step a: 3-Adamantan-2-yl-5-cyclohexyl-l,2-d\hydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 2- adamantanone was used in place of cycloheptanone in step a. 1H NMR (CDCl3) 7.40-7.33 (2H, m), 7.15-7.13 (IH, m), 6.85-6.82 (IH, m), 6.44 (IH, br s), 4.15 (IH, s), 2.74-2.65 (IH, m), 2.42 (2H, br s), 1.89-1.21 (22H, m).
Step b: The title compound was obtained using steps c-f of the method of preparation of example 1, except that 3-adamantan-2-yl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (DMSO-d6) 9.91 (IH, s), 7.67-7.65 (IH, m), 7.48-7.34 (5H, m), 7.31-7.18 (5H, m), 6.83 (IH, d), 3.89 (IH, s), 3.02 (IH, m), 2.30 (IH, s), 2.20 (IH, s), 1.78-1.59 (14H, m), 1.43-1.17 (7H, m). Found C 62.93, H 7.09, N 13.55%; C31H38N6O-2.1HCl-0.4 C4H8O2 requires: C 62.90, H 7.01, N 13.50%
Example 64: Η-[4-(5-Cyclohexyl-3-cyclooctyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l- yl) -phenyl] -guanidine.
Step a: 5-Cyclohexyl-3-cyclooctyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that cyclooctanone was used in place of cycloheptanone in step a. 1HNMR (CDCl3) 7.35-7.26 (2H, m), 7.11-7.06 (IH, m), 6.79 (IH, d), 6.08 (IH3 br s), 4.21-4.15 (IH, m), 2.74-2.67 (IH, m), 1.94-1.27 (24H, m).
Step b: l-(4-Amino-phenyl)-3-cyclooctyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one was obtained by using steps c and d of the method of preparation of example 1, except that 5-cyclohexyl-3-cyclooctyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.34-7.31 (IH, m), 7.21-7.16 (3H, m), 7.08 (IH, m), 6.76-6.64 (3H, m), 4.00 (IH, m), 3.67 (2H, br s), 2.85-2.78 (IH, m), 2.05-1.18 (24H, m).
Step c: The title compound was obtained using steps e and f of the method of preparation of example 1, except that l-(4-amino-phenyl)-3-cycloctyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one in step e. 1H NMR (DMSOd6) 9.91 (IH, s), 7.62-7.21 (HH, m), 6.77 (IH, d), 3.94 (IH, m), 3.05-3.01 (IH, m), 1.94-1.13 (24H, m). Found: C 62.97, H 7.54, N 14.70%; C29H38N6O-UHCl-O-S C4H8O2 requires: C 63.08, H 7.38, N 14.61%. Example 65: ~N-[4-(3-Cyclodecyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l- yl) -phenyl] -guanidine.
Step a: 3-Cyclodecyl-5-cyclohexyl~l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that cyclodecanone was used in place of cycloheptanone in step a. 1H NMR (CDCI3) 7.34-7.28 (2H, m), 7.10-7.05 (IH, m), 6.81 (IH, d), 6.22 (IH, bs), 4.53-4.45 (IH, m), 2.75-2.67 (IH, m), 1.90- 1.27 (28H, m).
Step b: l-(4-Amino-phenyl)-3-cyclodecyl-5-cyclohexyl-l ,2-dihydro-3H-l ,3 ,4-benzotriazepin-2- one was obtained by using steps c and d of the method preparation of example 1, except that 3- cyclodecyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.31-7.30 (IH, m), 7.27-7.18 (3H, m), 7.07 (IH, m), 6.77-6.64 (3H, m), 4.31-4.25 (IH, m), 3.67 (2H, br s), 2.85-2.78 (IH, m), 2.18-1.16 (28H, m).
Step c: The title compound was obtained using steps e and f of the method of preparation of example 1, except that l~(4-amino-phenyl)-3-cyclodecyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one in step e. 1H NMR (DMSO-d6) 9.93 (IH, s), 7.62-7.21 (HH, m), 6.79 (IH, d), 4.27 (IH, s), 3.02 (IH, m), 1.95-1.10 (28H, m). Found: C 63.74, H 7.93, N 13.72%; C3 ^2N6O-UHCl-0.5 C4H8O2 requires: C 63.85, H 7.75, N 13.54%.
Example 66: ~N-{4-[5-Cyclohexyl-2-oxo-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl]~phenyl}-guanidine
Step a: 5-Cyclohexyl-3-(3, 3, 5, 5-tetramethyl-cyclohexyl)-l ,2-dihydro-3H-l , 3, 4-benzotriazepin- 2-one was obtained using steps a and b of the method of preparation of example 52, except that 3,3,5,5-tetramethyl-cyclohexanone was used in place of cycloheptanone in step a. 1H NMR (CDCl3) 7.36-7.30 (2H, m), 7.12-7.07 (IH, m), 6.80 (IH, d), 6.05 (IH, s), 4.34-4.24 (IH, m), 2.76-2.68 (IH, m), 1.84-1.72 (5H, m), 1.54-1.21 (1OH, m), 1.10-1.07 (7H, m), 0.93 (6H, s).
Step b: The title compound was obtained using steps c-e of the method of preparation of example 1, except that 5-cyclohexyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c, followed by reaction of the product obtained, in place of 2-[4- (3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenylimino]- imidazolidine-l,3-dicarboxylic acid di-tert-buty\ ester, according to step b of the method of preparation of example 39. 1H NMR (DMSO-d6) 9.75 (IH5 s), 7.64 (IH, d), 7.43-7.37 (7H, m), 7.28-7.22 (3H, m), 6.79 (IH, d), 4.18 (IH, m), 3.06-2.99 (IH, m), 1.96-1.60 (8H, m), 1.35-0.80 (20H5 m). Found: C 59.24, H 6.55, N 12.24%; C31H42N6O-I^CF3COOH-CoH2O requires: C 59.25, H 6.56, N 12.27%.
Example 67: ~N-(4-{5-Cyclohexyl-3-[4-cis-(2-methoxy-phenyl)-cycϊohexyl]-2-oxo-l,2-dihydro- 3H-l,3,4-benzotriazepϊn~l-yl}-phenyl)-guanidine Step a: 5-Cyclohexyl-3-[4-cis-(2-methoxy-phenyl)-cyclohexylJ-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 4-(2-methoxy-phenyl)-cyclohexanone was used in place of cycloheptanone in step a. 1U NMR (CDCl3) 7.38-7.33 (2H, m), 7.16-7.11 (3H, m), 7.06-7.04 (IH, m), 6.85-6.81 (3H5 m), 6.20 (IH, br s), 4.25-4.23 (IH5 m), 3.79 (3H, s), 3.13 (IH, m), 2.75-2.67 (IH, m), 2.33-2.25 (2H, m), 1.84-1.43 (13H5 m), 1.33-1.22 (3H, m).
Step b: l-(4-Amino-phenyl)-3-[4-cis-(2-methoxy-phenyl)-cyclohexylJ-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained by using steps c and d of the method of preparation of example I5 except that 5-cyclohexyl-3-[4-cis-(2-methoxy-phenyl)-cyclohexyl]- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.43-7.40 (IH5 m), 7.30- 7.07 (5H, m), 6.86-6.64 (5H, m), 6.46 (IH, d), 4.18 (IH5 s)5 3.76 (3H, s), 3.69 (2H5 br s)5 3.01- 2.96 (IH, m), 2.84 (IH, m), 2.36-2.18 (2H, m), 1.99-1.24 (16H, m).
Step c: The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-amino-phenyl)-3-[4-cis-(2-methoxy-phenyl)-cyclohexyl]-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of l-(4-amino-phenyl)-3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin- l-yl)-phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39. 1H NMR (DMSO-d6) 9.73 (IH, s), 7.73-7.71 (IH, m), 7.51-7.24 (1OH, m), 7.06-7.01 (IH5 m), 6.88-6.81 (2H5 m)5 6.67-6.62 (IH, m), 6.22 (IH, d), 3.98 (IH5 s)5 3.68 (3H, s), 3.11-3.03 (IH5 m)5 2.90 (IH5 m), 2.26-1.08 (18H, m). Found: C 58.18, H 5.65, N 11.05%; C34H40N6O2-1.85CF3COOH requires: C 58.38, H 5.44, N 10.83%.
Example 68 N-{4-[3-(4-trms-Cyano-4-cis-phenyl-cyclohexyI)-5-cyclohexyl-2-oxo-l,2-dihydro- 3H-l,3,4-henzotriazepin-l-yl]-phenyl}-guanidine Step a: W-(trans-4-Cyano-cis-4-pnenyl-cyclohexyl)-hydrazinecarboxylic acid text-butyl ester andW-(cis-4-Cyano-trans-4-phenyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester- were prepared using step a of method of preparation of example 52, except that 4-phenyl 4-cyano cyclohexanone was used in place of cycloheptanone. The products were separated by by chromatography on silica gel with hexane-EtOAc (2:1) as eluant. The high Rf compound was JV-(trans 4-cyano-cis-4-phenyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester. 1H NMR (CDCl3) 7.53-7.51 (2H, m), 7.42-7.31 (3H, m), 5.75 (IH, s), 3.75 (IH, s), 3.32 (IH, s), 2.34- 2.23 (2H, m), 2.08-1.99 (2H, m), 1.90-1.86 (4H, m), 1.48 (9H, s).
The low Rf derivative was assigned as iV-(cis-4-cyano-trans-4-phenyl-cyclohexyl)- hydrazinecarboxylic acid tert-butyl ester. 1H NMR (CDCl3) 7.50-7.47 (2H, m), 7.42-7.32 (3H, m), 6.09 (IH, s), 4.05 (IH, s), 3.00-2.93 (IH, m), 2.24-2.19 (2H, m), 2.08-2.04 (2H, m), 1.78- 1.70 (4H, m), 1.48 (9H, s).
Step b : 4-(5-Cyclohexyl-2-oxo-l,2-dihydro-3H-l, 3, 4-benzotriazepin-3-yl)-l-cis-phenyl- cyclohexanecarbonitrile was obtained using step b of the method of preparation of example 52, except that N"-(trans 4-cyano-cis-4-phenyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester was used in place of N'-cycloheptyl-hydrazinecarboxylic acid tert-butyl ester^H ΝMR (CDCl3) 7.40-7.27 (7H, m), 7.17-7.12 (IH, m), 6.87 (IH, d), 6.55 (IH, br s), 4.26-4.18 (IH, m), 2.63 (IH, m), 2.32-2.17 (4H, m), 2.04-1.89 (4H, m), 1.73-1.63 (5H, m), 1.28-1.21 (5H, m).
Step c: 4-[l-(4-Amino~phenyl)-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-3-yl]~ 1-cis-phenyl-cyclohexanecarbonitrile was obtained by using steps c and d of the method of preparation of example 1, except that 4-(5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-3-yl)-l-cis-phenyl-cyclohexanecarbonitrile was used in place of 3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H ΝMR (CDCl3) 7.40-7.20
(6H, m), 7.11-7.08 (2H, m), 6.98-6.94 (2H, m), 6.89-6.84 (IH, m), 6.67 (IH, d), 4.21 (IH, s), 3.72 (2H, br s), 2.83-2.79 (IH, m), 2.34-2.26 (2H, m), 2.05-1.19 (16H, m).
Step d: The title compound was obtained using steps e and f of the method of preparation of example 1, except that 4-[l-(4-amino-phenyl)-5-cyclohexyl-2~oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-3-yl]-l-cis-phenyl-cyclohexanecarbonitrile was used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step e. 1H ΝMR (DMSO-d6) 9.78 (IH, s), 7.71-7.68 (IH, m), 7.54-7.21 (13H, m), 6.95-6.85 (3H, m), 4.02 (IH, s), 3.06-2.99 (IH, m), 2.05 (2H, m), 1.73-1.50 (12H, m), 1.36-1.08. Found: C 58.56, H 5.29, Ν 12.59%; C34H37N7O-LSSCF3COOH requires: C 58.76, H 5.08, N 12.72%.
Example 69 : Υ\-{4-[5-Cyclohexyl-3-(4, 4-diphenyl-cyclohexyl)-2-oxo-l,2-dihydro-3H-l, 3, 4- benzotriazepin-l~yl]-phenyl}-guanidine Step a: 5-Cyclohexyl-3-(4,4-diphenyl-cyclohexyl)-l,2~dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 4,4- diphenyl cyclohexanone was used in place of cycloheptanone in step a. 1H NMR (CDCl3) 7.43- 7.06 (13H, m), 6.78 (IH5 d), 6.19 (IH, br s), 4.18-4.15 (IH, m), 2.73-2.70 (2H, m), 2.59-2.52 (IH, m), 2.12-2.03 (4H, m), 1.75-1.66 (5H, m), 1.51-1.47 (2H, m), 1.23-1.07 (5H, m).
Step b: l-(4-Amino-phenyl)-5-cyclohexyl-3-(4, 4-diphenyl-cyclohexyl)-l,2-dihydro-3H~l,3,4- benzotriazepin-2-one was obtained by using steps c and d of the method of preparation of example 1, except that 5-cyclohexyl-3-(4,4-diphenyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.35-7.12 (15H, m), 6.75 (IH, m), 6.65-6.62 (2H, m), 4.02-4.00 (IH, m), 3.67 (2H, bs), 2.68-2.64 (3H, m), 2.18-1.24 (16H, m).
Step c: The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-amino-phenyl)-5-cyclohexyl-3-(4,4-diphenyl-cyclohexyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one was used in place of l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one followed by reaction of the product obtained, in place of 2-[4-(3 -benzyl-S-cyclohexyl^-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 -yl)- phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39. 1H NMR (DMSOd6) 9.70 (IH, s), 7.56-7.54 (IH, m), 7.42-7.07 (2OH, m), 6.76 (IH, d), 3.90 (IH, m), 2.87-2.83 (IH, m), 2.72 (2H, m), 2.00-1.08 (16H, m). Found: C 66.71, H 5.91, N 11.29%; C39H42N6O-LnCF3COOH requires: C 66.72, H 5.91, N 11.29%.
Example 70 : Η~[4-(5-Cyclohexyl-2-oxo-3-spiro[5.5]undec-3-yl-l,2-dihydro-3H-l, 3, 4- benzotriazepin-l-yl)-phenyl]-guanidine
Step a: S-Cyclohexyl^-spiroβ.SJundecS-yl-J^-dihydro-SH-lJ^-benzotriazepm^-one was obtained using steps a and b of the method of preparation of example 52, except that spiro[5.5]undec-3-one was used in place of cycloheptanone in step a. 1H NMR (CDCl3) 7.35- 7.27 (2H, m), 7.11-7.07 (IH, m), 6.79 (IH, d), 6.05 (IH, br s), 3.96-3.85 (IH, m), 2.76-2.69 (IH, m), 1.97-1.09 (28H, m).
Step b : l-(4-Amino-phenyl)-5-cyclohexyl-3-spiro[5.5]undec-3-yl-l, 2~dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained by using steps c and d of the method of preparation of example I5 except that 5-cyclohexyl-3-spiro[5.5]undec-3-yl-l,2-dihydro-3H-l5354- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.32-7.08 (5H, m), 6.76-6.63 (3H, m), 3.80- 3.71 (IH5 m), 3.67 (2H, bs), 2.83-2.79 (IH, m), 2.05-1.06 (28H, m). Step c: The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-amino-phenyl)-5-cyclohexyl-3-spiro[5.5]undec-3-yl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of l~(4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 -yl)- phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39. 1H NMR (DMSOd6) 9.75 (IH, s), 7.62 (IH, d), 7.44- 7.35 (7H, m), 7.28-7.22 (3H, m), 6.78 (IH, d), 3.70-3.62 (IH, m), 3.04-3.00 (IH, m), 1.98-1.06 (28H, m). Found: C 57.61, H 6.07, N 11.17%; C32H42N6O- 1.92CF3CO2H requires: C 57.73, H 5.94, N 11.27%.
Example 71 : 2-Amino-Η-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotria∑epin-1 -yl) -phenyl] '-acetamide
Step a: {[4-(3-Benzyl-5-cyclohexyl-2-oxo-l,2~dihydro-3H-l,3,4-benzotriazepin-l-yl)- phenylcarbamoyl]-methyl}-carbamic acid tert-butyl ester A solution of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin- 2-one (example 1, step d) (212mg, 0.5mmol), tert-butoxycarbonyl glycine (105mg, 0.60mmol), EDC (115mg, 0.60mmol), and N-hydroxybenzotriazole hydrate (81mg, 0.60mmol) in DCM (5mL) was stirred at ambient temperature for 16hr. The solution was diluted with DCM (2OmL), washed with saturated NaHCO3 (2OmL), H2O (2 x 2OmL), and dried (MgSO4). Filtration and evaporation of the solvent followed by chromatography of the residue on silica gel with hexane-ethylaceate (6:4) as eluant afforded the product.
Step b: The title compound was obtained using step f of the method used in the preparation of example 1, except that {[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-y^-phenylcarbamoylj-methylj-carbamic acid tert-butyl ester was used in place of N,N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-lJ2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine. 1H NMR (DMSO^6) 10.80 (IH, s), 8.22 (3H, br s), 7.66 (2H, d), 7.56 (IH, d), 7.38-7.11 (9H, m), 6.75 (IH, d), 4.80-4.20 (2H, d), 3.79 (2H, br s), 2.92 (IH, m), 1.73-1.00 (1OH, m). Found: C 63.11, H 6.31, N 12.79%; C29H31N5O2^HCl requires: C 62.81, H 6.00, N 12.63%. Example 72: 3-Amino-^-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dϊhydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-propionamide
The title compound was obtained using step a of the method of preparation of example 71, except that tert-butoxycarbonyl β-alanine was used in place of fert-butoxycarbonyl glycine, followed by reaction of the product obtained, in place of N,N -bis-(tert-butoxycarbonyl)-N"-[4- (3 -benzyl-5 -cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 -yl)-phenyl] -guanidine, according to step f of the method of preparation of example 1. 1H NMR (DMSO-d6/D2O) 7.60- 7.52 (3H, m), 7.36 (IH, t), 7.24-7.08 (8H, m), 6.71 (IH, d), 4.75 (IH, br s), 4.30 (IH, br s), 3.06 (2H, t), 2.87 (IH, m), 2.67 (2H, t), 1.69-1.15 (1OH, m). Found: C 65.35, H 6.49, N 12.34%; C30H33N5O2-LO HCl requires: C 65.05, H 6.30, N 12.64%.
Example 73 : 2-Amino-~N-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-3-methyl-butyramide
The title compound was obtained using step a of the method of preparation of example 71, except that tert-butoxycarbonyl. D/L)-valine was used in place of tert-butoxycarbonyl glycine, followed by reaction of the product obtained, in place of N,N-bis-(ter?-butoxycarbonyl)-N"-[4- (3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H NMR (DMSO-d6/D2O) 7.62 (2H, d), 7.55 (IH, d), 7.39-7.09 (9H, m), 6.74 (IH, d), 4.80 (IH, br s), 4.30 (IH, br s), 3.75 (IH, d), 2.89 (IH, m), 2.16 (IH, m), 1.71-0.95 (16H, m). Found: C 65.12, H 6.62, N 11.71%; C32H37N5O2-1.9HCl requires: C 65.02, H 6.62, N 11.85%.
Example 74: 2-Amino-4-methyl-pentanoic acid [4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro- 3H-l,3,4-benzotriazepin-l-yl)-phenyl]-amide
The title compound was obtained using step a of the method of preparation of example 71, except that tert-butoxycarbonyl D/L)-leucine was used in place of tert-butoxycarbonyl glycine, followed by reaction of the product obtained, in place of N,N -bis-(tert-butoxycarbonyl)-N"-[4- (3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6/D2O) 7.62 (2H, d), 7.56 (IH, d), 7.31-7.10 (9H, m), 6.73 (IH, d), 4.80 (IH, br s), 4.30 (IH, br s), 3.89 (IH, m), 2.90 (IH, m), 1.71-1.06 (13H, m), 0.91 (6H, m). Found: C 66.23, H 6.89, Ν 11.50%; C33H39N5O2-UHCl requires: C 66.09, H 6.84, N 11.68%.
Example 75 : N-ft-β-Benzyl-S-cyclohexyl^-oxo-l^-dihydro-SH-l^^-benzotriazepin-l-yl)- phenyl] -2-methylamino-acetamide
The title compound was obtained using step a of the method of preparation of example 71, except that N-tert-butoxycarbonyl N-methyl glycine was used in place of tert-butoxycarbonyl glycine, followed by reaction of the product obtained, in place of N,N-bis-(tert- butoxycarbonyl)-N"-[4-(3 -benzyl-5 -cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 - yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H NMR (DMSO-d6/D2O) 7.58 (2H, d), 7.53 (IH, d), 7.36 (IH, t), 7.28-7.08 (8H, m), 6.72 (IH, d), 4.80 (IH, br s), 4.38 (IH, br s), 3.88 (2H, m), 2.87 (IH, m), 2.60 (3H, s), 1.69-1.02 (1OH, m). Found: C 64.72, H 6.56, N 11.80%; C3OH33N5O2-LTHCI-(UC4HIOO requires: C 64.63, H 6.64, N 11.93%.
Example 76 : 2-Amino-~N-[4- (3-benzyl-5-cyclohexyl-2-oxo-l , 2-dihydro-3H-l , 3, 4- benzotriazepin-1-yl) -phenyl] -3 -phenyl-propionamide The title compound was obtained using step a of the method of preparation of example 71, except that tert-butoxycarbonyl (D/L)-phenylalanine was used in place of tert-butoxycarbonyl glycine, followed by reaction of the product obtained, in place of N,N-bis-(tert- butoxycarbonyl)-N/-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l- yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1HNMR (DMSO-d6/D2O) 7.54 (3H, m), 7.37-7.09 (14H, m), 6.72 (IH, d), 4.80 (IH, br s), 4.30 (IH5 br s), 4.15 (IH, m), 3.12 (2H, m), 2.90 (IH, m), 1.70-1.17 (1OH, m). Found: C 67.82, H 6.38, N 10.81%; C36H37N5O2-1.75HC1 requires: C 68.04, H 6.15, N 11.02%.
Example 77: 2-Amino-~N-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-1-yl) -phenyl] -2-phenyl-acetamide The title compound was obtained using step a of the method of preparation of example 71, except that tert-butoxycarbonyl (D/L)-phenylglycine was used in place of tert-butoxycarbonyl glycine, followed by reaction of the product obtained, in place of N,N-bis-(tert- butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 - yl)-ρhenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6/D2O) 7.55-7.05 (17H, m), 6.67 (IH, d), 4.99 (IH, s), 4.75 (IH, br s), 4.30 (IH5 br s), 2.84 (IH, m), 1.67-1.01 (1OH, m). Found: C 68.01, H 6.09, Ν 10.97%; C35H35N5O2-UHCl requires: C 67.76, H 5.97, N 11.29%.
Example 78: Pyrrolidine-2-carboxylic acid [4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H~ 1, 3, 4-benzotriazepin-l-yl)-phenyl]-amide The title compound was obtained using step a of the method of preparation of example 71, except that tert-butoxycarbonyl (D/L)-proline was used in place of fert-butoxycarbonyl glycine, followed by reaction of the product obtained, in place of N,N-bis-(tert- butoxycarbony^-iV'-^^S-benzyl-S-cyclohexyl^-oxo-l^-dihydro-SH-l^^-benzotriazepin-l- yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6/D2O) 7.62-7.54 (3H, m), 7.37-7.09 (9H, m), 6.72 (IH, d), 4.77 (IH, br s), 4.31 (2H, m), 3.24 (2H, m), 2.88 (IH, m), 1.93-0.82 (14H, m). Found: C 65.03, H 6.52, Ν 11.49%; C32H35Ν5O2-2HC1 requires: C 64.72, H 6.28, N 11.79%. Example 79 : fi)-2-Amino-~N-[4-(3-benzyl-5-cyclohexyl-2-oxo-l, 2-dihydro-3H-l , 3, 4- benzotriazepin-1 -yl) -phenyl] '-3 -hydroxy-propionamide
The title compound was obtained using step a of the method of preparation of example 71, except that N-tert-butoxycarbonyl-O-tert-butyl (L)-serine was used in place of tert- butoxycarbonyl glycine, followed by reaction of the product obtained, in place of 2-[4-(3- benzyl-5 -cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 , 3 ,4-benzotriazepin- 1 -yl)-phenylimino] - imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39. 1H ΝMR (DMSO-d6/D2O) 7.62-7.53 (3H, m), 7.36-7.09 (9H, m), 6.72 (IH, d), 4.80 (IH, br s), 4.30 (IH, br s), 3.97 (IH, t), 3.82 (2H, d), 2.88 (IH, m), 1.71-0.82 (1OH, m). Found: C 60.38, H 5.49, Ν 10.35%; C3OH33N5O3-UCF3COOH-O^ C4H8O2 requires: C 60.38, H 5.59, N 10.42%.
Example 80: 2-Amino-~N-[4-(3-benzyl-5-cyclohexyl-2-oxo-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-l-yl)-phenyl]-2-methyl-propionamide
The title compound was obtained using step a of the method of preparation of example 71, except that tert-butoxycarbonyl α-amino isobutyric acid was used in place of tert- butoxycarbonyl glycine, followed by reaction of the product obtained, in place of N,N -bis- (tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6/D2O) 7.66 (2H, d), 7.55 (IH, d), 7.37 (IH, t), 7.30-7.09 (8H, m), 6.72 (IH, d), 4.80 (IH, br s), 4.40 (IH, br s), 2.89 (IH, m), 1.70-1.06 (16H, m). Found: C 64.64, H 6.65, Ν 11.76%; C30H35N5O2-IJHCl-0.3 C4H8O2 requires: C 64.67, H 6.59, N 11.71%.
Example 81 : (S)-2-Amino-~N-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-3 -yl) -phenyl] -3 -methoxy-propionamide The title compound was obtained using step a of the method of preparation of example 71, except that tert-butoxycarbonyl (L)-serine methyl ether was used in place of tert- butoxycarbonyl glycine, followed by reaction of the product obtained, in place of N,N -bis- (tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-3-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6/D2O) 7.62 (2H, d), 7.54 (IH, d), 7.36-7.09 (9H, m), 6.73 (IH, d), 4.77 (IH, br s), 4.39 (IH, br s), 4.16 (IH, t), 3.78 (2H, m), 3.29 (3H, s), 2.88 (IH, m), 1.70- 1.15 (1OH, m). Found: C 63.35, H 6.57, Ν 11.04%; C31H35N5O3-1.5HC1-0.6 C4H8O2 requires: C 63.35, H 6.57, N 11.06%. Example 82: (S)-2-Amino-'N-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-3-yl)-phenyl]-3~cyclohexyl-propionamide
The title compound was obtained using step a of the method of preparation of example 71, except that fert-butoxycarbonyl Z-cyclohexyl alanine was used in place of fert-butoxycarbonyl glycine, followed by reaction of the product obtained, in place of N,N-bis-(tert- butoxycarbonyl)-N/-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-3- yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H NMR (DMSO-d6/D2O) 7.64 (2H, d), 7.57 (IH, d), 7.37-7.10 (9H, m), 6.74 (IH, d), 4.75 (IH, br s), 4.25 (IH, br s), 3.96 (IH, t), 2.91 (IH, m), 1.73-0.88 (23H, m). Found: C 68.41, H 7.15, N 10.95%; C36H43N5O2-LSHCl requires: C 68.33, H 7.09, N 11.07%.
Example 83 (S)-2,6-Diamino-hexanoic acid [4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- 1, 3, 4-benzotriazepin-3-yl) -phenyl] -amide
The title compound was obtained using step a of the method of preparation of example 71, except that tert-butoxycarbonyl £-lysine was used in place of fert-butoxycarbonyl glycine, followed by reaction of the product obtained, in place of N,7V-bis-(/er/-butoxycarbonyl)-iV/-[4- (S-benzyl-S-cyclohexyl^-oxo-l^-dihydro-SH-l^^-benzotriazepin-S-y^-phenylJ-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSOd6ZD2O) 7.61 (2H, d), 7.52 (IH, d), 7.36 (IH, t), 7.28-7.07 (8H, m), 6.72 (IH, d), 4.75 (IH, br s), 4.30 (IH, br s), 3.92 (IH, t), 2.86 (IH, m), 2.75 (2H, t), 1.80-0.99 (16H, m). Found: C 60.69, H 6.89, Ν 12.06%; C33H40N6Q2-2.8HCl-O.5efl.er requires: C 60.76, H 6.96, N 12.15%.
Example 84: (S)-2-Amino-N-[4-(3-biphenyl-2-ylmethyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- 1, 3, 4-benzotriazepin-3-yl)-phenyl]-3-methyl-butyramide
The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-biphenyl-2-ylmethyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 25, step a) and fert-butoxycarbonyl Z-valine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and ter/-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N/-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-3-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6/D2O) 7.58 (2H, d), 7.50 (IH, d), 7.37 (IH, t), 7.25-7.16 (9H, m), 7.06 (IH, d), 7.00 (2H, d), 6.68 (IH, d), 4.77 (IH, d), 4.17 (IH, d), 3.68 (IH, m), 2.82 (IH, m), 2.15 (IH, m), 1.68-0.99 (16H, m). Found: C 69.52, H 6.67, Ν 10.16%; C38H41N5O2- 1.9HC1-0.3 C4H8O2 requires: C 69.52, H 6.67, N 10.34%. Example 85 : (RJ^-Ammo-N-fe-β-biphenyl^-ylmethylS-cyclohexyl^-oxo-lJ-dihydroSH- 1, 3, 4-benzotriazepin-3-yl)-phenyl]-3-methyl-hutyramide
The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-biphenyl-2-ylmethyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 25, step a) and fert-butoxycarbonyl .D-valine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-3-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6/D2O) 7.58 (2H, d), 7.50 (IH, d), 7.37 (IH, t), 7.25-7.16 (9H, m), 7.06 (IH, d), 7.00 (2H, d), 6.68 (IH, d), 4.77 (IH, d), 4.17 (IH, d), 3.68 (IH, m), 2.82 (IH, m), 2.15 (IH, m), 1.68-0.99 (16H, m). Found: C 69.31, H 6.67, Ν 10.27%; C38H4IN5O2- 1.9HC1-0.4 C4H8O2 requires: C 69.33, H 6.70, N 10.21%.
Example 86: (2S),(3S)-2-Amino-3-methyl-pentanoic acid [4-(3-biphenyl-2-ylmethyl-5- cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-3-yl)-phenyl]-amide
The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-biphenyl-2-ylmethyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 25, step a) and tert-butoxycarbonyl i-isoleucine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepm-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-3-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6/D2O) 7.62 (2H, d), 7.53 (IH, d), 7.39 (IH, t), 7.27-7.18 (9H, m), 7.05 (3H, m), 6.70 (IH, d), 4.78 (IH, br s), 4.23 (IH, br s), 3.81 (IH, d), 2.86 (IH, m), 1.92-0.84 (19H, m). Found: C 69.92, H 6.81, Ν 10.24%; C39H43N5O2-LoHCl requires: C 69.81, H 6.69, N 10.49%.
Example 87: (S)-2-Amino-'N-[4-(3-biphenyl-2-ylmethyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- 1, 3, 4-benzotriazepin-3-yl) -phenyl] -3, 3-dimethyl-butyranιide
The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-biphenyl-2-ylmethyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 25, step a) and tert-butoxycarbonyl L-tert-butyl glycine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and tø-t-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N"-bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2- oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-3-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H NMR (DMSO-d6/D2O) 7.61-7.53 (3H, m), 7.39 (IH, t), 7.27-7.19 (9H, m), 7.09-7.03 (3H, m), 6.70 (IH, d), 4.90 (IH, br d), 4.25 (IH, br d), 3.64 (IH, s), 2.86 (IH, m), 1.71-1.03 (19H, m). Found: C 70.02, H 6.82, N 10.42%; C39H43N5O2- 1.5HC1 requires: C 70.11, H 6.71, N 10.48%.
Example 88 : (S)-2-Amino-'N-[4-(3-biphenyl-2-yImethyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- 1,3, 4-benzotriazepin-3-yl)-phenyl]-2-cyclohexyl-acetamide
The title compound was obtained using step a of the method of preparation of example 71, except that 1 -(4-amino-phenyl)-3 -biphenyl-2-ylmethyl-5 -cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4- benzotriazepin-2-one (example 25, step a) and tert-butoxycarbonyl Z-cyclohexyl glycine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(/ert-butoxycarbonyl)-N/-[4-(3-benzyl-5-cyclohexyl-2- oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-3-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6/D2O) 7.64 (2H, d), 7.54 (IH, d), 7.39 (IH, t), 7.28-7.04 (9H, m), 7.06 (3H, m), 6.70 (IH, d), 4.80 (IH, br d), 4.25 (IH, br d), 3.77 (IH, d), 2.87 (IH, m), 1.72-1.05 (21H, m). Found: C 69.91, H 6.95, Ν 9.68%; C41H45N5O2-LSHCl requires: C 69.88, H 6.69, N 9.73%.
Example 89: (S)~3-Amino-4-methyl-pentanoic acid [4-(3-biphenyl-2-ylmethyl-5-cyclohexyl-2- oxo-1 ,2-dihydro-3H-l , 3, 4-benzotriazepin-3-yl) -phenyl] -amide
The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-biphenyl-2-ylmethyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 25, step a) and fert-butoxycarbonyl Z-β-leucine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-3-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6/D2O) 7.59 (2H, d), 7.51 (IH, d), 7.37 (IH, t), 7.26-7.02 (12H, m), 6.67 (IH, m), 4.76 (IH, br d), 4.20 (IH, br d), 3.36 (IH, m), 2.84 (IH, m), 2.70 (2H, m), 1.91 (IH, m), 1.69-1.03 (1OH, m), 0.91 (6H, d). Found: C 68.31, H 6.78, Ν 9.82%; C39H43N5O2-1.8HC1-0.4 C4H8O2 requires: C 68.23, H 6.77, N 9.80%.
Example 90: (S)-3-Amino-5-methyl-hexanoic acid [4-(3-biphenyl-2-ylmethyl-5-cyclohexyl-2- oxo-l,2-dihydro-3H-l,3, 4-benzotriazepin-l -yl)-phenyl] -amide The title compound was obtained using step a of the method of preparation of example 71, except that 1 -(4-amino-phenyl)-3-biρhenyl-2-ylmethyl-5-cyclohexyl- 1 ,2-dihydro-3H-l ,3,4- benzotriazepin-2-one (example 25, step a) and tert-butoxycarbonyl Z-β-homo-leucine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(terf-butoxycarbonyl)-N"-[4-(3-benzyl-5-cycIohexyl-2- oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6/D2O) 7.59 (2H, d), 7.51 (IH, d), 7.38 (IH, t), 7.27-7.02 (12H5 m), 6.68 (IH, d)5 4.80 (IH, br d), 4.20 (IH, br d), 3.63 (IH, m), 2.85 (IH, m), 2.65 (2H, m), 1.70-1.04 (13H, m), 0.86 (6H, m). Found: C 69.45, H 6.87, Ν 10.06%; C40H45N5O2-IJHCl requires: C 69.46, H 6.81, N 10.13%.
Example 91: (2S),(3R)-2-Amino-3-methyl-pentanoic acid [4-(3-biphenyl-2-ylmethyl-5- cyclohexyl-2-oxo-l, 2-dihydro-3H-l, 3, 4-benzotriazepin-l-yl) -phenyl] -amide
The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-biphenyl-2-ylmethyl-5-cycIohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 25, step a) and tert-butoxycarbonyl i-alloisoleucine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H NMR (DMSO-d6/D2O) 7.58 (2H, d), 7.50 (IH, d), 7.37 (IH, t), 7.27-7.16 (9H, m), 7.06 (IH, d), 7.01 (2H, d), 6.68 (IH, d), 4.76 (IH, br d), 4.21 (IH, br d), 3.79 (IH, d), 2.83 (IH, m), 1.94 (IH, m), 1.69-0.85 (18H, m). Found: C 69.54, H 6.77, N 10.42%; C39H43N5O2-LoHCl requires: C 69.27, H 7.10, N 10.36%. Example 92: (S)-2-Amino-N-[4~(3-biphenyl-2-ylmethyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- 1, 3, 4-benzotriazepin-l ~yl) -phenyl] -propionamide
The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-biphenyl-2-ylmethyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 25, step a) and tert-butoxycarbonyl i-alanine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N^N-bis-^ert-butoxycarbonyO-N'-^^S-benzyl-S-cyclohexyl^-oxo-l^-dihydro-SH- l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6/D2O) 7.58 (2H, d), 7.50 (IH, d), 7.37 (IH, t), 7.26-7.16 (9H, m), 7.06 (IH, d), 7.00 (2H, m), 6.67 (IH, d), 4.75 (IH, br d), 4.20 (IH, br d), 3.95 (IH, d), 2.83 (IH, m), 1.67 (5H, m), 1.43 (3H, d), 1.30-1.02 (5H, m). Found: C 67.80, H 6.39, N 10.38%; C36H37N5O2-1.5HC1-0.6 C4H8O2 requires: C 67.90, H 6.43, N 10.31%.
Example 93 (S)- 2-Amino-N-[4-(5-cyclohexyl-3-cyclooctyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-1 -yl) -phenyl] '-3 -methyl-butyramide
The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-cyclooctyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 64, step b) and tert-butoxycarbonyl Z-valine were used in place of 1 -(4-aminophenyl)-3 -benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N, N -bis-(tert-butoxycarbonyl)-N' -[4-(3 -benzyl-S-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6) 10.83 (IH, s), 8.32 (3H, br s), 7.66-7.56 (3H, m), 7.39- 7.18 (4H, m), 6.70-6.68 (IH, m), 3.91-3.75 (2H, m), 2.99 (IH, m), 2.22-2.16 (IH, m), 1.94- 0.98 (3OH, m). Found: C 65.35, H 8.05, Ν 11.37%; C33H45N5O2-LoHCl-O^ C4H8O2 requires: C 65.51, H 7.84, N 11.30%.
Example 94 (S)-2-Arnino-~N-[4-(3-cyclodecyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-3-yl)-phenyl]-3-methyl-butyramide
The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-cyclodecyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 65, step b) and tert-butoxycarbonyl Z-valine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tørt-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N/-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6) 10.79 (IH, s), 8.31 (3H, br s), 7.65-7.57 (3H, m), 7.37- 7.31 (3H, m), 7.23-7.19 (IH, m), 6.72-6.69 (IH, m), 4.22 (IH, br s), 3.82-3.80 (IH, m), 2.99 (IH, m), 2.48-0.94 (35H, m). Found: C 66.72, H 8.14, Ν 10.79%; C35H49N5O2-1.5HC1-0.2 C4H8O2 requires: C 66.76, H 8.15, N 10.87%. Example 95 (S)-2-Amino-'N-{4-[5-cyclohexyl-3-(cis-4-naphthalen-2-yl-cyclohexyl)-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl]-phenyl}-3-rnethyl-butyramide
Step a: 5-Cyclohexyl-3-(cis-4-naphthalen-2-yl-cyclohexyl)-l,2-dihydro-3H-l, 3, 4- benzotfiazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 4-(naphthalen-2-yl)-cyclohexanone was used in place of cycloheptanone in step a. 1H NMR (CDCl3) 7.78-7.71 (3H, m), 7.65 (IH, s), 7.45-7.27 (5H, m), 7.14-7.12 (IH, m), 6.84 (IH, d), 6.19 (IH, bs), 4.26-4.19 (IH, m), 2.96-2.95 (IH, m), 2.67- 2.60 (IH, m), 2.31-2.25 (2H, m), 2.00-1.98 (2H, m), 1.84-1.62 (9H, m), 1.37-1.14 (5H, m).
Step b: l-(4-Amino-phenyl)-5-cyclohexyl-3-(cis-4-naphthalen-2~yl-cyclohexyl)-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one was obtained by using steps c and d of the method of preparation of example 1, except that 5-cyclohexyl-3-(cw-4-naphthalen-2-yl-cyclohexyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5~cyclohexyl-l,2- dihydro-3H-l,3,4-benzotπazepin-2-one in step c. 1H NMR (CDCl3) 7.75-7.60 (3H, m), 7.43-
7.25 (6H, m), 7.15-7.12 (2H, m), 6.92-6.89 (2H, m), 6.68-6.65 (2H, m), 4.19 (IH, s), 3.69 (2H, br s), 2.84 (IH, m), 2.70 (IH, m), 2.39 (2H, m), 1.90-1.24 (16H, m).
Step c: The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-5-cyclohexyl-3-(cis-4-naphthalen-2-yl-cyclohexyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one and fert-butoxycarbonyl L-valine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSOd6) 10.76 (IH ,s), 8.29 (3H, br s), 7.80-7.64 (6H, m), 7.50- 7.40 (4H, m), 7.30-7.25 (3H, m), 6.87-6.77 (2H, m), 3.99 (IH, s), 3.81-3.79 (IH, m), 3.00 (IH, m), 2.55 (IH, m), 2.20-2.16 (3H, m), 1.70-0.97 (22H, m). Found: C 69.94, H 7.20, Ν 9.92%; C41H47N5O2- 1.6HC1-0.2 C4H8O2 requires: C 69.94, H 7.05, N 9.76%.
Example 96 (S)-2-Amino-N-(4-{5-cyclohexyl'3-[cis-4-(2-methoxy-phenyl)-cyclohexylJ-2-oxo- 1 ,2'dihydrθ'3H-l ,3 ,4-benzotriazepin-l-yl}-phenyl)-3-methyl-butyramide
The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-[4-cw-(2-methoxy-phenyl)-cyclohexyl]-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one (example 67, step b) and tert-butoxycarbonyl X-valine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N)iV-bis-(/ert-butoxycarbonyl)-iV/-[4-(3-benzyl-5-cyclohexyl-2- oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H NMR (DMSO-d6) 10.71 (IH, s), 8.37 (3H, s), 7.79-
7.63 (3H, m), 7.46-7.42 (IH, m), 7.36-7.25 (3H, m), 7.05-7.00 (IH, m), 6.84-6.81 (2H, m),
6.66-6.61 (IH, m), 6.20-6.18 (IH, m), 3.96 (IH, m), 3.77-3.75 (IH, m), 3.68 (3H, s), 3.11 (IH, m), 2.90 (IH, m), 2.22-2.13 (3H, m), 1.82-0.92 (22H, m). Found: C 65.65, H 7.26, N 10.26%; C38H47N5O3^HCl requires: C 65.70, H 7.26, N 10.08%. Example 97: 2-Amino-Η-[4-(3-bicyclo[3.3.1]non-9-yl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- 1, 3, 4-benzotriazepin-l-yl)-phenyl]-3-methyl-butyramide
Step a: 3-Bicyclo[3.3. l]non-9-yl-5-cyclohexyl-l, 2-dihydro-3H-l , 3, 4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that bicyclo[3.3.1]non-9-one was used in place of cycloheptanone in step a. 1H NMR (CDCl3) 7.40- 7.32 (2H, m), 7.15-7.10 (IH, m), 6.84 (IH, d), 6.34 (IH, s), 3.94 (IH, s), 2.74-2.67 (IH, m), 2.39 (2H, s), 1.87-1.68 (1OH, m), 1.54-1.43 (6H, m), 1.29-1.21 (6H, m).
Step b: l-(4-Amino-phenyl)-3-bicyclo[3.3.1]non-9-yl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained by using steps c and d of the method of preparation of example 1, except that 3-bicyclo[3.3.1]non-9-yl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5~cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.40-7.37 (IH, m), 7.27-7.26 (IH, m), 7.12- 7.06 (3H, m), 6.83-6.79 (IH, m), 6.66-6.63 (2H, m), 3.90-3.88 (IH, m), 3.68 (2H, s), 2.86-2.80 (IH, m), 2.31 (2H, s), 1.97-1.06 (22H, m). Step c: The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-bicyclo[3.3.1]non-9-yl-5-cyclohexyl-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl I-valine were used in place of l-(4- aminophenyl)-3 -benzyl-5 -cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSOd6) 10.73 (IH, s), 8.27 (3H, br s), 7.65-7.62 (3H, m), 7.40-7.31 (IH, m), 7.25-7.11 (3H, m), 6.78-6.75 (IH, m), 3.79-3.77 (IH, m), 3.67 (IH, s), 3.01 (IH, m), 2.22-2.18 (3H, m), 1.79-0.94 (28H, m). Found: C 63.86, H 7.65, Ν 10.86%; C34H45N5O3- 2.2HC1-0.2 C4H8O2 requires: C 63.95, H 7.53, N 10.72%.
Example 98 (S)-2-Amino-'N-{4-[3-(trans-4-cyano-cis-4-phenyl-cyclohexyl)-5-cyclohexyl-2- oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl]-phenyl}-3-methyl-butyramide
The title compound was obtained using step a of the method of preparation of example 71, except that 4-[l-(4-amino-phenyl)-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-3- yl]-l-cis-phenyl-cyclohexanecarbonitrile (example 68, step c) and tert-butoxycarbonyl L- valine were used in place of l-(4-aminophenyl)-3-benzyl~5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N -bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2- oxo-l,2-dihydro-3H-l,3,4-benzotriazepm-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H NMR (DMSO-d6) 10.78 (IH, s), 8.28 (3H5 br s), 7.69- 7.64 (3H, m), 7.48-7.17 (7H, m), 6.92-6.81 (3H, m), 4.00 (IH, s), 3.81-3.79 (IH, m), 3.01 (IH, m), 2.22-2.18 (3H, m), 1.80-1.71 (HH, m), 1.35-0.97 (HH, m). Found: C 67.21, H 7.00, N 12.05%; C38H44N6O2-1.6HC1-0.3 C4H8O2 requires: C 67.11, H 6.90, N 11.98%. Example 99 (S)-2-Amino-~N-{4-[3-(ci$-4-cyano-trans-4-phenyl-cyclohexyl)-5-cyclohexyl-2- oxo-1, 2-dihydro-3H-l,3,4~benzotriαzepin-l-yl]-phenyl}-3-methyl-butyrαmide
Step a 4-(5-Cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriαzepin-3-yl)-l-trαns-phenyl- cyclohexαnecαrbonitrile was obtained using step b of the method of preparation of example 52, except that iV-(cis-4-cyano-trans-4-phenyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester (example 68, step a) was used in place of N'-cycloheptyl-hydrazinecarboxylic acid tert- butyl ester.Η ΝMR (CDCl3) 7.53-7.50 (2H, m), 7.42-7.27 (5H, m), 7.16-7.14 (IH, m), 6.84 (IH, d), 6.35 (IH, br s), 4.12-4.03 (IH, m), 2.80-2.73 (IH, m), 2.47-2.22 (5H, m), 2.05-1.72 (8H, m), 1.72-1.55 (3H, m), 1.36-1.21 (2H, m).
Step b: 4-[l-(4-Amino-phenyl)-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriαzepin-3-yl]- l-tv&ns-phenyl-cyclohexαnecαrbonitrile was obtained by using steps c and d of the method of preparation of example 1, except that 4-(5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepm-S-y^-l-trans-phenyl-cyclohexanecarbonitrile was used in place of 3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H ΝMR (CDCl3) 7.52-7.49
(2H, m), 7.41-7.12 (8H, m), 6.79 (IH, m), 6.60-6.65 (2H, m), 3.97-3.89 (IH, m), 3.70 (2H, br s), 2.90-2.83 (IH, m), 2.80-1.24 (18H5 m).
Step c The title compound was obtained using step a of the method of preparation of example 71, except that 4-[l-(4-amino-phenyl)-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-S-ylJI-l-trans-phenyl-cyclohexanecarbonitrile and /er/-butoxycarbonyl i-valine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,354- benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(ter/-butoxycarbonyl)-N/-[4-(3-benzyl-5-cyclohexyl-2~ oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1HNMR (DMSO-d6) 10.84 (IH, s), 8.32 (3H, br s), 7.68- 7.61 (3H, m), 7.55-7.53 (2H, m), 7.44-7.22 (7H, m), 6.73-6.71 (IH, m), 3.89-3.82 (2H5 m), 3.09-3.03 (IH, m), 2.20-1.05 (18H, m), 1.01-0.97 (6H, m). Found: C 66.76, H 6.91, N 11.98%; C38H44N6O2-UHCl-OJ C4H8O2 requires: C 66.76, H 6.88, N 11.92%.
Example 100: (S)-2-Amino-N-{4-[3-(cis-4-tert-butyl-cyclohexyl)-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriαzepin-l-yl]-phenyl}-3-methyl-butyrαmide Step a: 3-(Cis-4-tert-butyl~cyclohexyl)-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one was obtained using steps a and b of the method of preparation of example 52, except that 4-tert-butyl-cyclohexanone was used in place of cycloheptanone in step a. 1H NMR (CDCl3): 7.36-7.30 (2H, m), 7.12-7.07 (IH, m), 6.85-6.82 (IH, m), 6.45 (IH5 s), 4.19-4.14 (IH, m), 2.75-2.67 (IH, m), 2.31-2.26 (2H, m), 1.84-1.70 (5H, m), 1.56-1.24 (9H, m), 1.04-1.00 (3H, m), 0.67 (9H, s).
Step b: l-(4-Amino-phenyl)-3-(cis-4-t&Λ-butyl~cyclohexyl)-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using steps c and d of the method of preparation of example 1, except that 3-(cis-4-tert-butyl-cyclohexyl)-5-cyclohexyl l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c. 1H NMR (CDCl3): 7.35 (IH, m), 7.26-7.22 (IH, m), 7.12-7.09 (3H, m), 6.82 (IH, d), 6.66-6.63 (2H, m), 4.09 (IH5 s), 3.68 (2H, br s), 2.85 (IH, m), 2.34-2.23 (2H, m), 2.05-1.24 (13H, m), 0.93-0.67 (4H, m), 0.55 (9H, s).
Step c: The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-(cis-4-tert-butyl-cycIohexyl)-5-cyclohexyl-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl i-valine were used in place of l-(4- aminophenyl)-3 -benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N//-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6): 10.84 (IH, s), 8.33 (3H, br s), 7.71-7.58 (3H, m), 7.37-7.18 (4H, m), 6.79-6.76 (IH, m), 3.87-3.82 (2H, m), 3.03 (IH, m), 2.20-1.66 (9H, m), 1.36-0.48 (26H, m).. Found: C 66.19, H 8.37, Ν 10.60%; C35H49N5O2-LSHCl-O-S C4H8O2 requires: C 66.27, H 8.19, N 10.44%. Example 101: {S>)-2-Amino-Η-(4-{5-cyclohexyl-3-[cis-4-(4-methoxy-phenyl)-cyclohexyl]-2- oxo-1, 2-dihydro-3H-l, 3, 4-benzotriazepin-l -yl}-phenyl)-3-methyl-butyramide
Step a: 5-Cyclohexyl-3-[cis,-4-(4-methoxy-phenyl)-cyclohexyl]-l,2-dihydro-3H-l,3,4~ benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 4-(4-methoxy-phenyl)-cyclohexanone was used in place of cycloheptanone in step a. 1H NMR (CDCl3): 7.37-7.33 (2H, m), 7.15-7.08 (3H, m), 6.83-6.75 (3H, m), 6.24 (IH, br s), 4.22-4.16 (IH5 m), 3.79 (3H, s), 2.74-2.67 (2H, m), 2.22-2.18 (2H, m), 1.82-1.54 (HH, m), 1.44-1.24 (5H, m).
Step b: l-(4-Amino-phenyl)-5-cyclohexyl-3-[cis-4-(4-methoxy-phenyl)-cyclohexyl]-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained by using steps c and d of the method of preparation of example 1, except that 5-cyclohexyl-3-[cis-4~(4-methoxy-phenyl)-cyclohexyl]- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCl3): 7.40 (IH, m), 7.30-7.11 (5H, m), 6.86-6.83 (IH, m), 6.70-6.64 (5H, m), 4.12 (IH, s), 3.76 (3H, s), 3.69 (2H, br s), 2.84 (IH, m), 2.48-2.18 (3H, m), 1.99-1.72 (5H, m), 1.54-1.20 (1OH, m).
Step c: The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-5-cyclohexyl-3-[cis-4-(4-methoxy-phenyl)-cyclohexyl]- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and terϊ-butoxycarbonyl L-valine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and fert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N)N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSOd6) 10.92 (IH, s), 8.35 (3H, br s), 7.68-7.66 (3H, m), 7.47- 7.24 (4H, m), 6.83-6.81 (IH, m), 6.67-6.55 (4H, m), 3.94 (IH, s), 3.85 (IH, s), 3.66 (3H, s), 3.03 (IH, m), 2.48 (2H, m), 2.23-2.16 (3H, m), 1.90-0.98 (21H, m). Found: C 67.44, H 7.38, Ν 10.24%; C38H47N5O3- 1.4HC1-0.2 C4H8O2 requires: C 67.49, H 7.30, N 10.14%.
Example 102: (S)-2~Amino-N-{4-[5-cycIohexyl-3-(4,4-diphenyl-cycIohexyl)-2-oxo-l,2- dihydrθ'3H-l,3,4-benzotriazepin-l-yl]-phenyl}-3-methyl-butyramide
The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-5~cyclohexyl-3-(4,4-diphenyl-cycIohexyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one (example 69, step b) and tert-butoxycarbonyl i-valine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(ter/-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1HNMR (DMSO-d6) 10.82 (IH, s), 8.30 (3H, br s), 7.65-7.62 (2H, m), 7.50 (IH, m), 7.36-7.07 (14H3 m), 6.69-6.66 (IH, m), 3.87-3.81 (2H, m), 2.80-2.72 (3H, m), 2.17-0.92 (23H, m). Found: C 70.77, H 7.22, N 9.58%; C43H49N5O2-1.6HC1-0.2 C4H8O2 requires: C 70.72, H 7.07, N 9.42%. Example 103: (S)-2-Amino-~N-[4-(3-cyclododecyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-3-yl)-phenyl]-3-methyl-butyramide
Step a: 5-Cyclohexyl-3-cyclododecyl-l,2-dihydro~3H-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that cyclododecanone was used in place of cycloheptanone in step a. 1H NMR (CDCl3): 7.34-7.27 (2H, m), 7.10-7.05 (IH, m), 6.83 (IH, d), 6.37 (IH, d), 4.38 -4.29 (IH, m), 2.75-2.66 (IH, m), 1.83-1.23 (32H, m).
Step b: l-(4-Arnino-phenyl)-3-cyclododecyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained by using steps c and d of the method of preparation of example 1, except that 5-cyclohexyl-3-cyclododecyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.31-7.30 (IH5 m), 7.27-7.18 (3H, m), 7.07 (IH, m), 6.77-6.64 (3H, m), 4.31-4.25 (IH, m), 3.67 (2H, br s), 2.85-2.78 (IH, m), 2.18-1.16 (3OH, m).
Step c: The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-cyclododecyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and tert-butoxycarbonyl Z-valine were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N//-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSOd6): 10.67 (IH, br s), 8.20 (3H, br s), 7.63-7.57 (3H, m), 7.38- 7.19 (4H, m), 6.73-6.71 (IH, m), 4.06 (IH, m), 3.78-3.76 (IH, m), 3.00 (IH, m), 2.21-2.15 (IH, m), 1.89-0.97 (38H, m). Found: C 68.54, H 8.63, Ν 10.58%; C37H53N5O2- 1.2HC1-0.2 C4H8O2 requires: C 68.66, H 8.51, N 10.59%. Example 104: 2-Amino-~N-[4-(5-cyclohexyl-2-oxo-3-spiro[5.5]undec-3-yl-l,2-dihydro-3H- 1, 3, 4-benzotriazepin-3-yl)-phenyl]-3-methyl-butyramide
The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-5-cyclohexyl-3-spiro[5.5]undec-3-yl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 70, step b) and tert-butoxycarbonyl i-valine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and fert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(fert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6) 10.82 (IH, br s), 8.26 (3H, br s), 7.70-7.57 (3H, m), 7.37- 7.19 (4H, m), 6.71-6.68 (IH, m), 3.83-3.81 (IH, m), 3.68-3.59 (IH3 m), 3.01-2.98 (IH, m), 2.26-0.92 (35H, m). Found: C 65.57, H 7.91, Ν 10.54%; C36H49N5O2^HCl-0.1 C4H8O2 requires: C 65.69, H 7.58, N 10.52%.
Example 105: (S)-2-Amino-N-[4-(3-cyclodecyl-5-cyclohexyl-8-methyl-2-oxo-l,2-dihydro-3H- 1, 3, 4-benzotriazepin-l-yl) -phenyl] -3 -methyl-butyr amide Step a: 3-Cyclodecyl-5-cyclohexyl-8-methyl-l,2-dϊhydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that cyclododecanone was used in place of cycloheptanone in step a and (2-amino-4-methyl- phenyl)-cyclohexyl-methanone (example 11, step a) was used in place of (2-aminophenyl)- cyclohexyl-methanone in step b. 1H NMR (CDCl3): 7.23 (IH, d), 6.90 (IH3 d), 6.61 (IH, s), 6.16 (IH, s), 4.53-4.45 (IH, m), 2.72-2.64 (IH, m), 2.32 (3H, s), 1.90-1.26 (28H, m)
Step b : /- (4-Amino-phenyl)-3-cyclodecyl-5-cyclohexyl-8-methyl-l, 2-dϊhydro-3H-l, 3, 4- benzotriazepin-2-one was obtained by using steps c and d of the method of preparation of example 1, except that 3-cyclodecyl-5-cyclohexyl-8-methyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H- 1,3,4- benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.22-7.17 (3H, m), 6.92-6.87 (IH, m), 6.68- 6.64 (2H, m), 6.54 (IH, s), 4.29-4.26 (IH, m), 3.67 (2H, br s), 2.82-2.75 (IH, m), 2.20 (3H, s), 2.05-1.19 (28H, m).
Step c: The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-cyclodecyl-5-cyclohexyl-8-methyl-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl Z-valine were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(fert-butoxycarbonyl)-N/-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6) 10.81 (IH, s), 8.29 (3H, br s), 7.65-7.62 (2H, m), 7.45-7.41 (IH, m), 7.33-7.30 (2H, m), 7.04-7.02 (IH, m), 6.52 (IH, s), 4.22 (IH, br s), 3.84-3.82 (IH, m), 3.00 (IH, m), 2.18 (4H, m), 2.00-0.96 (34H, m). Found: C 67.64, H 8.51, Ν 10.77%; C36H51N5O2-IJHCl-OJ C4H8O2 requires: C 67.73, H 8.36, N 10.62%. Example 106: {S)-2-Amino-Η-{4-[5-cyclohexyl-8-methyl-2-oxo-3-(3,3,5,5-tetramethyl- cyclohexyl)-l,2-dihydro-3H-l,3A-benzotriazepin-l-yl]-phenyl}-3-methyl-butyramide
Step a: 5-Cyclohexyl-8-methyl-3-(3, 3, 5, 5-tetramethyl-cyclohexyl)-l , 2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using steps a and b of the method of preparation of example 52, except that 3,3,5,5-tetramethyl-cyclohexanone was used in place of cycloheptanone in step a and (2-amino-4-methyl-ρhenyl)-cyclohexyl-methanone (example 11, step a) was used in place of (2-aminophenyI)-cyclohexyl-methanone in step b. 1H NMR (CDCl3): 7.24-7.21 (IH, m), 6.91-6.88 (IH, m), 6.61 (IH, s), 6.09 (IH, s), 4.34-4.23 (IH, m), 2.73-2.65 (IH, m), 2.33 (3H, s), 1.83-1.72 (5H, m), 1.57-1.20 (HH, m), 1.06 (6H, s), 0.93 (6H3 s). Step b: l-(4-Amino-phenyl)-5-cyclohexyl-8-methyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained by using steps c and d of the method of preparation of example 1, except that 5-cyclohexyl-8-methyl-3-(3,3,5,5-tetramethyl- cyclohexyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCl3): 7.24-7.16 (3H, m), 6.90 (IH, d), 6.65 (2H5 dd), 6.55 (IH, s), 4.12 (IH5 m), 3.68 (2H, br s), 2.79 (IH, m), 2.21 (3H, s), 1.87-0.81 (1OH, m).
Step c: The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-5-cyclohexyl-8-methyl-3-(3,3,5,5-tetramethyl-cyclohexyl)- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl Z-valine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and ter^-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(te?"t-butoxycarbonyl)-N/-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6/D2O): 7.59 (2H, d), 7.46 (IH, d), 7.30 (2H, d), 7.03 (IH, d), 6.50 (IH, s), 3.99 (IH, m), 3.71 (IH, d), 2.95 (IH, m), 2.21 (3H, s), 1.89-0.79 (35H, m). Found: C 65.50, H 8.12, Ν 9.63%; C36H51N5O2-UHCl-CS C4H8O2 requires: C 65.55, H 8.29, N 9.75%.
Example 107: (S)-2-Amino-3-methyl-pentanoic acid [4-(3-cyclodecyl-5-cyclohexyl-8-methyl-2- oxo-1, 2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-amide
The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-cyclodecyl-5-cyclohexyl-8-methyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 105, step b) and tert-butoxycarbonyl Z-isoleucine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(terr-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6): 10.77 (IH, s), 8.29 (3H, br s), 7.64-7.61 (2H, m), 7.47- 7.45 (IH, m), 7.33-7.30 (2H, m), 7.04-7.02 (IH, m), 6.53 (IH, s), 4.22 (IH, br s), 3.86-3.84 (IH, m), 2.96 (IH, m), 2.18 (3H, s), 1.93-0.86 (37H, m). Found: C 68.45, H 8.60, Ν 10.77%; C37H53N5O2-1.3HC1-0.1 C4H8O2 requires: C 68.47, H 8.47, N 10.67%. Example 108: N-[4-(3-Aminomethyl-5-cyclohexyl-2-oxo-l, 2-dihydro-3H-l, 3, 4-benzotriazepin- 1-yl) -phenyl] -guanidine
Step a: NJ$'-Bis-(tert~butoxycarbonyI)-N''-[4-(3-N-teή-butoxycarbonyl-aminomethyl-5- cyclohexyl-2-oxo-l ,2-dihydro-3H-l , 3, 4-benzotriazepin-3-yl)-phenyl]-guanidine A solution of [5-cyclohexyl-l-(4-(N,N'-όw-(tert-butoxycarbonyl)-guanidino)-phenyl)-2-oxo- l,2-dihydro-3H-l,3,4-benzotriazepin-3-yl]-acetic acid (example 13, step d) (538mg, O.85mmol) and NEt3 (153μl, l.l lmmol) in dry acetone (7mL) was stirred at O0C under argon, and a solution of ethyl chloroformate (158μl, 1.7mmol) in acetone (3mL) added dropwise. After stirring at O0C for lhr a solution of sodium azide (85mg, 1.26mmol) in H2O (3mL) was added dropwise. The mixture was allowed to warm to ambient temperature and stirred for lhr and concentrated under reduced pressure (below 250C). The residue obtained was partitioned between H2O and toluene (1:1 / 2OmL). The organic layer was separated and dried (MgSO4), and upon filtration the solution was heated at reflux under argon for 2hr. On cooling, the solvent was evaporated, t-BuOH (5mL) added and the solution heated at reflux under argon for 3h. The reaction mixture was cooled, filtered and the solvent evaporated. Chromatography of the residue obtained using EtOAc-DCM-Hexane (2:9:9) as eluant afford the product (97mg, 16%). 1H NMR (CDCl3) 11.63 (IH, s), 10.40 (IH, s), 7.65 (2H5 d), 7.40-7.16 (5H, m), 6.74 (IH, d), 5.61 (IH, t), 4.75 (2H, br d), 2.83 (IH, m), 2.00-1.20 (1OH, m), 1.54 (9H, s), 1.48 (9H, s), 1.38 (9H, s). Step b: The title compound was obtained using step f of the method of preparation of example 1, except that N,N'-bis-(tert-butoxycarbonyl)-N"-[4-(3-N-tert-butoxycarbonyl-aminomethyl-5- cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine was used in place of N,N -bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyI-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine.. 1H ΝMR (DMSO-d6) 10.27 (IH, s), 8.40 (3H, br s), 7.64 (IH, d), 7.60 (4H, br s), 7.44-7.10 (6H, m), 6.80 (IH, d), 5.42 (2H, br s), 3.00 (IH5 m), 2.00-1.00 (1OH, m). Found: C 51.72, H 6.27, Ν 19.44%; C22H27Ν7O-3HC1 requires: C 51.32, H 5.87, N 19.04%.
Example 109: N-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H~l,3,4-benzotriazepin-l-yl)- phenyl]-3-guanidino-propionamide. The title compound was obtained using step a of the method of preparation of example 71, except that N,N-bis-(tert-butoxycarbonyl)guanidino-propionic acid was used in place of tert- butoxycarbonyl glycine, followed by reaction of the product obtained, in place of 2-[4-(3- benzyl-5 -cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 -yl)-phenylimino]- imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39. 1H NMR (DMSOd6) 10.20 (IH, s), 7.65 (2H, d), 7.56 (IH, d), 7.37 (IH, t), 7.27-7.11 (9H, m), 6.75 (lH,d), 4.80-4.25 (2H, br d), 3.41 (2H, q), 2.91 (IH, m), 2.61 (2H, t), 1.73-1.19 (1OH, m). Found: C 55.00, H 5.10, N 13.15%;
Figure imgf000129_0001
requires: C 54.90, H 4.87, N 12.81%. Example 110: N-[3-(3-Benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H~l,3,4-benzotriazepin-l-yl)- phenylj-guanidine
The title compound was prepared by the method of preparation of example 1, except that 1- iodo-3 -nitrobenzene was used in step c in place of l-iodo-4-nitrobenzene. 1H NMR (DMSO- d6) 10.03 (IH, s), 7.62 (IH, m), 7.60 (4H, br s), 7.43 (2H, m), 7.31-7.10 (9H, m), 6.90 (IH, d), 4.90-4.20: (2H, d), 2.95 (IH, m), 1.72-1.00 (1OH, m). Found: C 62.19, H 6.38, N, 15.19%; C28H30N6O^HCl requires: C 62.34, H 5.98, N 15.58%.
Example 111: N-^-β-Benzyl-S-cyclohexyl^-oxo-l^-dihydro-SH-l.S^-benzotriazepin-l- ylmethyl)-phenyl]-guanidine
Step a: 3-Benzyl-5-cyclohexyl-l-(4-nitro-benzyl)-l ,2-dihydro-3H-l ,3 ,4-benzotriazepine-2-one was obtained using step c of the method of preparation of example 20, except that 3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 1, step b) and 4-nitrobenzyl bromide were used in place of 5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and (3-bromopropenyl)-benzene. 1H NMR (CDCl3) 8.10 (2H, d), 7.42
(2H, d), 7.40-7.07 (9H, m), 5.30 (IH, d), 5.00 (IH, d), 4.75 (IH, d), 4.53 (IH, d), 2.68 (IH, m) 1.83-1.24 (1OH, m).
Step b: The title compound was obtained using steps d-f of the method of preparation of example 1, except that 3-benzyl-5-cyclohexyl-l-(4-nitro-benzyl)-l,2-dihydro-3H-l,3,4- benzotriazepine-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one in step d. 1H NMR (DMSO-d6) 9.77 (IH, s), 7.46 (IH, t), 7.38 (4H, br s), 7.25-7.06 (12H, m), 5.15 (IH, d), 4.83 (2H, dd), 4.35 (IH, d), 2.79 (IH, m), 2.00-1.00 (1OH, m). Found: C 63.06, H 6.38, N 15.45%; C29H32N6O-2HC1 requires: C 62.93, H 6.19, N 15.18%.
Example 112: N-[4-(3-Benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)- phenyl]~N',N"-dimethyl-guanidine Step a: l-μ-β-Benzyl-S-cyclohexyl-l-oxo-l^-dihydro-SH-l^A-benzotriazepin-l-yty-phenyl]- 3-methyl-thiourea
A solution of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin- 2-one (example 1, step d) (424mg, l.Ommol) and methyl isothiocyanate (150mg, 2.0mmol) in dry THF (3mL) was heated at reflux for 16hr. The solvent was evaporated and the residue obtained was triturated with hexane to afford the product as a pale yellow solid (355mg, 71%). 1H NMR (CDCl3) 7.75 (IH, bs), 7.48 (2H, d), 7.36-7.18 (1OH, m), 6.77 (IH, d), 6.10 (IH, m), 5.20-4.50 (2H, d), 3.14 (3H, d), 2.76 (IH, m), 1.84-1.20 (1OH, m). Step b: The title compound was obtained using step e of the method of preparation of example 1, except that methylamine and l-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro- 3H-l,3,4-benzotriazepin-l-yl)-phenyl]-3-methyl-thiourea were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and 1,3- ό«-(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea respectively. The compound was further characterised as the hydrochloride salt. 1H NMR (DMSO-d6) 9.58 (Ih, s), 7.80 (2H, br s), 7.62 (IH, d), 7.44-7.12 (HH, m), 6.81 (IH, d), 4.80-4.25 (2H, br d), 2.94 (IH, m), 2.84 (6K-, s), 1.74-1.00 (1OH, m). Found: C 61.41, H 6.75, N 14.20%; C30H34N6O-2HCl- H2O Requires: C 61.53, H 6.54, N 14.35%.
Example 113: N-[4-(3-Benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l- yl)-2-bromo-phenyl]-guanidine.
Step a: l-(4-Amino-3-bromo-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one
A solution of bromine (250μl, 0.49mmol) in DCM (1OmL) was added dropwise over 20min. to a solution of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin- 2-one (example 1, step d) (2.1Og, 5mmol) and pyridine (800μl, lOmmol) in DCM (3OmL) at O0C. The reaction mixture was stirred at O0C for Ihr, washed with 10% Na2S2O3 (3OmL), brine (3OmL) and dried (MgSO4). Filtration and evaporation of the solvent was followed by chromatography of the residue on silica gel with EtOAc-Hexane (1:4) as eluant to afford the product (1.17g, 47%). 1H NMR (CDCl3) 7.51 (IH, d), 7.32-7.09 (9H, m), 6.81 (IH, d), 6.71 (IH, d), 5.25-4.25 (2H, br s), 4.14 (2H, br s), 2.73 (IH, m), 1.83-1.25 (1OH, m).
Step b: The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-amino-3-bromo-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin~l-yl)- phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39. 1H NMR (DMSO-d6) 9.81 (IH, s), 7.90 (IH, s), 7.63- 7.13 (1Oh, m) 7.57 (4H, br s), 6.92 (IH, d), 4.90-4.25 (2H, br d), 2.97 (IH, m), 1.73-1.00 (1OH, m). Found: C 49.50, H 4.40, N 10.53%; C28H29N6BrO^CF3COOH requires: C 49.69, H 4.04, N 10.86%.
Example 114: (S)-2-Amino-'N-[4-(3-benzyl-5-cycIohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-3-methyl-butyramide Step a: (6-Fluoro-2-aminophenyl) cyclohexyl methanone was obtained by the method of preparation of example 5 step a, except that cyclohexylmagnesium chloride and 6-fluoro-2- aminobenzonitrile were used in place of isopropylmagnesium chloride and 2- aminobenzonitrile respectively.
Step b: 1 -(4-Aminophenyl)-3-benzyl-5-cyclohexyl-6-fluoro-l ,2-dihydro-3~Α-l ,3,4- benzotriazepin-2-one was obtained using steps a-d of the method of preparation of example 1, except that (6-fluoro-2-aminophenyl)-cyclohexyl-methanone was used in step a in place of (2- aminophenyl)-cyclohexyl-methanone.
Step c: The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-6~fluoro-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and fert-butoxycarbonyl i-valine were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. H ΝMR (MeOH-d4) 7.68 (2H, m), 7.37 (3H, m), 7.20 (5H, m), 7.00 (IH, t), 6.63 (IH, d), 4.92 (IH, dd), 4.46 (IH, d), 3.83 (IH, m), 2.87 (IH, m), 2.32 (IH, m), 1.75 (5H, m), 1.30 (5H, m), 1.10 (6H, m
Example 115: (S)-2-Amino-N-{4- [3-(2-cyclohexyl-benzyl)-5-cyclohexyl-2-oxo-l,2-dihydro- 3H-l,3,4-benzotriazepin-l-yl)-phenyl]-3-methyl-butyramide The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-aminophenyl)-5-cyclohexyl-3-(2-cyclohexyl~benzyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 51, step a) and fert-butoxycarbonyl /.--valine were used in place of 1 -(4-aminophenyl)-3-benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6) 7.64-7.02 (1OH, m), 6.70 (2H, m), 5.01 (IH, m), 4.26 (IH, m), 3.60 (2H, m), 2.87 (IH, m), 2.16 (IH, m), 1.65-0.83 (26H, m). Found: C 58.48, H 6.28, Ν 8.48%; C38H47N5O2^ HCl-0.1 C4H8O2 requires: C 58.14, H 6.68, N 8.82%. Example 116: (S)-2-Amino-N-{4-[5-cyclohexyl 3(2'-methyl-biphenyl-2-ylmethyl)-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl]-phenyl}-3-methyl-butyramide
The title compound was obtained using step a of the method of preparation of example 71, except that 1 -(4-aminophenyl)-5-cyclohexyl-3 -(2'-methyl-biphenyl-2-ylmethyl)- 1 ,2-dihydro- 3H-l,3,4-benzotriazepin-2-one (example 48, step a) and tert-butoxycarbonyl Z-valine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and terf-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N)N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2- oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSOd6-D2O 7.60-7.17 (HH, m), 6.97 (2H, m), 6.69 (IH, dd), 6.59 (2H, m), 4.56 (IH, dd), 3.99 (IH, m), 3.55 (IH, d), 2.84 (IH, m), 2.17 (IH, m), 1.89-0.95 (19H, m). Found: C 62.80, H 5.59, Ν 8.64%; C39H43N5O2 (free base)- 1.4CHC13-O.2 hexane requires C 62.60, H 5.96, N 8.77.
Example 117: (S)-2-Amino-N-[4-(5-cyclohexyl-3-octyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-3-methyl-butyramide
Step a: l-(4-Aminophenyl)-5-cyclohexyl-3-octyl-l ,2-dihydro-3H-l ,3 ,4-benzotriazepin-2-one was obtained using steps c and d of the method of preparation of example 20, except that 1- octyl bromide was used in place of (3-bromopropenyl)-benzene in step c.
Step b: The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-aminophenyl)-5-cyclohexyl-3-octyl-l,2-dihydro-3H-l,3,4-benzotriazepin- 2-one and fert-butoxycarbonyl L- valine were used in place of l-(4-aminophenyl)-3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert- butoxycarbonyl)-N//-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l- yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6) 7.65 (3H, m), 7.36-7.22 (4H, m), 6.70 (IH, m), 3.79 (IH, m), 3.33 (2H, m), 2.96 (IH, m), 1.92-0.99 (29H, m), 0.83 (3H, m). Found: C 59.94, H 7.40, Ν 10.36%; C33H47N5O2- 3.2 HCl requires: C 59.83, H 7.64, N 10.57%.
Example 118: (S)-2-Amino-N-{4-[5-cyclohexyl-2-oxo-3-(l-phenyl-ethyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl]-phenyl}-3-methyl-butyramide
Step a: l-(4-Aminopheψl)-5-cyclohexyl-3-(l-phenyl-ethyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using steps c and d of the method preparation of example 20, except that (l-bromo-ethyl)-benzene was used in place of (3-bromopropenyl)-benzene in step c. 1H NMR (CDCl3) 121-1.01 (1OH, m), 6.77 (IH, d), 6.64 (2H, d), 5.22 (IH, br s), 4.12 (2H, br s), 2.77 (IH, m), 1.82-1.25 (13H, m).
Step b The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl-5-cyclohexyl-(l-phenyl-ethyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 118, step a) and tert-butoxycarbonyl Z-valine were used in place of 1 -(4-aminophenyl)-3-benzyl-5 -cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6/D2O) 7.60 (2H, d), 7.36 (IH, t), 7.28-7.22 (9H, m), 6.72 (IH, d), 5.00 (IH, br s), 3.75 (IH, d), 2.95 (IH, m), 1.67-1.21 (14H, m), 0.97 (6H,m). Found: C 66.07, H 7.02, Ν 10.85%; C33H39N5O2- 1.4HC1-0.7 C4H8O2 requires: C 66.11, H 7.13, N 10.77%.
Example 119: (S)-N-[4-(3-Biphenyl-2-ylmethyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-3-methyl-2-methylamino-butyramide
The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-biphenyl-2-ylmethyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 25, step a) and tert-butoxycarbonyl-N-methyl-L-valine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2- oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6/D2O) 7.64 (2H, d), 7.54 (IH, d), 7.39 (IH, t), 7.27-7.20 (9H, m), 7.06 (IH, m), 7.00 (2H5 d), 6.71(1H, d), 4.80 (lH,br: d), 4.20 (lH,br d), 3.66 (IH, m), 2.90 (IH, m), 2.53 (3H5 s), 2.20 (IH, m), 1.71-1.17 (1OH, m), 1.00 (6H, m). Found: C 68.50, H 6.86, Ν 9.52%; C39H43N5O2-LSHCl-O1S C4H8O2 requires: C 68.60, H 6.94, N 9.48%.
Example 120 (S)- 2-Amino-N-{4-[5-cyclohexyl-3-(3,3-diphenyl-propyl)-2-oxo-l,2~dihydro-3H- 1, 3, 4-benzotriazepin-l-yl]-phenyl}-3-methyl-butyramide Step a: l-(4-Aminophenyl)-5-cyclohexyl-3-(3,3-diphenyl-propyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using steps c and d of the method of example 20, except that 3,3-diphenylpropyl bromide was used in place of (3-bromoproρenyl)-benzene in step c. 1H NMR (CDCl3) 7.36 (IH, d), 7.27-7.10 (14H, m), 6.79 (IH, d), 6.64 (2H, d), 3.82 (3H, m), 3.45 (2H, br s), 2.81 (IH, m), 2.38 (2H, m), 1.89-1.24 (12H, m). Step b The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl-5-cyclohexyl-(3,3-diphenyl-propyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and tert-butoxycarbonyl Z-valine were used in place of l-(4- ammophenyty-S-benzyl-S-cyclohexyl-l^-dihydro-SH-l^^-benzotriazepin^-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of ^N-bis-^ert-butoxycarbonyO-N'-^-CS-benzyl-S-cyclohexyl^-oxo-l^-dihydro-SH-l^^- benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6/D2O) 7.62 (IH, d), 7.56 (2H,d), 7.41 (IH, t), 7.38 (IH, t), 7.32-6.99 (12H, m), 6.73 (IH, d), 3.62 (2H, m), 3.20 (2H, m), 2.95 (IH, m), 2.15 (3H, m), 1.85-0.93 (16H, m). Found: C 69.73, H 6.94, Ν 9.99%; C40H45N5O2-I^HCl requires: C 69.61, H 6.82, Ν 10.15%.
Example 121 (S)-2-Amino-Η-{4-[5-cyclohexyl-2-oxo-3-naphthalen-2-ylmethyl-l,2-dihydro- SH-1, 3, 4-benzotriazepin-l-yl]-phenyl}-3-methyl-butyramide
Step a: l-(4-Amino-phenyl)-5-cyclohexyl-3-naphtalen-2-ylmethyl-l ,2-dihydro-3H-l ,3 ,4- benzotriazepin-2-one was obtained using steps c and d of the method of preparation of example 20, except that 2-bromomethyl-naphthalene was used in place of (3-bromoproρenyl)- benzene in step c. 1H ΝMR (CDCl3) 7.67 (IH, m), 7.65 (3H, m), 7.42 (2H, m), 7.29 (3H, m), 7.14 (3H, m), 6.83 (IH, d), 6.67 (2H, d), 5.20-4.65 (2H, br s), 3.80 (2H, br s), 2.70 (IH, m), 1.81-1.24 (1OH, m). Step b The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-5-cyclohexyl-3-naphthalen-2-ylmethyl-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl i-valine were used in place of l-(4- aminophenyl)-3 -benzyl-5 -cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N/-bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H NMR (DMSOd6) 10.76 (IH, s), 8.27(3H, br s), 7.81-7.58 (7H, m), 7.46 (8H, m), 6.78 (lH,d), 4.90 (IH, br s), 4.59 (IH, br s), 3.80 (IH, d), 2.92 (IH, m), 2.19 (IH, m), 1.72-0.97 (16H5 m). Found: C 66.35, H 6.70, N 10.29%; C36H39N5O2^.2HCl requires: C 65.97, H 6.34, N 10.68%.
Example 122 N-[3-Chloro-4-(5-cyclohexyl-3-cyclohexylmethyl-2-oxo-l,2-dihydro-3H~l,3,4~ benzotriazepin-l-yl)-phenyl]~guanidine
The title compound was obtained using steps a-e of the method of preparation of example 1 except that cyclohexylmethyl hydrazine was used in place of benzylhydrazine in step a and 2- chloro-l-iodo-4-nitrobenzene replaced 4-iodo-nitrobenzene in step d, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester, according to step b of the method of preparation of example 39. 1H NMR (DMSO-d6/D2O) 7.74 (IH, m), 7.63 (IH, d), 7.41-7.21 (4H, m), 6.68 (IH, d), 3.32 (2H, m) 2.92 (IH, m), 1.74- 0.74 (21H, m). Found: C 56.88, H 5.75, N 12.67%; C28H35CIN6O-I^CF3CO2H requires: C 56.58, H 5.65, N 13.00%.
Example 123 N-[4-(3-Biphenyl-2-ylmethyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-2-pyrrolidin-l~yl-acetamide Step a: N-[4-(3-Biphenyl-2-ylmethyl-5-cyclohexyl-2-oxo-l, 2-dihydro-3H-l ,3, 4-benzotriazepin- l-yl)-phenyl]-2-bromo-acetamide
To a solution of l-(4-amino-phenyl)-3-biphenyl-2-ylmethyl-5-cyclohexyl-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one (example 25, step a) (500mg, l.Ommol) and NEt3 (0.2ImL, l.lmmol) in DCM (1OmL) was added bromoacetyl bromide (O.lmL, l.lmmol) and the reaction mixture was stirred at ambient temperature for 2h. The reaction mixture was diluted with DCM (1OmL), washed with saturated aqueous NaHCO3/20mL), brine (2OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with EtOAc-hexane (3:7) as eluant (470mg, 75%). 1H NMR (CDCl3) 8.22 (IH, s), 7.45 (2H, d), 7.30-7.09 (14H5 m), 6.70 (IH, d), 5.00 (IH, br s), 4.30 (IH, br s), 3.96 ( 2H, s), 2.70 (lH,m), 1.79-1.24 (1OH, m).
Step b: To a solution of N-[4-(3-biphenyl-2-ylmethyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-3-yl)-phenyl]-2-bromo-acetamide (230mg, 0.37mmol) in DCM (5mL) was added pyrrolidine (310μl, 3.7mmol) and the reaction mixture was stirred at ambient temperature for 2h, diluted with DCM (1OmL), washed with saturated aqueous NaHCO3 (IOmL), brine (1OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the title compound which was purified by chromatography on silica gel with EtOAc as eluant (170mg, 75%). The compound was further characterised and tested as the hydrochloride salt . 1H NMR (DMSO-d6/D2O) 7.57 (2H, d), 7.50 (IH, d), 7.36 (IH, t), 7.26-7.17 (9H, m), 7.03 (3H, m), 6.67 (IH, d), 4.76 (IH, d), 4.18 (3H, br s), 3.25 (4H, br s), 2.84 (IH, m), 1.95 (4H, br s), 1.69-1.10 (1OH, m). Found: C 69.41, H 6.58, N 9.76%; C39H41N5O2-1.4HC1-0.6 C4H8O2 requires: C 69.48, H 6.65, N 9.79%. Example 124 N-[4-(3-Biphenyl-2-ylmethyl-5-cyclohexyl-2-oxo-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-l~yl)-phenyl]-2-dimethylamino-acetamide
The title compound was prepared by the method used in the preparation of example 123 except that dimethylamine was used in step b in place of pyrrolidine. 1H NMR (DMSOd6ZD2O) 7.61 (2H, d), 7.55 (IH, d), 7.36 (IH, t), 7.28-7.19 (9H, m), 7.05 (3H, m), 6.69 (IH, d), 4.80 (IH, br d), 4.20 (IH, br d), 4.13 (2H, s), 2.86 (7H, s), 172-1.21 (1OH, m). Found: C 67.41, H 6.46, N 9.95%; C37H39N5O2-UHCl-OJ C4H8O2 requires: C 69.48, H 6.65, N 9.79%.
Example 125: N-[4-(3-Benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yI)~ phenyl]-N,N'-dimethyl-guanidine Step a: N^'-Bis-ft&n-butoxycarbonyl^'-^-fS-benzyl-S-cyclohexyl^-oxo-lJ-difydw-SH- l,3,4-benzotriazepin-3~yl)-phenyl]-N,N"-dimethyl-guanidine
To a solution of N1N -bis-(tert-butoxycarbonyl)-N//-[4-(3-benzyl-5-cyclohexyl-2-oxo- l,2-dihydro-3H-l,3,4-benzotriazepin-3-yl)-phenyl]-guanidine (example 1, step e) (200mg, 0.3mmol) in DMF (3mL) was added sodium hydride (60% dispersion in mineral oil, 30mg, 0.72mmol) and the mixture was stirred at ambient temperature for 30 min. Iodomethane (6OmL, 0.72mmol) was added and the stirring was continued for 16h. The reaction mixture was partitioned between EtOAc-H2O (1:1 / 2OmL). The organic layer was separated, washed with brine (3 x 1OmL) and dried (MgSO4). Filtration and evaporation of the solvent was followed by chromatography on silica gel with EtOAc-hexane (1 :4) as eluant to afford firstly Ν,Ν'-bis-(tert-butoxycarbonyl)-Ν"-[4-(3-benzyl-5 -cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-l-yty-phenylj-N'jN'-dimethyl-guanidme (126mg, 61%) followed by N,N'-bis- (tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1,3,4- benzotriazepm-l-yl)-phenyl]-N,N"-dimethyl-guanidine (35mg, 17%) as the more polar component. 1H NMR (CDCl3) 7.42-7.14 (12H, m), 6.76 (IH, d), 4.95 (IH, br s), 4.50 (IH, br s), 3.37 (3H, s), 2.78 (4H,m), 1.83-1.24 (1OH, m).
Step b: The title compound was obtained using step f of the method of preparation of example 1, except that N,N'-bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-N,N"-dimethyl-guanidine was used in place of N,N-bis-(tert-butoxycarbonyl)-N/-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepm-l-yl)-phenyl]-guanidine. 1H ΝMR (DMSO-d6/D2O) 7.59 (IH, d), 7.43-7.11 (HH, m), 6.87 (IH, d), 4.76 (IH, br s), 4.44 (IH, br s), 3.24 (3H, s), 2.94 (IH, m), 2.75 (3H, s), 1.72-1.15 (1OH, m). Found: C 63.26, H 6.82, Ν 13.35%; C30H3ΛO-I.8HCI- 0.8 C4H8O2 requires: C 63.72, H 6.74, N 13.32%. Example 126: N-[4-(3-BenzyJ-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)- phenyl]-N'-cyclohexyl-N"-methyl~guanidine
Step a: l-β-β-Benzyl-S-cyclohexyl^-oxo-l^-dihydro-SH-lJΛ-benzotriazepin-l-yty-phenyl]- 3-cyclohexyl-thiourea was obtained using step a of the method of preparation of example 112, except that cyclohexyl isothiocyanate was used in place of methyl isothiocyanate. 1H NMR (CDCl3) 7.46 (IH, br s), 7. 38 (2H, d), 7.32-7.15 (1OH, m), 6.78 (IH, d), 5.92 (IH, d), 4.90 (IH, br s), 4.50 (IH, br s), 4.28 (IH, m),2.77 (IH, m), 2.06 (2H, m), 1.84-1.09 (18H, m).
Step b: The title compound was obtained using step e of the method of preparation of example 1, except that l-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)- phenyl]-3-cyclohexyl-thiourea and methylamine were used in place of l-(4-aminophenyl)-3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and \,3-bis-(tert- butoxycarbonyl)-2-methyl-2-thiopseudourea respectively. 1H NMR (CDCl3) 7.34-7.14 (1OH, m), 7.01 (2H, d), 6.76 (IH, d), 5.00-4.50 (2H, d), 3.53 (IH, m), 2.85 (3H, s), 2.74 (IH, m), 2.17-1.13 (2OH, m). The compound was further characterised and tested as the hydrochloride salt. Found: C 66.54, H 7.08, N 12.56%; C35H42N6O-I^HCl-OJ C4H8O2 requires: C 66.45, H 7.19, N 12.57%.
Example 127 N-[4-(3-Benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)- phenyl]-N'-methyl-pyrrolidine-l-carboxamidine
The title compound was obtained using step e of the method of preparation of example 1, except that l-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)- phenyl]-3-methyl-thiourea (example 112, step a) and pyrrolidine were used in place of l-(4- aminophenyl)-3 -benzyl-5 -cyclohexyl-1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one and 1 ,3-bis-
(fert-butoxycarbonyl)-2-methyl-2-thiopseudourea respectively. 1H NMR (DMSO-d6) 7.55 (IH, d), 7.37 (IH, t), 7.22-7.05 (9H, m), 6.75 (3H, m), 5.00-4.25 (2H, d), 3.19 (4H, br s), 2.91 (IH, s), 2.59 (3 H, s), 1.80-1.00 (14H, m). The compound was further characterised and tested as the hydrochloride salt. Found: C 63.72, H 6.83, N 13.40%; C33H38N6O-2HCl-0.75 H2O requires: C
63.81, H 6.74, N 13.53%.
Example 128: 2-Amino-N-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H~l,3, 4- benzotriazepin-l-yl)-phenyl]-N-methyl-acetamide
Step a: 3-Benzyl-5-cyclohexyl-l-(4-methylamino-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin- 2-one To a solution of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 1, step d) (420mg, l.Ommol), 37% formalin (80μl, l.lmmol) and HOAc (0.1 lμl, 2.0mmol) in DCE (5mL) was added sodium triacetoxy borohydride (360mg, 1.7mmol) in small portions. The reaction mixture was stirred for 2h at ambient temperature and diluted with DCM (1OmL). The organic layer was separated, washed with saturated NaHCO3 (2OmL), brine (2OmL) and dried (MgSO^. Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel using EtOAc-hexane (1 :4) as eluant to afford the product as a colourless foam (200mg, 46%). 1H NMR (CDCl3) 7.29-7.10 (1OH, m), 6.82 (IH, d), 6.58 (2H, d), 4.80 (2H, br s), 3.75 (IH, br s), 2.72 (4Hm), 1.82-1.26 (1OH, m).
Step b : ({[3-Benzyl-5-cyclohexyl-2-oxo)-l ,2-dihydro-3H-l , 3, 4-benzotriazepin-l-yl)-phenylJ- methyl-carbamoyl}-metyl)-carbamic acid tert-butyl ester
To a solution of 3-benzyl-5-cyclohexyl-l-(4~methylamino-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (130mg, 0.3mmol), teτY-butoxycarbonyl glycine (lOOmg, O.δmmol) and Z-Pr2NEt (210μl, 1.2mmol) in DCM (3mL) was added PyBrop (280mg, 0.6mmol) and the solution was stirred at ambient temperature for 16h. The reaction mixture was diluted with DCM (1OmL), washed with 5% KHSO4 (1OmL), saturated aqueous NaHCO3 (1OmL), brine (1OmL), dried, filtered and the solvent was evaporated. The crude product was purified by chromatography on silica gel using hexane-EtOAc (8:2) as eluant to afford the product as a colourless foam (70mg, 39%). 1U NMR (CDCl3) 7.50 (2H, d), 7.36 (2H, t), 7.27-7.16 (8H, m), 6.85 (IH, d), 5.38 (IH, br s), 5.05 (IH, br s), 4.80 (IH, br s), 3.69 (2H, br s), 3.27 (3H, s), 2.77 (IH, m), 2.05-1.21 (19H, m).
Step c: The title compound was obtained using step f of the method of preparation of example 1 except that ({[3-benzyl-5-cyclohexyl-2-oxo)-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)- phenyl]-methyl-carbamoyl}-methyl)-carbamic acid tert-butyl ester was used in place of N,N- bis-(tert-butoxycarbonyl)-N/-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine. 1H ΝMR (DMSO-d6/D2O) 7.59 (IH, d), 7.44-7.10 (HH, m), 6.80 (IH, d), 4.79 (IH, br s), 4.42 (IH, br s), 3.46 (2H, m), 3.21 (3H, s), 2.93 (IH, m), 1.72-1.04 (1OH, m). Found: C 64.32, H 6.38, Ν 11.83%; C30H33N5O2- 1.6HCl-0.4 C4H8O2 requires: C 64.42, H 6.47, N 11.89%.
Example 129: N-[4-(3-Benzyl-5-cyclohexyl-2~oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)- phenyl]-2-cyclohexylamino-acetamide
Step a: N-[4-(3-Benzyl~5-cyclohexyl-2-oxo-l ,2~dihydro-3H-l , 3, 4-benzotriazepin-l -yl) -phenyl] - 2-bromo-acetamide was obtained using step a of the method of preparation of example 123 except that l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l;,3,4-benzotriazepin-2- one (example 1, step d) was used in place of l-(4-amino-phenyl)-3-biphenyl-2-ylmethyl-5-cyclohexyl-l,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one . Step b: The title compound was prepared using step b of the method of preparation of example 123 except that N-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l- yl)-phenyl]-2-bromo-acetamide and cyclohexylamine were used in in place of N-[4-(3- biphenyl-2-ylmethyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]- 2-bromo-acetamide and pyrrolidine respectively. 1H NMR (CDCl3) 9.54 (IH, s), 7.59 (2H, d), 7.38-7.12 (1OH, m), 6.78 (IH, d), 4.80 (2H, br s), 3.40 (2H, s), 2.74 (IH, m), 2.45 (IH, m), 1.93-1.09 (2OH, m). Found: C 71.57, H 7.10, N 11.95%; C35H4IN5O2-LlH2O requires: C 71.93, H 7.47, N 11.98%.
Example 130: N-(2-Amino-ethyl)-4-(3-benzyl-5-cyclohexyl-2-oxo-l, 2-dϊhydro-SH-l , 3, 4- benzotriazepin-l-yl)-benzamide Step a: 4-(3-Ben∑yl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-benzoic acid methyl ester was prepared using step c of the method of preparation of example 1, except that methyl-4-iodobenzoate was used instead of 4-iodo-nitrobenzene. 1H NMR (CDCI3) 8.00 (2H, d), 7.48 (2H, d), 7.40-7.15 (8H, m), 6.85 (IH, d), 5.25-4.50 (2H, d), 3.91(3H, s), 2.75 (IH, m), 1.83-1.00 (1OH, m). Step b: 4-(3-Benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-benzoic acid was prepared using step d of the method of preparation of example 13, except that 4-(3- benzyl-5-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin- 1 -yl)-benzoic acid methyl ester was used instead of [5-cyclohexyl-l-(4-(N,N'-δω-(tert-butoxycarbonyl)-guanidino)- phenyl)-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl]-acetic acid ethyl ester. 1H ΝMR (CDCl3) 8.00 (2H, d), 7.50 (2H, d), 7.39-7.14 (8H, m), 6.89 (IH, d), 5.25-4.50 (2H, d), 2.78 (IH, m), 1.89-1.00 (1OH, m).
Step c: The title compound was obtained using step a of the method of preparation of example 71, except that 2-(amino-ethyl)-carbamic acid tert-butyl ester and 4-(3-benzyl-5-cyclohexyl-2- oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-benzoic acid were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l53,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N/-bis-(tert-butoxycarbonyl)-N/-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3;4- benzotriazeρin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6) 8.75 (IH, t), 8.02 (3H, br s), 7.92 (2H, d), 7.62 (IH, d), 7.43- 7.11 (9H5 m), 6.79 (IH, d), 5.00-4.25 (2H, d), 3.52 (2H, m), 2.97 (3H, m), 1.74-1.10 (1OH, m). Found: C 63.13, H 6.36, N 12.71%; C30H33N5O2^HCl requires: C 63.38, H 6.21, N 12.31%.
Example 131: N- [3- (3-Benzyl~5-cyclohexyl-2-oxo-l , 2-dihydro-3H-l, 3, 4-benzotriazepin-l - ylmethyl)-phenyl]-guanidine Step a: 3-Benzyl-5-cyclohexyl-l-(3-nitro-benzyl)-l ,2-dihydro-3H-l ,3 ' ,4-benzotriazepine-2-one was obtained using step c of the method of preparation of example 20, except that 3-benzyl-5- cyclohexyl~l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 1, step b) and 3-nitrobenzyl bromide were used in place of 5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and (3-bromopropenyl)-benzene. 1H NMR (CDCl3) 8.09 (2H, m), 7.60 (IH, d), 7.45-7.10 (1OH, m), 5.32 (IH, d), 4.99 (IH, d), 4.75 (IH, d), 4.53 (IH, d), 2.66 (IH, m) 2.00-1.00 (1OH, m).
Step b: The title compound was obtained using steps d-f of the method of preparation of example 1, except that 3-benzyl-5-cyclohexyl-l-(3-nitro-benzyl)-l,2-dihydro-3H-l,3,4- benzotriazepine-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one in step d. 1H NMR (DMSOd6) 9.91(1H, s), 7.48-7.00 (17H, t), 5.20-4.85 (IH, dd), 4.85-4.35 (2H, dd), 2.79 (IH, m), 1.80-1.00 (1OH, m). Found: C 62.82, H 6.36, N 15.25%; C29H32N6O-2HC1 requires: C 62.93, H 6.19, N 15.18%.
Example 132: 4-[5-Cyclohexyl-l~(4-guanidino-phenyl)-2-oxo-l ,2-dihydro-3H-l ,3 ,4- benzotriazepm-3-ylmethylJ-benzoic acid methyl ester The title compound was obtained using steps c-f of the method of preparation of example 20, except that 4-methoxycarbonylbenzyl bromide was used in step c in place of (3- bromopropenyl)-benzene. 1H NMR (DMSOd6-D2O) 7.81 (2H, d), 7.60-7.24 (9H, m), 6.79 (IH, d), 4.90 (IH, m), 4.46 (IH, m), 3.79 (3H, s), 2.91 (IH, m), 1.69-1.48 (5H, m), 1.19-1.12 (5H, m). Found: C 54.39, H 5.31, N 13.00%; C30H32N6O3-SJ HCl requires: C 54.63, H 5.46, N 12.74%.
Example 133 : N-fe-fi-Cyclohexyl^-oxoS-phenyl-l^-dihydroSH-LSJ-benzotriazepin-l- ylmethyl)-phenyl]-guanidine
Step a. 2-[Cyclohexyl-(phenyl-hydrazono)-methyl]-phenylamine
A solution of 2-aminophenyl cyclohexyl methanone (1.02g, 5.02mmol) and phenylhydrazine (0.98ml, lO.Ommol) in EtOH (12mL) was treated with HOAc (5drops) and heated at reflux for
48h. The mixture was diluted with EtOAc (4OmL) and washed with 10% KHSO4 solution
(4OmL), NaHCO3 (4OmL) brine (4OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with EtOAc-DCM (1:50) as eluant.
Step b : 5-Cyclohexyl-3-phenyl-l ,2-dihydro-3H-l , 3, 4-benzotriazepin-2-one
2-[Cyclohexyl-(phenyl-hydrazono)-methyl]-phenylamine was dissolved in DCM (5mL), and cooled to O0C whereupon NEt3 (523 μl, 3.76mmol) was added, followed by a solution of bis-
(trichloromethyl)carbonate (223mg, 0.75mmol) in DCM (2mL). The mixture was stirred at O0C for 20min. then partitioned between DCM (3OmL) and 2M HCl (3OmL). The organic layer was separated, washed with brine (3OmL), and dried (MgSO4). Filtration and evaporation of the solvent gave the product (319mg, 20%). 1H NMR (CDCl3) 7.53-7.50 (2H, m), 7.41-7.32 (4H, m), 7.17 (2H, m), 6.94 (IH, d), 6.62 (IH, br s), 2.78 (IH, m), 1.91-1.26 (1OH, m).
Step c: 5-Cyclohexyl-l-(4-nitrobenzyl)-3-phenyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step c of the method of preparation of example 20, except that 5- cyclohexyl-3 -phenyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and 4-nitrobenzylbromide were used in place of 5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one and (3-bromopropenyl)-benzene respectively. 1H NMR (CDCl3) 8.14 (IH, t), 8.09 (2H,d), 7.46 (IH, d), 7.44 (5H, m), 7.30 (4H, m), 5.41 (IH, d), 4.84 (IH, d), 2.83 (IH, m), 2.07 (IH, m), 1.79 (4H, m), 1.65 (IH, m), 1.24 (4H, m).
Step d: The title compound was obtained as the di-hydrochloride salt using step d-f of the method of preparation of example 1, except that 5 -cyclohexyl-l-(4-nitrobenzyl)-3 -phenyl- 1,2- dihydro-3H-l,3,4-benzotriazepin-2-one was used step d in place of 3-benzyl-5-cyclohexyl-l- (4-nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (DMSO^6) 9.83 (IH, s), 7.57 (6H, m), 7.29 (6H, m), 7.05 (2H, m), 5.20 (IH, d), 4.92 (IH, d), 2.97 (IH, m), 2.03 (IH, d), 1.68 (3H, m), 1.35 (6H, m), 1.08 (IH, m), 0.85 (IH, m). Found: C 62.94, H 6.40, N 15.28%; C28H3oN60-2HCl requires: C 62.34, H 5.98, N 15.58%. Example 134: 2-Aτnino-N-[4-(3-biphenyl-2-ylmethyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-l-ylmethyl)-phenyl]-acetamide
The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-biphenyl-2-ylmethyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 25, step a) was used in place of l-(4-aminophenyl)-3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N/-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (CDCl3) 10.13 (IH, br s), 8.60-6.55 (2OH, m), 5.00-3.80 (3H, m), 3.70 (2H, m), 2.61 (IH, m), 1.90-1.10 (10H3 m). Found: C 64.54, H 17, N 11.34%; C35H35N5Or2HCl-O.2DCM-O.5DMF requires: C 64.43, H 6.03, N 11.26%.
Example 135: 3-Biphenyl-2-ylmethyl-5-cyclohexyl-l-{4-[(lH-imidazol-2-ylmethyl)-amino]- phenyl}-l ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one The title compound was obtained using step a of the method of preparation of example 128, except that 1 -(4-amino-phenyl)-3 -biphenyl-2-ylmethyl-5 -cyclohexyl- 1 ,2-dihydro-3 H- 1 ,3 ,4- benzotriazepin-2-one (example 25, step a) and l-H-imidazol-2-carbaldehyde were used in place of 1 -(4-aminophenyl)-3-benzyl-5-cyclohexyl- 1 ,2-dihydro-3Η- 1 ,3,4-benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 7.29-7.05 (14H, m), 6.95 (2H, s), 6.75 (IH, d), 6.51 (2H, d), 4.95 (IH, br s), 4.42 (2H5 br s), 4.33 (2H, br s), 2.72 (IH, m), 1.78-1.27 (1OH, m). The compound was further characterized and tested as the hydrochloride salt. Found: C 66.34, H 5.83, N 11.99%; C37H36N5O-2.3HCl-0.4 C4H8O2 requires: C 66.25, H 5.98, N 12.01%.
Example 136: 3-Biphenyl-2-ylmethyl-5-cyclohexyl-l-{4-[(lH-imidazol-4-ylmethyl)-amino]- phenyl}-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one The title compound was obtained using step a of the method of preparation of example 128, except that 1 ~(4-amino-phenyl)-3 -biphenyl-2-ylmethyl-5 -cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4- benzotriazepin-2-one (example 25, step a) and l-H-imidazol-4-carbaldehyde were used in place of 1 -(4-aminophenyl)-3 -benzyl-5 -cyclohexyl- 1 ,2-dihydro-3 Η- 1 ,3 ,4-benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 7.50 (1Η, s), 7.29-7.08 (14Η, m), 6.84 (IH, s), 6.75 (IH, d), 6.58 (2H, d), 5.00 (IH, br s), 4.30 (2H, br s), 4.27 (2H, s), 2.72 (IH, m), 1.80- 1.26 (1OH, m). The compound was further characterized and tested as the hydrochloride salt. Found: C 65.57, H 6.07, N 1156%; C37H36N5O^.4HC1-0.7 C4H8O2 requires: C 65.49, H 6.08, N 11.51%.
Example 137: l-[4-(2-Amino-3-methyl-butylamino)-phenyl]-3-hiphenyl-2-ylmethyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
The title compound was obtained using step a of the method of preparation of example 128, except that 1 -(4-amino-phenyl)-3-biphenyl-2-ylmethyl-5-cyclohexyl- 1 ,2-dihydro-3H-l ,3,4- benzotriazepin-2-one (example 25, step a) and (iSj-(l-formyl-2-methyl-propyl)-carbamic acid ester were used in place of l-(4-aminophenyl)-3 -benzyl-5 -cyclohexyl- 1,2-dihydro- 3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6) 8.13 (3H, br s), 7.52 (IH, d), 7.37 (IH, t), 7.29-6.96 (1OH, m), 6.95 (2H, d), 6.72 (IH, d), 6.65 (2H, d), 4.76 (IH, br d), 4.21 (IH, br d), 3.30-3.13 (3H, m), 2.86 (IH, m), 2.01 (IH, m), 1.80-1.18 (10H5 m), 0.97 (6H, d). Found: C 67.14, H 7.08, N 9.94%; C38H43N5O-2.4HCI-O.4 C4H8O2 requires: C 67.13, H 6.91, N 9.88%.
Example 138: 3-Biphenyl-2-ylmethyl-5-cyclohexyl-l-[4-[(lH-imidazol-2-ylamino)-phenyl]- 1 ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one Step a: β-β-Biphenyl^-ylmethyl-S-cyclohexyl^-oxo-lJ-dihydro-SH-l.S^-benzotriazepin-l- yϊ) -phenyl] -thiourea
To a solution of l-(4-amino-phenyl)-3-biphenyl-2-ylmethyl-5-cyclohexyl-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one (example 25, step a) (500mg, lmmol) in toluene (5mL) was added thiophosgene (92μl, 1.2mmol) and the solution was heated at reflux for 1.5h. The solution was cooled, THF (5mL) was added and NH3 gas was bubbled into the solution for 5min. The reaction mixture was stirred at ambient temperature for 30min then the solvent was evaporated. The residue was dissolved in EtOAc (15mL), washed with saturated NaHCO3 (15mL), brine (15mL) and dried (MgSO4). Filtration and evaporation of the solvent afforded the product (560mg, 100%). 1H NMR (CDCl3): 8.32 (IH, br s), 7.35-7.07 (17H, m), 6.72 (IH, d), 6.16 (2H, br s), 5.00 (IH, br s), 4.30 (2H, br s), 2.71 (IH, m), 1.80-1.27 (1OH, m).
Step b: ft-β-Biphenyl^-ylmethylS-cyclohexyl^-oxo-l^-dihydroSH-l^^-benzotriazepin-l- yl)-phenyl]-N'-(2,2-dimethoxy-ethyl)-guanidine
A solution of [4-(3-biphenyl-2-ylmethyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-thiourea (560mg, l.Ommol) and iodomethane (300μl, 5.0mmol) in MeOH (5mL) was heated at reflux for 2h. The solvent was evaporated, and the residue dissolved in 2-propanol (5mL). Aminoacetaldehyde dimethyl acetal (22βμl, 2.0mmol) was added and the solution heated at reflux for 6h. The solvent was evaporated, the residue dissolved in EtOAc (15mL), washed with saturated NaHCO3 (15mL), brine (15mL) and dried (MgS04).Filtration and evaporation of the solvent afford the product (545mg, 87%). 1H NMR (CDCl3) 7.30-7.12 (15H, m), 6.91 (2H, d), 6.73 (IH, d), 5.00-4.30 (5H, m), 3.43 (8H, m), 2.72(1H, m), 1.79-1.27 (1OH, m).
Step c: A solution of [4~(3-biphenyl-2-ylmethyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-N'-(2,2-dimethoxy-ethyl)-guanidine (540mg, 0.86mmol) in 6N HCl (5mL) was stirred at ambient temperature for 4h. The solution was basified to pH8 by the addition of 2N NaOH and extracted with DCM (2 x 15mL) and the extracts dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatorgraphy on silica gel with NH3- MeOH-DCM: (0.5:5:95) as eluant to afford the title compound as a colourless foam (212mg, 44%). 1H NMR (CDCl3): 7.30-6.98 (17H, m), 6.72 (IH, d), 6.61 (2H, s), 4.95 (IH, br s),: 4.50 (IH, br s),: 2.70 (IH, m), 1.81-1.27 (1OH, m). The compound was further characterized and tested as the hydrochloride salt. Found: C 68.43, H 6.02, N 12.66%; C36H34N6O-1.6HC1-0.4 C4H8O2 requires: C 68.40, H 5.92, N 12.73%.
Example 139: 3-Biphenyl-2-ylmethyl-5-cyclohexyl-l-{4-[(thiazole-2-yhnethyl)-amino]- phenylj-l ,2-dihydro-3H-l , 3, 4-benzotriazepin-2-one The title compound was obtained using step a of the method of preparation of example 128, except that 1 -(4-amino-phenyl)-3 -biphenyl-2-ylmethyl-5 -cyclohexyl- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-2-one (example 25, step a) and thiazol-2-carbaldehyde were used in place of 1- (4-aminophenyl)-3-benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3): 7.74 (IH, d),: 7.29-7.09 (15H, m), 6.73 (IH, d), 6.62 (2H, d), 4.98 (IH, br s), 4.66 (2H, s), 4.55 (IH, br s), 4.41 (IH, br s), 2.67 (IH, m), 1.77-1.24 (1OH, m). Found: C 73.33, H 5.97, N 11.15%; C37H35N5OS-0.4EtOAc requires: C 73.40, H 6.06, N 11.16%.
Example 140 : 3-Benzyl-5-cyclohexyl~l-[4-(4, 5-dihydro-lH-imidazol-2-ylamino)-phenyl]-8- inethyl-1, 2-dihydro-3H-l, 3, 4-henzotriazepin-2-one The title compound was prepared by the method used in the: preparation of example 1 except that (2-amino-4-methyl-phenyl)-cyclohexyl-methanone was used in step a in place of (2- aminophenyl)-cyclohexyl-methanone and di-tert-butyl 2-thioxoimidazolidine-l,3- dicarboxylate replaced bis-(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea in step e. 1H NMR (DMSO-d6) 10.84 (IH, s), 8.37 (2H, s), 7.49 (IH, d), 7.39-7.08 (1OH, m), 6.60 (IH, s), 5.00-4.25 (2H, d), 3.65 (4H, s), 2.95 (IH, m), 2.21 (3H, s), 1.72-1.15 (1OH, m). Found C 64.29, H 6.55, N, 14.39%; C31H34N6O-2HC1 requires: C 64.24, H 6.26, N 14.50%.
Example 141 (S)-2~Amino-N-[4-(3-benzyl-5-cyclohexyl-8-methyl-2-oxo-l,2-dihydro-3H-l, 3, 4- benzotriazepin-1-yl) -phenyl] -3 -methyl-butyr amide
Step a: l-(4-Aminophenyl)-3-benzyl-5-cyclohexyl-8-methyl-l,2-dihydro-3H-l, 3, 4- bemotriazepin-2-one was prepared by the method used in steps a-d in the preparation of example 1 except that (2-amino-4-methyl-phenyl)-cyclohexyl-methanone was used in step a in place of (2-aminophenyl)-cyclohexyl-methanone. 1H NMR (CDCl3) 7.22-7.13 (8H, m), 6.94 (IH, d), 6.67 (2H, d), 6.60 (IH, s), 5.25-4.25 (2H, br s), 3.71 (2H, br s), 2.75 (IH, m), 2.23 (3H, s), 1.82-1.25 (1OH, m). Step b: The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl-8-methyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and fert-butoxycarbonyl i-valine were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of ^N-bis-^ert-butoxycarbony^-N'-^-CS-benzyl-S-cyclohexyl^-oxo-l^-dihydro-SH-l^^- benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6)10.87 (IH, s), 8.33 (3H, br s), 7.67 (2H, d), 7.48 (IH, d), 7.31 (2H, d), 7.24-7.07 (6H, m), 6.57 (IH, s), 5.00-4.25 (2H, d), 3.84 (IH, m), 2.95 (IH, m), 2.21 (IH, m), 2.19 (3H, s), 1.72-1.20 (1OH, m), 0.99 (6H, m). Found: C 64.62, H 7.00, Ν 11.87%; C33H39N5O2^HCl requires: C 64.91, H 6.76, N 11.47%.
Example 142: N^-β^-tert-Butyl-thiazol-Σ-ylmethylJS-cyclohexyl^-oxo-lJ-dihydro-SH- l,3,4-benzotriazepin-l-yl]-phenyl}-guanidine Step a: [S-Cyclohexyl-l-ft-nitro-phenylJ^-oxo-l^-dihydroSH-l.S^-benzotriazepinS-yl]- acetic acid N-hydroxysuccinimide ester was prepared using step d of the method of preparation of example 13 except that [5-cyclohexyl-l-(4-nitro-phenyl)-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-3-yl]-acetic acid ethyl ester (example 13, step a) was used in place of [5- cyclohexyl-l-(4-(N,N'-bis-(tert-butoxycarbonyl)-guanidino)-phenyl)-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester, followed by reaction of the product obtained in place of [5-cyclohexyl-l-(4-(N,N'-&w-(tert-butoxycarbonyl)-guanidino)-phenyl)-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-3-yl]-acetic acid according to step e of the method of preparation of example 13.
Step b: 2~[5-Cyclohexyl-l-(4-nitro-phenyl)-2-oxo-l ,2-dihydro-3H-l ,3 ,4-benzotriazepin-3-yl]- acetamide was prepared using step f of the method of preparation of example 13 except that [5- cyclohexyl-l-(4-nitro-phenyl)-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl]-acetic acid Ν- hydroxysuccinimide ester and ammonia were used in place of [5-cyclohexyl-l-(4-(N,N'-6w- (tert-butoxycarbonyl)-guanidino)-phenyl)-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-3-yl]- acetic acid N-hydroxysuccinimide ester and diphenylmethylamine respectively. 1H ΝMR (CDCl3) 8.20 (2H, d), 7.57 (2H, d), 7.52 (IH, d), 7.42 (2H, m), 6.88 (IH, d), 6.25 (IH, br), 5.45 (IH, br), 4.20 (2H, br d), 2.92 (IH, m), 1.75 (6H, m), 1.40 (4H, m).
Step c : 2-[5-Cyclohexyl-l-(4-nitro-phenyl)-2-oxo-l, 2-dihydro-3H-l, 3, 4-henzotriazepin-3-yl]- thioacetamide
A solution of 2-[ 5-cyclohexyl-l-(4-nitro-phenyl)-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin- 3 -yl] -acetamide (289mg, 0.69mmol) and Lawesson's reagent (277mg, 0.69mmol) in toluene (5mL) was heated under reflux for 6h. The solution was decanted from the tarry precipitate, diluted with EtOAc, washed with NaHCO3, brine and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with EtOAc-DCM (3:22) as eluant (105mg, 35%). 1H NMR (CDCl3): 8.19 (2H, d), 8.90 (IH, br), 7.58 (2H, d), 7.51 (IH, m), 7.40 (3H3 m), 6.87 (IH, d), 4.64 (2H, br), 2.92 (IH, m), 1.75 (6H, m), 1.30 (4H, m).
Step d: 3-(4-tQxt-Butyl-thiazol-2-ylmethyl)'5-cyclohexyl-l-(4-nitro-phenyl)-l,2-dihydro-3H- 1, 3, 4-benzotriazepin-2-one A solution of 2-[5-cyclohexyl-l-(4-nitro-phenyl)-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin- 3-yl]-thioacetamide (lOOmg, 0.23mmol) and 1-bromopinacolone (40μl, 0.29mmol) in EtOH (5mL) was heated under reflux for 2 Ih. The mixture was diluted with EtOAc, washed with NaHCO3, brine and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with EtOAc-DCM (1:24) as eluant (92mg, 77%). 1H NMR (CDCl3) 8.17 (2H5 d), 7.55 (2H, d), 7.40 (3H, m), 6.93 (IH, d), 6.70 (IH, s), 5.30 (IH, br s), 4.90 (IH, br s), 2.86 (IH, m), 1.75 (6H, m), 1.30 (9H, s), 1.25 (4H, m).
Step e: The title compound was obtained using steps d-f of the method of preparation of example 1 except that 3-(4-tert-butyl-thiazol-2-ylmethyl)-5-cyclohexyl-l-(4-nitro-phenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was used in step d in place of 3~benzyl-5-cyclohexyl- l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (MeOΗ-d4) 7.59 (IH, d), 7.46 (2H, d), 7.36 (IH, m), 7.34 (3H, m), 7.16 (IH, s), 6.89 (IH, d), 4.98 (2H, br), 3.00 (IH, m), 1.80 (6H, m), 1.34 (9H, s), 1.30 (4H, m).
Example 143 : 3-Cyclodecyl-5-cyclohexyl-l~{4-[(lH-imidazol-2-ylmethyl)-amino]-phenyl}-8- methyl-1 ,2-dihydro-3H-l ,3 ,4-benzotriazepin-2~one
The title compound was obtained using step a of the method of preparation of example 128, except that l-(4-amino-phenyl)-3-cyclodecyl-5-cyclohexyl-8-methyl-l,2-dihydro~3H-l,3,4- benzotriazepin-2-one (example 105, step b): and l-H-imidazol-2-carbaldehyde were used in place of 1 -(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3Η-l,3,4-benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 7.22-7.16 (3H, m), 6.97 (2H, s), 6.90-6.88 (IH, m), 6.55-6.53 (3H, m), 4.47 (IH, br s), 4.32-4.25 (3H, m), 2.78-2.75 (IH, m), 2.20 (3H, s), 2.17-1.27 (28H, m). The compound was further characterized and tested as the hydrochloride salt. Found: C 66.13, H 7.80, N 12.53%; C35H46N6O-UHCl-O^ C4H8O2 requires: C 66.20, H 7.73, N 12.66%. Example 144: 5-CyclohexylA-{4-[(lH4midazol-2-ylmethyl)-amino]-phenyl}-8-methyl-3- (3, 3, 5, 5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l, 3, 4-henzotriazepin-2-one
The title compound was obtained using step a of the method of preparation of example 128, except that 1 -(4-amino-phenyl)-5-cyclohexyl-8-methyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one (example 106, step b) and l-H-imidazol-2- carbaldehyde were used in place of l-(4-aminophenyl)~3-benzyl-5-cyclohexyl-l,2-dihydro-3Η- l,3,4-benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 7.27-7.16 (3H, m), 6.98 (2H, s), 6.90 (IH, d), 6.56 (3H, m), 4.35 (2H, s), 4.14 (IH5 m), 2.79 (IH, m), 2.21 (3H, s), 1.84-0.82 (28H, m). The compound was further characterized and tested as the hydrochloride salt. Found: C 65.21, H 7.69, N 11.42%; C35H46N6O-UHCl-I^ C4H8O2 requires: C 65.21, H 7.85, N 11.58%.
Example 145 2-Amino-N-[4-(3-benzyl-5-cyclohexylmethyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-1-yl) -phenyl] -acetamide Step a: l-(4-Amino-phenyl)-3-benzyl-5-cyclohexylmethyl-l,2-dihydro-3H-l,3,4-benzotriazepin- 2-one was obtained using steps c and d of the preparation of example 1, except that 3-benzyl-5- cyclohexylmethyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one: (example 9, step d) was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.34-7.14 (1OH, m), 6.83 (IH, d), 6.66 (2H, dd), 4.80 (2H, br s), 3.71 (2H, br s), 2.62 (2H, br s),1.76-1.50 (6H, m), 1.30-0.97 (5H, m).
Step b: The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-benzyl-5-cyclohexylmethyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6) 10.86 (IH, s), 8.24 (3H, br s), 7.66-7.59 (3H, m), 7.40 (IH, t), 7.28-7.08 (8H, m), 6.76 (IH, d), 4.80 (1, br s), 4.30 (IH, br s), 3.79 (2H, q), 2.90 (IH, br s), 2.40 (IH, br s), 1.70-1.40 (6H, m), 1.25-0.90 (5H, m). Found: C 62.53, H 6.33, Ν 11.89%; C30H33Ν5O2-1.6HCl-l.3H2O requires: C 62.41, H 6.49, N 12.13%.
Example 146 N-[4-(3-Benzyl-2-oxo-5-piperidin-l -ylmethyl-1 ,2-dihydro-3H-l ,3,4- benzotriazepin-1-yl) -phenyl] -guanidine
Step a N-Amino-N-benzyl-N'-(2-ethynylphenyl)-urea
A solution of 2-ethynylaniline (8.49g, 72mmol) and NEt3 (30.3mL, 217mmol) in DCM (5OmL) was added to a solution of bis-(trichloromethyl)carbonate (10.75g, 36mmol) in DCM (15OmL), keeping the reaction temperature below 10°C. The mixture was stirred at ambient temperature for Ih, cooled in an ice bath and a solution of benzylhydrazine (10.7Og, 88mmol) in DCM (5OmL) was added dropwise. The cooling bath was removed and the mixture was stirred at ambient temperature for 2h. The mixture was diluted with DCM (15OmL) and was washed with saturated NaHCO3 solution (3 x 10OmL). The organic layer was separated and dried (MgSCU). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with EtOAc-hexane (2:5) as eluant to afford the product (14.19g, 74%). 1H NMR (CDCl3) 9.59 (IH, s), 8.44 (IH, d), 7.44-7.33 (7H, m), 6.95 (IH, t), 4.81 (2H5 s), 3.64 (2H, s), 3.40 (IH, s).
Step b 3-Benzyl-5-methyl-l ,2-dihydro-3H-l ,3 ,4-benzotriazepin-2-one
A mixture of N-amino~N-benzyl-N'-(2-ethynylphenyl)-urea (14.61g, 55mmol) and HgO (1.19g, 5.5mmol) in THF-5% H2SO4 (1:1 / 36OmL) was heated at 90°C for Ih. On cooling, the mixture was partitioned between EtOAc (40OmL) and saturated NaHCO3 solution (20OmL), then filtered. The organic layer was separated, washed with saturated NaHCO3 solution (2 x 10OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product, which was purified by chromatography on silica gel with EtOAc-hexane (2:5) as eluant to afford the product (7.1Og, 49%). 1H NMR (CDCl3) 7.38-7.33 (2H, m), 7.27-7.22 (5H, m), 7.14 (IH, t), 6.87-6.82 (2H, m), 4.84 (2H, s), 2.35 (3H, s). Step c 3-Benzyl-5-methyl-l'(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step c of the method of preparation of example 1, except that 3-benzyl-5- methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (CDCl3) 8.15 (2H5 d), 7.56- 7.46 (4H, m), 7.40-7.37 (IH, m), 7.26-7.15 (5H, m), 7.00 (IH, d), 4.86 (2H, br s), 2.47 (3H, s). Step ά 3-Benzyl-5-bromomethyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
A solution of bromine (1.14g, 7.1mmol) in AcOH (7mL) was added to a solution of 3-benzyl- 5-methyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (2.5Og, 6.5mmol) in DCM (14mL), then the mixture was heated at 6O0C for 16 h. On cooling, the solution was diluted with EtOAc (10OmL) and was washed with saturated NaHCO3 solution (3 x 5OmL). The organic layer was dried (MgSO4), filtered and the solvent was removed at reduced pressure. The residue was purified by chromatography on silica gel with DCM followed by MeOH-DCM (1 : 100- 1 :25) as eluant to afford the product (1.62g, 54%). 1H NMR (CDCl3) 8.19 (2H, dd), 7.64 (2H, d), 7.50-7.47 (2H, m), 7.40 (IH, d), 7.27-7.15 (SH, m), 6.94 (IH, d), 4.86 (2H, br s), 4.51 (2H, s). Step e 3-Benzyl-l-(4-nitro-phenyl)-5-piperidin-l-ylmethyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one
A solution of 3-benzyl-5-bromomethyl-l~(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (130mg) in DCM (ImL) was added to ice-cooled piperidine (ImL). The cooling bath was removed and the mixture was stirred at ambient temperature for 10 min. The solvents were removed at reduced pressure, then the residue was taken up in EtOAc (3OmL) and was washed with saturated NaHCO3 solution (3 x 15mL). The organic layer was dried (MgSO4), filtered and the solvent was removed at reduced pressure. The residue was purified by chromatography on silica gel with EtOAc-hexane (1:2) as eluant to afford the product (131mg, 100%). 1H NMR (CDCl3) 8.15 (2H, d), 7.75 (IH, d), 7.55-7.40 (3H5 m), 7.37 (IH, t), 7.23-7.15 (3H, m), 7.09 (2H, dd), 6.99 (IH, dd), 4.85 (2H, br s), 3.50 (2H, br s), 2.25 (4H, br m), 1.41-1.30 (6H, brm).
Step f l-(4-Amino-phenyl)-3-benzyl-5-piperidin-l-ylmethyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using step d of the method of preparation of example 1, except that 3 -benzyl- 1 -(4-nitro-phenyl)-5 -piperidin- 1 -ylmethyl- 1 ,2-dihydro-3H- 1 ,3 ,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (CDCl3) 7.67 (IH, d), 7.28-7.12 (9H, m),
7.81 (IH, d), 6.66 (2H, d), 4.79 (2H, br s), 3.70 (2H, br s), 3.48 (2H, s), 2.33-2.30 (4H, m), 1.53-1.35 (6H, m).
Step g: The title compound was obtained using steps e and f of the method of preparation of example 1, except that l-(4-amino-phenyl)-3-benzyl-5-piperidin-l-ylmethyl-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one was used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl- l,2-dihydro-3H-l,354-benzotriazepin-2-one in step e. 1H NMR (DMSO-d6) 10.17 (IH, s), 9.76 (IH, br s), 7.72 (IH, d), 7.60-7.50 (7H, m), 7.37-7.17 (8H, m), 6.86 (IH, d), 4.73-4.68 (4H, m), 3.11 (2H, br s), 2.89 (2H, br m), 1.75-1.60 (5H, br m), 1.25 (IH, br m). Found: C 55.81, H 5.86, N 15.48%; C28H31N7O-3HCl-0.5H2O-0.3 C4H802e requires: C 55.99, H 6.02, N 15.65%.
Example 147 2-Amino-N-[4-(3-ben∑yl-2-oxo-5-piperidin-l-ylmethyl-l,2-dihydro-3H-l,3,4- bemotriazepin-1-yl) -phenyl] -acetamide The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-benzyl-5-piperidin-l-ylmethyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 146, step f) was used in place of l~(4-aminophenyl)~3-benzyl- 5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one followed by reaction of the product obtained, in place of N,N-bis-(fcr/-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6) 10.82 (IH, s), 9.65 (IH, br s), 8.20 (3H, br s), 7.70-7.65 (3H, m), 7.51-7.43 (3H, m), 7.36-7.16 (6H, m), 6.83 (IH, d), 4.72-4.65 (4H, m), 3.80 (2H, d), 3.11 (2H, m), 2.88 (2H, m), 1.75-1.65 (5H, br m), 1.30 (IH, br m). Found: C 55.45, H 6.03, Ν 13.22%; C29H32Ν6O2-2.7HC1-1.9H2O requires: C 55.35, H 6.17, N 13.36%. Example 148 2-Amino-N-[4-(3-benzyl-5-cyclohexylsulfanylmethyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl]-acetamide
Step a 3-Benzyl-5-cyclohexylsulfanyhnethyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one Sodium (16mg, 0.70mmol) was added to MeOH (ImL) to give a solution, to which was added cyclohexanethiol (173uL, 1.41mmol). The solution was stirred at ambient temperature for 5h, then a solution of 3-benzyl-5-bromomethyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 146, step d) (300mg, 0.64mmol) in THF (ImL) was added dropwise. The solution was stirred at ambient temperature for 20min, then was diluted with EtOAc (2OmL) and was washed with H2O (2 x 1OmL) and saturated brine (1OmL). The organic layer was dried (MgSO4), filtered and the solvent was removed at reduced pressure. The residue was purified by chromatography on silica gel with EtOAc-hexane (1:5) as eluant to afford the title compound (241mg, 75%). 1H NMR (CDCl3) 8.15 (2H, dd), 7.61-7.48 (4H, m), 7.40 (IH, t), 7.25-7.13 (5H, m), 7.03 (IH5 d), 4.85 (2H, br s), 3.77 (2H, s), 2.45 (IH, m), 1.80-1.45 (5H, m), 1.20-0.90 (5H, m).
Step b l-(4~Amino-phenyl)-3-benzyl-5~cyclohexylsulfanylmethyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using step d of the method of preparation of example 1, except that 3 -benzyl-5 -cyclohexylsulfanylmethyl- 1 -(4-nitro-phenyl)- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (CDCl3) 7.44 (IH, d), 7.28-7.14 (9H, m), 6.83 (IH, d), 6.66 (2H, dd), 4.79 (2H5 br s), 3.90-3.70 (4H, m), 2.68 (IH, m), 1.93 (2H, m), 1.69 (2H, m). 1.55 (2H, m), 1.30-1.13 (4H, m).
Step c {^-(S-BenzylS-cyclohexylsulfanylmethyl^-oxo-l^-dihydroSH-l^^-benzotriazepin- l-ylj-phenylcarbamoylj-methylj-carbamic acid tevt-butyl ester was obtained using step a of the method of preparation of example 71, except that l-(4-amino- phenyl)-3-benzyl-5-cyclohexylsulfanylmethyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one. 1H NMR (CDCl3) 8.15 (IH, br m), 7.52-7.43 (5H, m), 7.32-7 '.17 (7H, m), 6.79 (IH, d), 5.20 (IH, br s), 4.80 (2H, br s), 3.92 (2H, d), 3.76 (2H, s), 2.66 (IH, m), 1.93 (2H, m), 1.65 (2H, m), 1.50-1.48 (1OH, m), 1.29-1.14 (5H, m).
Step d: The title compound was obtained using step f of the method of preparation of example 1 except that {[4-(3-benzyl-5-cyclohexylsulfanylmethyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepm-l-yl)-phenylcarbamoyl]-methyl}-carbamic acid tert-butyl ester was used in place of in place of ΛζN-bis-(tert-butoxycarbonyl)-N/-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine. 1H NMR (DMSO-d6) 10.65 (IH, s), 8.14 (3H, br s), 7.73 (IH, d), 7.61 (2H, d), 7.45-7.11 (9H, m), 6.78 (IH, d), 4.64 (2H, br s), 4.05-3.75 (4H, m), 2.57 (IH, m), 1.84 (2H, m), 1.60 (2H, m), 1.43 (IH, m), 1.21-0.99 (5H, m). Found: C 60.82, H 5.99, N 11.55%; C3OH33N5O2S-IJHCl-O^ C4H8O2 requires: C 60.92, H 6.03, N 11.53%.
Example 149 2-Amino-N-[4-(3-benzyl-5-cyclohexanesulfonylmethyl-2-oxo-l,2-dϊhydro-3H- 1,3, 4-benzotriazepin-l -yl) -phenyl] -acetam ide
Step a {[4-(3-Benzyl-5-(yclohexanesulfor^lmet^l-2^oxo-l,2-dihydro-3H-l,3t4-benzotriazepm- l-yl)-phenylcarbamoyl]-methyl}-carbamic acid tert-butyl ester 3-Chloroperoxybenzoic acid (70mg, 0.31mmol) was added to an ice-cooled solution of {[4-(3- benzyl-S-cyclohexylsulfanylmethyl^-oxo-l^-dihydro-SH-ljS^-benzotriazepin-S-yl)- phenylcarbamoyl]-methyl}-carbamic acid tert-butyl ester (example 148, step c) (200mg, 0.32mmol) in DCM (5mL). The mixture was stirred at ice-bath temperature for 1.5h. A further portion of 3-chloroperoxybenzoic acid (20mg, 0.09mmol) was added after the first hour. The mixture was diluted with DCM (2OmL) and was washed with saturated NaHCO3 solution (3 x 1OmL). The organic layer was dried (MgSO4), filtered and the solvent was removed at reduced pressure. The residue was purified by chromatography on silica gel with EtOAc-hexane (7:10) to neat EtOAc as eluant to afford the product (87mg, 41%). 1H NMR (CDCl3) 8.15 (IH, br s), 7.55-7.46 (4H, m), 7.35 (IH, t), 7.28-7.16 (7H, m), 6.80 (IH, d), 5.20 (IH, br m), 4.85 (2H, br s), 4.37 (2H, s), 3.92 (2H, d), 2.89 (IH, m), 2.09 (2H, m), 1.75 (2H, m), 1.65-1.35 (12H, m), 1.25-0.95 (3H, m).
Step b: The title compound was obtained using step f of the method of preparation of example 1 except that {[4-(3-benzyl-5-cyclohexanesulfonylmethyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenylcarbamoyl]-methyl}-carbamic acid tert-bxxtyl ester was used in place of in place of N)N-bis-(fert-butoxycarbonyl)-N/-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro~3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine. 1H ΝMR (DMSO-d6) 10.60 (IH, s), 8.09 (3H, s), 7.78 (IH, d), 7.61 (2H, d), 7.46-7.41 (3H, s), 7.31-7.12 (6H, m), 6.78 (IH, d), 4.90-4.50 (4H, m), 3.78 (2H, s), 2.98 (IH, m), 2.05 (2H, m), 1.73 (2H, m), 1.55 (IH, m), 1.37- 1.29 (2H, m), 1.09-1.02 (3H, m). Found: C 56.32, H 5.62, Ν 10.47%; C30H33N5O4S- 1.2HC1- 0.4CHCl3 requires: C 56.07, H 5.36, N 10.75%.
Example 150 2-Amino-N-[4-(3-benzyl-2-oxo-5-phenoxymethyl-l ,2-dϊhydro-3H-l ', 3, 4- benzotriazepin-1-yl) -phenyl] -acetamide
Step a 3-Benzyl-l-(4-nitro-phenyl)-5-phenoxymethyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one A mixture of 3-benzyl-5-bromomethyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 146, step d) (300mg, 0.64mmol), phenol (73mg, 0.78mmol) and K2CO3 (134mg, 0.97mmol) in DMF (3mL) was stirred at ambient temperature for 16h. The mixture was diluted with EtOAc (2OmL) and was washed with saturated Na2CO3 solution (3 x 1OmL), H2O (1OmL) and saturated brine (1OmL). The organic layer was dried (MgSO4), filtered and the solvent was removed at reduced pressure. The residue was purified by chromatography on silica gel with EtOAc-hexane (1:5-3:10) as eluant to afford the product (251mg, 81%). 1HNMR (CDCl3) 8.01 (2H, d), 7.64 (IH, d), 7.48-7.30 (2H, m), 7.30-7.09 (9H, m), 6.91-6.83 (4H, m), 5.23 (2H, s), 4.91 (2H, s). Step b l-(4-Amino-phenyl)-3-benzyl-5-phenoxymethyl-l ,2-dihydro-3H-l ,3 ,4-benzotriazepin-2- one was obtained using step d of the method of preparation of example 1, except that 3-benzyl- l-(4-nitro-phenyl)-5-phenoxymethyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3 -benzyl-5 -cyclohexyl- 1 -(4-nitrophenyl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one . 1H NMR (CDCl3) 7.50 (IH, d), 7.28-7.14 (9H, m), 6.98-6.91 (3H, m), 6.80-6.76 (3H, m), 6.55 (2H, d), 5.18 (2H, s), 4.84 (2H, s), 3.68 (2H, br s).
Step c: The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-benzyl-5-phenoxymethyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of l-(4-aminophenyl)-3 -benzyl-5 -cyclohexyl- 1,2- dihydro-3H-l,3,4-benzotriazepin-2-one, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1HNMR (DMSO-d6) 10.65 (IH, s), 8.16 (3H, br s), 7.78 (IH, d), 7.50 (2H, d), 7.40 (IH, t), 7.30-7.11 (8H, m), 6.97-6.88 (5H, m), 6.71 (IH, d), 5.33 (2H, br m), 4.70 (2H, br s), 3.77 (2H, br s). Found: C 61.99, H 5.09, N 11.70%; C30H27N5(Vl .5HC1-0.2CHC13 requires: C 62.10, H 4.95, N 11.99%.
Example 151 2-Amino-N-{4-[3-benzyl-5-(4-cycIohexyl-phenoxymethyl)-2-oxo-l,2-dihydro-3H- 1, 3, 4-benzotriazepin-l -yl]-phenyl}-acetam ide
The title compound was prepared by a similar method to that used in the preparation of example 150 except that 4-cyclohexyl-phenol was used in step a in place of phenol. 1H NMR (DMSO-dβ) 10.71 (IH, s), 8.18 (3H, br s), 7.76 (IH, d), 7.53 (2H, d), 7.45 (IH, t), 7.26-7.07 (8H, m), 6.93 (2H, d), 6.86 (2H, d), 6.69 (IH, d), 5.28 (2H, br s), 4.70 (2H, br s), 3.78 (2H, br s), 2.42 (IH, m), 1.80-1.60 (5H, m), 1.40-1.10 (5H, m). Found: C 66.93, H 6.19, N 10.52%; C36H37N5O3-UHCl requires: C 66.66, H 6.01, N 10.80%. Example 152 2-Aιnino-N-{4~[3-benzyl-5-(2-cyclohexylφhenoxymethyl)-2-oxo-l,2~dihydro-3H- I13, 4-benzotriazepin-l-yl]-phenyl}-acetamide
The title compound was prepared by a similar method to that used in the preparation of example 150 except that 2-cyclohexyl-phenol was used in step a in place of phenol. 1H NMR (DMSO-d6) 10.65 (IH, s), 8.17 (3H, br s), 7.77 (IH, d), 7.49 (2H, d), 7.39 (IH, t), 7.27-7.10 (9H, m), 6.85 (IH, m), 6.80 (2H, d), 6.70 (IH, d), 5.35 (2H, br s), 4.70 (2H, br s), 3.75 (2H3 m), 2.50 (IH, m), 1.50 (3H, m), 1.30-0.90 (7H, m). Found: C 66.18, H 6.14, N 10.37%; C36H37N5O3-I^HCl requires: C 65.92, H 5.97, N 10.68%.
Example 153 (S)-2-Amino-N-[4-(3-henzyl-2-oxo-5-phenoxymethyl-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-1 -yl) -phenyl] -3 -methyl-butyr amide
The title compound was obtained using step a of the method of preparation of example 71, except that 1 -(4-amino-phenyl)-3 -benzyl-5 -phenoxym ethyl- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-2-one (example 150, step b) and tert-butoxycarbonyl Z-valine were used in place of 1 -(4-aminophenyl)-3-benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and N-fe/Y-butoxycarbonylglycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N/-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro- 3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6) 10.72 (IH, s), 8.28 (3H, br s), 7.77 (IH, d), 7.53 (2H, d), 7.40 (IH, t), 7.28-7.11 (8H, m), 6.96-6.89 (5H, m), 6.72 (IH, d), 5.33 (2H, br s), 4.70 (2H, br s), 3.78 (IH5: m), 2.20 (IH, m), 1.00-0.79 (6H, m). Found: C 63.60, H 6.02, Ν 11.16%; C33H33Ν5O3-2.OHCI requires: C 63.87, H 5.68, N 11.29%.
Example 154 2-Amino-N-{4-[3-benzyl-5-(4-methoxy-phenoxymethyl)-2-oxo-l,2-dihydro-3H~ 1, 3, 4-benzotriazepin-l-yl]-phenyl}-acetamide
The title compound was prepared by a similar method to that used in the preparation of example 150 except that 4-methoxy-phenol was used in step a in place of phenol. 1H NMR (DMSO-de) 10.68 (IH, s), 8.18 (3H, br s), 7.76 (IH, d), 7.51 (2H, d), 7.40 (IH, t), 7.27-7.11 (6H, m), 6.87-6.78 (6H, m), 6.70 (IH, d), 5.27 (2H, br), 4.69 (2H, br), 3.78 (2H, m), 3.68 (3H, s). Found: C 62.88, H 5.31, N 11.41%; C31H29N5O4-LOHCl requires: C 62.57, H 5.19, N 11.77%. Example 155 2-Amino-N-{4-[3-benzyl-5-(naphthalen~l-yloxymethyl)-2~oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-l-ylj-phenyl}-acetamide
The title compound was prepared by a similar method to that used in the preparation of example 150 except that naphthalen-1-ol was used in step a in place of phenol. 1H NMR (DMSO-de) 10.65 (IH, s), 8.18 (3H, br s), 7.90-7.70 (3H, m), 7.50-7.13 (14H, m), 6.76 (2H, d), 6.68 (IH, d), 5.57 (2H, br s), 4.71 (2H, br s), 3.76 (2H, m). Found: C 66.56, H 5.32, N 10.70; C34H29N5O3-IJHCl-O-O C4H8O2 requires: C 66.66, H 5.39, N 10.68%.
Example 156 4-{l-[4-(2-Aιnino-acetylamino)-phenyl]-3-benzyl-2~oxo-l,2-dih.ydro-3H-l,3,4- benzotriazepin-5-ylmethoxy}-benzoic acid methyl ester
The title compound was prepared by a similar method to that used in the preparation of example 150 except that 4-hydroxy-benzoic acid methyl ester was used in step a in place of phenol. 1H NMR (DMSO-d6) 10.68 (IH5 s), 8.17 (3H, br s), 7.85 (2H, d), 7.78 (IH, d), 7.50 (2H, d), 7.65 (IH, t), 7.30-7.05 (8H, m), 6.91 (2H, d), 6.71 (IH, d), 5.45 (2H, br s), 4.68 (2H, br s), 3.83-3.75 (5H, m). Found: C 61.59, H 5.14, N 10.76; C32H29N5O5-LoHCl-OJ C4H8O2 requires: C 61.50, H 5.13, N 10.80%.
Example 1572-Amino-N-(4-{5-[4-(2-amino-acetylamino)-phenoxymethyl]-3-benzyl-2-oxo-l,2- dihydro-3H-l , 3, 4-benzotriazepin-l-yl}-phenyl)-acetamide
The title compound was prepared by a similar method to that used in the preparation of example 150 except that (4-hydroxy-phenyl)-carbamic acid tert-butyl ester was used in step a in place of phenol. 1H NMR (DMSO-d6) 10.98 (IH, s), 10.55 (IH, s), 8.26 (6H, br s), 7.76 (IH, d), 7.53-7.47 (4H, m), 7.39 (IH, t), 7.27-7.18 (4H, m), 7.12 (2H, d), 6.88 (2H, d), 6.74 (2H, d), 6.68 (IH, d), 5.34 (2H, br s), 4.69 (2H, br s), 3.81 (4H, br s). Found: C 55.87, H 5.33, N 13.22; C32H3iN7θ4-3HCl-0.6 C4H8O2 requires: C 55.84, H 5.29, N 13.25%. Example 158 2-Amino-N-{4-[3-benzyl-5-(4-cyano-phenoxymethyl)-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl]-phenyl}-acetamide
The title compound was prepared by a similar method to that used in the preparation of example 150 except that 4-hydroxy-benzonitrile was used in step a in place of phenol. 1H NMR (DMSO-de) 10.76 (IH, s), 8.21 (3H, br s), 7.80-7.71 (3H, m), 7.55 (2H, d), 7.42 (IH, m), 7.28-7.08 (8H, m), 6.99 (2H, d), 6.73 (IH, d), 5.47 (2H, br s)5 4.68 (2H, br s), 3.78 (2H, br d). Found: C 62.25, H 4.83, N 13.41; C3iH26N6O3-1.7HCl-0.4 C4H8O2 requires: C 62.37, H 4.96, N 13.39%.
Example 159 N-{4-[5-(4-Acetylamino-phenoxymethyl)-3-benzyl-2~oxo-l,2-dihydro-3H~l,3,4~ benzotriazepin-l-yl]-phenyl}-2-amino-acetamide The title compound was prepared by a similar method to that used in the preparation of example 150 except that N-(4-hydroxy-phenyl)-acetamide was used in step a in place of phenol. 1H NMR (DMSO-d6): 10.77 (IH, s), 9.85 (IH, s), 8.22 (3H, br s), 7.65 (IH, d), 7.54 (2H, d), 7.47-7.40 (3H, m), 7.29-7.11 (6H, m), 6.97 (2H, d), 6.86 (2H, d), 6.70 (IH, d), 5.27 (2H, br s), 4.69 (2H, br s), 3.78 (2H5 br q), 2.01 (3H, s). Found: C 59.41, H 5.40, N 12.16; C32H3oN6θ4-2HCl-0.4H20 -0.5 C4H8O2 requires: C 59.46, H 5.40, N 12.24%.
Example 160 4-{l-[4-(2-Amino-acetylamino)-phenyl]-3-benzyl-2-oxo-l, 2-dϊhydro-SH-l, 3, 4- benzotriazepin-5~yl]methoxy}-benzωnide The title compound was prepared by a similar method to that used in the preparation of example 150 except that 4-hydroxy-benzamide was used in step a in place of phenol. 1H NMR (DMSO-dβ) 10.72 (IH, s), 8.21 (3H, br s), 7.83-7.77 (4H, m), 7.52 (2H, d), 7.41 (IH, t), 7.27- 7.11 (7H, m), 7.02-6.94 (4H, m), 6.71 (IH, d), 5.40 (2H, br s), 4.69 (2H, br s), 3.70 (2H, m). Found: C 59.55, H 5.19, N 12.72; C31H28N6O4-2HCl-0.4 C4H8O2 requires: C 59.62, H 5.10, N 12.80%.
Example 161 : N-{4-[5-Cyclohexyl-2-oxo-3-(5-phenyl-[l,3,4]oxadiazol-2-ylmethyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl]-phenyl}-guanidine
Step a: Benzoic acid ((N,N''-bis-(tert-butoxycarbonyl)-Nf-3-[l-(4-guanidino-phenyl)-5- cyclohexyl^-oxo-l^-dihydro-SH-l^^-benzotriazepin-l-ylJJ-acetylJ-hydrazide was prepared using step f of the method of preparation of example 13 except that benzoic hydrazide was used in place of diphenylmethylamine. 1H NMR (CDCl3): 11.61 (IH, br), 10.39 (IH, s), 10.45 (IH, br), 9.80 (IH, br), 7.77 (2H, d), 7.64 (2H, d), 7.51 (2H, t), 7.44 (2H, t), 7.35 (3H, m), 7.25 (IH, m), 6.83 (IH, d), 4.27 (2H, br), 2.95 (IH, m), 1.80 (6H, m), 1.54 (9H, s), 1.50 (9H, s), 1.29 (4H, m).
Step b. N,N'-bis-(tert-butoxycarbonyl)-N"-l-(4-guanidino-phenyl)-5-cyclohexyl-3-(5-phenyl- [1 ,3,4]oxadiazol-2-ylmethyl)-l ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one
To a solution of benzoic acid ((N,N'-bis-(te^-butoxycarbonyl)-N"-3-[l-(4-amino-phenyl)-5- cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 -yl])-acetyl)-hydrazide (35 Omg,
046mmol) in MeCN (3mL) and CCl4 (3mL) were added PPh3 (160mg, O.όlmmol) and DBU (390μl, 1.22mmol) and the mixture was stirred at ambient temperature for 5h. The solvent was evaporated and the residue purified by chromatography on silica gel with EtOAc-DCM (1:9) as eluant (193mg; 57%). 1H NMR (CDCl3): 11.62 (IH, br), 10.40 (IH, s), 7.97 (2H, d), 7.65 (2H, d), 7.49 (3H, m), 7.35 (3H, m), 7.27 (IH, m), 7.19 (IH, t), 6.81 (IH, d), 5.00 (2H, br), 2.78 (IH, m), 1.83 (5H, m), 1.54 (9H, s), 1.50 (9H, s), 1.29 (5H, m). Step c. The title compound was obtained using step f of the method of preparation of example 1, except that N,N'-bis-(tert-butoxycarbonyl)-N"-l-(4guanidinophenyl)-5-cyclohexyI-3-(5- phenyl-[l,3,4]oxadiazol-2-ylmethyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of N,iV-bis-(tert-butoxycarbonyl)-N/-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine. 1H NMR (MeOH-d4) 7.87 (2H, d), 7.64-7.30 (1OH, m), 6.87 (IH, d), 4.25 (2H, br s), 2.98 (IH, m), 1.80 (6H, m), 1.37 (4H, m). Found: C 56.93, H 6.05, N 15.91%; C30H30N8C^HCl-I-SH2O-O-SEt2O requires: C 57.02, H 6.28, N 16.02%. Example 162: N-[3-Benzyl-5-cyclohexyl-l-(4-guanidino-phenyl)-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-7-yl]-acetamide
Step a. N-[3-Benzyl-5-cyclohexyl-l -(4-nitro-phenyl)-2-oxo-l ,2-dihydro-3H-l ,3,4- benzotriazepιn-7-ylJ-acetamide
To a solution of 3-benzyl-7-bromo-5-cyclohexyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 10, step c) (200mg, 0.37mmol) in PhCH3 were added CuI
(4mg, 0.02mmol), K2CO3 (105mg, 0.75mmol) and acetamide (27mg, 0.45mmol). The flask was evacuated then purged with argon, N,N'-dimethylethylenediamine (4μl, 0.04mmol) was added and the mixture was heated under reflux for 2Oh. The resultant black mixture was diluted with DCM, filtered and the filtrate evaporated. The residue was chromatographed on silica gel with EtOAc-DCM (1:9) as eleuant to give the product (163mg, 86%). 1H NMR
(CDCl3): 8.13 (2H, d), 7.83 (IH, s), 7.50 (2H, d), 7.41 (IH, d), 7.22 (6H, m), 5.05 (IH, br),
4.60 (IH, br), 2.79 (IH, m), 2.22 (3H, s), 1.75 (5H, m), 1.27 (5H, m).
Step b: N5N' ' -Bis-(tevt-butoxycarbonyl)-'N" '-[4-(7-acetamido-3-benzyl-5-cyclohexyl-2-oxo-l ,2- dihydro-3H-l ,3,4-benzotriazepin-l -yl) -phenyl] -guanidine was obtained using steps d and e of the method of preparation of example 1 except that N-[3-benzyl-5-cyclohexyl-l-(4- nitrophenyl)-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-7-yl]-acetamide was used in step d in place of 3 -benzyl-5-cyclohexyl- 1 -(4-nitro-phenyl)- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one. 1H NMR (CDCl3): 11.64 (IH, s), 10.36 (IH, s), 7.66 (IH, s), 7.56 (3H, d), 7.31 (3H, d), 7.20 (5H, m), 6.68 (IH, d), 4.95 (IH, m), 4.50 (IH, m), 2.72 (IH, m), 2.11 (3H, s), 1.75 (6H, m), 1.55 (9H, s), 1.44 (9H, s), 1.25 (4H, m).
Step c: The title compound was obtained using step b of the method of preparation of example 39 except that N,N'-Bis-(tert-butoxycarbonyl)-N"-[4-(7-acetamido-3-benzyl-5-cyclohexyl-2- oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine was used in place of 2-[4- (3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenylimino]- imidazolidine-l,3~dicarboxylic acid di-fert-butyl ester. 1H NMR (DMSO-d6) 10.10 (IH, s), 9.74 (IH, s), 7.74 (IH, s), 7.58 (IH, d),: 7.44 (4H, m), 7.35 (2H, d), 7.20 (7H, m), 6.76 (IH, d), 4.80 (IH, m), 4.45 (IH, m),: 2.75 (IH, m), 2.03 (3H, s), 1.75 (6H, m), 1.25 (4H, m). Found: C 57.99, H 5.24, N 14.15%; C30H33N7O2- 1.33 CF3CO2H requires: C 58.09, H 5.12, N 14.52%. Example 163 : N-[4-(7-Amino~3-benτyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l, 3, 4- benzotriazepin-1-yl) -phenyl] -guanidine
The title compound was obtained using step f of the method of preparation of example 1 except that N,N'-bis-(tert-butoxycarbonyl)-N"-[4-(7-acetamido-3-benzyl-5-cyclohexyl-2-oxo- l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine (example 162, step b) was used in place of N,N-bis-(ter/-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-
3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine. 1H NMR (DMSO-d6/D2O) 7.34 (2H, d), 7.17
(7H, m), 6.63 (IH, d), 6.85 (2H, d), 4.80 (IH, m ), 4.40 (IH, m), 2.77 (IH, m), 1.75 (6H, m),
1.25 (4H, m). Found: C 56.59, H 5.97, N 16.27%; C28H3iN7O-3.1 HCl requires: C 56.49, H 5.78, N 16.47%.
Example 164 : N-{4-[3-Benzyl-5-cyclohexyl-2-oxo- 7-(2-oxo-pyrrolidin-l-yl)-l,2-dihydro-3H- 1, 3, 4-benzotriazepin-l -yl]-phenyl}-guanidine
The title compound was obtained using the method of preparation of example 162 except that pyrrolidone was used in place of acetamide in step a. 1H NMR (DMSO-d6) 9.92 (IH, br), 7.80- 7.15 (13H, m), 6.80 (IH, d), 4.79 (IH, m), 4.37 (IH, m), 3.84 (2H, m), 2.92 (2H, m), 2.49 (2H, m), 2.04 (2H, m), 1.70 (6H, m), 1.30 (4H, m). Found: C 59.32, H 5.45, N 13.80%; C32H35N7O2-1.35 CF3CO2H requires: C 59.23, H 5.21, N 13.90%.
Example 165: 3-Benzyl-5-cyclohexyl-l-(4-guanidino-phenyl)-2-oxo-l,2-dihydro-3H-l, 3, 4- benzotriazepine-7-carboxylic acid dibenzylamide Step a: l~(4-Aminophenyl)-3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepine-7-carboxylic acid dibenzylamide
A microwave vial charged with 3-benzyl-7-bromo-5-cyclohexyl-l-(4-nitrophenyl)- 1,2- dihydro-3H-l,3,4-benzotriazepin-2-one (example 10, step c) (144mg, 0.27mmol), Mo(CO)6 (60mg), BINAP (28mg, 0.05mmol), Herrman's catalyst (16mg, O.Olmmol), 4M K2CO3 (200μl, 0.8mmol), dibenzylamine (75mL, 0.34mmol) and diglyme (ImL). The vessel was sealed and irradiated at 15O0C for 15min. On cooling, the mixture was filtered, concentrated and the residue chromatographed on silica gel with EtOAc-DCM (1 :4) as eluant to afford the product. 1H NMR (CDCl3) 7.25 (1OH, m), 7.10 &7H, m), 7.04 (2H, d), 6.75 (IH, d), 6.58 (2H, d), 4.50 (6H, br), 3.75 (2H, dt), 2.35 (IH, m), 1.70 (5H5 m), 1.25 (5H, m). Step b. The title compound was obtained using step e of the method of preparation of example 1, except that l-(4-ammophenyI)-3-benzyl-5-cyclohexyI-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepine-7-carboxylic acid dibenzylamide was used in place of l-(4-aminophenyl)-3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo-l52-dihydro-3H-l,354~ benzotriazepin-l-yl)-phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester according to step b of the method of preparation of example 39.1H NMR (CDCl3) 9.77 (IH, m), 7.50-7.00 (21H, m), 6.91 (2H5 m), 6.78 (IH, d), 4.74 (4H, m), 4.44 (2H, m), 2.45 (IH, m), 1.72 (5H, m)5 l.l 7 (5H5 Hi)- MS MH+ 690
Example 166: N-ft-β-Benzyl-S-cyclohexyl^-oxo^-fpiperidine-I-carbonylJ-l^-dihydroSH- 1, 3, 4-benzotriazepin-l-ylJ-phenyl}-guanidine
The title compound was obtained using the method of preparation of example 165 except that piperidine was used in place of dibenzylamine in step a. 1H NMR (MeOH-d4) 7.50 (3H, m), 7.38 (3H, m), 7.16 (5H, m), 6.94 (IH5 d), 4.75 (2H5 br s), 3.70 (2H5 m), 3.46 (2H, m), 2.90 (IH5 m), 1.82- 1.25 (16H5 m).
Example 167: 3-Benzyl-5-cyclohexyl-l-(4~guanidino-phenyl)-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepine-7-carboxylic acid benzylamide
The title compound was obtained using the method of preparation of example 165 except that benzylamine was used in place of dibenzylamine in step a. 1H NMR (MeOH-d4) 8.00 (IH, s), 7.86 (IH5 d), 7.48 (2H5 d), 7.33 (6H5 m),: 7.25 (IH, m), 7.18, (5H5 m), 6.94 (IH5 d), 4.85 (IH, br s), 4.56 (2H, br s), 4.50 (IH5 br s), 2.94 (IH5 m), 1.80 (5H5 m), 1.24 (5H5 m).
MS MH+ 600
Example 168: N-[4-(3-Benzyl-7-benzylamino-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-1-yl) -phenyl] -guanidine
Step a: 3-Benzyl-7-amino-5-cyclohexyl-l-(4-nitro-phenyl)-l,2-dihydro-3H~l,3,4- benzotriazepin-2-one was obtained using step f of the method of preparation of example 1 except that N-[3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-2-oxo-l52-dihydro-3H-l,3,4- benzotriazepin-7-yl]-acetamide (example 162, step a) was used in place of N,N~bis-(tert~ butoxycarbonyl)-N"-[4-(3 -benzyl-S-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 - yl)-phenyl]-guanidine. 1H NMR: (CDCl3) 8.10 (2H5 d), 7.45 (2H, d), 7.22 (5H, m), 6.83 (2H5 m), 6.67 (IH5 s), 5.30 (IH, d), 4.60 (IH, br d), 3.80 (2H, m), 2.70 (IH, m),1.75 (6H m), 1.25 (4H5 m).
Step b: 3-Benzyl-7-benzylamino~5-cyclohexyl-l-(4-nitrophenyl)-l,2-dϊhydt'o-3H-l,3,4- benzotriazepin-2-one was obtained using step a of the method of preparation of example 128, except that 3-benzyl-7-amino-5-cyclohexyl-l -(4-nitrophenyl)-l,2-dihydro-3H-l,354- benzotriazepin-2-one and benzaldehyde were used in place of l-(4-aminophenyl)-3-benzyl-5- cyclohexyl-l52-dihydro-3H-l53,4-benzotriazepin-2-one and formalin respectively. 1H NMR: (CDCl3) 8.09 (2H, d), 7.35 (7H, m), 7.22 (5H, m), 6.84 (IH, d), 6.75 (IH, d), 6.54 (IH, s), 5.00 (IH, br d), 4.63 (IH, br d), 4.37 (2H, s), 2.62 (IH, m),1.75 (6H m), 1.25 (4H, m).
Step c. The title compound was obtained using steps d and e of the method of preparation of example 1, except that 3-benzyl-7-benzylamino-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one was used in step d in place of 3-benzyl-5-cyclohexyl-l-(4- nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3Η-l,3,4-benzotriazepin- l-yl)-phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester according to step b of the method of preparation of example 39. 1H NMR (DMSO-d6) 9.59 (IH, br s), 7.6-7.1 (14H, m), 6.65 (IH, d), 6.60 (IH, d), 6.54 (IH, d), 4.75 (IH, d), 4.35 (IH, d), 4.27 (2H, s), 2.72 (IH, m), 1.75-1.0 (1OH, m). Found: C 60.57, H 5.31, N 13.15%; C35H37N7O-Lo CF3CO2H requires: C 60.72, H 5.15, N 12.96%.
Example 169: N-[4-(3-Benzyl-5-cyclohexyl-7-dimethylamino-2-oxo-l ,2-dihydro-3H-l ,3 ,4- benzotriazepin-1-yl) -phenyl] -guanidine Step a: 3-Benzyl-5-cyclohexyl-7-dimethylamino-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one
A solution of 3-benzyl-7-amino-5-cyclohexyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 168, step a) (204mg, 0.43mmol), MeI (250μl), and K2CO3 (120mg, 0.87mmol) in EtOH (6mL) was heated under reflux overnight. After evaporation of the solvent the residue was taken up in EtOAc and washed with H2O, brine and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with EtOAc-hexane (3:7) as eluant to afford the product (90mg; 42%). 1HNMR (CDCl3) 8.09 (2H, d), 7.45 (32H, d), 7.19 (5H, m), 6.92 (IH, d), 6.81 (IH, dd), 6.59 (IH, d), 5.03 (IH, br), 4.60 (IH3 br), 3.03 (6H, s), 2.77 (IH, m), 1.75 (6H, m), 1.25 (4H, m).
Step b: The title compound was obtained using steps d and e of the method of preparation of example 1, except that 3-benzyl-5-cyclohexyl-7-dimethylamino-l-(4-nitro-phenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was used in step d in place of 3-benzyl-5-cyclohexyl- l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, followed by reaction of the product obtained, in place of 2-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3Η-l,3,4- benzotriazepin-l-yl)-phenylimino]-imidazolidine-l,3-dicarboxylic acid di-tert-butyl ester according to step b of the method of preparation of example 39. 1H NMR (MeOH-d4) 7.46 (2H, d), 7.28 (2H, d), 7.17 (5H, m),: 7.25 (2H,m), 6.83 (IH, dd), 4.85 (IH, br s), 4.50 (IH, br s), 2.97 (6H, s), 2.90 (IH, m), 1.75 (5H, m), 1.37 (5H, m). Found: C 58.22, H 5.75, N 13.51%; C30H35N7O-I.5 CF3CO2H-0.4 C4H8O2 requires: C 58.04, H 5.59, N 13.69%.
Example 170 : (S)-2-Amino-N-[4-(3-benzyl-5-cyclohexyl-2-oxo- 7-m-tolyl-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl]-3-methyl-butyramide Step a: 3-Benzyl-5-cyclohexyl-l-(4-nitro-phenyl)-7-m-tolyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one
A solution of 3-benzyl-7-bromo-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 10, step c) (220mg, 0.41mmol), Pd(PPh3)4 (46mg, 0.04mol), m-tolylboronic acid (73mg, 0.54mmol) and 2M K2CO3 (0.4ImL, 0.82mmol) in EtOH-PhCH3 (1:3 / 12mL) was heated at reflux under argon for Hh. On cooling, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 solution, brine and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with Et2O-hexane (1:3) as eluant (145 mg; 63 %). 1H NMR (CDCl3) 8.16 (2H, d), 7.64 (IH, d), 7.58 (3H, m), 7.39 (4H, m), 7.20 (5H, m), 7.02 (IH, d), 5.12 (IH, br), 4.63 (IH, br), 2.82 (IH, m), 2.46 (3H, s), 1.75 (5H, m), 1.25 (5H, m).
Step b : 3-Benzyl-5-cyclohexyl-l-(4-amino-phenyl)-7-m-tolyl-l,2-dϊhydro-3H-l,3,4- benzotriazepin-2-one was obtained using step d of the method of preparation of example 1, except that 3 -benzyl-5-cyclohexyl- 1 -(4-nitro-phenyl)-7-/w-tolyl- 1 ,2-dihydro-3H- 1 ,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitro-phenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one.
Step c: The title compound was obtained using step a of the method of preparation of example 71, except that 3-benzyl-5-cyclohexyl-l-(4-amino-phenyl)-7-m-tolyl-l,2-dihydro-3Η-l,3,4- benzotriazepin-2-one and tert-butoxycarbonyl Z-valine were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N)N-bis-(tert-butoxycarbonyl)-N//-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSO-d6) 10.60 (IH, br s), 7.90 (2H, br s), 7.82 (IH, s), 7.67 (3H, d), 7.50 (2H, m), 7.48 (3H, d), 7.25 (6H, m), 6.80 (IH, d), 4.85 (IH, br s), 4.40 (IH, br s), 3.72 (IH, m), 2.36 (3H, s), 2.16 (IH, m), 1.75 (5H, m), 1.25 (5H, m), 0.99 (6H, t). Found: C 68.41, H 6.44, Ν 10.09%; C39H43N5O2^ HCl requires: C 68.21, H 6.464, N 9.83%.
Example 171 : (S)-2-Amino-N-{4-[5-cyclohexyl-3-(4-methoxy-benzyl)-2-oxo-7-pyridin-3-yl-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl]-phenyl}-3-methyl-butyramide Step a: 7-Bromo-5-cyclohexyl-3-(4-methoxy-benzyl)-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using steps a-c of the method of preparation of example 1 except that 4-methoxybenzyl hydrazine was used in step a in place of benzylhydrazine
Step b: 7-Bromo-5-cyclohexyl-3-(4-methoxy-benzyl)-l-(4-nitrophenyl)-7-pyridin-3-yl 1,2- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step a of the method of preparation of example 170, except that 3-pyridylboronic acid was used in place of rø-tolylboronic acid.
Step c : 3-Benzyl-5-cyclohexyl-l-(4-amino-phenyl)-7-pyridin-3-yl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using step d of the method of preparation of example 1, except that 5-cyclohexyl-3 -(4-methoxy-benzyl)- 1 -(4-nitrophenyl)-7-pyridin-3 -yl- 1 ,2-dihydro- 3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitro-phenyl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one.
Step d: The title compound was obtained using step a of the method of preparation of example 71, except that 3-benzyl-5-cyclohexyI-l-(4-amino-phenyl)-7-pyridin-3-yl-l,2-dihydro-3Η- l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl Z-valine were used in place of l-(4-amino- phenyl^-benzyl-S-cyclohexyl-l^-dihydro-SH-l^^-benzotriazepin^-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of NΛN-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazeρin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSOd6) 11.00 (IH, s), 9.17 (IH, s), 8.77 (IH, d), 8.63 (IH, d), 8.36 (3H, br s), 8.07 (IH, s), 7.88 (lH,m), 7.84 (IH, d), 7.71 (2H, d), 7.33 (2H, d), 7.13 (2H, d), 6.88 (IH, d), 6.79 (2H, d), 4.71 (IH, br s), 4.38 (IH, br s), 3.68 (3H5 s), 3.16 (IH, m), 2.20 (IH, m), 1.75 (6H, m), 1.25 (5H, m), 1.00 (6H, m). Found: C 60.25, H 6.20, Ν 10.36%; C38H42N6O2^ HCl-1.1 DCM requires: C 59.92, H 5.95, N 10.71%.
Example 172: (S)-2-Amino-N-[4-(3-benzyl-5-cyclohexyl~7-furan-3-yl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-l~yl)-phenyl]-3-methyl-butyramide
Step a: S-Cyclohexyl-S-ø-methoxy-benzylj-l-ø-nitr-ophenylJ^-furan-S-yl-l^-dihydm-SH- l,3,4-benzotriazepin-2-one was obtained using step a of the method of preparation of example 170, except that 3-furan boronic acid was used in place of m-tolylboronic acid.
Step b : l-(4-Amino-phenyl)-3-benzyl-5-cyclohexyl-7-furan-3-ylA,2-dihydro-3H~l,3,4- benzotriazepin-2-one was obtained using step d of the method of preparation of example 1, except that 5 -cyclohexyl-3 -(4-methoxy-benzyl)- 1 -(4-nitro-phenyl)-7-furan-3 -yl- 1 ,2-dihydro- 3H-l,3,4-benzotriazeρin-2-one was used in place of 3-benzyl-5-cyclohexyl~l-(4-nitro-phenyl)~ 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one. Step c: The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl-7-furan-3-yl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and tert-butoxycarbonyl i-valine were used in place of l-(4-amino- phenyl)-3~benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N1N ~bis-(t<2rt-butoxycarbonyl)-N' -[4-(3 -benzyl-S-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (MeOH-d4) 7.95 (IH, s), 7.68 (2H, d), 7.62 (IH, s), 7.55 (2H, m),: 7.38 (2H, d), 7.17 (5H, m), 6.82 (2H, m), 4.85 (IH, br s), 4.23 (IH, br s), 3.81 (IH, d), 2.96 (IH, m), 2.30 (IH3 m), 1.75 (6H, m), 1.30 (4H, m), 1.13 (6H, m). Found: C 67.47, H 6.38, Ν 10.60%; C36H39N5O3-1.5 HCl requires: C 67.21, H 6.34, N 10.89%.
Example 173: (S)-2-Amino-N-[4-(3-benzyl-5-cyclohexyl-2-oxo-7-o-tolyl-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-3-methyl-butyramide
Step a: 5-Cyclohexyl-3-(4-methoxy-benzyl)-l-(4-nitro-phenyl)-7-o-toly -1 ,2-dihydro-3H-l ,3,4- benzotriazepin-2-one was obtained using step a of the method of preparation of example 170, except that o-tolylboronic acid was used in place of rø-tolylboronic acid.
Step b : l-ft-Amino-phenylJS-benzyl-S-cyclohexyl^-o-tolyl-l^-dihydro-SH-lJJ- benzotriazepin-2-one was obtained using step d of the method of preparation of example 1, except that 5-cyclohexyl-3-(4-methoxy-benzyl)-l-(4-nitro-phenyl)-7-furan-3-yl-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitro-phenyl)- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one.
Step c: The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl-7-o-tolyl-l,2-dihydro-3Η-l,3,4- benzotriazepin-2-one and ferf-butoxycarbonyl Z-valine were used in place of l-(4-amino- phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N)N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H NMR (MeOH-d4) 7.74 (2H, d), 7.44 (2H, d), 7.40 (IH, m), 7.28 (1OH, m),: 6.89 (IH, d), 4.85 (IH, br s), 4.70 (IH, br s), 3.90 (IH, m), 2.89 (IH, m), 2.37 (IH, m), 2.27 (3H, s), 1.80 (6H, m), 1.34 (4H, m), 1.16 (6H, m). Found: C 70.07, H 6.67, N 10.21%; C39H43N5O2-LS HCl requires: C 69.88, H 6.70, N 10.45%.
Example 174: ($)-2-Amino-N-{4-[3-benzyl-5-cyclohexyl-7-(3-hydroxy-phenyl)-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl]-phenyl}-3-methyl-butyramide Step a: 5-Cyclohexyl-3-(4-methoxy-benzyl)-l-(4-nitro-phenyl)-7- (3-hydroxy-phenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step a of the method of preparation of example 170, except that 3-hydroxyphenylboronic acid was used in place of /n-tolylboronic acid. Step b : l-ø-Amino-phenylJS-benzyl-S-cyclohexyl-J-β-hydroxy-phenyty-lJ-dihydro-SH- l,3,4-benzotriazepin-2-one was obtained using step d of the method of preparation of example 1, except that 5-cyclohexyl-3-(4-methoxy-benzyl)-l-(4-nitrophenyl)-7-(3-hydroxy-phenyl)- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4- nitrophenyl)- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one. Step c: The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl-7-(3-hydroxy-phenyl)-l,2-dihydro- 3Η-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl L-valine were used in place of l-(4- amino-phenyl^-benzyl-S-cyclohexyl-l^-dihydro-SH-ljS^-benzotriazepin^-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSOd6) 10.95 (IH, s), 9.58 (IH, s), 8.36 (3H, br s), 7.75 (IH, s), 7.72 (2H, d), 7.65 (IH, d), 7.34 (2H, d), 7.16 (6H, m), 7.05 (2H, m), 6.78 (2H, m), 4.80 (IH, br s), 4.45 (IH, br s), 3.88 (IH, m), 3.08 (IH, m), 2.20 (IH, m), 1.75 (5H, m), 1.25 (5H, m), 0.89 (6H, m). Found: C 66.75, H 6.65, Ν 9.56%; C38H4IN5O3-1.8 HCl-0.4 Et2O requires: C 66.70, H 6.90, N 9.82%.
Example 175 : (S^^-Amino-N-ft-β-benzyl-S-cyclohexyl^-oxo-J-pyridin^-yl-l^-dihydro-SH- l,3,4-benzotriazepin-l-yl)-phenyl]-3-methyl-butyramide
Step a: S-Cyclohexyl-S-ø-methoxy-benzylj-l-ø-nitrophenylj-y-pyridin^-yl-l^-dihydro-SH- 1 ,3,4-benzotriazepin-2-one was obtained using step a of the method of preparation of example 170, except that 4-pyridine boronic acid was used in place of w-tolylboronic acid.
Step b : l-(4-Amino-phenyl)-3-benzyl-5-cyclohexyl-7-pyridin-4-yl-l ,2-dihydro-3H-l ,3 ,4- benzotriazepin-2-one was obtained using step d of the method of preparation of example 1, except that 5 -cyclohexyl-3 -(4-methoxy-benzyl)- 1 -(4-nitro-phenyl)-7-pyridin-4-yl- 1 ,2-dihydro- 3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitro-phenyl)- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one.
Step c: The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl-7-pyridin-4-yl-l,2-dihydro-3Η- l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl Z-valine were used in place of l-(4-amino- phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N)N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (DMSOd6) 11.00 (IH, s), 8.88 (IH, d), 8.36 (2H, m), 8.28 (2H, d), 8.22 (IH, s), 8.00 (IH, d), 7.73 (2H3 d), 7.35 (2H, d), 7.25 (4H, m), 6.92 (IH, d), 4.80 (IH, br s), 4.40 (IH, br s), 3.86 (IH, m), 3.17 (IH. m), 2.20 (IH, m), 1.75 (6H, m), 1.25 (4H, m), 1.01 (6H, m). Found: C 61.94, H 6.18, Ν 11.38%; C37H40N6O2-S^ HCl requires: C 61.69, H 6.06, N 11.67%. Example 176: 2-Ainino-N-[4-(3-benzyl-5-cyclohexyl-2-oxo-7-phenylamino-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl]-3-methyl-butyramide
Step a: {l-[4-(3-Benzyl-7-bromo~5-cyclohexyl-2-oxo-l ,2-dihydro-3H-l ,3 ,4-benzotriazepin-l- yl)-phenylcarbamoyl]-2-methyl-propyl}-carbamic acid tert-butyl ester was obtained using step a of the method of preparation of example 71, except that 3-benzyl-7-bromo-5-cyclohexyl-l- (4-aminophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 10, step d) and tert- butoxycarbonyl Z-valine were used in place of l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively.
Step b: {l-[4-(3-Benzyl-5-cyclohexyl-2-oxo-7-phenylamino-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenylcarbamoyl]-2-methyl-propyl}-carbamic acid tert-butyl ester A microwave vessel was charged with {l-[4-(3-benzyl-7-bromo-5-cyclohexyl-2-oxo-l,2- dihydro-SH-l^^-benzotriazepin-l-y^-phenylcarbamoyy^-methyl-propylj-carbamic acid tert-butyl ester (158mg, 0.22mmol), aniline (20μl, 0.22mmol), PdOAc2 (1.5mg, 3mol%), 2- (dicyclohexylphosphino)-2',4',6'-triisopropyl-l,r-biphenyl (6mg, 0.13mmol), Cs2COs (lOOmg, 0.31mmol), celite (50mg), PhCH3 (1.6mL), and t-BuOH (1.4mL). The vial was sealed and heated at 15O0C for 15min. in a microwave apparatus. On cooling, the mixture was filtered and evaporated. The residue obtained was then purified by chromatography on silica gel with EtOAc-DCM (1 :4) as eluant to afford the product.
Step c: The title compound was obtained using step f of the method of preparation of example 1, except that {l-[4-(3-benzyl~5-cyclohexyl-2-oxo-7-phenylamino-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yty-phenylcarbamoyl^-methyl-propylj-carbamic acid tert-butyl ester was used in place of N,N'-bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazeρm-3-yl)-phenyl]-guanidine. 1H NMR (MeOH-d4) 7.47 (2H, d), 7.35 (2H, d), 7.19 (7H, m), 7.05 (4H, m), 6.88 (IH, t), 6.68 (IH, d), 4.87 (IH, br s), 4.45 (IH, br s), 4.12 (IH, d), 2.73 (IH, m), 2.25 (IH, m), 1.75 (5H, m), 1.28 (5H, m), 1.09 (3H, d), 0.98 (3H5 d).
Example 177 (S)-l-[4-(2-Amino-3-methyl-butylamino)-phenyl]-5-cyclohexyl-8-methyl'3- (3, 3, 5, 5-tetramethyl-cyclohexyl) -1, 2-dihydro-3H-l , 3, 4-benzotriazepin-2-one The title compound was obtained using step a of the method of preparation of example 128, except that l-(4-amino-phenyl)-5-cyclohexyl-8-methyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one (example 106, step b) and (Sj-(I -formyl-2-methyl- propyl)-carbamic acid tert-butyl ester were used in place of l-(4-aminophenyl)-3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5- cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin- 1 -yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H NMR (DMSO-d6/D2O) 7.40 (IH, d), 7.03 (2H, d), 6.97 (IH, d), 6.62 (2H, d), 6.49 (IH, s), 3.94 (IH, m), 3.54 (IH, m), 3.10 (IH, m), 2.98 (IH, s), 2.14 (3H, s), 1.98-0.82 (36H, m). Found: C 64.73, H 8.41, N 9.53%; C36H53N5O- 2.3HC1-0.8 C4H8O2 requires: C 64.84, H 8.56, N 9.63%.
Example 178 3-Biphenyl-2-ylmethyl-5-cyclohexyl-l-{4-[2-(lHAmidazol-2-yl)-ethylamino]- phenylj-l, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
The title compound was obtained using step a of the method of preparation of example 128, except that 1 -(4-amino-phenyl)-3 -biphenyl-2-ylmethyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4- benzotriazepin-2-one (example 25, step a) and (l-trityl-lH-imidazol-2-yl)-acetaldehyde (Martinez-Perez, J.A., et a!., Synlett, (1999), 12, 1875) were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,N'-his-(tert- butoxycarbonyl)-N"-[4-(3 -benzyl-S-cyclohexyW-oxo- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin- 1 - yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (CDCl3) 7.29-7.12 (12H, m), 7.02 (2H, d), 6.88 (2H, s), 6.75 (IH, d), 6.46 (2H, d), 5.00 (IH, br s), 4.30 (IH, br s), 3.37 (2H, t), 2.81 (2H, t), 2.68 (IH, m), 1.79-1.27 (1OH, m). Found: C 66.30, H 6.21, Ν 11.17%; C38H38Ν6O-2.2HCl-0.8 C4H8O2 requires: C 66.38, H 6.30, N 11.27%. Example 179 5-Cyclohexyl-l-{4-[2-(lH-imidazol-2-yl)-ethylamino]-phenyl}-8-methyl-3- (3, 3, 5, 5-tetramethyl-cyclohexyl)-l, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
The title compound was obtained using step a of the method of preparation of example 128, except l-(4-amino-phenyl)-5-cyclohexyl-8-methyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one (example 106, step b) and (l-trityl-lH-imidazol-2-yl)- acetaldehyde (Martinez-Perez, J.A., et al, Synlett, (1999), 12, 1875) were used in place of 1- (4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place
Figure imgf000166_0001
butoxycarbonyl)-N' -[4-(3 -benzyl-S-cyclohexyl^-oxo- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin- 1 - yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (CDCl3) 7.27-7.16 (3H, m), 6.96 (2H, s), 6.90 (IH, d), 6.65-6.55 (3H, m), 4.15 (2H, m), 3.48 (2H, t), 2.93 (2H, t), 2.80 (IH, m), 2.21 (3H, s), 1.86-0.83 (28H, m). Found: C 65.79, H 7.59, Ν 11.09%; C36H48N6O-UHCl-Ll C4H8O2 requires: C 65.60, H 7.97, N 11.36%
Example 180 (S)-2-Amino-N-[4-(3-cyclodecyl-5-cyclohexyl-8-methyl-2-oxo-l,2-dihydro-3H- 1,3, 4-benzotriazepin-l-yl)-benzyl]-3-methyl-butyramide
Step a: 4-(3-Cyclodecyl-5-cyclohexyl-8-methyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l- yl)-benzaldehyde was obtained using step c of the method of preparation of example 1, except that 3-cyclodecyl-5-cyclohexyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 105, step a) and 4-iodobenzaldehyde were used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one and 4-iodo-nitrobenzene respectively. 1H NMR (CDCI3) 9.91 (IH, s), 8.05-8.02 (2H, d), 7.62-7.59 (2H, d), 7.35-7.33 (IH, d), 7.14-7.12 (IH, d), 6.88 (IH, s), 4.53 (IH, m), 2.88-2.81 (IH, m), 2.31 (3H, s), 2.05-0.89 (28H, m).
Step b: 3-Cyclodecyl-5-cyclohexyl-l-(4-hydroxymethyl-phenyl)-8-methyl-l,2-dihydro-3H- 1, 3, 4-benzotriazepin-2-one Sodium borohydride (40mg, l.Ommol) was added portion-wise to a solution of 4-(3- cyclodecyl-5-cyclohexyl-8-methyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)- benzaldehyde (250mg, 0.50mmol) in THF (5mL). The reaction mixture was stirred for 2hr and further sodium borohydride (20mg, 0.5mmol) was added. After stirring for 16hr the mixture was concentrated under reduced pressure and the residue partitioned between DCM (3OmL) and saturated NaHCO3 (3OmL). The organic layer was separated, washed with brine (3OmL) and dried (MgSO4). Filtration and evaporation of the solvent afforded the crude product which was purified by chromatography on silica gel with EtOAc-hexane (1:4) as eluant (202mg, 81%). 1H NMR (CDCl3) 7.45-7.42 (2H, d), 7.35-7.32 (2H, d), 7.27-7.24 (IH, m), 6.96-6.94 (IH, m), 6.55 (IH, m), 4.70-4.68 (2H, d), 4.34 (IH, m), 2.81 (IH, m), 2.22 (3H, s), 2.05-1.24 (29H, m).
Step c: 2-[4-(3-Cyclodecyl-5-cyclohexyl-8-methyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin- l-yl)-benzyl]-isoindole-l,3-dione
Diisopropyldiazodicarboxylate (120μL, 0.60mmol) was added to an ice-cooled solution of 3- cyclodecyl-5-cyclohexyl-l-(4-hydroxymethyl-phenyl)-8-methyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (200mg, 0.40mmol), Ph3P (160mg, O.όOmmol) and phthaliniide (90mg, O.όOmmol) in THF (5mL). The reaction was allowed to warm to ambient temperature and stirred for 18hr. Evaporation of the solvent afforded the crude product which was purified by chromatography on silica gel with EtOAc-hexane (1:4) as eluant (190mg, 76%). 1H NMR (CDCl3) 7.86-7.83 (2H, m), 7.72-7.97 (2H, m), 7.42-7.37 (4H, m), 7.24-7.21 (IH, m), 6.95- 6.93 (IH, m), 6.54 (IH, s), 4.83 (2H, s), 4.30 (IH, m), 2.79 (IH, m), 2.21 (3H, s), 2.05-1.22 (28H, m).
Step d: l-(4-Aminomethyl-phenyl)-3-cyclodecyl-5-cyclohexyl-8-methyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one A solution of 2-[4-(3-Cyclodecyl-5-cyclohexyl-8-methyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-benzyl]-isoindole-l,3-dione (190mg, 0.30mmol) and hydrazine hydrate (120μL, 3.0mmol) in EtOH (1OmL) was heated under reflux for lhr. The mixture was allowed to cool and the resultant suspension was filtered and the solid was washed with chloroform. The filtrate was evaporated to afford the product (140mg, 93%). 1H NMR (CDCl3) 7.41-7.38 (2H, m), 7.30-7.23 (3H, m), 6.95-6.92 (IH, m), 6.54 (IH, s), 4.32 (IH, m), 3.87 (2H, s), 2.81 (IH, m), 2.21 (3H, s), 2.05-1.23 (3OH, m).
Step e: The title compound was obtained using step a of the method of preparation of example 71, except that l-(4-aminomethyl-phenyl)-3-cyclodecyl-5-cyclohexyl-8-methyl-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one and tørt-butoxycarbonyl Z-valine were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N'-[4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-3-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (CDCl3) 7.70 (IH, br s), 7.39 (2H, d), 7.25 (3H, m), 6.94 (IH5 d), 6.53 (IH, s), 4.48 (2H, m), 4.32 (IH, m), 3.29 (IH, d), 2.81 (IH, m), 2.34 (IH, m), 2.22 (3H, s), 2.05-1.24 (28H, m), 0.99 (3H, d), 0.84 (3H, d). Found: C 67.44, H 8.55, Ν 10.35%; C37H53N5O2-1.7HCl requires: C 67.26, H 8.34, N 10.60%.
Example 181 l-{4-[2-(lH-Imidazol-2-yl)-ethylamino]-phenyl}-8-methyl-5-(tetrahydro-pyran~ 4-yl)-3-(3, 3, 5, 5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l, 3, 4-benzotriazepin-2-one Step a: Tetrahydro-pyran-4-carbonitrile
Potassium tert-butoxide (26.9g, 0.24mol) was added over 30min. to a solution of tetrahydro- 4H-pyran-4-one (1Og, O.lmol) and tosylmethylisocyanide (25.38g, 0.13mol) in EtOH-DME (1:35 / 36OmL) under argon at O0C. The reaction mixture was stirred for Ih. then heated at 4O0C for Ih. On cooling, the precipitated solid was removed by filtration and washed with DME. The filtrates were combined and evaporated to dryness. The residue obtained was dissolved in EtOAc, washed successively with H2O, 5%KHSO4, saturated NaHCO3, brine and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with hexane-EtOAc (4:1) as eluant (4.86g, 44%). 1H NMR (CDCl3) 3.93-3.86 (2H, m), 3.64-3.56 (2H, m), 2.86 (IH, m), 1.98-1.81 (4H, m).
Step b : (2-Amino-4-methyl-phenyl)-(tetrahydro-pyran-4-yl)-methanone
To an ice-cooled solution of tetrahydro-pyran-4-carbonitrile (4.8g, 43.3mmol) and w-toluidine (9.26mL, 86.5mmol) in toluene (20OmL) was added a solution of BCl3 (1.0M in xylene, 43.3mL, 43.3mmol) dropwise, whilst maintaining the temperature below 5°C. After addition, the reaction mixture was stirred at ambient temperature for lhr and then re-cooled in ice. AlCl3 (5.8Og, 43.3mmol) was added portion-wise and the reaction mixture was heated under reflux for 5h, allowed to cool and stirred at ambient temperature for 18h. 2M HCl (65mL) was added and the reaction mixture heated under reflux for 2.5hr. The reaction was allowed to cool and on neutralisation (pH 7) by the addition of 2M NaOH was extracted with EtOAc. The extract was washed with brine and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with hexane- EtOAc (4:1) as eluant (2.9Og, 31%). 1HNMR (CDCl3) 7.62 (IH, d), 6.49 (IH, s), 6.47 (IH, d), 6.27 (IH, d), 6.27 (2H, br s), 4.05 (2H, m), 3.60-3.44 (3H, m), 2.28 (3H, s), 1.93 (2H, m), 1.73 (2H, m). Step c: S-Methyl-S-ftetrahydro-pyran^-ylJ-S-β^J^-tetramethyl-cyclohexylj-lJ-dihydro-SH- 1,3, 4-benzotriazepin-2-one
A solution of (2-amino-4-methyl-phenyl)-(tetrahydro-pyran-4-yl)-methanone (2.9Og, 13.2mmol) and NEt3 (4.OmL, 29.0mmol) in DCM (5OmL) was added dropwise to a solution of triphosgene (1.3Og, 4.40mmol) in DCM (5OmL) at -400C. The reaction mixture was stirred at this temperature for 20min whereupon a solution of N'-(3,3,5,5-tetramethyl-cyclohexyl)- hydrazinecarboxylic acid tert-butyl ester (example 66, step a) (3.6g, 13.2mmol) in DCM (25mL) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and was washed with H2O, saturated NaHCO3, brine and dried (MgSO4). The residue obtained following filtration and evaporation was dissolved in DCM (3OmL) and TFA (3OmL) and stirred for lhr. The mixture was evaporated to dryness and the residue dissolved in DCM, washed with 10% aqueous K2CO3, and dried (MgSO4). Filtration and evaporation of the solvent afforded the product (5.23g, 99%). 1H NMR (CDCl3) 7.22 (IH, d), 6.91 (IH, d), 6.66 (IH, s), 6.42 (IH, br s), 4.31 (IH, m), 4.04 (2H, m), 3.49 (2H, m), 2.95 (IH, m), 2.33 (3H, s), 1.89-1.79 (4H, m), 1.51 (4H, m), 1.26 (IH, m), 1.07 (7H, m), 0.93 (6H, s). Step d: l-(4-Amino-phenyl)-8-methyl-5~(tetrahydro-pyran-4-yl)-3-(3, 3, 5, 5-tetramethyl- cyclohexyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps c and d of the method of preparation of example 1, except that 8-methyl-5-(tetrahydro-pyran-4-yl)-3-(3,3,5,5- tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCI3) 7.22 (IH, d), 7.15 (2H, d), 6.92 (IH, d), 6.67 (2H, d), 6.58 (IH, s), 4.14 (3H, m), 3.70 (2H5 br s), 3.54 (2H, t), 3.06 (IH5 m), 2.21 (3H, s), 1.83-1.19 (10H5 m), 1.05 (6H5 s), 0.90 (6H, s).
Step e The title compound was obtained using step a of the method of preparation of example 128, except l-(4-amino-phenyl)-8-methyl-5-(tetrahydro-pyran-4-yl)-3-(3,3,5,5-tetramethyl- cyclohexyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)- acetaldehyde (Martinez-Perez, J.A., et ah, Synlett, (1999), 12, 1875) were used in place of 1- (4-aminophenyl)-3-benzyl-5-cyclohexyl-l52-dihydro-3H-l,354-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert- butoxycarbonyl)-N"-[4-(3-benzyl-5-cyclohexyl-2-oxo-l52-dihydro-3H-l,3,4-benzotriazepin-l- yl)-phenyl]-guanidine5 according to step f of the method of preparation of example 1. 1H ΝMR (CDCl3) 7.22 (IH, d), 7.16 (2H5 d), 6.93 (2H, s), 6.92 (IH, d), 6.57 (3H, d), 4.17-4.09 (3H5 m), 3.57-3.47 (4H5 m), 3.07 (IH5 m), 2.93 (2H, t), 2.21 (3H, s), 2.00-1.19 (1OH, m), 1.04 (6H5 s), 0.90 (6H, s). Found: C 62.74, H 7.39, Ν 12.21 %; C35H46N6O2^-SHCl requires: C 62.51, H 7.26, N 12.50% Example 182 S-Cyclohexyl-l^-fflH-imidazol^-ylmethylJ-aminoJ-phenylJS-methyl-S- (tetrahydro-pyran-4-yl)- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
Step a: 5-Cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l ,2-dihydro-3H-l ,3 ,4-benzotriazepin- 2-one was obtained using step b of the method of preparation of example 181, except that (2- amino-4-methyl-phenyl)-cyclohexyl-methanone (example 11, step a) and N'-(tetrahydro-pyran- 4-yl)-hydrazinecarboxylic acid tert-butyl ester (example 61 step a) were used in place of (2- amino-4-methyl-phenyl)-(tetrahydro-pyran-4-yl)-methanone and N'-(3,3,5,5-tetramethyl- cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester respectively. 1H NMR (CDCl3) 7.25-6.63 (3H5 m), 6.47 (IH, br s), 4.15 (IH, m), 4.05-3.44 (4H, m), 2.69 (IH, m), 2.33 (3H5 s), 2.14- 1.20 (14H, m). Step b: l-(4-Aminoψhenyl)-5-cyclohexyl-8-methyU3-(tetrahydroφyran'4-yl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one was obtained using steps c and d of the method of preparation of example I5 except that 5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c. 1HNMR (CDCl3) 7.25-6.55 (7H, m), 5.08 (2H5 br s), 4.04-4.32 (5H, m), 2.80 (IH, m), 2.21 (3H, s), 2.20-1.25 (14H, m). Step c: The title compound was obtained using step a of the method of preparation of example 128, except l-(4-amino-phenyl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde (Kirk, K.L., J. Org. Chem., (1978), 43, 4381) were used in place of l-(4-aminophenyl)-3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-5- cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-3-yl)-phenyl]-guanidine, according to step f: of the method of preparation of example 1. 1H ΝMR (CDCl3) 9.80 (IH, br s), 7.31-6.54 (9H, m), 4.46 (IH, br s), 4.37 (2H, br s), 4.03-3.38 (5H, m), 2.80 (IH, m), 2.21 (3H, s), 2.20- 1.20 (14H, m). Found: C 56.94, H 6.09, Ν 12.47 %; C30H36N6O2^HCl-0.8 CH2Cl2 requires: C 56.61, H 6.10, N 12.86%
Example 183 5-Cyclohexyl-3-(3,4-dihydro-2H-benzoβJ[l,4]dioxepin-3-yl)-l-{4-[2-(lH- imidazol-2-yl)-ethylamino]ψherψl}-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
Step a: N'-(3,4-Dihydro-2H-benzo[b][l,4]dioxepin-3-yl)-hydrazinecarboxylic acid tert-butyl ester was obtained using the method of preparation of example 52, step a except that benzo[έ][l,4]dioxepin-3-one (Eur. Pat. 1405851) was used in place of cycloheptanone. 1H NMR (CDCl3) 7.60 (IH, s), 6.96-6.90 (4H, m), 6.10 (IH, br s), 5.01 (IH, s), 4.86 (IH, s), 4.26- 4.25 (2H, m), 3.56 (IH, m), 1.51 (9H, s).
Step b : 5-Cyclohexyl-3-(3, 4-dihydro-2H-benzo[b][l, 4]dioxepin-3-yl)-8-methyl-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one was obtained using step b of the method of preparation of example 181, except that (2-amino-4-methyl-phenyl)-cyclohexyl-methanone (example 11, step a) and N'-(3,4-dihydro-2H-benzo[b][l,4]dioxepin-3-yl)-hydrazinecarboxylic acid tert-butyl ester were used in place of (2-amino-4-methyl-phenyl)-(tetrahydro-pyran-4-yl)-methanone and
N'-(3,3,5,5-tetramethyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester respectively. 1H NMR (CDCl3) 7.27-6.65 (8H, m), 4.76 (IH, m), 4.55-4.39 (4H, m), 2.68 (IH, m), 2.35 (3H, s),
1.83-1.20 (1OH, m).
Step c : l-(4-Amino-phenyl)-3-(3, 4-dihydro-2H-benzo[b][l, 4]dioxepin-3-yl)5-cyclohexyl-8- methyl-1 ,2-dihydro-3H-l ,3,4-benzotriazepin-2~one was obtained using steps c and d of the method of preparation of example 1, except that 5-cyclohexyl-3-(3,4-dihydro-2H- benzo[b][l,4]dioxepin-3-yl)-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.27-6.58 (HH, m), 4.90-3.90 (7H, m), 2.79 (IH, m), 2.23 (3H, s), 2.00-1.25 (1OH, m). Step d: The title compound was obtained using step a of the method of preparation of example 128, except 1 -(4-amino-phenyl)-3 -(3 ,4-dihydro-2H-benzo [b] [ 1 ,4]dioxepin-3 -yl)5 -cyclohexyl- 8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)- acetaldehyde (Martinez-Perez, J.A., et ah, Synlett, (1999), 12, 1875) were used in place of 1- (4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert- butoxycarbonyl)-N"- [4-(3 -benzyl-5 -cyclohexyl^-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 - yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (CDCl3) 7.27-6.54 (13H, m), 4.92-4.10 (5H, m), 3.48-2.92 (4H, m), 2.79 (IH, m), 2.22 (3H, s), 2.00-1.10 (1OH, m). Found: C 58.98, H 5.75, Ν 11.54 %; C35H38N6O3^HCI-OJOCH2CI2 requires: C 59.17, H 5.82, N 11.32%
Example 184 5-Cyclohexyl-l-{4-[2-(lH-imidazol-2-yl)-ethylamino]-phenyl}-3,8-dimethyl-l,2- dihydro-3H-l, 3, 4-benzotriazepin-2-one
Step a: 5-Cyclohexyl-3, 8-dimethyl-l-(4-nitro-phenyl)-l , 2-dihydro-3H-l, 3, 4-benzotriazepin-2- one was obtained using steps a, b and c of the method of preparation of example 20 except that (2-amino-4-methyl-phenyl)-cyclohexyl-methanone (example 11, step a) was used in place of (2-amino-phenyl)-cyclohexyl-methanone in step a and methyl iodide was used in place of (3- bromopropenyl)-benzene in step c. 1HNMR (CDCl3) 8.14 (2H, d), 7.52 (2H, d), 7.38 (IH, d), 7.17 (IH, d), 6.75 (IH, s), 3.17 (3H, s), 2.83 (IH, m), 2.32 (3H, s), 1.74-1.19 (1OH, m). Step b: 1 -(4-Amino-phenyl)-5-cyclohexyl-3,8-dimethyl-l ,2-dihydro-3H-l ,3,4-benzotriazepin- 2-one was obtained using step d of the method of preparation of example 1 except that 5- cyclohexyl-3,8-dimethyl- 1 -(4-nitro-phenyl)- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one. 1H NMR (CDCl3) 7.25 (IH, d), 7.13 (2H, d), 6.93 (IH, d), 6.65 (2H, d), 6.58 (IH, s), 3.73 (2H, br s), 3.07 (3H, s), 2.77 (IH, m), 2.22 (3H, s), 1.84-1.24 (1OH, m).
Step c: The title compound was obtained using step a of the method of preparation of example 128, except l-(4-amino-phenyl)-5-cyclohexyl-3,8-dimethyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-acetaldehyde (Martinez-Perez, J.A., et ah, Synlett, (1999), 12, 1875) were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N"-[4-(3-benzyl-5- cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1HNMR (CDCl3) 7.25 (IH, d), 7.10 (2H, d), 6.94 (3H, m), 6.59 (IH, s), 6.50 (2H, d), 3.41 (2H, t), 3.07 (3H, s), 2.85 (2H, t), 2.80 (IH, m), 2.21 (3H, s), 1.80-1.21 (1OH, m). Found: C 58.97, H 6.47, N 14.75 %; C27H32N6O-2.6HC1- 0.2C4Hi0O requires: C 58.97, H 6.52, N 14.84%
Example 185 l-(4-((lH-imidazol-2-yl)methylamino)phenyl)-5-cyclohexyl-3-(3, 3,5,5- tetramethylcyclohexyl)-l , 2-dihydro-3H-pyrido[3, 4-JJ[1, 3, 4]triazepin-2-one Step a: N-((3-(Cyclohexyl)hydroxymethyl)pyridin-4-yl)pivalamide
«-Butyl lithium (1.6M in hexanes; 15.6mL, 25mmol) was added to a solution of N-(pyridin-4- yl)pivalamide (Zabell, A.P.R. et al, Bioorg. Med. Chem., (2004), 12, 1867) (1.77g, lO.Ommol), and TMEDA (3.3mL, 25.0mmol) in Et2O (4OmL) at -78°C under argon. The mixture was stirred for 15min. then at -10°C for 3hr. The mixture was cooled to -78°C whereupon a solution of cyclohexanecarboxaldehyde (1.45mL, 12mmol) in Et2O (5mL) was added dropwise. Once addition was complete the mixture was allowed to warm to 0°C and stirred at for 2h. The reaction mixture was washed with H2O, saturated NaHCO3 solution, brine and dried (MgSO4). Filtration and evaporation of the solvent afforded the crude product which was purified by chromatography on silica gel with EtOAc-DCM (19:1) as eluant (1.06g, 37%). 1H NMR (CDCl3) 9.82 (IH, br s), 8.37 (2H, s), 8.04 (IH, s), 4.42 (IH, d), 3.52 (IH, br s), 2.14 (IH, d), 1.81-1.65 (4H, m), 1.33-1.08 (14H, m).
Step b: N-(3-Cyclohexanecarbonyl-pyridin-4-yl)pivalamide
DMSO (ImL, H.lmmol) in DCM (7mL) was added to a solution of oxalyl chloride (0.62mL, 7.03mmol) in DCM (25mL) at -78°C under argon. After stirring for 10 min. a solution of N- ((3-(cyclohexyl)hydroxymethyl)pyridin-4-yl)pivalamide (1.Og, 3.45mmol) in DCM (7mL) was added dropwise. The reaction mixture was stirred for 15 min. and NEt3 (3.93mL, 28.2mmol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 2hr. The mixture was washed with H2O, sat NaHCO3 and dried (MgSO4). Filtration and evaporation of the solvent was followed chromatography on silica gel with EtOAc-DCM (19:1) as eluant to afford the product (0.67g, 67%). 1H NMR (CDCl3) 12.16 (IH, br s), 9.14 (IH, s), 8.71 (IH, d), 8.58 (IH, d), 3.36 (IH, m), 1.95-1.29 (19H, m).
Step c: (4-Aminopyridin-3-yl)cyclohexylmethanone
A solution of N-(3-cyclohexanecarbonyl-pyridin-4-yl)pivalamide (0.3g, 1.04mmol) in 3M HCl (3OmL) was heated under reflux for 18hr. On cooling, the pH was adjusted to 8 and the mixture extracted with EtOAc and the extracts were dried (MgSO4). Filtration and evaporation of the solvent afforded the product (0.15g, 67%). 1H NMR (CDCl3) 8.84 (IH, s), 8.10 (IH, d), 7.20 (2H, br s), 6.50 (IH, d), 3.23 (IH, m), 1.87-1.20 (1OH, m). Step d: 5-Cyclohexyl-3-(3, 3, 5, 5-tetramethylcyclohexyl)-l,2-dihydro-3H-pyrido[3, 4- fJ[l,3,4]triazepin-2-one was obtained using step b of the method of preparation of example
181, except that (4-aminopyridin-3-yl)cyclohexylmethanone was used in place of (2-amino-4- methyl-phenyl)-(tetrahydro-pyran-4-yl)-methanone. 1H NMR (CDCl3) 8.56 (IH, s), 8.44 (IH, d), 6.72 (IH, d), 6.40 (IH, m), 4.33 (IH, m), 2.73 (IH, m), 1.84-1.11 (28H, m).
Step e: l-(4-Aminophenyl)-5-cyclohexyl-3-(3,3, 5, 5-tetramethylcycIohexyl)-l,2-dihydro-3H- pyrido[3,4-fj [1 ,3,4]triazepin-2-one was obtained using steps c and d of the method of preparation of example 1 except that 5-cyclohexyl-3-(3,3,5,5-tetramethylcyclohexyl)-l,2- dihydro-3H-pyrido[3,4-fJ[l,3,4]triazepin-2-one was used in place of 3-benzyl-5-cyclohexyl- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCl3) 8.57 (IH5 s), 8.33 (IH, d), 7.13 (2H, d), 6.70 (2H, d), 6.58 (IH, d), 4.20 (IH, m), 3.76 (2H, br s), 2.81 (IH, m), 1.93-1.25 (IH, m), 1.20 (6H, s), 1.09 (6H, s).
Step f: The title compound was obtained using step a of the method of preparation of example 128, except l-(4-aminophenyl)-5-cyclohexyl-3-(3,3,5,5-tetramethylcyclohexyl)-l ,2-dihydro- 3H-pyrido[3,4-fJ[l,3,4]triazepin-2-one and (l-trityl-lH-imidazol-2-yl)-acetaldehyde (Martinez-Perez, J.A., et al, Synlett, (1999), 12, 1875) were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzo.triazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,N'-bis-(tert- butoxycarbonyl)-N "-[4-(3 -benzyl-5 -cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 - yl)-phenyl]-guanidine, according to step f of the method of preparation of example 1. 1H ΝMR (CDCl3) 8.57 (IH, s), 8.34 (IH, d), 7.61 (3H, m), 7.18 (IH, d), 7.15 (IH, s), 6.66 (IH, d), 6.56 (IH, d), 4.48 (2H3 s), 4.19 (IH, m), 2.78 (IH, m), 1.88-1.20 (16H5 m), 1.09 (6H, s), 0.92 (6H, s).
Example 186 2-Amino-N-(4-(5-cyclohexyl- 7, 8-dimethoxy~2-oxo-3-(3, 3, 5, 5-tetramethyl- cyclohexyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl)-3~methyl-butyramide
Step a (2-Amino-4,5-dimethoxyphenyl)cyclohexylmethanone was obtained using step a of example 181 except that cyclohexanecarbonitrile and 3,4-dimethoxyaniline were used in place of tetrahydropyran-carbonitrile and m-toluidine respectively.
Step b 5-Cyclohexyl- 7, 8-dimethoxy-3-(3, 3, 5, 5-tetramethyl-cyclohexy!)-! , 2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step b of example 181 except that (2-amino-4,5- dimethoxyphenyl)cyclohexylmethanone was used in place of (2-amino-4-methyl- phenyl)tetrahydropyran-4-ylmethanone. 1HNMR (CDCl3) 6.78 (IH, s), 6.35 (IH, s), 6.22 (IH, br s), 4.33-4.32 (IH, m), 3.88 (3H, s), 3.86 (3H, s), 2.68-2.64 (IH, m), 1.84-1.72 (5H, m), 1.55- 1.20 (HH, m), 1.06 (6H, s), 0.93 (6H, s). Step c l-(4-Amino-phenyl)-5-cyclohexyl-7,8-dimethoxy-3-(3,3,5,5-tetranιethyl-cyclohexyl)-l,2- dihydro-3H-l ,3 ,4-benzotriazepin-2-one was obtained using steps c and d of example 1, except that 5-cyclohexyl-7,8-dimethoxy-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.20-7.15 (2H, m), 6.76 (IH, s), 6.67-6.62 (2H, m), 6.24 (IH, m), 4.16-4.14 (IH, m), 3.90 (3H, s), 3.66 (3H, s), 3.64 (3H, s), 2.78-2.71 (IH5 m), 2.02-1.73 (8H, m), 1.34-0.91 (2OH, m).
Step d The title compound was obtained using step a of example 71, except that l-(4-amino- phenyl)-5 -cyclohexyl-7, 8-dimethoxy-3 -(3,3,5,5 -tetramethyl-cyclohexyl)- 1 ,2-dihydro-3H- l,3,4-benzotriazepin-2-one and fert-butoxycarbonyl i-valine were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert- butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N"-(4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3Η-l,3,4- benzotriazepin-l-yl)-phenyl)-guanidine, according to step f of example 1. 1H ΝMR (DMSO- d6) 10.73 (IH, s), 8.27 (3H, br s), 7.63-7.60 (2H, m), 7.33-7.30 (2H, m), 7.08 (IH, s), 6.25 (IH, s), 4.01-3.98 (IH, m), 3.80 (4H, m), 3.54 (3H, s), 3.05-3.01 (IH, m), 2.19-2.17 (IH, m), 2.00- 1.45 (8H, m), 1.38-0.84 (26H, m). Found: C 64.52, H 8.25, Ν 10.52%; C37H53N5O4-LSHCl requires C 64.73, H 8.25, H 10.52%.
Example 187 5-Cyclohexyl~8-ethyl-l-(4-((lH-imidazol-2-ylmethyl)-amino)-phenyl)-3-(3, 3, 5, 5- tetramethyl-cyclohexyl)-! , 2-dihydro-3H-l,3,4-benzotriazepin-2-one
Step a (2-Amino-4-ethylphenyl)cyclohexylmethanone was obtained using step b of example 181 except that cyclohexanecarbonitrile and 3-ethylaniline were used in place of tetrahydropyran-carbonitrile and rø-toluidine respectively.
Step b 5-Cyclohexyl-8-ethyl-3-(3, 3, 5, 5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step c of example 181 except that (2-amino-4- ethylphenyl)cyclohexylmethanone was used in place of (2-amino-4-methyl-phenyl)tetrahydro- pyran-4-ylethanone. 1H NMR (CDCl3) 721-1.24 (IH, m), 6.94-6.91 (IH, m), 6.62 (IH, s), 6.07 (IH, s), 4.32-4.24 (IH, m), 2.73-2.59 (3H, m), 1.84-1.72 (5H, m), 1.58-1.21 (14H, m), 1.06 (6H, s), 0.93 (6H, s). Step c l-(4-Amino-phenyl)-5-cyclohexyl-8-ethyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps c and d of example 1, except that 5-cyclohexyl-8-ethyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.26-7.12 (3H, m), 6.94-6.92 (IH, m), 6.70- 6.67 (2H, m), 6.56 (IH, s), 4.17-4.12 (IH, m), 3.69 (2H, br s), 2.79 (IH, m), 2.54-2.46 (2H, m), 1.88-0.90 (3 IH, m).
Step d The title compound was obtained using step a of example 128, except that l-(4-amino- phenyl)-5-cyclohexyl-8-ethyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of 1- (4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl- 1 -(4-(4,5-dihydro- lH-imidazol-2-ylamino)-phenyl)- 1 ,2-dihydro-3H-l ,3 ,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 9.43 (IH, s), 7.24- 7.17 (3H, m), 7.04-6.92 (3H, m), 6.60-6.54 (3H, m), 4.49-4.42 (3H, m), 4.19-4.08 (IH5 m), 2.79 (IH, m), 2.54-2.46 (2H, m), 2.05-1.65 (9H, m), 1.32-0.89 (22H, m). The compound was further characterised and tested as the HCl salt. Found: C 63.57, H 7.70, N 11.51%; C36H48N6O-2.5HC1 -0.7C4H8O2 required C 63.52, H 7.71, N 11.46%.
Example 188 (S)-2-Amino-N-(4-(3-biphenyl-2-ylmethyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- 1,3, 4-benzotriazepin~3-yl)-phenyl)-2-(lH-imidazol-5-yl)acetamide
The title compound was obtained using step a of example 71, except that l-(4-amino-phenyl)- 3-biphenyl-2-ylmethyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 25, step a) and έw-tert-butoxycarbonyl i-histidine were used in place of l-(4-aminophenyl)-3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N -bis-(fert- butoxycarbonyl)-N/-(4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-3- yl)-phenyl)-guanidine, according to step f of example 1. 1H NMR (DMSO-d6/D2O) 8.94 (IH, s), 7.66-7.36 (5H, m), 7.27-7.17 (9H, m), 7.08-7.01 (3H, m), 6.68 (IH, d), 4.78 (IH, d), 4.28 (IH, t), 4.18(1H, d), 3.36-3.20 (2H, m), 2.84 (IH, m), 1.70-0.81 (1OH, m). Found: C 63.79, H 6.18, N 11.97%; C39H39N7O2^.2 HCl-1.2 C4H8O2 requires: C 63.87, H 6.22, N 11.90%.
Example 189 3-Cyclodecyl-5-cyclohexyl-8-methyl-l-(4-((lH-imidazol-2-ylmethyl)-amino-2- methyl-phenyl)-l,2-dihydro-3H-l,3,4~benzotriazepin-2-one
Step a l-(4-Amino-2-methyl-phenyl)-3-cyclodecyl-5-cyclohexyl-8-methyl-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one was obtained by using steps c and d of example 1, except that 3- cyclodecyl-5-cyclohexyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 105, step a) and 5-iodo-3-nitro-toluene were used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one and 4-iodo-nitrobenzene in step c. 1H NMR (CDCl3) 7.39 (IH, br s), 7.24 (IH, d), 6.87 (IH, d), 6.60 (IH, dd), 6.23 (2H, m), 4.27 (IH, m), 3.64 (2H, br s), 2.20 (3H, s), 2.05-1.24 (3 IH, m). Step b The title compound was obtained using step a of example 128, except that l-(4-amino- 2-methyl-phenyl)-3 -cyclodecyl-5 -cyclohexyl-8-methyl- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin- 2-one (example 189, step a) and l-H-imidazol-2-carbaldehyde were used in place of l-(4- aminopheny^-S-benzyl-S-cyclohexyl-l^-dihydro-SΗ-ljS^-benzotriazepin^-one and formalin respectively. 1H NMR (CDCl3) 7.24 (2H, d), 6.97 (2H, s), 6.98 (2H5 s), 6.88 (IH, d), 6.52 (2H, m), 6.42 (IH, s), 4.40 (3H, br s), 4.26 (IH, m), 2.77 (IH, m), 2.20 (3H, s), 1.96-1.24 (3 IH, m). The compound was further characterized and tested as the HCl salt. Found: C 65.38, H 7.66, N 12.31%; C36H48N6O-2.3HC1 requires: C 65.05, H 7.63, N 12.64%.
Example 190 3-(Biphenyl-2-ylmethyl)-5-cyclohexyl-8-methylΛ-(4-((lHAmidazol-2-ylmethyl)- amino)-phenyl)-l, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
Step a l-f^Amino-phenylJS-φiphenyl^-ylmethylJ-S-cyclohexylS-methyl-l^-dihydro-SH- l,3,4-benzotriazepin-2-one was obtained using step c of example 20 except that 5-cyclohexyl- 8-methyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 184, step b) and 2-bromomethyl-biphenyl were used in place of 5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one and (3-bromopropenyl)-benzene respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one, according to step d of example 1. 1H NMR (CDCl3) 7.27-7.09 (12H, m), 6.95 (IH, d), 6.63 (2H, d), 6.53 (IH, s), 5.00 (IH, br s), 4.30 (IH, br s), 3.68 (2H, br s), 2.65 (IH, m), 2.25 (3H, s), 1.77-1.25 (10, m). Step b The title compound was obtained using step a of example 128, except l-(4-amino- phenyl)-3-(biphenyl-2-ylmethyl)-5-cyclohexyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin- 2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of l-(4-amino- phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl- l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one, according to step b of example 39. 1HNMR (CDCl3) 9.70 (IH, br s), 7.28-7.05 (12H, m), 6.95 (3H, m), 6.53 (3H, m), 5.00 (IH, br s), 4.42-4.35 (4H, m), 2.65 (IH, m), 2.52 (3H, s), 1.77-1.26 (1OH, m). The compound was further characterised and tested as the HCl salt. Found: C 67.30, H 6.20, N 11.37%; C38H38N6O-2.2HC1 -0.8C4H8O2 required C 67.38, H 6.35, N 11.44%.
Example 191 3-Cyclodecyl-5-cyclohexyl-7-methyl-l-(4-((lH-imidazol-2-ylmethyl)-amino)- phenyl)-! ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one Step a 2-Amino-5-methyl-benzonitrile was obtained using steps a, b and c of example 7, except that 5-methyl-2-nitrobenzoic acid was used in place of 5-fluoro-2-nitrobenzoic acid in step a. 1HNMR (CDCl3) 7.18 (IH, s), 7.14 (IH, d), 6.67 (IH, d), 4.25 (2H, br s), 2.23 (3H, s).
Step b (2-Amino-5-methyl-phenyl)-cyclohexyl-methanone was obtained by example 5 step a, except that cyclohexylmagnesium chloride and 2-amino-5-methyl-benzonitrile were used in place of isopropylmagnesium chloride and 2-aminobenzonitrile respectively. 1HNMR (CDCl3) 7.53 (IH, d), 7.09 (IH, dd), 6.59 (IH, d), 6.11 (2H, br s), 3.28 (IH, m), 2.28 (3H, s), 1.19-1.25 (1OH, m).
Step c 3-Cyclodecyl-5-cyclohexyl-7-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps a and b of example 52, except that cyclododecanone was used in place of cycloheptanone in step a and (2-amino-5-methyl-phenyl)-cyclohexyl-methanone was used in place of (2-aminophenyl)-cyclohexyl-methanone in step b. 1H NMR (CDCl3) 7.13-6.66 (3H, m), 6.09 (IH, br s), 4.47 (IH, m), 2.70 (IH, m), 2.33 (3H, s), 2.00-1.20 (28H, m).
Step d 1 -(4-Amino-phenyl)-3-cyclodecyl-5-cyclohexyl- 7 -methyl- 1 ,2-dihydro-3H-l , 3, 4- benzotriazepin-2-one was obtained by using steps c and d of example 1, except that 3- cyclodecyl-5-cyclohexyl-7-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.20-6.61 (7H, m), 4.27 (IH, m), 3.65 (2H, br s), 2.79 (IH, m), 2.32 (3H, s), 2.10- 1.20 (28H, m). Step e The title compound was obtained using step a of example 128, except that l-(4-amino- phenyl)-3 -cyclodecyl-5 -cyclohexyl-7-methyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and lH-imidazol-2-carbaldehyde were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 9.73 (IH, br s), 7.20-6.52 (9H, m), 4.43-4.24 (4H, m), 2.80 (IH, m), 2.32 (3H, s), 2.20-1.20 (28H, m). The compound was further characterised and tested as the HCl salt. Found: C 65.69, H 7.71, N 12.86%; C35H46N6O^OHCl requires C 65.71, H 7.56, N 13.14%.
Example 192 5-Cyclohexyl-3-(3,4-dihydro-2H-benzo[b][l,4]dioxepin-3-yl)-8-methyl-l-(4- ((lH-imidazol-2-ylmethyl)-amino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except l-(4-amino-phenyl)-3- (3,4-dihydro-2H-benzo[b][l,4]dioxepin-3-yl)5-cyclohexyl-8-methyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (Example 183, step c) and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N)N/-bis-(tert-butoxycarbonyl)-N"-(4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro- 3H-l,3,4-benzotriazepin-3-yl)-phenyl)-guanidine, according to step f of example 1. 1H NMR (CDCl3) 11.00-9.00 (IH, br s), 7.31-6.56 (13H, m), 4.90-4.20 (8H, m), 2.78 (IH, m), 2.23 (3H, s), 2.10-1.20 (1OH, m). Found: C 63.28, H 6.13, N 11.87 %; C34H36N6O3^HCl-O-O Et2O requires: C 62.99, H 6.39, N 12.11% Example 193 3-Cyclodecyl-5-cyclohexyl-7,8-dimethyl-l-(4-((lH-imidazol-2-ylmethyl)-amino)- phenyl)-! ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one
Step a 4,5-dimethyl-2-aminobenzonitrile was obtained using the step c of example 7, except that 4,5-dimethyl-2-nitrobenzonitrile {J.Med. Chem., (1970) 13, 882) was used in place of 5- fluoro-2-nitrobenzonitrile. 1H NMR (CDCl3) 7.12 (IH, s), 6.55 (IH, s), 4.18 (2H, br), 2.21 (3H, s), 2.13 (3H, s).
Step b (2-Amino-4, 5 -dimethyl) (cyclohexyl)methanone was obtained by example 5 step a, except that cyclohexylmagnesium chloride and 4,5-dimethyl-2-aminobenzonitrile were used in place of isopropylmagnesium chloride and 2-aminobenzonitrile respectively. 1HNMR (CDCl3) 7.47 (IH, s), 6.48 (IH, s), 6.09 (2H, br), 3.26 (IH, m), 2.18 (6H, s), 1.84 (4H, d), 1.75 (IH, d), 1.40 (5H, m).
Step c l-(4-Amino-phenyl)-3-cyclodecyl-5-cyclohexyl-7 ,8-dimethyl-l ,2-dihydro-3H-l ,3,4- henzotriazepin-2-one was obtained using steps a and b of example 52, except that cyclododecanone was used in place of cycloheptanone in step a and (2-amino-4,5- dimethyl)(cyclohexyl)methanone was used in place of (2-aminophenyl)-cyclohexyl-methanone in step b. 1H NMR (CDCl3) 7.15 (2H, d), 7.04 (IH, s), 6.61 (2H, d), 6.50 (IH, s), 4.27 (IH, m), 3.71 (2H, br), 2.76 (IH, m), 2.20 (3H, s), 2.08 (3H, s), 2.0-1.2 (28H, m).
Step d 3-Cyclodecyl-5-cyclohexyl-7,8-dimethyl-l-(4-((l-trityl-lH-imidazol-2-ylmethyl)- amino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step a of example 128, except that l-(4-amino-phenyl)-3-cyclodecyl-5-cyclohexyl-7,8-dimethyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one and l-trityl-lH-imidazole-2-carboxaldehyde were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one and formalin respectively. 1H NMR (CDCl3) 7.34 (1OH, m), 7.16 (6H, m), 7.00 (4H, m), 6.83 (IH, s), 6.44 (IH, s), 6.19 (2H, d), 4.60 (IH, m), 4.16 (IH, m), 3.24 (2H, br d), 2.75 (IH, m), 2.20 (3H, s), 2.08 (3H, s), 2.0-1.25 (28H, m). Step e A solution of 3-cyclodecyl-5-cyclohexyl-7,8-dimethyl-l-(4-((l-trityl-lH-imidazol-2- ylmethyl)-amino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (680mg, O.δlmmol) in 5% HOAc-MeOH (25mL) was heated under reflux for 2h. The solvent was evaporated and the residue dissolved in DCM. The mixture was washed sequentially with 10% K2CO3, H2O, then brine and dried over MgSO4. Filtration and evaporation of the solvent was followed by chromatography (DCM-MeOH-NH3 (95:5:0.5)) of the residue gave the title product (308mg, 65%). 1H NMR (CDCl3) 9.3 (IH, br s), 7.19 (2H, d), 7.00 (3H, m), 6.57 (2H, d), 6.46 (IH, s), 4.42 (3H, m), 4.24 (IH, m), 2.78 (IH, m), 2.22 (3H, s), 2.11 (3H, s), 2.05-1.20 (28H, m). The compound was further characterized and tested as the HCl salt. Found: C 66.77, H 7.64, N 12.26%; C36H48N6O^JHCl requires: C 63.69, H 7.53, N 12.38%.
Example 194 2-Amino-N-(4-(5-cyclohexyl-2-oxo-3-(3, 3-dimethyl-5-(4-methoxyphenyl)- cyclohexyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl)-3-methyl-butyramide
Step a 5-Cyclohexyl-3-(3, 3-dimethyl-5-(4-methoxyphenyl)-cyclohexyl)-l,2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using steps a and b of example 52, except that 3,3- dimethyl-5-(4-methoxyphenyl)-cyclohexanone was used in place of cycloheptanone in step a. 1H NMR (CDCl3) 7.39-7.26 (4H, m), 7.14-7.10 (IH, m), 6.86-6.82 (3H, m), 6.39 (IH, s), 4.49- 4.41 (IH, m), 3.79 (3H, s), 3.00-2.95 (IH, m), 2.75-2.71 (IH, m), 2.34 (IH, m), 2.04 (IH, m), 1.92-1.19 (14H, m), 0.80 (3H, s), 0.70 (3H, s).
Step b l-(4-Amino-phenyl)-5-cyclohexyl-3-(3,3-dimethyl-5-(4-methoxyphenyl)-cyclohexyl)- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps c and d of example 1, except that 5-cyclohexyl-3-(3,3-dimethyl-5-(4-methoxyphenyl)-cyclohexyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.40-7.11 (7H, m), 6.84-6.78 (3H, m), 6.68-
6.66 (2H, m), 4.29 (IH, s), 3.79 (3H, s), 3.70 (2H, br s), 2.86-2.44 (3H, m), 2.12-1.68 (8H, m), 1.42-1.24 (8H, m), 0.77 (3H, s), 0.66 (8H, m).
Step c The title compound was obtained using step a of example 71, except that l-(4-amino- phenyl)-5 -cyclohexyl-7, 8-dimethoxy-3 -(3 ,3-dimethyl-5 -(4-methoxyphenyl)-cyclohexyl)- 1,2- dihydro-3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl Z-valine were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N)N-bis-(tert-butoxycarbonyl)-N"-(4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl)-guanidine, according to step f of example 1. 1H ΝMR (DMSO-d6) 10.91 (IH, s), 8.32 (3H, br s), 7.71-7.65 (3H, m), 7.39-7.17 (4H, m), 7.06-6.96 (2H, m), 6.83-6.71 (3H, m), 4.08 (IH, s), 3.85-3.84 (IH, m), 3.70 (3H, s), 3.0 (IH, m), 2.50- 0.98 (24H, m), 0.73 (3H, s), 0.56 (3H, s). Found: C 68.81, H 7.74, Ν 9.84%; C40H5IN5O3- 1.33HC1 requires C 68.79, H 7.55, H 10.03%.
Example 195 (S)-2-Arnino-N-(4-(7-benzylamino-5-cyclohexyl-2-oxo-3-(l-phenyl-ethyl)-l, 2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl)-3-methyl-butyramide Step a 7-Bromo-5-cyclohexyl-3-(4-methoxy-benzyl)-l-(4-nitrophenyl)-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using steps a-c of example I, except that 4- methoxybenzylhydrazine and (2-amino-5-bromophenyl) cyclohexyl methanone (Example 10, step b) were used in place of benzylhydrazine and (2-aminophenyl) cyclohexylmethanone respectively in step a.
Step b 7-Bromo-5-cyclohexyl-l-(4-nitrophenyl)-3-(l-phenylethyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using steps b and c of example 20 except that 7-bromo-5- cyclohexyl-3 -(4-methoxy-benzyl)- 1 -(4-nitrophenyl)-l ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2- one was used in place of 5-cyclohexyl-3-(4-methoxy-benzyl)-l-(4-nitrophenyl)-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one in step b and 1-bromoethylbenzene was used in place of 3- bromopropenylbenzene in step c. 1H NMR (CDCl3) 8.12 (2H, br m). 7.7-7.1 (9H, m), 6.84 (IH, m), 5.40 (IH, m), 2.75 (IH, m), 2.0-1.2 (13H, m).
Step c N-(3-(l-Phenylethyl)-5-cyclohexyl-l~(4-nitro-phenyl)-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-7-yl)-acetamide was obtained using step a of example 162, except that 7- bromo-5-cyclohexyl-l-(4-nitrophenyl)-3-(l-phenylethyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-7-bromo-5-cyclohexyl-l-(4-nitro-phenyl)- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one.
Step d 3-(l-Phenylethyl)-7-amino-5-cyclohexyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step f of example 1 except that N-(3-(l-phenylethyl)- 5-cyclohexyl- 1 -(4-nitro-phenyl)-2-oxo- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-7-yl)-acetamide was used in place of N,N-bis-(tert-butoxycarbonyl)-N"-(4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl)-guanidine.
Step e 7-Benzylamino-l-(4-nitrophenyl)-5-cyclohexyl-3-(l-phenylethyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using step a of example 128, except that 3-benzyl-7-amino- 5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and benzaldehyde were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and formalin respectively. 1H ΝMR (CDCl3) 8.03 (2H, m), 7.61 (IH, m), 7.3-7.1 (HH, m), 6.9-6.4 (3H, m), 5.46 (IH, m), 4.35 (2H, m), 2.60 (IH, m), 2.0-1.0 (13H, m).
Step f l^-aminophenylJ^-benzylamino-S-cyclohexyl-S-fl-phenylethylJ-l^-dihydroSH- l,3,4-benzotriazepin-2-one was obtained using step d of example 1, except that 7- benzylamino-l-(4-nitrophenyl)-5-cyclohexyl-3-(l-phenylethyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazeρin-2-one. 1H ΝMR (CDCl3) 7.38-7.18 (HH, m), 7.11 (2H, d), 6.60 (2H, d), 6.56 (2H, m), 6.46 (IH, br), 5.25 (IH, br s), 4.31 (2H, br s), 4.0-3.75 (2H, m),
2.61 (IH3 m), 1.75 (9H, m), 1.25 (4H, m).
Step g The title compound was obtained using steps a and b of example 71 except that l-(4- aminophenyl)-7-benzylamino-5-cyclohexyl-3-(l-phenylethyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and tert-butoxycarbonyl Z-valine were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and and tert- butoxycarbonyl glycine respectively. 1H NMR (DMSO-d6) 10.81 (IH, br s), 8.33 (3H, br s), 7.57 (2H, m), 7.25 (HH, m), 6.70 (2H, m), 6.50 (IH, d), 5.08 (IH, br s), 4.28 (2H, m), 2.72 (IH, br s), 2.19 (IH, m), 1.85-1.05 (13H, m), 0.98 (6H, m). Found: C 64.35, H 6.87, N 11.17%; C4oH46N602-2.8HCl requires C 64.59, H 6.61, H 11.30%.
Example 196 5-Cyclohexyl-3-(6, 7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-l-(4-((lH- imidazol-2-ylmethyl)-amino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
Step a Nr-(5,6,8,9-tetrahydrobenzo[7]annulen-7-yl)hydrazinecarboxylic acid tert-butyl ester was obtained using step a of example 52 except that 5,6,8,9-tetrahydrobenzo[7]anmιlen-7-one was used in place of cycloheptanone.
Step b 5-Cyclohexyl-3-(6, 7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-l ,2-dihydro-l ,3,4- benzotriazepin-2-one was obtained using step c of of example 181 except that N'-(5,6,8,9- tetrahydrobenzo[7]annulen-7-yl)hydrazinecarboxylic acid tert-butyl ester and (2- aminophenyl)cyclohexylmethanone were used in place of N'-(3,3,5,5-tetramethyl-cyclohexyl)- hydrazinecarboxylic acid tert-butyl ester and (2-amino-4-methyl-phenyl)tetrahydro-pyran-4- ylethanone respectively.
Step c 5-Cyclohexyl-l-(4-amino-phenyl)-3-(6, 7 ,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-l ,2- dihydro-l, 3, 4-benzotriazepin-2-one was obtained using steps c and d of example 1 except that 5-cyclohexyl-3-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-l,2-dihydro-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.33-7.08 (9H, m), 6.75 (IH, d), 6.65 (2H, d), 4.09 (IH, m), 3.69 (2H, s), 2.71 (5H, m), 1.83-0.89 (14H, m).
Step d The title compound was obtained using step a of example 128, except that 5- cyclohexyl- 1 -(4-amino-phenyl)-3 -(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)- 1 ,2-dihydro- l,3,4-benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of 1 -(4-amino-phenyl)-3 -benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-ρhenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.32-7.10 (1OH, m), 6.98 (IH, s), 6.74 (IH, d), 6.52 (2H, d), 4.35 (IH, br s), 4.29 (2H, m), 4.07 (IH, m), 2.75 (4H, m), 2.39 (IH, m), 1.79-1.23 (14H, m). The compound was further characterised and tested as the HCl salt. Found: C 60.58, H 5.93, N 11.37%; C35H38N6O-2HCl-0.3 dioxan-0.9 CH2Cl2 requires: C 60.66, H 6.06, N 11.44%. Example 197 3-(Biphenyl-2-ylmethyl)-5-cyclohexyl-8-methyl-l-(4-(2-(lH-imidazol-2-yl)- ethylamino) -phenyl) -1 ,2-dihydro-3H-l , 3, 4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- 3-(biphenyl-2-ylmethyl)-5-cyclohexyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 190, step a) and (l-trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4- amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.27-7.11 (1OH, m), 7.03 (2H, d), 6.93 (IH, d), 6.92 (2H, s), 6.60 (IH, s), 6.47 (IH, d), 5.02 (IH, br s), 4.40 (IH, br s), 3.40 (2H, t), 2.85 (2H, t), 2.66 (IH, m), 2.24 (3H, s), 1.80-1.24 (1OH, m). The compound was further characterised and tested as the HCl salt. Found: C 66.83, H 6.49, N 11.64%; C39H4oN60-2.5HCl requires C 66.92, H 6.12, N 12.01%.
Example 198 5-Cyclohexyl-8-methoxy-l-(4-((lH-imidazol-2-ylmethyl)-amino)-phenyl)-3- (3, 3, 5, 5-tetramethyl-cyclohexyl)-l ,2-dihydro-3H-l ,3, 4-benzotriazepin-2-one Step a (2-Amino-4-methoxyphenyl)cyclohexylmethanone was obtained using step b of example 181 except that cyclohexanecarbonitrile and 3 -methoxy aniline were used in place of tetrahydro-pyran-carbonitrile and m-toluidine respectively. 1H NMR (CDCl3) 7.71-6.07 (3 H, m), 6.43 (2H, br s), 3.80 (3H, s), 3.20 (IH, m), 1.87-1.24 (1OH, m).
Step b 5-Cyclohexyl-8-methoxy-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using step c of of example 181 except that (2-amino-4- methoxyphenyl)cyclohexylmethanone was used in place of (2-amino-4-methyl- phenyl)tetrahydro-pyran-4-ylmethanone. 1H NMR (CDCl3) 7.27-7.24 (IH, m), 6.65-6.62 (IH, dd), 6.33 (IH, d), 6.27 (IH, s), 4.34-4.24 (IH, m), 3.80 (3H, s), 2.70-2.62 (IH, m), 1.83-1.72 (5H, m), 1.56-1.20 (1OH, m), 1.10-1.06 (7H, m), 0.93 (6H, s). Step c l-(4-Amino-phenyl)-5-cyclohexyl-8-methoxy-3-(3,3,5,5-tetrωnethyl-cyclohexyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps c and d of example 1, except that 5-cyclohexyl-8-methoxy-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c. 1H NMR (CDCl3) 1.21-125 (IH, m), 7.20-7.16 (2H, m), 6.68- 6.63 (3H, m), 6.27 (IH, d), 4.21-4.17 (IH, m), 3.67 (2H, br s), 3.65 (3H, s), 2.79-2.72 (IH, m), 2.02-0.90 (28H, m).
Step d The title compound was obtained using step a of example 128, except l-(4-amino- phenyl)-5-cyclohexyl-8-methoxy-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of 1- (4-amino-phenyl)-3 -benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCI3) 9.40 (IH, br s), 7.28-7.17 (3H, m), 7.00 (2H, s)5 6.67 (3H, m), 6.26 (IH, d), 4.42-4.40 (3H, m), 4.20-4.10 (IH, m), 3.66 (3H, s), 2.76-2.72 (IH, m), 2.05-0.83 (28H, m). The compound was further characterised and tested as the HCl salt. Found: C 64.89, H 7.77, N 12.41%; C35H46N6O2- 1.6HCl-0.5C4H8O2 requires C 64.86, H 7.59, N 12.27%.
Example 199 7~Benzylamino-5-cyclohexyl-3-(l-phenyl-ethyl)-l-(4-((lH-imidazol-2-ylmethyl)- amino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that l-(4-aminophenyl)- 7-benzylamino-5-cyclohexyl-3 -(I -phenylethyl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one (example 195, step f) and l-trityl-lH-imidazol-2-carboxaldehyde were used in place of l-(4- amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-cyclodecyl-5- cyclohexyl-7,8-dimethyl-l-(4-((l-trityl-lH-imidazol-2-yhnethyl)-amino)-phenyl)-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one, according to step e of example 193. The compound was further characterised and tested as the HCl salt. 1H NMR (DMSO-d6) 14.31 (IH, br s), 7.56 (2H, s), 7.25 (12H, m), 6.95 (2H, m), 6.60 (4H5 m), 6.45 (IH, d), 5.00 (IH, br s), 4.58 (2H, s), 4.18 (2H, s), 2.68 (IH, m), 1.8-1.1 (13H, m). Found: C 64.66, H 6.34, N 12.45%; C39H41N7O- 2.5HCl-0.6C4H8O2 requires C 4.76, H 6.34, N 12.77%.
Example 200 l-(4-((lH-Imidazol-2-yhnethyl)-amino)-phenyl)-8-methyl-5-(tetrahydro-pyran-4- yl)-3-(3, 3, 5, 5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except l-(4-amino-phenyl)-8- methyl-5-(tetrahydro-pyran-4-yl)-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (Example 181, step d) and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N)N-bis-(fe?-t-butoxycarbonyl)-N'-(4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro- 3H-l,3,4-benzotriazepin-l-yl)-phenyl)-guanidine, according to step f of example 1. 1H NMR (CDCl3) 7.22 (IH, d), 7.17 (2H, d), 6.99 (2H, s), 6.92 (IH, d), 6.58 (3H, m), 4.40 (3H, m), 4.17-4.08 (3H, m), 3.53 (2H, t), 3.06 (IH, m), 2.22 (3H, s), 1.80-0.89 (22H, m). The compound was further characterised and tested as the HCl salt. Found: C 62.76, H 7.32, N 12.75 %; C34H44N6O2^JHCl requires: C 62.71, H 7.16, N 12.91%
Example 201 5-Cyclohexyl-8-methyl-l-(4-(3-(lH-imidazol-2-yl)propylamino)-phenyl)-3- (3, 3, 5, 5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
Step a 3-(l-Trityl-lH-imidazole-2-yl)-acrylic acid ethyl ester
A solution of l-trityl-lH-imidazole-2-carbaldehyde (25.Og, 73.9mmol) and (carbethoxymethylene)tripnenylphosphorane (30.9g, 88.7mmol) in TΗF (400 niL) was heated at reflux for 16 h. The solvent was evaporated and the residue was purified by chromatography (hexane-EtOAc (7:3)) to afford the product (17.8g, 59%). 1H NMR (CDCl3) 7.33 (9H, m), 7.15-7.02 (7H, m), 6.87 (IH, s), 6.69 (IH, d), 6.52 (IH, d), 4.00 (2H, q), 1.32 (3H, t).
Step b 3-(l-Trityl-lH-imidazole-2-yl)-propionic acid ethyl ester To a solution of 3-(l-trityl-lH-imidazole-2-yl)-acrylic acid ethyl ester (17.8g, 43.55mmol) in TΗF (500 mL) was added palladium on charcoal (10%, 2.Og) and the mixture was stirred under hydrogen for 6h. The reaction mixture was filtered through Celite and the filtrate evaporated. Column chromatography (hexane-EtOAc (7:3-6:4)) of the residue afforded the product (9.76g, 54%). 1HNMR (CDCl3) 7.35-7.30 (9Η, m), 7.17-7.12 (6H, m), 6.94 (IH, s), 6.73 (IH, s), 4.01 (2H, q), 2.30-2.25 (2H, m), 2.20-2.14 (2H, m), 1.16 (3H, t).
Step c 3-(l-Trityl-lH-imidazole-2-yl)-propionic acid
To a solution of 3-(l-trityl-lH-imidazole-2-yl)-propionic acid ethyl ester (9.76g, 23.8mmol) in EtOH (150 mL) was added 2N NaOH (20 mL) and the solution was heated at reflux for 2h. After cooling the solvent was evaporated, the residue was taken up in H2O (5 mL) and acidified to pH=5 by the addition of 5% KHSO4. The mixture was extacted with DCM (100 mL), the organic phase was washed with H2O (100 mL), brine (100 mL), and dried (MgSO4). Filtration and evaporation of the the solvent was afforded the product (9.08g, 100%). 1H NMR (CDCl3) 12.6-10.8 (IH, br s), 7.36 (9H, m), 7.13-7.06 (6H, m), 6.96 (IH, s), 6.76 (IH, s), 2.31 (2H, m), 2.15 (2H, m). Step d N-Methoxy-'N-methyl-3-(l-trityl-lH-imidazol-2-yl)-propionamide
To a solution of 3-(l-trityl-lH-imidazole-2-yl)-propionic acid (9.07g, 23.7mmol), N5O- dimethyl-hydroxylamine HCl (2.3 Ig, 23.7 mmol) and diisopropylethylamine (4.54 mL, 26.07mmol) in DCM (150 mL) were added EDC (4.55g, 23.7mmol) and ΗOBt (3.2Og, 23.7 mmol) and the reaction mixture was stirred at room temperature for 16h. The reaction mixture was washed with H2O (100 mL), 5% KHSO4 (100 mL), saturated aqueous NaHCO3 (100 mL), brine (100 mL) and dried (MgSO4). Filtration and evaporation of the the solvent gave the crude product which was purified by chromatography (MeOH-DCM (1:20-1:10) to afford the product (3.6Og, 36%). 1H NMR (CDCl3) 7.32 (9H, m), 7.15 (6H, m), 6.96 (IH, s), 6.74 (IH, s), 3.58 (3H, s), 3.05 (3H, s), 2.40 (2H, m), 2.22 (2H, m).
Step e 3-(l-Trityl-lH-imidazole-2-yl)-propionaldehyde
A solution of N-methoxy-N-methyl-3-(l-trityl-lH-imidazol-2-yl)-propionamide (3.6Og, 8.46mmol) in TΗF (40 mL) was added over 5 mins to a suspension of LiAlH4 (0.44g, 11.6mmol) in THF (60 mL) at 00C. The reaction mixture was stirred at O0C for 30 mins, then at room temperature for Ih. The reaction mixture was cooled to 00C and 2N NaOH (2.4 mL) was slowly added. The solid that formed was removed by filtration and the filtrate evaporated. The residue obtained was suspended in EtOAc (60 mL), washed with 5% KHSO4 (60 mL), saturated NaHCO3 (60 mL), brine (60 mL) and dried (MgSO4). Filtration and evaporation of the the solvent gave the crude product which was purified by chromatography (MeOH- DCM (1:50)) to afford the product (1.17g, 38%). 1H NMR (CDCl3) 9.55 (IH, s), 7.35-7.10 (15H, m), 6.94 (IH, s), 6.75 (IH, s), 2.40 (2H, m), 2.20 (2H, m).
Step f The title compound was obtained using step a of example 128, except that l-(4-amino- phenyl)-5-cyclohexyl-8-methyl-3-(3,3,5,5-tetramethyI-cycIohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 106, step b) and 3-(l-trityl-lH-imidazol-2-yl)-propionaldehyde were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.23 (IH, d), 7.13 (2H, d), 6.93-6.88 (3H, m), 6.57 (IH, s), 6.48 (2H, d), 4.15 (IH, m), 3.13 (2H, t), 2.74 (3H, m), 2.20 (3H, s), 1.99-0.89 (3OH, m). The compound was further characterized and tested as the HCl salt. Found: C 63.17, H 7.71, N 11.77%; C37H50N6O-3HCl requires: C 63.07, H 7.58, N 11.93%.
Example 202. 5-Cyclohexyl-l-(4-((lH-imidazol-2-ylmethyl)-ωnino)-benzyl)-8-methyl-3- (3, 3, 5, 5-tetramethyl-cyclohexyl) -1, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
Step a 2-(4-(5-Cyclohexyl-8-methyl-2-oxo-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydrθ'3H- l,3,4-benzotriazepin-l-ylmethyl)-phenyl)-isoindole-l,3-dione was obtained using step c of example 20, except that 5-cyclohexyl-8-methyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one (example 106, step a) and 2-(4-bromomethyl-phenyl)- isoindole-l,3-dione (Glen, Robert C; Martin, Graeme R.; Hill, Alan P.; Hyde, Richard M.; Woollard, Patrick M.; et al., J. Med. Chem. (1995), 38(18), 3566-3580) were used in place of 5 -cyclohexyl- 1 -(4-nitrophenyl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and (3 - bromopropenyl)-benzene. 1H NMR (CDCl3) 7.94 (2H, m), 7.77 (2H, m), 7.39-7.20 (5H, m), 6.90 (2H, d), 5.29 (IH, d), 4.66 (IH, d), 4.20 (IH, m), 2.73 (IH, m), 2.31 (3H, s), 1.97-0.89 (28H, m).
Step b l-(4-Amino-benzyl)-5-cyclohexyl-8-methyl~3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one. 2-(4-(5-Cyclohexyl-8-methyl~2-oxo-3-(3,3,5,5- tetramethyl-cyclohexyl)- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin- 1 -ylmethyl)-ρhenyl)-isoindole- 1,3-dione (319mg, 0.50mmol) and hydrazine hydrate (250mg, 5.0mmol) were stirred in EtOH at 80 0C for 5h. After cooling, the white solid precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was suspended in chloroform and the white precipitate was again removed by filtration. The filtrate was concentrated in vacuo to afford a white solid (210 mg, 83%). 1H NMR (CDCl3) 7.14 (2H, d), 7.01 (2H, d), 6.87 (2H5 m), 6.50 (2H, d), 5.12 (IH, d), 4.19 (IH, m), 3.57 (2H, brm), 2.70 (IH, m), 2.31 (3H, s), 1.97-0.98 (28H, m).
Step c. The title compound was obtained using step a of example 128, except l-(4-amino- benzyl)-5-cyclohexyl-8-methyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and (l~trityl-lH-imidazol~2-yl)-carboxaldehyde were used in place of 1- (4-amino-phenyl)-3 -benzyl-5 -cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyI)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step b of example 39. 1HNMR (CDCl3) 7.16 (IH, d), 7.04- 7.00 (4H, m), 6.86 (2H, s), 6.48 (2H, d), 5.10 (IH, d), 4.50 (IH, d), 4.40 (2H, s), 4.17 (2H, m), 2.71 (IH, m), 2.28 (3H, s), 1.94-0.85 (28H, m). Found: C 73.09, H 8.10, N 14.05%; C36H48N6O-O-S H2O requires: C 73.30, H 8.37, N 14.24%.
Example 203 5-Cyclohexyl-9-methyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l-(4-(2-(lH-imidazol- 2-yl)-ethylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
Step a (2-Amino~3-methylphenyl)(cyclohexyl)methanone was obtained using step b of example 181 except that cyclohexanecarbonitrile and 2-methylaniline were used in place of tetrahydro- pyran-carbonitrile and λrø-toluidine respectively.
Step b 5-Cyclohexyl-9-methyl-3-(3, 3, 5, 5-tetramethyl-cyclohexyl)-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step c of of example 181 except that (2-amino-3- methylphenyl)(cyclohexyl)methanone was used in place of (2-amino-4-methyl- phenyl)(tetrahydro-pyran-4-yl)-methanone. 1H NMR (dδ-DMSO) 7.94 (IH, s), 7.32-7.25 (2H, m), 7.04-6.99 (IH, m), 4.07-3.99 (IH, m), 2.84 (IH, br s), 2.26 (3H, s), 1.73-1.60 (5H, m), 1.43-1.08 (1OH, m), 1.01-0.87 (13H, m).
Step c l-(4-Amino-phenyl)-5-cyclohexyl-9-methyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps c and d of example 1, except that 5-cyclohexyl-9-methyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3~benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.29-7.16 (5H, m), 6.57-6.54 (2H, m), 4.20- 4.14 (IH, m), 3.52 (2H, br s), 2.96-2.88 (IH, m), 2.05-0.85 (3 IH, m). Step d The title compound was obtained using step a of example 128, except l-(4-amino- phenyl)-5-cyclohexyl-9-methyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-acetaldehyde (Synlett, (1999), 12, 1875) were used in place of l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-ρhenyl)-l,2- dihydro-3H-l,3j4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 9.40 (IH ,br s), 7.33-7.16 (5H, m), 6.96 (2H , s), 6.54 (2H, d), 4.17-4.09 (2H, m), 3.49 (2H, t), 3.03-2.88 (3H, m), 1.96-0.85 (31H, m). The compound was further characterised and tested as the HCl salt. Found: C 63.80, H 7.50, N 11.96%; C36H48N6O^JSHCl requires C 63.49, H 7.51, N 12.34%.
Example 204 5-Cyclohexyl-l-(3-((lH-imidazol-2-ylmethyl)-amino)-phenyl)-3-(3 ,3 ,5 ,5- tetramethyl-cyclohexyl)- 1, 2-dihydro-3H-l, 3, 4-benzotria∑epin-2-one
Step a. 5-Cyclohexyl-l-(3-ωnino-phenyl)-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-l,3,4- benzotriazepin-2-one was made using steps c and d of example 1 except that 5-cyclohexyl-3- (3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-l,3,4-benzotriazepin-2-one and 3- iodonitrobenzene were used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and 4-iodonitrobenzene respectively in step c. 1H NMR (CDCl3) 7.37 (2H, d), 7.23-7.06 (2H, m), 6.93 (IH, s), 6.84 (IH, d), 6.64 (IH, d), 6.57 (IH, d), 4.19 (IH, m), 3.68 (2H, brm), 2.84 (IH, m), 1.86-0.82 (28H, m). Step b. The title compound was obtained using step a of example 128, except 5-cyclohexyl-l- (3-amino-phenyl)-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-l,3,4-benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of l-(4-amino-phenyl)-3~ benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5- dihydro- lH-imidazol-2-ylamino)-phenyl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (DMSO-d6) 14.0 (IH5 brs), 7.59-7.13 (7H, m), 6.74 (IH, m), 6.50 (2H, m), 6.64 (IH, d), 4.57 (2H, s), 4.01 (IH, m), 2.97 (IH, m), 1.90-0.83 (28H, m). The compound was further characterised and tested as the HCl salt. Found: C 66.40, H 7.47, N 12.57%; C34H44N6O-1.4HC1-0.7 dioxan requires: C 66.41, H 7.72, N 12.63%.
Example 205 5-Cyclohexyl-8-methyl-l-(4-((lH-imidazol-2-ylmethyl)-amino)-phenyl)-3-(cvs-4- phenyl-cyclohexyl)- 1, 2-dihydro-3H-l, 3, 4-henzotriazepin-2-one
Step a 5-Cyclohexyl-8-methyl-3-(cis-4-phenyl-cyclohexyl)-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step c of example 181, except that (2-amino-4- methyl-phenyl)(cyclohexyl)methanone (Example 11 step a) and iV-(cis-4-phenyl-cyclohexyi)- hydrazinecarboxylic acid tert-butyl ester were used in place of (2-amino-4-methyl- phenyl)(tetrahydro-pyran-4-yl)methanone and iV -(3 ,3 , 5 ,5 -tetramethyl-cyclohexyl)- hydrazinecarboxylic acid tert-butyl ester respectively. 1H NMR (CDCl3) 7.27-7.13 (6H, m), 6.95 (IH, d), 6.62 (IH, s), 6.20 (IH, s), 4.22 (IH, m), 2.78 (IH, m), 2.69-2.62 (IH, m), 2.35 (3H, s), 2.23-2.19 (2H, m), 1.86-1.55 (HH, m), 1.42-1.23 (5H, m).
Step b l-(4-Amino-phenyl)-5-cyclohexyl-8-methyl-3-(cis-4-phenyl-cyclohexyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one was obtained using steps c and d of example 1, except that 5- cyclohexyl-8-methyl-3-(cw-4-phenyl-cyclohexyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.32-7.27 (IH, m), 7.14-7.00 (6H, m), 6.81-6.78 (2H, m), 6.78-6.64 (3H, m), 4.17-4.12 (IH, m), 3.69 (2H, br s), 2.81 (IH, m), 2.52 (IH, m), 2.35-2.28 (5H, m), 1.87- 1.24 (16H, m).
Step c The title compound was obtained using step a of example 128, except l-(4-amino- phenyl)-5-cyclohexyl-8-methyl-3-(cw-4-phenyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of 1- (4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 1H NMR (CDCl3) 9.40 (IH, br s), 7.32-7.29 (IH, m), 7.16-7.01 (8H, m), 6.79-6.77 (2H, m), 6.64-6.56 (3H, m), 4.40 (3H, m), 4.13 (IH, s), 2.81 (IH, m), 2.52 (IH, m), 2.37-2.21 (5H, m), 1.84-1.30 (16H, m). The compound was further characterised and tested as the HCl salt. Found: C 67.29, H 6.71, N 12.50%; C37H42N6O^OHCl requires C 67.36, H 6.72, N 12.74%. Example 206 5-Cyclohexyl-8-nιethylA-(4-((lE4midazol-2-ylmethyl)-amino)-phenyl)-3-(\xwas,- 4-phenyl-cyclohexyl)- 1 ,2-dihydro-3H-l ,3,4-benzotriazepin-2~one
Step a 5-CycIohexy!-8~methy!-3-(t!cans-4-phenyl-cyclohexyl)-l, 2-dϊhydro-3H-l, 3, 4- benzotriαzepin-2-one was obtained using step c of example 181, except that (2-amino-4- methyl-phenyl)(cyclohexyl)methanone (Example 11 step a) and N-(frvms-4-phenyl- cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester were used in place of (2-amino-4-methyl- phenyl)(tetrahydro-pyran-4-yl)methanone and JV-(3,3,5,5-tetramethyl-cyclohexyl)- hydrazinecarboxylic acid tert-butyl ester respectively. 1H ΝMR (CDCl3) 7.32-7.18 (6H, m),
6.92 (IH, d), 6.62 (IH, s), 4.06-4.02 (IH, m), 2.75-2.68 (IH, m), 2.54-2.50 (IH, m), 2.34 (3H, s), 2.05-1.25 (18H, m).
Step b l-(4-Amino-phenyl)-5-cyclohexyl-8-methyl-3-(trans-4-phenyl-cyclohexyl)-l,2-dihydro- 3H-1 ,3,4-benzotriαzepin-2-one was obtained using steps c and d of example 1, except that 5- cyclohexyl-8-methyl-3-(trα«j'-4-phenyl-cyclohexyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H ΝMR (CDCl3) 7.31-7.17 (8H, m), 6.92 (IH, d), 6.68-6.65 (2H, m), 6.56 (IH5 s), 3.92-3.84 (IH, m), 3.69 (2H, br s), 2.82 (IH, m), 2.56-2.48 (IH, m), 2.21-1.19 (21H, m).
Step c The title compound was obtained using step a of example 128, except l-(4-amino- phenyl)-5-cyclohexyl-8-methyl-3 -(tfrørø-4-phenyl-cyclohexyl)- 1 ,2-dihydro-3H- 1 ,3,4- benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of 1- (4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyI)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step b of example 39. 1H ΝMR (CDCl3) 9.40 (IH, br s), 7.30-7.14 (8H, m), 6.99 (2H, s), 6.99-6.90 (IH, d), 6.59-6.55 (3H, m), 4.39 (3H, br s), 3.87 (IH, m), 2.81 (IH, m), 2.56-2.48 (IH, m), 2.21-1.25 (21H, m). The compound was further characterised and tested as the HCl salt. Found: C 67.73, H 6.80, Ν 12.66%; C37H42N6O- 1.93HCl requires C 67.63, H 6.74, N 12.79%.
Example 207 8-Chloro-5-cyclohexyl-l~(4-((lH-imidαzol-2-ylmethyl)~αmino)-phenyl)-3~ (3, 3, 5, 5-tetrαmethyl-cyclohexyl)-l, 2-dihydro-3H-l, 3, 4-benzotriαzepin-2-one Step a (2-Amirιo-4-chloro-phenyl)-cyclohexyl-methanone was obtained using step b of example 181 except that cyclohexanecarbonitrile and 3-chloroaniline were used in place of tetrahydro- pyran-carbonitrile and m-toluidine respectively. 1H NMR (CDCl3) 7.68 (IH, d), 6.66-6.59 (2H, m), 6.37 (2H, br m), 3.21 (IH, m), 1.87-1.73 (5H, m), 1.57-1.24 (5H, m). Step b 8-Chloro-5-cyclohexyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benztriazepin-2-one was obtained using step c of example 181, except that (2-amino-4-chloro- phenyl)-cyclohexyl-methanone was used in place of (2-amino-4-methyl-phenyl)(tetrahydro- pyran-4-yl)methanone. 1H NMR (DMSO-d6) 8.93 (IH5 s), 7.51 (IH, d), 7.15-7.09 (2H, m), 4.12 (IH, m), 2.81 (IH, m), 1.75-1.65 (5H, m), 1.45-1.15 (1OH, m), 1.10-0.80 (13H, m). Step c 8-Chloro-5-cyclohexyl-l-(4-nitro-phenyl)-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one. A mixture of 8-chloro-5-cyclohexyl-3-(3,3,5,5- tetramethyl-cyclohexyl)-l52-dihydro-3H-l,3,4-benztriazepin-2-one (2.41g, 5.8mmol), 4- fluoronitrobenzene (899mg, 6.4mmol) and K2CO3 (2.4Og, 17.4mmol) in DMF (45mL) was stirred at 700C for 6 hr. The reaction mixture was diluted with EtOAc (25OmL) and was washed with 2M HCl (3 x 10OmL) and brine (10OmL). The organic phase was dried with MgSO4, filtered and the solvent was removed at reduced pressure. The residue was purified by chromatography (DCM-hexane (3:5)) to afford the title compound (1.66g, 53%). 1H NMR (CDCl3) 8.17 (2H, d), 7.52 (2H, d), 7.42 (IH, d), 7.32 (IH, d), 6.94 (IH, s), 4.29 (IH, m), 2.88 (IH, m), 2.00-1.65 (8H, m), 1.45-0.80 (2OH, m). Step d l-(4-Amino-phenyl)-8~chloro-5-cyclohexyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step d of example 1, except that 8- chloro-5-cyclohexyl-l-(4-nitro-phenyl)-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitro-phenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (CDCl3) 7.26 (IH, d), 7.16-7.12 (2H, m), 7.05 (IH, dd), 6.74 (IH, s), 6.68-6.64 (2H5 m), 4.17 (IH, m), 3.73 (2H, br s), 2.76 (IH, m), 1.98-1.50 (8H, m), 1.50-0.80 (20H5 m).
Step e The title compound was obtained using step a of example 128, except that l-(4-amino- phenyl)-8-chloro-5-cyclohexyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of 1- (4-amino-ρhenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl- 1 -(4-(4,5-dihydro- 1 H-imidazol-2-ylamino)-phenyl)- 1 ,2-dihydro-3H-l ,3 ,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (DMSO-d6) 11.85 (IH, br s), 7.59 (IH, d), 7.21 (IH, d), 7.01 (2H, d), 6.90 (2H, s), 6.67-6.63 (3H, m), 6.24 (IH, m), 4.23 (2H, d), 4.01 (IH, m), 2.49 (IH, m), 2.05-1.45 (8H, br m), 1.45-1.10 (7H, m), 1.10-0.80 (13H, m). The compound was further characterised and tested as the HCl salt. Found: C 61.04, H 6.77, N 12.38%; C34H43N6OCl^HCl-O-SH2O requires: C 61.03, H 6.93, N 12.56%.
Example 208 2-Amino-N-(4-(5-cyclohexyl-9-methyl-2-oxo-3-(3,3,5,5-tetramethyl-cyclohexyl)- l,2-dihydro-3H~l,3,4-benzotriazepin-l-yl)~phenyl)-3-methyl-butyramide The title compound was obtained using step a of example 71, except that l-(4-amino-phenyl)- 5-cyclohexyl-9-methyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 203, step c) and tert-butoxycarbonyl L-valine were used in place of l-(4-aminophenyl)-3-benzyI-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of N,N'-bis-(tert-butoxycarbonyl)-N"-(4-(3-ben2yl-5-cyclohexyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl)-phenyl)-guanidine, according to step f of example 1. 1H NMR (DMSO-d6 10.64 (IH, br s), 8.26 (3H, br s), 7.55-7.48 (3H, m), 7.41-7.33 (2H, m), 7.14-7.12 (2H, m), 4.10-4.06 (IH, m), 3.77-3.75 (IH, m), 3.12-3.05 (IH, m), 2.14 (IH, m), 1.86-0.81 (37H, m). Found: C 68.98, H 8.49 N 11.12%; C36H51N5O2-LIlHCl requires C 69.04, H 8.39, H 11.18%.
Example 209 5-Cyclohexyl-8-methyl-l-(4-(2-(lH-imidazol-2-yl)-ethyIamino)-phenyl)-3~(trans- 4-phenyl-cyclohexyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)-5-cyclohexyl-8-methyl- 3-(trαrø-4-phenyl-cyclohexyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 206 step b) and (l-trityl-lH-imidazol-2-yl)-acetaldehyde (Synlett, (1999), 12, 1875) were used in place of l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 9.20 (IH, br s), 7.33-7.14 (8H, m), 6.97-6.90 (3H, m), 6.61-6.57 (3H, m), 4.19 (IH, br s), 3.88 (IH, m), 3.54- 3.50 (2H, m), 3.00-2.95 (2H, m), 2.82-2.78 (IH, m), 2.56-2.48 (IH, m), 2.28-1.27 (21H, m). The compound was further characterised and tested as the HCl salt. Found: C 67.38, H 7.01, N 12.26%; C38H44N6O-2.1HC1 requires C 67.38, H 6.86, N 12.41%.
Example 210 8~Chloro-5-(^clohexyl-l-(4-(2-(lH-imidazol-2-yl)-eihylamino)-phenyl)-3- (3, 3, 5, 5-tetramethyl-cyclohexyl)-! , 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
Step a 8-Chloro-5-cyclohexyl-3-(3,3,5,5~tetramethyl-cyclohexyl)-l-(4-(2-(l-trityl-lH-imidazol- 2-yl)-ethylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
The title compound was obtained by example 207 step e except that (l-trityl-lH-imidazol-2- yl)-acetaldehyde was used in place of l-trityl-lH-imidazole-2-carbaldehyde. 1H NMR (CDCl3) 7.32-7.24 (1OH, m), 7.14-7.05 (9H, m), 6.98 (IH, s), 6.75 (2H, m), 6.40 (2H, d), 4.55 (IH, m), 4.15 (IH, m), 2.96 (2H, t), 2.75 (IH, m), 2.20 (2H, t), 2.00-1.45 (8H, m), 1.45-1.20 (8H, m), 1.05 (6H, s), 0.91 (6H, s).
Step b A solution of 8-chloro-5-cyclohexyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l-(4-(2-(l- trityl- lH-imidazol-2-yl)-ethylamino)-phenyl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one (205mg) in 10% MeOH-HOAc (2mL) was heated at reflux for 9h. The mixture was diluted with EtOAc (2OmL) and was washed with saturated NaHCO3 solution (3 x 1OmL). The organic phase was dried with MgSO4, filtered and the solvent was removed at reduced pressure. The residue was purified by chromatography (MeOH-DCM (1:10)) to afford the title compound (99mg, 68%). 1H NMR (CDCl3) 7.27 (IH, m), 7.16 (2H, d), 7.06 (IH, d), 6.97 (2H, s), 6.75 (IH, s), 6.60 (IH, d), 4.16 (IH, br m), 3.53 (2H, t), 2.98 (2H, t), 2.76 (IH, br m), 2.10- 1.50 (8H, m), 1.50-0.80 (2OH, m). The compound was further characterised and tested as the HCl salt. LC-MS(ES) m/z: 601/603 (M+H)+, 623/625 (M+Na)+.
Example 211 5-Cyclohexyl-3-cyclooctyl-8-methyl-l-(4-((lH-imidazol-2-ylmethyl)-amino)- phenyl)-! ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one
Step a 5-Cyclohexyl-3-cyclooctyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step c of example 181, except that (2-amino-4-methyl- phenyl)(cyclohexyl)methanone (Example 11 step a) and N'-cyclooctyl-hydrazinecarboxylic acid tert-butyl ester were used in place of (2-amino-4-methyl~phenyi)(tetrahydro-pyran-4- yl)methanone and iV-(3,3,5,5-tetramethyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester respectively. 1H NMR (CDCl3) 7.23-6.62 (3H, m), 6.26 (IH, br s), 4.17 (IH, m), 2.67 (IH, m), 2.32 (3H, s), 2.0-1.1 (24H ,m).
Step b 5-Cyclohexyl-3-cyclooctyl-8-methyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one. 5-Cyclohexyl-3 -cyclooctyl-δ-methyl- 1 ,2-dihydro-3H- 1 ,3,4- benzotriazepin-2-one (2.54g, 7.44mmol) was dissolved in dry DMF (40 mL) and sodium hydride (60 % dispersion in mineral oil / 327mg, 8.2mmol) added. The mixture was stirred at rt for 2h and 4-fluoronitrobenzene (0.87mL, 8.2mmol) added. The mixture was stirred at rt overnight and the solvent evaporated. The residue was suspended in EtOAc (10OmL), washed successively with brine (2 x 10OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave a yellow gum which was recrystalised from EtOAc-hexanes (1 :9) to afford the product as a pale yellow crystals (2.02g, 79%). 1H NMR (CDCl3) 8.13-6.83 (7H, m), 4.22 (IH, m), 2.86 (3H, s), 2.26-1.00 (24H, m).
Step c 1-(4-Am ino-phenyl) S-cyclohexylS-cyclooctylS-methyl-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step d of example 1, except that 5-cyclohexyl-3- cyclooctyl-8-methyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one.
Step d The title compound was obtained using step a of example 128, except that l-(4-amino- phenyl)-5-cyclohexyl-3-cyclooctyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of l-(4-amino-phenyl)-3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5- dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3j4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 9.80 (IH, br s), 7.31-6.53 (9H, m), 4.46 (IH, br s), 4.34 (2H, br s), 4.02 (IH, m), 2.78 (IH5 m), 2.20 (3H, s), 2.10-1.20 (24H, m). The compound was further characterised and tested as the HCl salt. Found: C 61.73, H 7.00, N 12.66%; C33H42N6O-2.0HCl-0.49 DCM requires C 61.57, H 6.94, N 12.86%.
Example 212 5-Cyclohexyl-3-cyclononyl-8-methyl-l-(4-((lH-imidazol~2-ylmethyl)-amino)- phenyl)-! ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one
Step a N'-Cyclononylhydrazinecarboxylic acid tert-butyl ester was obtained using steps a of example 52, except that cyclononanone (Leonard, Schimelpfenig, J. Org. Chem. (1958), 23, 1708) was used in place of cycloheptanone.
Step b 5-Cyclohexyl-3-cyclononyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step c of example 181, except that (2-amino-4-methyl- phenyl)(cyclohexyl)methanone (Example 11 step a) and N'-cyclononylhydrazinecarboxylic acid tert-butyl ester were used in place of (2-amino-4-methyl-phenyl)(tetrahydro-pyran-4- yl)methanone and N-(3,3,5,5-tetramethyl~cyclohexyl)-hydrazmecarboxylic acid tert-butyl ester respectively. Step c 5-Cyclohexyl-3-cyclononyl-8-methyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using step b of example 211 except that 5-cyclohexyl-3- cyclononyl~8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 5- cyclohexyl-3-cyclooctyl-8-methyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one.
Step d l-(4-Amino-phenyl)-5-cyclohexyl-3-cyclononyl-8-methyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using step d of example 1, except that 5-cyclohexyl-3- cyclononyl-8-methyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one. Step e The title compound was obtained using step a of example 128, except that l-(4-amino- phenyl)-5-cyclohexyl-3-cyclononyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of l-(4-amino-phenyl)-3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,354-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl~l-(4~(4,5- dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 9.70 (IH, br s), 7.20-6.53 (9H, m), 4.39 (3H5 br s), 4.13 (IH , m), 2.78 (IH, m), 2.21 (3H, s), 2.10-1.25 (26H, m). The compound was further characterised and tested as the HCl salt. Found: C 62.80, H 7.24, N 12.66%; C34H44NeO-2.OHCl-O.39 DCM requires C 62.70, H 7.16, N 12.76%.
Example 213 5-Cyclohexyl-3-cycloundecyl-8-methyl-l-(4-((lH-imidazol-2-ylmethyl)-amino)- phenyl)-! ,2-dihydro-3H-l ,3, 4-benzotriazepin-2-one
Step a N'-Cycloundecanoylhydrazinecarboxylic acid tert-butyl ester was obtained using step a of example 52, except that cycloundecanone was used in place of cycloheptanone. Step b 5-Cyclohexyl-3-cycloundecanoyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step c of example 181, except that (2-amino-4-methyl- ρhenyl)(cyclohexyl)methanone (Example 11 step a) and N'- cycloundecanoylhydrazinecarboxylic acid tert-butyl ester were used in place of (2-amino-4- methyl-phenyl)(tetrahydro-ρyran-4-yl)methanone and iV-(3,3,5,5-tetramethyl-cyclohexyl)- hydrazinecarboxylic acid tert-butyl ester respectively.
Step c 5-Cyclohexyl-3~cycloundecanoyl-8-methyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using step b of example 211 except that 5-cyclohexyl-3- cycloundecanoyl-δ-methyl-l^-dihydro-SH-ljS^-benzotriazepin^-one was used in place of 5- cyclohexyl-3-cyclooctyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one. Step d l-(4-Amino-phenyl)-5-cyclohexyl-3-cycloundecanoyl-8-methyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using step d of example 1, except that 5-cyclohexyl-3- cycloundecanoyl-8-methyl-l -(4-nitro-phenyl)- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one. Step e The title compound was obtained using step a of example 128, except that l-(4-amino- phenyl)-5-cyclohexyl-3-cycloundecanoyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one and (l-trityl-lH-imidazol-2~yl)-carboxaldehyde were used in place of l-(4-amino-phenyl)~ 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5- dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 9.49 (IH, br s), 7.46-6.53 (9H, m), 4.40 (3H, br s), 4.05 (IH, m), 2.78 (IH, m), 2.21 (3H5 s), 2.10-1.10 (3OH, m). The compound was fUrther characterised and tested as the HCl salt. Found: C 66.79, H 7.80, N 12.26%; C36H48N6O-2.0HCl-0.25 Hexane requires C 66.70, H 7.99, N 12.45%.
Example 214 5-Cyclohexyl-3~cycloundecyl-8-methyl-l-(4-(2-(lH-imidazol-2-yl)-ethylamino)- phenyl)-l ,2-dihydro-3H-l , 3, 4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- 5-cyclohexyl-3-cycloundecanoyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 213, step d) and (l-trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4- amino-phenyl)-3 -benzyl-5 -cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3 -benzyl-5 - cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.35-6.54 (1OH, m), 4.06 (IH, m), 3.49 (3H, m), 2.91 (2H, m), 2.79 (IH, m), 2.20 (3H, s), 2.10-1.10 (3OH, m). The compound was further characterised and tested as the HCl salt. Found: C 65.20, H 7.78, N 11.90%; C37H5oN60-2.0HCl-0.25 DCM requires C 64.94, H 7.68, N 12.20%.
Example 215 5-Cyclohexyl-3-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-l-(4-((lH-imidazol- 2-ylmethyl)-amino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one Step a 5-Cyclohexyl-3-(2,2,6,6-tetramethyl-tetrahydro-pymn-4-yl)A,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using step c of example 181, except that (2-amino- phenyl)(cyclohexyl)methanone and iV-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)- hydrazinecarboxylic acid tert-butyl ester were used in place of (2-amino-4-methyl- phenyl)(tetrahydro-pyran-4-yl)methanone and iV-(3,3,5,5-tetramethyl-cyclohexyl)- hydrazinecarboxylic acid tert-butyl ester respectively. 1H NMR (CDCl3) 7.37-7.31 (2H, m), 7.11 (IH, t), 6.83 (IH, d), 6.29 (IH, s), 4.55-4.44 (IH, m), 2.77-2.69 (IH, m), 2.05-1.21 (26H, m).
Step b l-(4-Amino-phenyl)-5-cyclohexyl-3-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps c and d of example 1, except that 5-cyclohexyl-3-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4~ benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.36-7.34 (IH, m), 7.27-7.10 (3H, m), 6.79- 6.65 (4H, m), 4.42-4.32 (IH, m), 3.69 (2H, br s), 2.84-2.80 (IH, m), 2.05-1.22 (26H, m). Step c The title compound was obtained using step a of example 128, except l-(4-amino- phenyl)-5-cyclohexyl-3-(2,2,6,6-tetramethyI-tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of 1- (4-amino-phenyl)-3-benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-ρhenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCI3) 9.53 (IH, br s), 7.36-7.34 (IH, m), 7.26-7.08 (4H, m), 7.00 (2H, s), 6.77-6.75 (IH, m), 6.60-6.57 (2H, m), 4.41-4.31 (4H, m), 2.83 (IH, m), 2.05-1.22 (24H, m). The compound was further characterised and tested as the HCl salt. Found: C 63.46, H 7.38, N 12.92%; C33H42N7O2-UHCl-O^C4H8O2 requires C 63.39 H 7.23, N 12.82%.
Example 216 5-CyclohexylA-(4-((l-methylAH-imidazol-2-ylmethyl)-amino)ψhenyl)-8-methyl- 3-(3, 3, 5, 5~tetramethyl-cyclohexyl)-l , 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- 5-cyclohexyl-8-methyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 106, step b) and 1 -methyl- lH-imidazol-2-carbaldehyde (Alcalde, Ermitas; Alemany, Montserrat; Gisbert, Maria; Tetrahedron, (1996), 52 (48), 15171- 15188) were used in place of l-(4-aminophenyl)~3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 7.26-7.22 (3H, m), 6.99 (IH, s), 6.91-6.87 (2H, m), 6.70 (2H5 d), 6.57 (IH, s), 4.42 (IH, br s), 4.34 (2H, s), 4.15 (IH, m), 3.67 (3H, s), 2.87 (IH, m), 2.21 (3H, s), 1.86-0.82 (28H, m). The compound was further characterized and tested as the HCl salt. Found: C 64.74, H 7.56, N 12.14%; C36H48N6O- 2.5HC1 requires: C 64.38, H 7.58, N 12.51%.
Example 217 3-(l-Butyl~pentyl)-5-cyclohexyl-l-(4-((lH-imidazol-2-ylmethyl)-amino)-phenyl)- l,2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
Step a 3-(l-Bntyl-pentyl)-5-cyclohexyl-l,2-dϊhydro-3H-l,3,4-benzotnazepin-2-one was obtained using step c of example 181, except that (2-amino-4-methyl- phenyl)(cyclohexyl)methanone (Example 11 step a) and TV-(I -butyl-pentylhydrazinecarboxylic acid tert-butyl ester were used in place of (2-ammo-4~methyl-phenyl)(tetrahydro-pyran-4- yl)methanone and N'-(3,3,5,5-tetømethyI-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester respectively. 1H NMR (CDCl3) 7.34-7.30 (2H, m), 7.11-7.06 (IH, m), 6.80-6.77 (IH, m), 5.97 (IH, s), 4.15-4.05 (IH, m), 2.76-2.67 (IH, m), 1.84-0.80 (28H, m).
Step b l-(4-Amino-phenyl)-3-(l-butyl-pentyl)-5-cyclohexyl-l,2~dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using steps c and d of example 1, except that 3-(l-butyl- pentyl)-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.30-7.20 (4H, m), 7.08 (IH, m), 6.77 (IH, m), 6.67-6.62 (2H, m), 3.89-3.80 (IH5 m), 3.66 (2H, br s), 2.85-2.79 (IH, m), 2.12-0.78 (28H, m). Step c The title compound was obtained using step a of example 128, except l-(4-amino- phenyl)-3-(l -butyl-pentyl)-5-cyclohexyl~ 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one and (1 - trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of l-(4-amino-phenyl)-3-benzyI-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5~dihydro-lH- imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 9.50 (IH, br s), 7.35-7.19 (4H, m), 7.11-7.08 (IH, m), 6.99 (2H, s), 6.76 (IH, d), 6.59-6.56 (2H, m), 4.41 (3H, br s), 3.89-3.80 (IH, m), 2.85-2.78 (IH, m), 2.05-0.77 (28H, m). The compound was further characterised and tested as the HCl salt. Found: C 62.77, H 7.47, N 13.17%; C33H44N6O^.5HCl requires C 62.72 H 7.42, N 13.30%. Example 218 5-Cyclohexyl-3-cyclononyl-8-methyl-l-(4-(2-(lH-imidazol-2-yl)-ethylamino)- phenyl)-l, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- 5-cyclohexyl-3-cyclononoyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 212, step d) and (l-trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4-amino- phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl- 1 ~(4-(4,5-dihydro- lH-imidazol-2-ylamino)-phenyl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2- one, according to step b of example 39. 1H NMR (CDCl3) 7.31-6.50 (1OH, m), 4.14 (IH, m), 3.42-2.85 (4H, m), 2.75 (IH, m), 2.23 (3H, s), 2.20-1.25 (26H, m). The compound was further characterised and tested as the HCl salt. Found: C 65.58, H 7.51, N 12.07%; C35H46N6O- 1.8HC1-0.6 C4H8O2 requires C 65.55, H 7.74, N 12.26%.
Example 219 5-Cyclohexyl-3-cyclooctyl-8-methyl-l-(4-(2-(lH-imidazol-2-yl)-ethylamino)- phenyl)-l, 2-dihydro-3H-l,3, 4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- 5-cyclohexyl-3-cyclooctyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 211, step c) and (l-trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4-amino-phenyl)- 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5- dihydro- lH-imidazol-2-ylamino)-phenyl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.31-6.50 (1OH, m), 4.02 (IH, m), 3.42- 2.85 (4H, m), 2.75 (IH, m), 2.19 (3H, s), 2.20-1.25 (24H, m). The compound was further characterised and tested as the HCl salt. Found: C 61.33, H 6.98, N 11.62%; C34H44N6O- 3.0HC1-0.5 C4H8O2 requires C 61.23, H 7.28, N 11.90%. Example 220 5-Cyclohexyl-8-methyl-3-(tetrahydro-pyran-4yl)-(4-(2-(lH-imidazol-2-yl)- ethylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- 5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 182, step b) and (l-trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4- amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.25-6.52 (1OH, m), 4.05-3.41 (7H, m), 2.90 (2H, t), 2.77 (IH, m), 2.21 (3H, s), 2.20-1.25 (14H, m). The compound was further characterised and tested as the HCl salt. Found: C 56.18, H 6.25, N 12.27%; C31H38N6O2-S .7HC1-0.2 C4H8O2 requires C 56.23, H 6.43, N 12.37%.
Example 221 2-Amino-N-(4-(3-(l-benzyl-piperidin-4-yl)-5-cyclohexyl-8-methyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl)-3-methyl-butyramide
Step a l^-Amino-phenylJ-S-fl-benzyl-piperidin^-ylJ-S-cyclohexylS-methyl-l^-dihydro-SH- l,3,4-benzotriazepin-2-one was obtained using steps a and b of example 52, except that 1- benzyl-piperidin-4-one was used in place of cycloheptanone in step a and (2-amino-4-methyl- phenyl)-cyclohexyl-methanone (example 11, step a) was used in place of (2-aminophenyl)- cyclohexyl-methanone in step b. 1H NMR (CDCl3) 7.35-7.27 (7H, m), 7.12-7.07 (IH, m), 6.79
(IH, d), 6.05 (IH, br s), 3.95-3.92 (IH, m), 3.53 (2H, s), 2.94-2.88 (2H, m), 2.75-2.67 (IH, m), 2.13-2.04 (4H, m), 1.87-1.73 (7H, m), 1.54-1.24 (5H, m).
Step b The title compound was obtained using step a of example 71, except that tert- butoxycarbonyl .Z)-valine was used in place of tert-butoxycarbonyl glycine, followed by reaction of the product obtained, in place of N)N-bis-(fer/-butoxycarbonyl)-N'-(4-(3-benzyl-5- cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl)-guanidine, according to step f of example 1 .1H ΝMR (CDCl3) 11.40 ( IH , m ) , 9.94 ( IH , m ) , 8.60-6.40 (13H, m), 4.80 (2H, br m), 4.19 (2H, m), 3.98 (IH, s), 3.50 (IH, m), 3.40-0.90 (28H, m). The compound was further characterised and tested as the trifloroacetate salt. Found: C 53.98, H 5.27, Ν 8.43%; C38H48Ν6O2-2.9TFA-0.4 DCM requires C 53.87, H 5.29, N 8.53%. Example 222 5-Cyclohexyl-3-(6, 7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-8-methyl-l-(4- ((lH-imidazol-2-ylmethyl)-amino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
Step a 5-Cyclohexyl-8-methyl-3-(6, 7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one was obtained using step c of example 181, except that (2- amino-4-methyl-phenyl)(cyclohexyl)methanone (Example 11 step a) and N'-(5,6,8,9- tetrahydrobenzo[7]annulen-7-yl)hydrazinecarboxylic acid tert-butyl ester (example 196 step a) were used in place of (2-amino-4-methyl-phenyl)(tetrahydro-pyran-4-yl)methanone and N1- (3,3,5,5-tetramethyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester respectively.
Step b 5-Cyclohexyl-8-methyl-l-(4-amino-phenyl)-3-(6, 7,8,9-tetrahydro-5H-benzocyclohepten- 7-yl)-l,2-dihydro-l,3,4-benzotriazepin-2-one was obtained using steps c and d of example 1, except that 5-cyclohexyl-8-methyl-3-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.26-7.13 (5H, m), 6.90
(IH, d), 6.62 (IH, s), 6.18 (IH, s), 4.25 (IH, m), 2.83 (4H, m), 2.60 (IH, m), 2.33 (3H, s), 2.10 (2H, m), 1.86-1.19 (12H, m).
Step c The title compound was obtained using step a of example 128, except that 5-cyclohexyl- 8-methyl-l-(4-amino-phenyl)-3-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-l,2-dihydro- l,3,4-benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and foπnalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 9.50 (IH, br s), 7.35-7.19 (4H, m), 7.11-7.08 (IH, m), 6.99 (2H, s), 6.76 (IH, d), 6.59-6.56 (2H, m), 4.41 (3H, br s), 3.89-3.80 (IH, m), 2.85-2.78 (IH, m), 2.05-0.77 (28H, m). The compound was further characterised and tested as the HCl salt. 1H NMR (CDCl3) 7.27-7.10 (1 IH, m), 6.60 (3H, m), 4.47 (3H, m), 4.07 (IH, m), 2.76 (5H, m), 2.21 (3H, s), 1.96-1.24 (14H, m). Found: C 73.23, H 7.02, N 14.00%; C36H40N6O-IH2O requires: C 73.19, H 7.17, N 14.23%.
Example 223 5-Cyclohexyl-3-(6, 7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-8-methyl-l-(4-(2- (lH-imidazol-2-yl)-ethylamino)-phenyl)-l, 2-dihydro-3H-l , 3, 4-benzotriazepin-2-one The title compound was obtained using step a of example 128, except that 5-cyclohexyl-8- methyl- 1 -(4-amino-phenyl)-3 -(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)- 1 ,2-dihydro- l,3,4-benzotriazepin-2-one (example 222, step b) and (l-trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4-amino-phenyl)~3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-ρhenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.27-7.18 (8H, m), 6.98 (2H, m), 6.88 (IH, d), 6.63-6.56 (3H, m), 4.11 (IH, m), 4.07 (IH, m), 3.53 (2H5 m), 3.00 (2H, m), 2.76 (5H, m), 2.21 (3H, s), 1.80-1.27 (14H, m). Found: C 73.15, H 7.10, N 13.54%; C37H42N6O-IH2O requires: C 73.48, H 7.33, N 13.90%.
Example 224 5-Cyclohexyl-l-(4-(2-(lH-imidazol-2-yl)-ethylamino)-phenyl)-8-methyl-3- (pyridin-2-yl)-l ,2-dihydro-3H-l ,3 ' ,4-benzotriazepin-2-one
Step a. (2~amino-4-methyl-phenyl)-pyridin-2-yl-methanone. n-BuLi (1.6M in THF / 52mL, 84mmol) was added dropwise to a mixture of 2-amino-4-methylbenzonitrile (5g, 37.9mmol) and 2-bromopyridine (10.17g, 64.4mmol) in toluene (100 mL) at -5O0C. After stirring for Ih at -50 0C, the reaction mixture was allowed to warm to O0C then carefully added to 3N HCl (10OmL) whilst maintaining the temperature below 1O0C. The organic layer was separated and extracted with 3N HCl (10OmL). The combined acid extracts were carefully basified with a 25% NaOH solution (50OmL) and stirred overnight at 40C. The resulting brown precipitate was isolated by filtration, washed with H2O (3 x 30 mL) and dried to afford the product (7.2g, 90%). 1HNMR (DMSO-d6) 8.62 (IH, m), 7.96 (IH, m), 7.66 (IH, m), 7.52 (IH, m), 7.28 (3H, m), 6.63 (IH, m), 6.26 (IH, m), 2.20 (3H, s).
Step b 8-Methyl-5-pyridin-2-yl-3-(3, 3, 5, 5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l, 3, 4- benzotriazepin-2-one. was obtained using step c of example 181, except that (2-amino-4- methyl-phenyl)-pyridin-2-yl-methanone was used in place of (2-amino-4-methyl- phenyiχtetrahydro-pyran-4-yl)methanone. 1H NMR CDCl3 8.60 (IH, d), 7.99 (IH, d), 7.82 (IH, dt), 7.32 (IH5 dt), 7.04 (IH, d), 6.87 (IH, d), 6.71 (IH, s), 6.65 (IH, brm), 4.47 (IH, m), 2.34 (3H, s), 1.73-1.62 (4H, m), 1.18-0.93 (14H, m).
Step c l-(4-Aminoψhenyl)-8-methyl-5-pyridin-2-yl~3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps c and d of example 1, except that 8-methyl-5-pyridin-2-yl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c. 1H NMR CDCl3 8.66 (IH, d), 8.12 (IH, m), 7.84 (IH5 dt), 7.36
(2H, d), 7.25 (2H, d), 6.92 (IH5 d), 6.66 (3H, m), 4.36 (IH, m), 3.75 (2H, brm), 2.23 (3H, s), 1.63-0.91 (18H, m).
Step d The title compound was obtained using step a of example 128, except that l-(4-amino- phenyl)-8-methyl-5-pyridin-2-yl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4- amino-phenyl)-3 -benzyl-5 -cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl- 1 -(4-(4, 5 -dihydro- 1 H-imidazol-2-ylamino)-phenyl)- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-2-one, according to step b of example 39. 1HNMR (CDCl3) 8.61 (IH, m), 8.14 (IH, d), 7.83 (IH, dt), 7.38-7.10 (9H, m), 6.95 (IH, s), 6.57 (2H, d), 4.36 (IH, m), 3.51 (2H,m), 3.00 (2H, m), 2.23 (3H, s), 1.72-0.91 (18H, m). The compound was further characterised and tested as the HCl salt. Found: C 59.71, H 6.39, N 12.78%; C35H41N7O- 3.4HCl-0.7H2O requires: C 59.63, H 6.62, N 12.88%.
Example 225 5-Cyclohexyl-8-methyl-3-quinolin-8-ylmethyl-l-(4-(2-(lH-imidazol-2-yl)- ethylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one Step a S-Cyclohexyl-S-methyl-l^-amino-pheny^-S-quinolin-S-ylmethyl-l^-dihydro-SH- 1 ,3,4-benzotriazepin-2-one was obtained using step b, c and d of example 20, except that 5- cyclohexyl-3 -(4-methoxy-benzyl)-8-methyl- 1 -(4-nitrophenyl)- 1 ,2-dihydro-3H- 1 ,3,4- benzotriazepin-2-one (example 190, step a) was used instead of 5-cyclohexyl-3-(4-methoxy- benzyl)-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step b and 2- bromomethyl-biphenyl replaced (3-bromopropenyl)-benzene in step c. 1H NMR (CDCl3) 8.85 (IH, m), 8.14 (3H, m), 7.68 (IH, d), 7.55 (2H, m), 7.44-7.32 (5H, m), 6.87 (IH, s), 5.83 (IH, m), 5.47 (IH, m), 2.73 (IH, m), 2.34 (3H, s), 1.71-1.12 (1OH, m).
Step b The title compound was obtained using step a of example 128, except that 5- cyclohexyl-8-methyl- 1 -(4-amino-phenyl)-3 -quinolm-8-ylmethyl- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4- aminophenyl)-3 -benzyl-5 -cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3 -benzyl-5 -cyclohexyl- l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one, according to step b of example 39. 1HNMR (CDCl3) 8.91 (IH, d), 8.09 (IH, d), 7.64 (IH, d), 7.38-7.21 (6H, m), 6.94 (IH, d), 6.65 (3H, m), 5.56 (2H, m), 3.74 (2H, m), 2.72 (IH, m), 2.24 (3H, s), 1.78-1.28 (1OH, m). The compound was further characterised and tested as the HCl salt. Found: C 57.36, H 5.56, N 11.85%; C36H37N7O-4.7-HCl/0.6dioxan requires: C 57.08, H 5.80, N 12.13%.
Example 226 3-Cyclodecyl-5-phenoxymethyl-l-(4-(2-(lH-imidazol-2-yl)-ethylamino)-phenyl)- 1 ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one
Step a N-tert-Butoxycarbonyl-amino-N-cyclodecyl-N'-(2-ethynylphenyl)-urea was obtained using step a of example 146 except that N'-cyclodecyl-hydrazinecarboxylic acid tert-butyl ester was used in place of benzylhydrazine. 1H NMR (CDCl3) 8.41-8.33 (2H, m br), 7.41 (IH, d), 7.33 (IH, t), 6.95 (IH, t), 6.30-5.95 (IH, br m), 5.06 (IH, m), 3.43 (IH, m), 1.85-1.35 (27H, m).
Step b 3-Cyclodecyl-5-metkyl-l!2-dϊhydro-3H-l,3,4-benzotriazepin-2-one. A solution of N- tert-butoxycarbonyl-amino-N-cyclodecyl-N'-(2-ethynylphenyl)-urea (1.94g, 4.7mmol) and HgO (102mg, 0.47mmol) in THF (3OmL) and 10% H2SO4 (4mL) was stirred at 90°C for 3 hr. The reaction mixture was diluted with EtOAc (10OmL) and was washed with saturated NaHCO3 solution (3 x 5OmL). The precipitate that formed was isolated by filtration. The organic phase was separated and dried (MgSO4). Filtration and evaporation of the solvent gave a further crop of material that was combined with the precipitate obtained previously, suspended in wo-propyl alcohol (3OmL) with j9-toluenesulfonic acid monohydrate (389mg, 2.0mmol) and heated at reflux for 8h. The reaction mixture was diluted with EtOAc (15OmL) and was washed with saturated NaHCO3 solution (3 x 5OmL). The organic phase was dried (MgSO4), filtered and the solvent was removed at reduced pressure to give the product (1.53g, 100%). 1H NMR (CDCl3) 7.35-7.31 (2H, m), 7.08 (IH, t), 6.78 (IH5 d), 6.15 (IH, s), 4.49 (IH, m), 2.40 (3H, s), 1.92-1.89 (2H, m), 1.72-1.25 (16H, m).
Step c 3-Cyclodecyl-5-methyl-l -(4-nitro-phenyl)-l, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one was obtained using step of example 211 except that S-cyclodecyl-S-methyl-l^-dihydro-θH- l,3,4-benzotriazepin-2-one was used in place of 5-cyclohexyl-3-cyclooctyl-8-methyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (CDCl3) 8.12 (2H, d), 7.52-7.45 (4H, m), 7.37 (IH, t), 7.07 (IH, d), 4.57 (IH, m), 2.51 (3H, s), 1.95-1.30 (18H, m).
Step d S-BrornomethylS-cyclodecyl-l^-nitro-pheny^-lJ-dihydroSH-l^^-benzotriazepin- 2-one was obtained using step d of example 146 except that 3-cyclodecyl-5-methyl-l-(4-nitro- phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3 -benzyl-5 -methyl- 1- (4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (CDCl3) 8.15 (2H, d), 1.59-1 Al (4H, m), 7.39 (IH, t), 6.99 (IH, d), 4.58 (3H, m), 2.00-1.85 (2H, br m), 1.80-1.30 (16H, m).
Step e 3-Cyclodecyl-l-(4-nitro-phenyl)-5-phenoxymethyl-l,2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained by example 150 step a except that 5-bromomethyl-3- cyclodecyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3 -benzyl-5-bromomethyl- 1 -(4-nitro-phenyl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one. 1H NMR (CDCl3) 7.99 (2H, d), 7.66 (IH, d), 7.45 (IH, t), 7.36 (IH, t), 7.17-7.09 (4H, m), 6.92- 6.86 (4H, m), 5.28 (2H, s), 4.58 (IH, m), 1.90 (2H, br m), 1.80-1.35 (16H, m).
Step f l-(4-Amino-phenyl)-3-cyclodecyl-5-phenoxymethyl-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step d of example 1, except that 3-cyclodecyl-l-(4- nitro-phenyl)-5-phenoxymethyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (CDCl3) 7.53 (IH, d), 7.29-7.24 (3H, m), 7.09 (IH, t), 7.01-6.97 (3H, m), 6.87 (2H, d), 6.72 (IH, d), 6.56 (2H, d), 5.25 (2H, s), 4.35 (IH5 m), 3.77 (2H5 br s), 1.95-1.70 (2H, m), 1.75- 1.35 (16H, m).
Step g The title compound was obtained using step a of example 128, except that l-(4-amino- phenyl)-3 -cyclodecyl-5 -phenoxymethyl- 1 ,2-dihydro-3 H- 1 ,3 ,4-benzotriazepin-2-one and ( 1 - trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4-aminophenyl)-3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5-dihydro-lH- imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (DMSOd6) 11.75 (IH, br s), 7.70 (IH5 d), 7.33-7.24 (3H, m), 7.16 (IH, t), 7.00-6.88 (5H5 m), 6.76-6.68 (3H, m), 6.47 (2H5 d), 5.81 (IH5 br s), 5.34 (2H, br s), 4.20 (IH, m), 3.28 (2H, t), 2.84 (2H5 t), 1.85-1.30 (18H5 m). The compound was further characterised and tested as the HCl salt. Found: C 63.02, H 6.63 N 12.09%; C36H42N6O2- 2HCl-0.3CH2Cl2-0.2H2O requires C 62.94, H 6.55, H 12.13%.
Example 227 3-Cyclodecyl-5-(4-methoxyphenoxymethyl)-l-(4-(2-(lH-imidazol-2-yl)- ethylamino)-phenyl)-l,2-dϊhydro-3H-l,3,4-benzotriazepin-2-one.
Step a 3-Cyclodecyl-l-(4-nitro-phenyl)-5-(4-methoxyphenoxymethyl)-l,2-dihydro-3H-l,3, 4- benzotriazepin-2-one was obtained using step a of example 150 except that 5-bromomethyl-3- cyclodecyl- 1 -(4-nitro-phenyl)- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one and 4-methoxy- phenol were used in place of 3-benzyl-5-bromomethyl-l-(4-nitro-phenyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one and phenol respectively.
Step b l-ft-Amino-phenyty-S-cyclodecyl-S-ft-methoxyphenoxymethylJ-l^-dihydro^H-lyS^- benzofriazepin-2-one was obtained using step d of example 1, except that 3-cyclodecyl-l-(4- nitro-phenyl)-5-(4-methoxyphenoxymethyl)-l52-dihydro-3H-l5354-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one .
Step c The title compound was obtained using step a of example 128, except that l-(4-amino- phenyl)-3 -cyclodecyl-5 -(4-methoxyphenoxymethyl)- 1 ,2-dihydro-3H- 1 , 354-benzotriazepin-2- one and (l-trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4-aminophenyl)-3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l53,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5- dihydro- 1 H-imidazol-2-ylamino)-phenyl)- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazeρin-2-one, according to step b of example 39. 1H NMR (DMSO-d6) 11.75 (IH, m), 7.69 (IH, d), 7.32 (IH, t), 7.16 (IH, t), 6.90-6.81 (6H, m), 6.73-6.67 (3H, m), 6.46 (2H, d), 5.83 (IH, br s), 5.28 (2H, br s), 4.19 (IH, m), 3.68 (3H, s), 3.28 (2H, t), 2.84 (2H, t)5 1.85-1.30 (18H, m). The compound was further characterised and tested as the HCl salt. Found: C 61.98, H 6.6O3 N 11.50%; C37H44N6θ3-2HCl-0.3CH2Cl2-0.2H2O requires C 61.98 H 6.55, N 11.63%.
Example 228 N-(4-(5-Cyclohexyl-8-methyl-3~(3,3,5,5-tetramethylcyclohexyl)-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl)-3-(lH-imidazol-2-yl)propionamide
The title compound was obtained using step a of example 71, except that l-(4-amino-phenyl)- 5-cyclohexyl-8-methyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 106, step b) and 3-(l-trityl-imidazol-l-H-2-yl)-propionic acid (example 201, step c) were used in place of l-(4-aminophenyl)~3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5~dihydro-lH- imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 8.97 (IH, br s), 7.49 (IH, d), 7.35 (2H, d), 7.25 (IH, d), 6.96 (2H, s), 6.94 (IH, d), 6.52 (IH, s), 4.16 (IH5 m), 3.07 (2H, m), 2.80 (3H, m), 2.20 (3H, s), 1.86-0.90 (28H, m). The compound was further characterised and tested as the HCl salt. Found: C 65.98, H 7.63, N 13.80%; C37H48N6O2-UHCl requires C 66.14 H 7.46, N 12.51%.
Example 229 l-(4-(3-(lH-Imidazol-2-yl)-propylamino)-phenyl)-8-methyl-5-(tetrahydro-pyran- 4-yl)-3-(3, 3, 5, 5-tetramethyl-cyclohexyl)-l , 2-dihydro-3H-l , 3, 4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except l-(4-amino-phenyl)-8- methyl-5-(tetrahydro-pyran-4-yl)-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (Example 181, step d) and 3-(l-trityl-lH-imidazol-2-yl)-proρionaldehyde (ref) were used in place of l-(4-aminophenyI)-3-benzyl-5-cycIohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,N-bis-(fert-butoxycarbonyl)-.V-(4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro- 3H-l,3,4-benzotriazepin-l-yl)-phenyl)-guanidine, according to step f of example 1. 1H NMR (CDCl3) 7.22 (IH, d), 7.13 (2H, d), 6.94 (2H, s), 6.91 (IH, d), 6.60 (IH, s), 6.50 (2H, d), 4.17- 4.09 (3H, m), 3.58 (2H, t), 3.16 (2H, t), 3.06 (IH, m), 2.77 (2H, t), 2.21 (3H, s), 2.02 (2H, t), 1.99-1.07 (1OH, m), 1.04 (6H, s), 0.89 96H, s). The compound was further characterised and tested as the HCl salt. Found: C 61.46, H 7.20, N 11.60 %; C36H48N6O2-SHCl requires: C 61.20, H 7.28, N 11.89%
Example 230 N-Cyano-N'-ft-fS-cyclohexyl-S-methyl-S-ftetrahydro-pyran^-yty^-oxo-l^- dihydro-3R-l,3,4-benzotriazepin-l-yl)-phenyl)-N"-methyl-guanidine Step a tert-butyl cyanamide(methylthio)methyl methylcarbamate
N-Cyano-N'-methyl-S-methylcarbamidothiolate (1.28g, lOmmol), di-tert-butyldicarbonate (2.18g, lOmmol) and 4-DMAP (lOOmg) were dissolved in THF (25mL) and the reaction mixture stirred at rt for Ih. The reaction mixture was evaporated and purification of the residue by chromatography (DCM-EtOAc (1:9)) afforded the product as colourless oil (2.36g, 100%). 1H NMR (CDCl3) 3.30 (3H, s), 2.58 (3H, s), 1.54 (9H, s).
Step b The title compound was obtained as the HCl salt using steps e and f of example 1, except that 1 -(4-amino-phenyl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)- 1 ,2-dihydro- 3H-l,3,4-benzotriazepin-2-one (example 182, step b) and tert-butyl cyanamide(methylthio)methyl methylcarbamate were used in place of l-(4-aminophenyl)-3- benzyl-5 -cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and l,3-bis-(fert-butoxycarbonyl)-2-methyl-2-thiopseudourea respectively. 1H NMR (CDCl3) 7.54 (IH, br s), 7.46 (2H, d), 7.31-7.21 (3H, m), 7.00 (IH, d), 6.55 (IH, s), 5.00 (IH, br s), 4.00 (3H, m), 3.46 (2H, t), 2.86 (4H, m), 2.26 (3H, s), 2.00-1.20 (1OH, m). The compound was further characterised and tested as the HCl salt. Found: C 52.62, H 6.64, N 14.86%; C29H35N7O2-3HC1-2H2O requires C 52.85, H 6.42, N 14.87%.
Example 231 5-Cyclohexyl-3,8-dimethyl-l-(4-(3-(lH-imidazol-2-yl)propylamino)-phenyl)-l,2- dihydro-3H-l , 3, 4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- 5-cyclohexyl-3,8-dimethyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 184, step c) and 3-(l-trityl-lH-imidazol-2-yl)-propionaldehyde were used in place of l-(4-amino-phenyl)- 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5- dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.25 (IH, d), 7.09 (2H, d), 6.93 (3H, m), 6.60 (IH, s), 6.47 (2H, d), 3.12 (IH, m), 3.07 (3H, s), 2.77-2.70 (3H5 m), 2.21 (3H, s), 1.95- 1.30 (12H, m). The compound was further characterised and tested as the HCl salt. Found: C 57.56, H 6.60, N 14.11%; C28H34N6O-3.2HC1 requires C 57.37 H 6.39, N 14.33%.
Example 232 5-Cyclohexyl-3-(l-phenyl-piperidin-4-yl)-l-(4~((lH-imidazol-2-ylmethyl)- amino)-phenyl)-l ,2-dihydro-3H-l , 3, 4-benzotriazepin-2-one
Step a S-Cyclohexyl-S-fl-phenyl-piperidin^-ylJ-l^-dihydro-SH-lJJ-ben∑otriazepin^-one was obtained using step c of example 181, except that (2-amino- phenyl)(cyclohexyl)methanone (Example 11 step a) and N7-(l-phenylpiperidin-4- yl)hydrazinecarboxylic acid tert-butyl ester were used in place of (2-amino-4-methyl- phenyl)(tetrahydro-pyran-4-yl)methanone and iV-(3,3,5,5-tetramethyl-cyclohexyl)- hydrazinecarboxylic acid tert-butyl ester respectively. 1H NMR (CDCl3) 7.37-7.23 (4H, m), 7.12 (IH, m), 6.98-6.95 (2H, m), 6.83-6.80 (2H, m), 6.23 (IH, s), 4.14-4.04 (IH, m), 3.77-3.73 (2H, m), 2.85-2.71 (3H, m), 2.22-2.16 (2H, m), 1.90-1.71 (7H, m), 1.55-1.22 (5H, m).
Step b l-(4-Amino-phenyl)-3-(l-phenyl-piperidin-4-yl)-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using steps c and d of example 1, except that 5-cyclohexyl- 3-(l-phenyl-piperidin-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.34 (IH, m), 7.27-7.15 (6H, m), 6.96-6.76 (4H, m), 6.66-6.60 (2H, m), 3.99-3.91 (IH, m), 3.70 (4H, m), 2.83-2.76 (3H, m), 2.18-1.24 (14H, m).
Step c The title compound was obtained using step a of example 128, except l-(4-amino- phenyl)-5-cyclohexyl-3-(l-phenyl-piperidin-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of l-(4-amino-phenyl)-3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5~cyclohexyl-l-(4-(4,5- dihydro- 1 H-imidazol-2-ylamino)-phenyl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 9.47 (IH, br s), 7.37 (IH, m), 7.27-7.17 (5H, m), 7.14-7.08 (IH, m), 7.02-6.93 (4H, m), 6.84-6.74 (2H, m), 6.60-6.58 (2H, m), 4.42- 4.40 (3H, m), 3.97-3.90 (IH, m), 3.71-3.67 (2H, m), 2.82-2.75 (3H, m), 2.50-1.24 (14H, m). The compound was further characterised and tested as the HCl salt. Found: C 61.04, H 6.51, N 13.75%; C35H39N7O-S1IOHCl-OJC4H8O2 requires C 60.96, H 6.29, N 13.95%.
Example 233 3-Cyclodecyl-5-methyl-l-(4-(2-(lH-imidazol-2-yl)-ethylamino)-phenyl)-l,2- dihydro-3H-l, 3, 4-benzotriazepin-2-one Step a l-(4-Amino-phenyl)-3-cyclodecyl-5-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step d of example 1, except that 3-cyclodecyl-5-methyl-l-(4-nitro-phenyl)- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 226 step c) was used in place of 3- benzyl-5-cyclohexyl-l -(4-nitro-phenyl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one. 1H NMR (CDCl3) 7.34 (IH, d), 7.25-7.18 (3H, m), 7.07 (IH, t), 6.76 (IH, d), 6.66 (2H, d), 4.30 (IH, m), 3.90 (2H, br), 2.49 (3H, s), 1.95-1.70 (4H, m), 1.70-1.30 (14H, m).
Step b The title compound was obtained using step a of example 128, except that l-(4-amino- phenyl)-3 -cyclodecyl-5 -methyl- 1 ,2-dihydro-3H- 1 , 3 ,4-benzotriazepin-2-one and ( 1 -trityl- 1 H- imidazol-2-yl)-acetaldehyde were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2- ylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (DMSOd6) 11.75 (IH, br s), 7.54 (IH, d), 7.31 (IH, t), 7.15-7.06 (3H, m), 6.89 (2H, s), 6.69 (IH, d), 6.56 (2H, d), 5.84 (IH, br s), 4.15 (IH, m), 3.31 (2H, t), 2.85 (2H, t), 2.45 (3H, s), 2.80-1.25 (18H, m). The compound was further characterised and tested as the HCl salt. Found: C 58.85, H 6.91, N 13.47%; C3OH38N6O^HCI-O-SCH2CI2-CSH2O requires C 58.80 H 6.79, N 13.49%
Example 234 5-cyclohexyl-3-cyclodecyl-8-methyl-l-(2-methyl-4-(3-(lH-imidazol-2- yl)propylamino)-phenyl)-l , 2-dihydro~3H-l, 3, 4-benzotriazepin-2-one The title compound was obtained using step a of example 128 except that l-(4-amino-2- methyl-phenyl)-3-cyclodecyl-5-cyclohexyl-8-methyI- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2- one (example 189 step a) and 3-(lH-imidazol-2-yl)-propionaldehyde were used in place of 1- (4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step b of example 39. 1HNMR (CDCl3) 7.33-6.32 (9H3 m), 4.26 (IH, m), 3.24-2.71 (5H, m), 2.19 (3H, s), 2.10-1.25 (33H, m). The compound was further characterised and tested as the HCl salt. Found: C 65.73, H 7.92, N 11.06%; C38H52N6O- 2.0HCl-0.8C4H8O2 requires C 65.78, H 8.09, N 11.17%. Example 235 3-Benzyl-5-cyclohexyl-l-(4-(2-(lH-imidazol-2-yl)-ethylamino)-phenyl)-8-methyl- 1, 2-dihydro-3H-l, 3, 4-benzotriazepin~2-one
The title compound was obtained using step a of example 128 except that l-(4-amino-2- methyl-phenyl)-3-benzyl-5-cyclohexyl-8-methyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one (example 189 step a) and (l-trityl-3-(lH-imidazol-2-yl)-acetaldehyde {Synlett. 1999, 12, 1875) were used in place of l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.27-7.11 (8H, m), 6.95 (2H, s), 6.93 (IH, d), 6.61 (IH, s), 6.54 (2H, d), 4.80 (2H, br s), 3.46 (2H, t), 2.89 (2H, t), 2.78(1H, m), 2.24 (3H, s), 1.82-1.26 (1OH, m). The compound was further characterised and tested as the HCl salt. Found: C 63.19, H 6.27, N 13.10%; C39H40N6O- 2.7HC1 requires C 62.95, H 6.19, N 13.35.
Example 236 5-Cyclohexyl-3-(2-methoxyethyl)-8-methyl-l-(4-(2-(lH-imidazol-2-yl)- ethylamino)-phenyl)-l , 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one. Step a l~(4-Amino-phenyl)-5-cyclohexyl-3-(2-methoxyethyl)-8-methyl-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step c of example 20 except that 5-cyclohexyl-8- methyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 184, step b) and bromoethyl-methyl-ether were used in place of 5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one and (3-bromopropenyl)-benzene respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one, according to step d of example 1. 1H NMR (CDCI3) 7.23 (IH, d), 7.13 (2H, d), 6.92 (IH, d), 6.66 (2H, d), 6.56 (IH, s), 4.06 (IH, br s), 3.75 (3H, br s), 3.61 (2H, m), 3.28 (3H, s), 2.78 (IH, m), 2.21 (3H, s), 1.84-1.24 (1OH, m). Step b The title compound was obtained using step a of example 128, except l-(4-amino- phenyl)-5 -cyclohexyl-3-(2-methoxyethyl)-8-methyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2- one and (l-trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4-aminophenyl)-3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5- dihydro- lH-imidazol-2-ylamino)-phenyl)- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.24 (IH, d), 7.10 (2H, d), 6.95 (2H, s), 6.92 (IH, d), 3.75 (2H, br s), 3,61 (2H, m), 3.46 (2H, t), 3.27 (3H, s), 2.91 (2H, t), 2.78 (IH, m), 2.21 (3H, s), 1.85-1.20 (1OH, m). Found: C 58.20, H 6.70, N 13.59 %; C29H36N6O2-2.8HC1 requires: C 57.89, H 6.50, N 13.97% Example 237 5-Cyclohexyl-l-(4-(2-(lH-imidazol-2-yl)ethyl-amino)-phenyl)-3-(l-phenyl- piperidin-4-yl)-l ,2-dihydro-3H-l , 3, 4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except l-(4-amino-phenyl)-5- cyclohexyl-3-(l-phenyl-piperidin-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 232 step b) and (l-trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4-amino- phenyl)-3-benzyI-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl- l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one, according to step b of example 39.
1H NMR (CDCl3) 9.30 (IH, br s), 7.37-7.34 (IH, m), 7.27-7.06 (6H, m), 7.00-6.93 (4H, m), 6.84-6.76 (2H, m), 6.27 (2H, d), 4.21 (IH, br s), 3.98-3.91 (IH, m), 3.71-3.67 (2H, m), 3.53- 3.50 (2H5 m), 3.03-2.98 (2H, m), 2.83-2.75 (3H, m), 2.18-1.32 (14H, m). The compound was further characterised and tested as the HCl salt. Found: C 60.06, H 6.50, N 13.21%; C36H41N7O-S-SOHCl-O^C4H8O2 requires C 60.16, H 6.41, N 13.06%. Example 238 5-Cyclohexyl-l-(4-((lH-imidazol-2-yhnethyl)-amino)-phenyl)-8-methyl-3- (2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-l ,2-dihydro-SH-l ,3 ,4-benzotriazepin-2-one
Step a 5-Cyclohexyl-8-methyl-3-(2,2, 6, 6-tetramethyl-tetrahydro-pyran-4-yl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one was obtained using step c of example 181, except that (2-amino-4- methyl-phenyl)(cyclohexyl)methanone and N'-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)- hydrazinecarboxylic acid tert-butyl ester were used in place of (2-amino-4-methyl- phenyl)(tetrahydro-pyran-4-yl)methanone and N'-(3,3,5,5-tetramethyl-cyclohexyl)- hydrazinecarboxylic acid tert-butyl ester respectively. 1H ΝMR (CDCl3) 7.27-7.23 (IH, m),
6.93-6.90 (IH, m), 6.63 (IH, s), 6.17 (IH, s), 4.54-4.43 (IH, m), 2.74-2.66 (IH, m), 2.34 (3H, s), 1.84-1.21 (26H, m).
Step b l-(4-Λmino-phenyl)-5-cyclohexyl-8-methyl-3-(2,2, 6, 6-tetramethyl-tetrahydro-pyran-4- yl)-l,2-dihydro-3H-l,3,4-benzotriazepin~2-one was obtained using steps c and d of example 1, except that 5-cyclohexyl-8-methyl-3-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one in step c. 1H ΝMR (CDCl3) 7.27-7 '.23 (IH, m), 7.17-7.14 (2H, m), 6.93-6.91 (IH, m), 6.69-6.65 (2H, m), 6.57 (IH, s), 4.40-4.30 (IH, m), 3.73 (2H, br s), 2.83- 2.77 (IH5 m), 2.22 (3H, s), 2.13-1.22 (26H, m).
Step c The title compound was obtained using step a of example 128, except l-(4-amino- phenyl)-5-cyclohexyl-3-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of 1- (4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step b of example 39. 1H ΝMR (CDCl3) 1H ΝMR (CDCl3) 9.20 (IH, br s), 7.27-7.16 (4H, m), 7.01 (2H, s), 6.94-6.91 (IH, m), 6.63-6.56 (3H, m), 4.45- 4.29 (4H, m), 2.80-2.77 (IH, m), 2.22 (3H, s), 2.12-1.21 (26H, m). The compound was further characterised and tested as the HCl salt. Found: C 62.39, H 7.21, Ν 12.52%; C34H44N6O2- 2.41HC1 requires C 62.19, H 7.12, N 12.80%.
Example 239 5-Cyclohexyl-J-(4-(2-(lH-imidazol-2-yl)ethyl-amino)-phenyl)-8-methyI-3- (2,2,6,6-tetramethyl-tetrahydro~pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except l-(4-amino-phenyl)-5- cyclohexyl-3-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-2-one (example 238 step b) and (l-trityl-lH-imidazol-2-yl)-acetaldehyde {Synlett, (1999), 12, 1875) were used in place of l~(4-amino-phenyl)-3-benzyl-5-cyclohexyl- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2- ylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin~2-one, according to step b of example 39. 1H NMR (CDCl3) 9.20 (IH, br s), 7.26-7.16 (4H, m), 6.97-6.91 (3H, m), 6.62-6.59 (3H, m), 4.40-4.21 (2H, m), 3.54-3.50 (2H, m), 3.00-2.96 (2H, m), 2.81-2.78 (IH, m), 2.22 (3H, s), 2.17-1.22 (26H, m). The compound was further characterised and tested as the HCl salt. Found: C 61.96, H 7.43, N 11.80%; C35H46N6O2^-SHCl-0.4C4H8O2 requires C 61.99, H 7.35, N 11.85%.
Example 240 5-Cyclohexyl-l-(4-(2-(lH-imidazol-2-yl)ethyl-amino)-phenyl)-8-methyl-3- phenyl-l ,2-dihydro-3H-l ,3, 4-benzotriazepin-2-one
Step di. E/Z-2-(Cyclohexyl'(phenyl-hydrazono)-methyl)-5-methyl-phenylamine
A mixture of (2-amino-4~methylphenyl)(cyclohexyl)methanone (l.lg, 5mmol), phenylhydrazine (1.ImL, lOmmol) and acetic acid (5 drops) in EtOH (3mL) was heated in a microwave (CEM Explorer) for 30 minutes at 195 0C (pressure 249 bar). The reaction mixture was allowed to cool to room temperature, dissolved in EtOAc and washed successively with 10 %KHSO4, saturated NaHCO3 and dried (MgSO4). Filtration and evaporation of the solvent gave an oil which was chromatographed (2:1 CH2Cl2-hexane) to give the product as a mixture of E/Z isomers.
Step b. 5-Cyclohexyl-8-methyl-3-phenylA,2-dϊhydro-3H-l,3,4-b&nzotriazepin-2-one. A solution of triphosgene (1.8g, 6mmol) in CH2Cl2 (3OmL) was added dropwise to a mixture of E/Z-2-(cyclohexyl-(phenyl-hydrazono)-methyl)-5-methyl-phenylamine (4.6g, 15mmol) and NEt3 (4mL, 28mmol) in CH2Cl2. After stirring for Ih, the reaction mixture was diluted with 2N HCl (1OmL) and CH2Cl2 (2OmL) and the organic layer was separated, washed with H2O (2OmL) and dried (MgSO4). Filtration and evaporation of the solvent was followed by chromatography (Et2O) of the residue to afford the product as a brown solid (960mg, 19%). 1H CDCl37.52 (2H, d), 7.31 (3H, m), 7.18 (IH, t), 6.99 (IH, d), 6.72 (IH5 s), 6.49 (IH, brs), 2.74 (IH, m), 2.38 (3H, s), 1.89-1.27 (1OH, m).
Step c. l-(4-Amino-phenyl)-5-cyclohexyl-8~methyl-3-phenyl-l, 2~dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using steps c and d of example 1 except that 5-cyclohexyl- 8-methyl-3 -phenyl- l,2-dihydro-3H-l, 3, 4-benzotriazepin-2-one was used in place of 3-benzyl- 5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H CDCl37.50 (2H, m), 7.30 (3H, m), 7.15 (2H, m), 7.05 (IH, t), 6.96 (IH, d), 6.70 (IH, s), 6.64 (2H, d), 3.71 (2H, brm), 2.89 (IH, m), 2.26 (3H, s), 1.94-1.26 (1OH, m). Step d. The title compound was obtained using step a of example 128, except that l-(4-amino- phenyO-S-cyclohexyl-S-methyl-S-phenyl-l^-dihydro-SH-ljS^-benzotriazepin^-one and (1- trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of l-(4~amino-phenyl)-3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5-dihydro-lH- imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step b of example 39. 1H DMSOd-6/D2O 7.55 (3H, m), 7.29 (4H, m), 7.06 (4H, m), 6.65 (3H, m), 3.43 (2H, m), 3.14 (2H, t), 3.07 (IH, m), 2.21 (3H, s), 1.86-1.71 (5H, m), 1.44-1.22 (5H, m). The compound was further characterised and tested as the HCl salt. Found: C 63.33, H 5.97, N 12.81%; C32H34N6O-2.3-HCl/0.5dioxan requires: C 63.15, H 6.28, N 12.99%.
Example 241 5-Cyclohexyl-l-(4-(2-(lH-imidazol-2-yl)-ethylamino)-phenyl)-8-methyl-3- propyl-1, 2-dihydro-3H-l, 3, 4-benzotriazepin-2~one
Step a 1 -(4-Amino-phenyl)-5-cyclohexyl-8-methyl3-propyl-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step c of example 20 except that 5-cyclohexyl-8- methyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 184, step b) and 1-iodopropane were used in place of 5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one and (3-bromopropenyl)-benzene respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one, according to step d of example 1. 1H NMR (CDCl3) 7.24 (IH, d), 7.15 (2H, d), 6.92 (IH, d), 6.65 (2H, d), 6.56 (IH, s), 3.78 (2H, br s), 3.46 (2H, br s), 2.77 (IH, m), 2.22 (3H, s), 1.83-1.24 (12H, m), 0.79 (3H, t).
Step b The title compound was obtained using step a of example 128, except l-(4-amino- phenyl)-5-cyclohexyl-8-methyl-3-propyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and (1- trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4-aminophenyl)-3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5-dihydro-lH- imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step b of example 39. 1R NMR (CDCl3) 7.25 (IH, d), 7.14 (2H, d), 6.96-6.91 (3H, m), 6.58-6.53 (3H, m), 3.47 (4H, m), 2.93 (2H, t), 2.77 (IH, m), 2.21 (3H, s), 1.84-1.21 (12H, m), 0.79 (3H, t). Found: C 60.50, H 6.84, N 13.91 %; C29H36N6O-2.5HCl-0.3C4H10O requires: C 60.65, H 6.99, N 14.05%
Example 242 8-Bromo-5-cyclohexyl-l-(4-((lH-imidazol-2-ylmethyl)-amino)-phenyl)-3- (3, 3, 5, 5-tetramethyl-cyclohexyl)-l, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one Step a (2-Amino-4-bromo-phenyl)cyclohexyl-methanone was obtained using step b of example 181 except that cyclohexanecarbonitrile and 3-bromoaniline were used in place of tetrahydro- pyran-4-carbonitrile and m-toluidine respectively.
Step b 8-Bromo-5-cyclohexyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H~l,3,4- benzotriazepin-2-one was obtained using steps a and b of example 52, except that 3,3,5,5- tetramethyl-cyclohexanone was used in place of cycloheptanone in step a and (2-amino-4- bromo-phenyl)cyclohexyl-methanone was used in place of (2-aminophenyl)-cyclohexyl~ methanone in step b.
Step c l-aminopheψl-8-bromo-5-cyclohexyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro~ 3H-l,3,4-benzotriazepin-2-one was obtained using steps c and d of example 1 except that 8- bromo-5-cyclohexyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4-benzotriazepin- 2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one in step c.
Step d. The title compound was obtained using step a of example 128, except that 1- aminophenyl-8-bromo-5-cyclohexyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3Η-l,3,4- benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of 1- (4-amino-phenyl)-3-benzyl-5 -cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl- 1 -(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.20 (2H, s), 7.12 (2H, d), 6.98 (2H, s), 6.88 (IH, s), 6.53 (2H, m), 4.55 (IH, br), 4.29 (2H, br s), 4.15 (IH, m), 2.75 (IH, m), 1.80 (8H, m), 1.25 (7H, m), 1.04 (7H, m), 0.95 (6H, s). The compound was further characterized and tested as the HCl salt. Found: C 56.54, H 6.31, N 11.52%; C34H43BrN6O-2.5 HCl requires: C 56.44, H 6.34, N 11.61%. Example 243 8-CMoro-5-cyclohexylA-(4-(2-(lHAmidazol-2-yl)ethyl-amino)-phenyl)-3- (tetrahydro-pyran-4-yl)-l , 2-dihydro-3H-l, 3, 4-benzotriozepin-2-one
Step a J-(4-Amino-pheψl)-8-chloro-5-cyclohexyl-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one was obtained by steps a-d of example 207 except that N'- (tetrahydro-pyran-4-yl)-hydrazinecarboxylic acid tert-butyl ester was used in step b in place of N'-(3,3,5,5-tetramethyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester. 1H NMR (CDCl3) 7.28 (2H, d), 7.14-7.06 (3H, m), 6.67 (2H, d), 4.06-3.97 (3H, m), 3.77 (2H, br s), 3.46 (2H, m), 2.74 (IH, m), 2.20-1.25 (14H, m). Step b The title compound was obtained by steps a-b of example 210 except that l-(4-amino- phenyl)-8-chloro-5-cyclohexyl-3 -(tetrahydro-pyran-4-yl)- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-2-one was used in step a in place of l-(4-amino-phenyl)-8-chloro-5-cyclohexyl- 3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (DMSOd6) 11.80 (IH, br m), 7.61 (IH, d), 7.24 (IH, d), 7.01 (2H, d), 6.90 (2H, s), 6.70 (IH, s), 6.60 (2H, d), 5.94 (IH, br m), 3.95-3.80 (3H, m), 3.35-3.29 (4H, m), 2.97 (IH, m), 2.86 (2H, t), 2.20-1.15 (14H, m). The compound was further characterised and tested as the HCl salt. Found: C 55.36, H 5.86, N 12.56%; C3OH35N6O2CI-LOHCI-OJCH2CI2 requires C 55.46, H 5.76, N 12.64%. Example 244 S-Cyclohexyl-l-ø-ffS-methyl-lH-imidazol^-ylmethylJ-aminoJ-phenyty-S-inethyl- 3-(S, 3, 5, 5-tetramethyl-cyclohexyl)-! ,2-dihydro-3H-l ,3, 4-benzotriazepin-2-one
Step a 4-methyl-l-trityl~l-H.-imidazol-2-carbaldehyde n-Butyl lithium (1.6M in hexanes, 2.5ml, 3.96mmol) was added to a solution of 4-methyl-l- trityl-lH-imidazole (1.07g, 3.3mmol) (J.Org.Chem., (1978), 43, 4381.) in TΗF (50ml) at O0C. The reaction mixture was stirred at rt for 2h then cooled to O0C and DMF (3.5ml) added. After Ih at rt the mixture was poured into H2O (10OmL) and extracted with EtOAc (2 x 75mL). The organic layer was separated and dried (MgSO4). Filtrtaion and and evaporation of the solvent gave the product as a solid which was washed with ether and dried (0.74g, 64%). 1H NMR (CDCl3) 9.13 (IH, s), 7.32 (1OH, m), 7.15 (6H, m), 6.73 (IH, s), 2.28 (3H, s). Step b The title compound was obtained using step a of example 128, except that l-(4-amino- phenyl)-5 -cyclohexyl-8-methyl-3 -(3 ,3 ,5,5-tetramethyl-cyclohexyI)- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-2-one (example 106, step b) and 4-methyl-l-trityl-l-H-imidazol-2- carbaldehyde were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-cyclodecyl-5-cyclohexyl-7,8-dimethyl-l-(4-((l-trityl-lH-imidazol-2- ylmethyl)-amino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step e of example 193. 1H NMR (CDCl3) 7.18 (3H, m), 6.90 (IH, d), 6.65 (IH, s), 6.54 (3H, m), 4.33 (2H, s), 4.14 (IH, m), 2.79 (IH, m), 2.22 (3H, s), 2.20 (3H, s), 2.00-0.89 (28H, m). The compound was further characterized and tested as the HCl salt. Found: C 65.27, H 7.51, N 12.42%; C36H48N6O^J HCl requires: C 65.05, H 7.63, N 12.64%.
Example 245 3-(l-Benzoyl-piperidin-4-yl)-5-cyclohexyl-l-(4-((lH-imidazol-2-ylmethyJ)- amino)-phenyl)-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
Step a 3-(l-Benzoyl-piperidin-4-yl)-5-cyclohexyl-8-methyl-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step c of example 181, except that (2-amino-4- methyl-phenyl)(cyclohexyl)methanone and N1 -(I -benzoyl-piperidin-4-yl)-hydrazinecarboxylic acid tert-butyl ester were used in place of (2-amino-4-methyl-phenyl)(tetrahydro-pyran-4- yl)methanone and N7-(35355,5-tetramethyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester respectively. 1H NMR (CDCl3) 7.41 (5H, m), 7.25-7.23 (IH5 m), 6.94-6.91 (IH, d), 6.61 (IH, s), 6.16 (IH, s), 4.78 (IH, br m), 4.23-4.13 (IH, m), 3.79 (IH, br m), 3.07-2.84 (2H5 br m), 2.74-2.67 (IH, m), 2.34 (3H, s), 2.00-1.19 (14H, m).
Step b l-f^Amino-phenylJ-S-fl-benzoyl-piperidin-^ylJ-S-cyclohexylS-methyl-l^-dihydro- 3 H-I ,3,4-benzotriazepin-2-one was obtained using steps c and d of example 1, except that 3- (1 -benzoyl-piperidin-4-yl)-5-cyclohexyl-8-methyl- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.40 (5H, m), 7.27-7.20 (IH, m), 7.15-7.11 (2H, m), 6.94-6.92 (IH, m), 6.69-6.65 (2H, m), 6.56 (IH, s), 4.68 (IH, br s), 4.09-3.99 (IH, m), 3.70 (3H, br s), 3.05-2.81 (3H, m), 2.22-1.27 (17H, m).
Step c The title compound was obtained using step a of example 128, except l-(4-amino- phenyl)-5-cyclohexyl-3-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of 1- (4-amino-phenyl)-3 -benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl- 1 -(4-(4, 5 -dihydro- 1 H-imidazol-2-ylamino)-phenyl)- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 10.0-9.20 (IH, br s), 7.39 (5H, s), 7.27-7.22 (IH, m), 7.17-7.14 (2H, d), 6.99 (2H, s), 6.95 (IH, d), 6.61-6.54 (3H, m), 4.66 (IH, br s), 4.43 (3H, m), 4.03 (IH, m), 3.73 (IH, br s), 3.05-2.80 (3H, m), 2.26- 1.33 (17H, m). The compound was further characterised and tested as the HCl salt. Found: C 64.65, H 6.48, N 13.95%; C37H41N7O2-I^HCl-O.2C4H8O2 requires C 64.61, H 6.38, N 13.95%. Example 246 5-Cyclohexyl-8-methyl-l-(4-(4-(lH-imidazol-2-yl)butylamino)-phenyl)-3- (3, 3, 5, 5-tetramethyl-cyclohexyl)-l , 2-dihydro-3H-l,3, 4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- 5-cyclohexyl-8-methyl-3-(3,3,5,5,-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 106, step b) and and 4-(l-trityl-lH-imidazol-2-yl)- butyraldehyde (ref), were used in place of l-(4-amino-phenyl)-3 -benzyl-5-cyclohexyl- 1,2- dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4~(4,5~dihydro-lH-imidazol-2- ylammo)~phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepm-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.23 (IH5 m), 7.14 (2H5 d), 6.91 (3H, m), 6.58 (IH5 s), 6.50 (2H, d), 4.15 (IH, m), 3.08 (2H, t), 2.79 (IH, m), 2.67 (2H, t), 2.20 (3H5 s), 1.81-1.08 (16H5 m), 1.04 (6H, s), 0.90 (6H, s). The compound was further characterised and tested as the HCl salt. Found: C 64.69, H 7.77, N 11.07%; C38Hs2N6θ-2.7HCl-0.5C4H10O requires C 64.54, H 8.08, N 11.29%.
Example 247 l-(4-(2-(lH-imidazol-2-yl)ethyl-amino)-phenyl)-8-methyl-5-(teirahydro-pyran-4- yl)-3-(2,2,6,6-tetramethyl-tetrahydro-pyran-4'yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one Step a 8-Methyl-5-(tetrahydro-pyran-4-yl)-3-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step c of example 181, except that iV-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-hydrazinecarboxylic acid tert-butyl ester was used in place of iV-(3,3,5,5-tetramethyl-cycIohexyl)-hydrazinecarboxylic acid tert-butyl ester. 1H NMR (CDCl3) 7.25-7.22 (IH, m), 6.94-6.92 (IH, m), 6.65 (IH, s), 6.22 (IH, s), 4.55-4.47 (IH, m), 4.07 (2H, m), 3.53-3.45 (2H, m), 3.01-2.94 (IH, m), 2.34 (3H, s), 1.88-1.66 (8H, m), 1.32 (6H, s), 1.24 (6H, s).
Step b l-(4-Amino-phenyl)-8-methyl-5-(tetrahydro-pyran-4-yl)-3-(2,2, 6, 6-tetramethyl- tetrahydro~pyran-4-yl)l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps c and d of example 1, except that 8-methyl-5-(tetrahydro-pyran-4-yl)-3-(2,2,6,6-tetramethyl- tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.27-7.22 (IH, m), 7.16-7.13 (2H, m), 6.94-6.92 (IH, m), 6.69-6.60 (3H, m), 4.40-4.33 (IH, m), 4.06 (2H, m), 3.75 (2H, br s)5 3.58-3.49 (2H, m), 3.09-3.06 (IH, m), 2.22 (3H, s), 2.18- 1.22 (2OH, m). Step c The title compound was obtained using step a of example 128, except l-(4-amino- phenyl)-8-methyl-5-(tetrahydro-pyran-4-yl)-3-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)l,2- dihydro-3H-l,3,4-benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-acetaldehyde (Synlett, (1999), 12, 1875) were used in place of l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2- ylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 9.08 (IH, s), 7.27-7.15 (3H, m), 6.98-6.92 (3H, m), 6.64-6.60 (3H, m), 4.40-4.09 (4H5 m), 3.57-3.45 (4H, m), 3.08-3.00 (3H, m), 2.23-1.24 (23H, m). The compound was further characterised and tested as the HCl salt. Found: C 61.28, H 7.11, N 12.27%; C34H44N6θ3-2.2HCl-0.2C4H8O2 requires C 61.23, H 7.06, N 12.31%.
Example 248 3-(3, 4-Dihydro-2H-benzo[b][l, 4]dioxepin-3-yl)-8-methyl-l-(4-(3-(lH-imidazol-
2-yl)propyl-amino)-phenyl)-5-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one Step a 8-Methyl-5-(tetrahydro-pyran-4-yl)-3-(3, 4-dihydro-2H-bemo[b] [1, 4]dioxepin-3-yl)- 1 ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one was obtained using step c of example 181, except that N'-(3,4-dihydro-2H-benzo[b][l,4]dioxepin-3-yl)-hydrazmecaτboxy\ic acid tert-butyl ester was used in place of iV-(3,3,5,5-tetramethyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester.
Step b l-(4-Amino-phenyl)-8-methyl-5-(tetrαhydro-pyrαn-4-yl)-3-(3,4-dihydro-2H- benzo[b][l,4]dioxepin-3-yl)-l,2-dihydro-3H-l,3,4-benzotriαzepin-2-one was obtained using steps c and d of example 1, except that 8-methyl-5-(tetrahydro-pyran-4-yl)-3-(3,4-dihydro-2H- benzo[b][l,4]dioxepin-3-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c.
Step c The title compound was obtained using step a of example 128, except l-(4-amino- phenyl)-8-methyl-5-(tetrahydro-pyran-4-yl)-3-(3,4-dihydro-2H-benzo[b][l,4]dioxepin-3-yl)- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and 3-(lH-imidazol-2-yl)-propionaldehyde were used in place of l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 7.45-6.41 (14H, m), 4.80- 2.80 (17H, m), 2.23 (3H, s), 2.10-1.50 (4H, m). The compound was further characterised and tested as the HCl salt. Found: C 61.12, H 5.91, N 10.65 %;
Figure imgf000216_0001
requires C 60.80, H 6.25, N 11.02%.
Example 249 5-Cyclohexyl-l-(4-((lH-imidazol-2-ylmethyl)-amino)-phenyl)-3-(l- methαnesulfonyl-piperidin-4-yl)-8-methyl-l,2-dihydro-3H-l,3,4-benzotriαzepin-2-one
Step a N'-fl-tert-butoxycαrbonyl-piperidin^-yiyhydrαzimcαrboxylic acid tert-butyl ester was obtained using step a of example 52 except that l-tert-butoxycarbonylpiperidin-4-one was used in place of cycloheptanone.
Step b 5-Cyclohexyl-3-piperidin-4-yl-8-methyl~l ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one was obtained using step c of example 181, except that N-(l-teτt-butoxycarbonyl-piperidin-4-yl)- hydrazinecarboxylic acid tert-butyl ester was used in place of -/V-^^AS-tetramethyl- cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester.
Step c S-Cyclohexyl-S-fl-tert-butoxycarbonyl-piperidin^-ylJS-methyl-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-2-one 5-Cyclohexyl-3-piperidin-4-yl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, ά\-tert~ butyldicarbonate (11.75g, 53.8mmol) and 4-DMAP (5.5Og5 41.4mmol) were dissolved in DCM (12OmL) and the reaction mixture heated at reflux for 1.5h. On cooling, the reaction mixture was washed with 10% KHSO4 (5OmL), brine (5OmL) and dried (MgSO4). Filtration and evaporation of the solvent followed by purification of the residue by chromatography (DCM- MeOH-NH3OH (20:1:0.1)) afforded the product (13.9g, 76%). 1U NMR (CDCl3) 7.24-7.21 (IH, m), 6.93-6.90 (IH, m), 6.60 (IH, s), 6.16 (IH, s), 4.12-4.07 (3H, m), 2.82-2.68 (3H, m), 2.33 (3H, s), 1.93-1.19 (23H, m). Step d S-Cyclohexyl-S-fpiperidin^-yty-S-methyl-l-ft-nitrophenyfy-l^-dihydroSH-l^^- benzotriazepin-2-one was obtained using step c of example 1, except that 5-cyclohexyl-3-(l- tert-butoxycarbonyl-piperidin-4-yl)-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5- dihydro- lH-imidazol-2-ylamino)-phenyl)-l ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 8.15-8.10 (2H, m), 7.49-7.45 (2H, m), 7.38-7.36 (IH, m), 7.18-7.16 (IH, m), 6.80 (IH, s), 4.11-4.01 (IH, m), 3.18 (2H, br s), 2.90- 2.70 (3H, m), 2.33-1.15 (18H, m).
Step e 5~Cyclohexyl-3-(l-methanesulfonyl-piperidin-4-yl)-8-methyl-l-(4-nitrophenyl)-l,2~ dihydro-3H-l, 3, 4-benzotriazepin-2-one
To an ice-cooled solution of 5-cyclohexyl-3-(piperidin-4-yl)-8-methyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one (500mg, l.Oδmmol) and NEt3 (227μL, 1.63mmol) in DCM (3mL) was added methanesulfonyl chloride (126μL, 1.63mmol). The reaction was stirred at rt for 18h and then diluted with DCM (4OmL), washed with 10% KHSO4 (5OmL), brine (5OmL) and dried (MgSO4). Filtration and evaporation of the solvent afforded the product (0.6g, 100%). 1H NMR (CDCl3) 8.17-8.13 (2H, m), 7.52-7.48 (2H, m), 7.39-7.35 (IH, m), 7.18-7.16 (IH, m), 6.74 (IH, s), 4.08-3.98 (IH, m), 3.86 (2H, m), 2.90-2.78 (6H, m), 2.34- 2.14 (5H, m), 2.07-1.21 (14H, m).
Step f l-(4-Aminophenyl)-5-cyclohexyl-3-(l-methamsulfonyl-piperidin-4-yl)-8-methyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step d of example 1, except that 5- cyclohexyl-3 -(I -methanesulfonyl-piperidin-4-yl)-8-methyl-l -(4-nitroρhenyl)- 1 ,2-dihydro-3H- l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one.
Step g The title compound was obtained using step a of example 128, except l-(4- aminophenyl)-5-cyclohexyl-3-(l-methanesulfonyl-piperidin-4-yl)-8-methyl-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 9.34 (IH, br s), 7.27-7.14 (3H, m), 7.01-6.92 (3H5 m), 6.62-6.55 (3H, m), 4.44 (3H, s), 3.90-3.76 (3H, m), 2.79-2.75 (6H, m), 2.29-1.31 (17H, m). The compound was further characterised and tested as the HCl salt. Found: C 56.92, H 6.37 N 14.14%; C31H39N7O3S-I^HCl-OJC4H8O2 requires C 56.97, H 6.48, N 14.09%.
Example 250 4-(5-Cyclohexyl-l-(4-((lH~imidazol-2-yltnethyl)-amino)-phenyl)-8-methyl-2-oxo~ 1 ,2-dihydro-3H-l ,3,4-benzotriazepin-l-yl)-piperidine-l-carboxylic acid phenylamide
Step a 4-(5-cyclohexyl-8-methyl-l-(4-nitrophenyl)-l ,2-dihydro-2-oxo-3H-l ,3 ,4-benzotriazepin- 3-yl)-N-phenylpiperidine-l-carboxamide was obtained using example 249 step e except that phenylisocyanate was used in place of methanesulfonyl chloride.
Step b 4-(l-(4-Aminophenyl)-5-cyclohexyl-8-methyl-l,2-dihydro-2-oxo-3H-l,3,4- benzotriazepin-3-yl)-N-phenylpiperidine-l-carboxamide was obtained using step d of example 1, except that 4-(5-cyclohexyl~8-methyl-l-(4-nitrophenyl)-l,2-dihydro-2-oxo-3H-l,3,4- benzotriazepin-3-yl)-N-phenylpiperidine-l-carboxamide was used in place of 3-benzyl-5- cyclohexyl- 1 -(4-nitrophenyl)- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one.
Step c The title compound was obtained using step a of example 128, except 4-(l-(4- aminophenyl)-5-cyclohexyl-8-methyl-l,2-dihydro-2-oxo-3H-l,3,4-benzotriazepin-3-yl)-N- phenylpiperidine-1-carboxamide and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one and formalin respectively, followed by reaction of the product obtained, in place of 3- benzyl-5-cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 9.34 (IH, br s), 7.61-7.16 (7H, m), 7.04-6.92 (4H, m), 6.62-6.55 (3H, m), 6.37 (IH, s), 4.44 (3H, s), 4.12- 3.98 (3H, m), 2.99-2.79 (3H, m), 2.22-1.24 (17H, m). The compound was further characterised and tested as the HCl salt. Found: C 64.12, H 6.49 N 15.79%; C37H42N8O2-LoHCl-O^C4H8O2 requires C 64.24, H 6.45, N 15.85%
Example 251 5-Cyclohexyl-l-(4-((lH-imidazol-2-yhnethyl)-amino)-phenyl)-8-methyl-3-(l- phenyl-piperidin-4-yl) - 1, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
Step a 5~Cyclohexyl-8-methyl-3~(l-phenyl-piperidin-4-yl)-l,2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step c of example 181, except that (2~amino-4- methyl-phenyl)(cyclohexyl)methanone (Example 11 step a) and iV-(l-phenyl-piperidin-4-yl)- hydrazinecarboxylic acid tert-butyl ester were used in place of (2-amino-4-methyl- phenyl)(tetrahydro-pyran-4-yl)methanone and N7-(3,3,5,5-tetramethyl-cyclohexyl)- hydrazinecarboxylic acid tert-butyl ester respectively. 1H NMR (CDCl3) 7.28-7.23 (3H, m), 6.98-6.80 (4H, m), 6.61 (IH, s), 6.07 (IH, s), 4.14-4.02 (IH, m), 3.76-3.72 (2H, m), 2.85-2.76 (2H, m), 2.69 (IH, m), 2.34 (3H, s), 2.21-2.16 (2H, m), 1.89-1.71 (7H, m), 1.53-1.21 (5H, m).
Step b l-(4-Amino-phenyl)-5-cyclohexyl~8-methyl-3-(l-phenyl-piperidin-4-yl)-l,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one was obtained using steps c and d of example 1, except that 5- cyclohexyl-8-methyl-3-(l -phenyl-piperidin-4-yl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.27-7.18 (5H, m), 6.96-6.95 (2H, m), 6.93 (IH, m), 6.68 (2H, d), 6.56 (IH, s), 3.97-3.88 (IH, m), 3.78-3.70 (4H, m), 2.83-2.76 (3H, m), 2.28-1.25 (17H,m).
Step c The title compound was obtained using step a of example 128, except l-(4-amino- phenyl)-5 -cyclohexyl-8-methyl-3-(l -phenyl-piperidin-4-yl)- 1 ,2-dihydro-3H- 1 ,3 ,4- benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of 1- (4-amino-phenyI)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 9.34 (IH, br s), 7.27-7.19 (5H, m), 7.00-6.92 (5H, m), 6.84-6.79 (IH, m), 6.59-6.55 (3H, m), 4.46-4.38 (3H, m), 3.96-3.87 (IH, m), 3.70-3.66 (2H, m), 2.82-2.75 (3H, m), 2.29-1.24 (17H, m). The compound was further characterised and tested as the HCl salt. Found: C 61.88, H 6.45, N 13.68%; C36H41N7O-S-OHCl-O^C4H8O2 requires C 61.84, H 6.43, N 13.72%. Example 252 5-Cyclohexyl-3-(2-methylbenzyl)-l-(4-(2-(lH-imidazol-2-yl)ethyl-amino)- phenyl)-8-methyl-l ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one
Step a l-(4-Amino-phenyl)-5-cyclohexyl-8-methyl-3-(2-methylbenzyl)-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step c of example 20 except that 5-cyclohexyl-8- methyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 184, step b) and 2-methylbenzyl bromide were used in place of 5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one and (3-bromoproρenyl)-benzene respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one, according to step d of example 1. 1H NMR (CDCl3) 7.24 (IH, d), 7.15 (2H, d), 6.92 (IH, d), 6.65 (2H5 d), 6.56 (IH, s), 3.78 (2H, br s), 3.46 (2H, br s), 2.77 (IH, m), 2.22 (3H, s), 1.83-1.24 (12H, m), 0.79 (3H, t).
Step b The title compound was obtained using step a of example 128, except that l-(4-amino- phenyl)-5-cyclohexyl-8-methyl-3-(2-methylbenzyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one and (l-trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4-aminophenyl)-3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5- dihydro- lH-imidazol-2-ylamino)-phenyl)-l ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one, according to step b of example 39. 1HNMR (CDCl3) 7.25 (IH, d), 7.14 (2H, d), 6.96-6.91 (3H, m), 6.58-6.53 (3H, m), 3.47 (4H, m), 2.93 (2H, t), 2.77 (IH, m), 2.21 (3H, s), 1.84-1.21 (12H5 m), 0.79 (3H, t). Found: C 60.50, H 6.84, N 13.91 %; C29H36N6O^-SHCl-O1SC4H10O requires: C 60.65, H 6.99, N 14.05%
Example 253 3-Cyclodecyl-5-cyclohexylidenemethyl-l-(4-(2-(lH-imidazol-2-yl)-ethylamino)- phenyl)-] ,2-dihydro-3H~l 3, 4-benzotriazepin-2-one
Step a 3-Cyclodecyl-l-(4-nitro-phenyl)-2-oxo-l ,2-dihydro-3H-l ,3 ,4-benzotriazepine-5- carbaldehyde
A suspension of 5-bromomethyl-3-cyclodecyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 226 step d) (960mg, 1.9mmol) in DMSO (15mL) was stirred at 120°C for 2h. The mixture was diluted with EtOAc (8OmL) and was washed with brine (3 x 4OmL). The organic phase was dried (MgSO4), filtered and the solvent was removed at reduced pressure. The residue was purified by chromatography (EtOAc-hexane (3:10)) to afford the product (767mg, 91%). 1H NMR (CDCl3) 9.81 (IH, s), 8.15 (2H, d), 7.68 (IH, d), 7.53-7.48 (3H, m), 7.38 (IH, t), 6.95 (IH, d), 4.87 (IH, m), 2.00 (2H, m br), 1.85-1.35 (16H, m).
Step b 3-Cyclodecyl-5-cyclohexylidenemethyl-l-(4-nitro-phenyl)-l ,2-dihydro-3H-l ,3 ,4- benzotriazepin-2-one A solution of butyl lithium in hexanes (1.0M, 0.49mL, 0.49mmol) was added to an ice-cooled suspension of cyclohexyltriphenylphosphonium bromide (209mg, 0.49mmol) in Et2O (2mL) and the mixture was stirred at ice-bath temperature for 4h. A solution of 3-cyclodecyl-l-(4- nitrό-phenyl)-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepine-5-carbaldehyde (200mg,
0.45mmol) in Et2O (ImL) was added to the reaction mixture which was then allowed to reach rt and was stirred overnight. The reaction mixture was diluted with EtOAc (2OmL) and was washed with saturated NH4Cl (3 x 1OmL). The organic phase was dried (MgSO4), filtered and the solvent was removed at reduced pressure. The residue was purified by chromatography (EtOAc-hexane (1:5)) to afford the product (174mg, 76%). 1H NMR (CDCl3) 8.11 (2H, d), 7.51-7.44 (4H3 m), 7.35 (IH, t), 7.09 (IH, d), 6.16 (IH, s), 4.62 (IH, m), 2.31 (2H, t), 2.18 (2H, t), 2.00-1.25 (24H, m).
Step c l'(4-Amino-phenyl)-3-cyclodecyl-5-cyclohexylidenemethyl-l,2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step c of example 7 except that 3-cyclodecyl-5- cyclohexylidenemethyl- 1 -(4-nitro-phenyl)- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazeρin-2-one was used in place of 5-fluoro-2-nitrobenzonitrile. 1H NMR (CDCl3) 7.29-7.19 (4H, m), 7.05 (IH, t), 6.77 (IH, d), 6.66 (2H, d), 6.14 (IH, s), 4.34 (IH, m), 3.68 (2H, br s), 2.31 (2H, t), 2.21 (2H, t), 1.90-1.30 (24H, m).
Step d The title compound was obtained using step a of example 128, except l-(4-amino- phenyl)-3-cyclodecyl-5-cyclohexylidenemethyl- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4-aminophenyl)-3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and fonnalin respectively, followed by reaction of the product obtained, in place of 8-chloro-5-cyclohexyl-3-(3,3,5,5- tetramethyl-cyclohexyl)-l-(4-(2-(l-trityl-lH-imidazol-2-yl)-ethylamino)-phenyl)-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one according to step b of example 210. 1H NMR (DMSOd6) 11.80 (IH, br s), 7.32 (2H, m), 7.12 (IH, t), 7.03 (2H, d), 6.89 (2H, s), 6.73 (IH, d), 6.57 (2H, d), 6.14 (IH, s), 5.80 (IH, br s), 4.21 (IH, m), 3.31 (2H, t), 2.85 (2H, t), 2.26 (2H5 m), 2.17 (2H, m), 2.00-1.20 (24H, m). The compound was further characterised and tested as the HCl salt. Found: C 61.84, H 7.18, N 11.91%; C36H46N6O-1.2HCl-1.0CH2Cl2-0.9H2O requires C 61.95, H 7.28, N 11.71%. Example 254 5-Cyclohexyl-l-(4~((lH-imidazol-2-yhnethyl)~amino)'phenyl)-3-(l- ethoxycarbonyl-piperidin-4-yl)-8-methyI-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
Step a S-CyclohexylS-fl-ethoxycarbonyl-piperidin^-ylJ-S-methyl-l-ft-nitrophenylJ-lJ- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using example 249 step e except that ethylchloroformate was used in place of methanesulfonyl chloride. Step b S-CyclohexylS-fl-ethoxycarbonyl-piperidin^-ylJS-methyl-l^-aminophenyl)-!^- dihydro-3H-l,3,4-benzotnazepin-2-one was obtained using step d of example 1, except that 5- cyclohexyl-3-(l-ethoxycarbonyl-piperidin-4-yl)-8-methyl-l-(4-nitrophenyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one. Step c The title compound was obtained using step a of example 128, except that 5-cyclohexyl- 3-(l -ethoxycarbonyl-piperidin-4-yl)-8-methyl-l -(4-aminophenyl)- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of 1- (4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 9.34 (IH, br s), 7.35-7.16 (3H, m), 7.01 (2H, s), 6.93 (IH, d), 6.64-6.60 (2H, m), 6.65 (IH, s), 4.47-4.36 (3H, m), 4.17-4.09 (4H, m), 3.97-3.87 (IH, m), 2.83-2.78 (3H, m), 2.22 (3H, s), 2.08-1.23 (17H, m). The compound was further characterised and tested as the HCl salt. Found: C 59.79, H 6.59 N 14.71%; C33H41N7O3-S-IHCl requires C 59.62, H 6.69, N 14.75%
Example 255 5-Cyclohexyl-8-methoxy-l-(4-((lH-imidazol-2-ylmethyl)-amino)-phenyl)-3- (tetrahydro~pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one Step a 5-Cyclohexyl-8-methoxy-3-(tetrahydropyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using step c of of example 181 except that (2-amino-4- methoxyphenyl)(cyclohexyl)methanone and iV-(tetrahydropyran-4-yl)-hydrazinecarboxylic acid tert-butyl ester were used in place of (2-amino-4-methyl-phenyl)(tetrahydro-pyran-4- yl)methanone and iV-(3,3,5,5-tetramethyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester respectively. 1H NMR (CDCl3) 7.29-7.26 (IH, m), 6.67-6.63 (IH, dd), 6.32-6.29 (2H5 m), 4.19-4.12 (IH, m), 4.05-3.99 (2H5 m), 3.81 (3H, s), 3.52-3.43 (2H, m), 2.70-2.63 (IH, m), 2.14-2.06 (2H, m), 1.84-1.24 (12H, m).
Step b l-(4-Amino-phenyl)-5-cyclohexyl-8-methoxy-3-(3, 3, 5, 5-tetramethyl-cyclohexyl)-l ,2- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps c and d of example 1, except that 5-cyclohexyl-8-methoxy-3-(tetrahydropyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c. 1H NMR (CDCl3) 7.29-7.26 (IH5 m), 7.16 (2H, d), 6.68-6.64 (3H, m), 6.30 (IH, d), 4.05-3.97 (3H, m), 3.78-3.66 (5H, m), 3.50-3.42 (2H, m), 2.80-2.73 (IH, m), 2.13-1.22 (14H5 m) Step c The title compound was obtained using step a of example 128, except that l-(4-amino- phenyl)-5-cyclohexyl-8-methoxy-3-(tetrahydrpyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of 1- (4-amino-phenyl)-3-benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl- 1 -(4-(4,5 -dihydro- 1 H-imidazol-2-ylamino)-phenyl)- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 9.36 (IH, s), 7.29- 7.27 (IH5 m), 7.20-7.14 (2H, m), 7.00 (2H, s), 6.68-6.58 (3H5 m), 6.25 (IH5 d), 4.45-4.39 (3H5 m), 4.04-3.97 (3H5 m), 3.67 (3H5 s), 3.50-3.42 (2H, m), 2.80-2.73 (IH, m), 2.13-1.24 (14H, m). The compound was further characterised and tested as the HCl salt. Found: C 59.74, H 6.46, N 13.61%; C30H36N6O3^HCl -0.2C4H8O2 required C 59.74, H 6.45, N 13.57%.
Example 256 ~N-l-Naphthyl-2-(5-cyclohexyl-l -(4-((I H-imidazol-2-ylmethyl)-amino)-phenyl)-8- methyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-3-y)-acetamide Step a. (N'-((2-Amino-4-methylphenyl)-cyclohexyl-methylene)-hydrazino)-acetic acid ethyl ester. A mixture of (2-amino-4-methylphenyl)-cyclohexyl-methanone (20.3g, O.lmol) and ethyl hydrazinoacetate HCl (23.25g, 0.15mol) and pyridine (12.1ml, 0.15mol) was heated at reflux in EtOH (400ml) for 72h. On cooling, un-reacted ethyl hydrazinoacetate HCl crystallised from the solution and was removed by filtration. The filtrate was evaporated and the residue was partitioned between saturated NaHCO3 (250ml) and EtOAc (250ml). The organic phase was washed with brine (250ml), dried over MgSO4 then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (EtOAc-hexane (1:4)) to afford the product as a pale yellow foam (21.2g, 71%). Step b. (5-Cyclohexyl-8-methyl-2-oxo-l,2-dihydro-3¥L-l,3,4-benzotriazepin-3-yl)- acetic acid ethyl ester.
To a solution of (N'-((2-amino-4'methylphenyl)-cyclohexyl-methylene)-hydrazino)-acetic acid ethyl ester. (23.39g, 77.0mmol) and triethylamine (26.8ml, 0.19mol) in DCM (300ml) at O0C, a solution of triphosgene (11.4g, 39mmol) in DCM (100ml) was added drop-wise over Ih. The reaction mixture was stirred at this temperature for Ih, washed with H2O (300ml), saturated NaHCO3 (300ml) and brine (300ml). The organic phase was dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The crude product was re-crystallised from Et2O-hexane (1:3) to afford the product as a yellow solid (15.8g, 62%). 1H NMR (CDCl3) 7.27-7.25 (IH, m), 6.95 (IH, d), 6.63 (IH, s), 6.35 (IH, s), 4.31 (2H, s), 4.20 (2H, q), 2.71-2.62 (IH, m), 2.34 (3H, s), 1.81-1.68 (5H, m), 1.49-1.20 (8H, m).
Step c (l^-Aminopheny^-S-cyclohexylS-methyl^-oxo-l^-dihydro^H-lJ^-benzotriazepin- 3-yl)~acetic acid ethyl ester was obtained using steps c and d of example 1, except that (5- cyclohexyl-8-methyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-3-yl)-acetic acid ethyl ester was used in place of S-benzyl-S-cyclohexyl-l^-dihydro-SH-l^^-benzotriazepin^-one in step c. 1H NMR (CDCl3) 7.28-7.26 (IH, m), 7.15-7.10 (2H, m), 6.95 (IH, d), 6.69-6.45 (3H, m), 4.31 (2H, br s), 4.15 (2H, q), 3.70-3.68 (2H, m), 2.82-2.74 (IH, m), 2.21 (3H, s), 1.92-1.19 (13H, m).
Step d (5-Cyclohexyl-l-(4-((l-trityl-lH4midazol-2-ylmethyl)-amino)-phenyl)-8-methyl-2-oxo- 1 ,2-dihydro-3H-l ,3,4-benzotriazepin-3-yl)-acetic acid ethyl ester was obtained using step a of example 128, except that (l-(4-aminophenyl)-5-cyclohexyl-8-methyl-2-oxo-l,2-dihydro-3H- l,3,4-benzotriazepin-3-yl)-acetic acid ethyl ester and (l-trityl-lH-imidazol-2-yl)- carboxaldehyde were used in place of l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 7.42-7.14 (16H, m), 7.03-6.98 (3H, m), 6.92-6.89 (IH, m), 6.83 (IH, s), 6.53 (IH, s), 6.20 (2H, d), 4.38-4.08 (4H, m), 3.29 (2H, s), 2.78-2.72 (IH, m), 2.19 (3H, s), 1.85-1.18 (13H, m). Step e N-J-Naphthyl-2-(5-cyclohexyl-l-(4-((l-trityl-JH-imidazol-2-ylmethyl)-amino)-phenyl)- 8-methyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-3-y)-acetamide was obtained using steps d, e and f of example 13 except that (5-cyclohexyl-l-(4-((l-trityl-lH-imidazol-2-ylmethyl)- amino)-phenyl)-8-methyl-2-oxo-l,2-dihydro-3H-l,3s4-benzotriazepin-3-yl)-acetic acid ethyl ester was used in place of (5-cycIohexyl-l-(4-(N,N-bis-(tert-butoxycarbonyl)-guanidino)- phenyl)-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-3-yl)-acetic acid ethyl ester in step d and 1-naphthylamine was used in place of diphenylmethylamine in step f. 1H ΝMR (CDCl3) 8.71 (IH, s), 8.20 (IH, m), 7.59-7.00 (25H, m), 6.84 (IH, m), 6.67 (IH, s), 6.24 (2H, d), 4.66-4.63 (2H, m), 4.34 (IH, br m), 3.29 (2H, br s), 2.83 (IH, m), 2.30 (3H, s), 2.05-1.18 (1OH, m). Step f The title compound was obtained using step b of example 39 except that Ν-1-naphthyl- 2-(5 -cyclohexyl- 1 -(4-((I -trityl- lH-imidazol-2-ylmethyl)-amino)-phenyl)-8-methyl-2-oxo- 1 ,2- dihydro-3H-l,3,4-benzotriazepin-3-y)-acetamide was used in place of 3-ben2yl-5-cyclohexyl- l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one. 1HNMR (CDCl3) 9.36 (IH, s), 8.87 (IH, s), 8.14 (IH, d), 7.82 (IH, d), 7.62-7.60 (IH, m), 7.45-7.21 (5H, m), 7.15 (2H, d), 7.05 (IH, d), 6.94 (2H, s), 6.71 (IH, s), 6.59 (2H, d), 4.63- 4.52 (2H, m), 4.41-4.36 (3H, m), 2.90-2.84 (IH, m), 2.30 (3H, s), 2.05-1.20 (1OH, m). The compound was further characterised and tested as the HCl salt. Found: C 64.52, H 5.99, N 13.58%; C37H37N7O2-1.9HCl -0.5C4H8O2 required C 64.60, H 5.96, N 13.52%.
Example 257 3,8-Dimethyl-5-cyclohexyl-l-(4-((l-methyl-lH-imidazol-2-ylmethyl)-amino)- phenyl)-! ,2-dihydro-3H-l ,3 ,4-ben∑otriazepin-2-one
The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- S-cyclohexyl-Sjδ-dimethyl-l^-dihydro-SH-l^^-benzotriazepin^-one (example 184, step c) and 1 -methyl- lH-imidazol-2-yl-carboxaldehyde were used in place of l-(4-amino-phenyl)-3- benzyl-S-cyclohexyl-l^-dihydro-SH-l^^-benzotriazepm^-one and formalin respectively. 1H NMR (CDCl3) 7.25 (IH, d), 7.19 (2H, d), 6.99 (IH, s), 6.93 (IH, d), 6.87 (IH, s), 6.70 (2H, d), 6.59 (IH, s), 4.34 (2H, s), 3.66 (3H, s), 3.07 (3H, s), 2.77 (IH, m), 2.22 (3H, s), 1.95-1.31 (1OH, m). The compound was further characterised and tested as the HCl salt. Found: C 61.29, H 6.56, N 15.55%; C27H32N6O-2HC1 requires C 61.03 H 6.46, N 15.82%.
Example 258 3,8-Dimethyl-5-cyclohexyl-l-(4-((lH-imidazol-2-ylmethyl)-amino)~phenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- S-cyclohexyl-Sjδ-dimethyl-l^-dihydro-SH-ljS^-benzotriazepin^-one (example 184, step c) and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of l-(4-amino-phenyl)-3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin~2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5- dihydro-lH-imidazol-2-ylamino)-phenyl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.25 (IH, d), 7.12 (2H, d), 6.95 (3H, m), 6.54 (3H, m), 4.50 (IH, br s), 4.30 (2H, s), 3.07 (3H, s), 2.77 (IH, m), 2.22 (3H, s), 1.84-1.26 (1OH, m). The compound was further characterised and tested as the HCl salt. Found: C 61.19, H 6.41, N 15.96%; C28H34N6O-1.9HCl-0.2C4Hi0O requires C 61.12 H 6.49, N 15.96%.
Example 259 l-(4~(2-(lH-imidazol-2-yl)ethyl-amino)-phenyl)-8-methyl-5-(pyridin-4-yl)-3- (3, 3, 5, 5-tetramethylcyclohexyl)-l ,2-dihydro-3H-l , 3, 4-benzotriazepin-2-one
Step a (2-amino-4-methyl-phenyl)-pyridin-4-yl-methanone was obtained using step a of exmple 224 except that 4-bromopyridine was used in place of 2-bromopyridine.
Step b 8-Methyl-5-pyridin-4-yl-3-(3, 3, 5, 5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step c of example 181, except that (2-amino-4- methyl-phenyl)-pyridin-4-yl-methanone was used in place of (2-amino-4-methyl- phenyl)(tetrahydro-pyran-4-yl)methanone. Step c l^-Amino-phenylj-S-methylS-pyridin^-ylS-fS.SJ^-tetramethyl-cyclohexylJ-l^- dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using steps c and d of example 1, except that 8-methyl-5-pyridin-4-yl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l,2-dihydro-3H~l,3,4- benzotriazepin-2-one in step c. Step d The title compound was obtained using step a of example 128, except that l-(4-amino- phenyl)-8-methyl-5-pyridin-4-yl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4- amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 8.73 (2H, d), 7.59 (2H, m), 7.21 (2H, m), 6.98 (4H, m), 6.68 (IH, s), 6.58 (2H, d), 4.37 (IH, m), 3.52 (2H,m), 3.20 (2H5 m), 2.26 (3H, s), 1.60-0.90 (18H, m).
Example 260 3-(2-Biphenylmethyl)-5-cyclohexyl-8-methyl-l-(4-(3-(lH-imidazol-2- yl)propylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- 3-(biphenyl-2-ylmethyl)-5 -cyclohexyl-8-methyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one (example 190, step a) and 3-(l-trityl-lH-imidazol-2-yl)-propionaldehyde were used in place of l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.32-7.11 (1OH, m), 7.02 (2H, d), 6.92 (3H, m), 6.55 (IH, s), 6.44 (2H, d), 5.00-4.25 (3H, br d), 3.11 (2H, t), 2.71 (2H, t), 2.65 (IH, m), 2.24 (3H, s), 1.96 (2H, t), 1.91-1.26 (1OH, m). The compound was further characterised and tested as the HCl salt. Found: C 67.64, H 6.49, N 11.41%; C4oH42N60-2.5HCl requires C 67.33 H 6.28, N 11.78%.
Example 261 l-(4-(2-(lH-imida∑ol-2-yl)-ethylamino)-phenyl)-8-methyl-5-(tetrahydropyran-4- yl)-3-(6, 7, 8, 9-tetrahydro-5H-benzo[7]annulen- 7-yl)-l ,2-dihydro-3H-l , 3, 4-benzotriazepin-2- one
Step a 5-Cyclohexyl-8-methyl-3-(6, 7 ,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-l ,2-dihydro- 3H-1 ,3,4-benzotriazepin-2-one was obtained using step c of example 181, except that N'- (5,6,8,9-tetrahydrobenzo[7]annulen-7-yl)hydrazinecarboxylic acid tert-butyl ester (example 196 step a) was used in place of (2-amino-4-methyl-phenyl)(tetrahydro-pyran-4-yl)methanone.
Step b l-(4-Amino-phenyl)-5-(tetrahydropyran-4-yl)-8-methyl-3-(6, 7 ,8,9-tetrahydro-5H- benzocyclohepten-7-yl)-l ,2-dihydro-l ,3 ,4-benzotriazepin-2-one was obtained using steps c and d of example 1, except that 5-(tetrahydropyran-4-yl)-8-methyl-3-(6,7,8,9-tetrahydro-5H- benzocyclohepten-7-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one in step c.
Step c The title compound was obtained using step a of example 128, except that l-(4-amino- phenyl)-5-(tetrahydropyran-4-yl)-8-methyl-3-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)- l,2-dihydro-l,3,4-benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one, according to step b of example 39. 1H CDCl3 7.20- 7.10 (7H, m), 6.96 (3H, m), 6.56 (3H, m), 4.06 (3H, m), 3.46 (4H, m), 2.94 (IH, m), 2.76 (6H, m), 2.21 (3H, s), 2.00 (2H, m), 1.96-1.71 (8H, m). The compound was further characterised and tested as the HCl salt. Found: C 60.89, H 6.00, N 11.16%; C36H4oN602-3.3-HCl/0.3 dioxan requires: C 60.74, H 6.26, N 11.42%.
Example 262 5-Cyclohexyl-8-methyl-l-(4-((lH-l,2,4-triazol~3-yl)methyl-amino)-phenyl)-3- (3, 3, 5, 5-tetramethylcyclohexyl)-l, 2-dihydro-3H-l , 3, 4-benzotriazepin-2-one The title compound was obtained using step e of example 207 and except that l-(4-amino- phenyl)-5-cyclohexyl-8-methyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 106 step b) and l-trityl-lH-(l,2,4)triazole-3-carbaldehyde (prepared in 3 steps from lH-(l,2,4)triazole-3-carboxylic acid methyl ester by N-protection with trityl chloride, lithium aluminium hydride reduction and Swern oxidation) were used in place of l-(4-amino-phenyl)-8-chloro-5-cyclohexyl-3-(3,3,5,5-tetramethyl-cyclohexyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one and l-trityl-lH-imidazole-2-carbaldehyde respectively, followed by reaction of the product obtained, in place of 8-chloro-5-cyclohexyl-3-(3,3,5,5- tetramethyl-cyclohexyl)-l-(4-(2-(l-trityl-lH-imidazol-2-yl)-ethylamino)-phenyl)-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one according to step b of example 210. 1H NMR (DMSO-d6) 13.80 (IH, br s), 8.44/7.85 (IH5 2 x br s), 7.41 (IH, d), 7.00-6.95 (3H, m), 6.65-6.53 (2H, m), 6.51 (IH, s), 6.30 (IH, br m), 4.40-4.20 (2H, m), 3.96 (IH, m), 2.93 (IH, t), 2.16 (3H, s), 1.90- 1.50 (8H, m), 1.50-0.75 (2OH, m). The compound was further characterised and tested as the HCl salt. Found: C 62.89, H 7.27, N 15.04%; C34H45N7O-UHCl -0.3CH2Cl2 required C 62.87, H 7.28, N 14.96%.
Example 263 7-Benzylamino-3, 8-dimethyl-5-cyclohexyl-l-(4-(2-(lH-imidazol-2-yl)- ethylamino)-phenyl)-l,2-dϊhydro-3H-l,3,4-benzotriazepin-2-one
Step a S-CyclohexylS^-dimethyl-l^-dihydro-SH-l.S^-benzotriazepin^-one was obtained using step c of example 181, except that (2-amino-4-methyl-phenyl)-cyclohexyl-methanone (example 11, step a) and N'-methyl-hydrazincarboxilic acid ferf-butyl ester (R.E. Melendez, W.D. Lubell: J.A.C.S., 2004, 126, 6759-6764) were used in place of (2-aminophenyl)- cyclohexyl-methanone and N'-(3,3,5,5-tetramethyl-cyclohexyl)-hydrazinecarboxylic acid tert- butyl ester respectively . 1H NMR (CDCI3) 7.25 (IH, d), 6.93 (IH, d), 6.61 (IH, s), 6.28 (IH, s), 3.13 (3H, s), 2.65 (IH, m), 2.34 (3H, s), 1.84-1.21(1OH, m). Step b 5-Cyclohexyl-3,8-dimetl^l-7-nitro-l,2-dϊhydro-3H-l,3,4-benzotriazepin-2-one
To a solution of 5-cyclohexyl-3,8-dimethyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (1.8g, 7.0mmol) in concentrated H2SO4 (3OmL) was added a solution of KNO3 in concentrated H2SO4 (15mL) at O0C. The solution was stirred at room temperature for 16h, and then poured into ice (30Og). The reaction mixture was extracted with DCM (2 x 5OmL) and the extracts were washed with H2O (5OmL)5 saturated NaHCO3 (5OmL)5 brine (5OmL) and dried (MgSO4). Filtration and evaporation of the solvent afforded the product as a yellow solid (2.Og, 90%). 1H NMR (CDCl3) 8.09 (IH5 s), 7.46 (IH, s), 6.81 (IH, s), 3.18 (3H, s), 2.63 (4H5 m), 1.84- 1.71(5H5 m); 1.51-1.22 (5H5 m). Step c 7-Amino-5-cyclohexyl-3,8-dimethyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step d of example 1 except that 5-cyclohexyl-3,8-dimethyl-7~nitro-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (CDCl3) 6.64 (IH, s), 6.55 (IH, s), 6.34 (IH, br s), 3.56 (2H, br s), 3.10 (3H, s), 2.61 (IH, m), 2.15 (3H, s), 1.85-1.21 (1OH, m).
Step d 2-(5-Cyclohexyl-3,8-dimethyl-2-oxo-l,2-dihydro-lH-l,3,4-benzotriazepin-7-yl)- isoindole-1, 3-dione
A mixture of 7-amino-5-cyclohexyl-3,8-dimethyl-l,2-dihydro~3H-l,3,4-benzotriazepin-2-one (1.6g, 5.6mmol) and phthalic anhydride (0.82g, 5.6 mmol) in DMF (5mL) was heated in the microwave at 15O0C for 10 mins. H2O (30 mL) was added and the mixture was extracted with EtOAc (5OmL). The organic layer was separated, washed with saturated NaHCO3 (5OmL), brine (5OmL) and dried (MgSO4). Filtration and evaporation of the solvent afforded the product as a pale yellow solid (2.05g, 89%). 1U NMR (CDCl3) 7.97 (2H, m), 7.83 (2H, m), 7.19 (IH, s), 6.83 (IH, s), 6.56 (IH, s), 3.16 (3H, s), 2.60 (IH, m), 2.19 (3H, s), 1.83-1.21 (1OH, m).
Step e 2-(5-Cyclohexyl-3, 8-dimethyl-l-(4-nitro-phenyl)-2-oxo-l,2-dihydro-lH-l, 3, 4- benzotriazepin-7-yI)-isoindole-l, 3-dione was obtained using step b of example 211 except that 2-(5-cyclohexyl-3,8-dimethyl-2-oxo-l,2-dihydro-lH-l,3,4-benzotriazepin-7-yl)-isoindole-l,3- dione was used in place of 5-cyclohexyl-3-cyclooctyl-8-methyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one. 1H NMR (CDCl3) 8.20 (2H, d), 8.00 (2H, m), 7.85 (2H, m), 7.60 (2H, d), 7.35 (IH, s), 6.88 (IH, s), 3.19 (3H, s), 2.76 (IH, m), 2.17 (3H, s), 1.83-1.24 (1OH, m).
Step f 2-(l-(4-Amino-phenyl)-5-cyclohexyl-3,8-dimethyl-2-oxo-l,2-dihydro-lH-l,3,4- benzotriazepin-7-yl)-isoindole-l, 3-dione was prepared using step d of example 1 except that 2- (5 -cyclohexyl-3 , 8-dimethyl- 1 -(4-nitro-phenyl)-2-oxo- 1 ,2-dihydro- IH-1 ,3 ,4-benzotriazepin-7- yl)-isoindole-l,3-dione was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (CDCl3) 7.96 (2H, m), 7.82 (2H, m), 7.19- 7.13 (3H, m), 6.75-6.68 (3H, m), 4.50 (2H, br s), 3.10 (3H, s), 2.70 (IH, m), 2.10 (3H, s), 1.97- 1.24 (1OH, m).
Step g 2-(5-Cyclohexyl-3,8-dimethyl-2-oxo-l-(4-(2-(l-trityl-lH-imidazol-2-yl)-ethylamino)- phenyl)-!, 2-dihydro-l H-1, 3, 4-benzotriazepin-7~yl)-isoindole-l, 3-dione was obtained using step a of example 128, except that 2-(l-(4-amino-phenyl)-5-cyclohexyl-3,8-dimethyl-2-oxo- 1 ,2-dihydro- IH-1 ,3 ,4-benzotriazepin-7-yl)-isoindole- 1 ,3 -dione and (1 -trityl- lH-imidazol-2- yl)-acetaldehyde were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one and formalin respectively. 1HNMR (CDCl3) 7.96 (2H, m), 7.82 (2H, m), 7.32-7.06 (18H, m), 6.99 (IH, s), 6.74 (2H, s), 4.60 (IH, br s), 3.09 (3H, s), 3.00 (2H, t), 2.70 (IH, m), 2.22 (2H, t), 2.06 (3H, s), 1.98-1.02 (1OH, m).
Step h 7-Amino-5-cyclohexyl-3, 8-dimethyl-l-(4-(2-(l-trityl-lH-imidazol-2-yl)- ethylamino)- phenyl)-l,2-dihydro-3H-l,3,4-henzotriazepin-2-one A solution of 2-(5-cyclohexyl-3,8-dimethyl-2-oxo-l-(4-(2-(l-trityl-lH-imidazol-2-yl)- ethylamino)-phenyl)- 1 ,2-dihydro- IH- l,3,4~benzotriazepin-7-yl)-isoindole- 1 ,3 -dione (0.94g, 1.1 mmol) and hydrazine monohydrate (0.55 mL, 11 mmol) in EtOH (20 mL) was heated at reflux for 2h. The mixture was cooled, the precipitate filtered and the filtrate was evaporated. The residue was suspended in CHCl3, the precipitate removed by filtration and the filtrate evaporated to afford the product as an off-white solid (0.738g, 94%). 1H NMR (CDCl3) 7.31- 7.27 (9H, m), 7.14-6.98 (9H, m), 6.73 (IH, s), 6.62 (IH, s), 6.49 (IH, s), 6.37 (2H, d), 3.50 (2H, br s), 3.05 (3H, s), 2.96 (2H, t), 2.72 (IH, m), 2.22 (2H, t), 2.02 (3H, s), 1.96-1.27 (1OH, m).
Step i 7-Benzylamino-5-cyclohexyl-3,8-dimethyl-l-(4-(2-(l-trityl-lH-imidazol-2-yl)- ethylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step a of example 128, except that 7-ammo-5-cyclohexyl-3,8-dimethyl-l-(4-(2-(l-trityl-lH-imidazol-2- yl)-ethylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and benzaldehyde were used in place of l-(4-aminophenyl)-3-benzyl-5~cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and formalin respectively followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2- dihydro-3H~l,3,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCI3)
7.39-7.29 (5H, m), 7.08 (2H, d), 6.93 (2H, s), 6.50 (2H, d), 6.44 (IH, s), 4.39 (2H, br s), 3.94
(IH3 br s), 3.41 (2H, t), 3.04 (3H, s), 2.86 (2H, t), 2.53 (IH, m), 2.03 (3H, s), 2.00-1.21 (1OH, m). The compound was further characterised and tested as the HCl salt. Found: C 58.31, H 6.36, N 13.74%; C34H39N7O-3.9HC1 requires C 58.13 H 6.15, N 13.96%.
Example 264 5-Cyclohexyl-8-methyl-3-(tetrahydro-pyran-4yl)-(4-(2H-pyrazol-3-yl- methylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
Step a S-Cyclohexyl-l-ft-tø-ft-methoxy-benzylJ^H-pyrazol-S-ylmethylJ-aminoJ-phenylJ-S- methyl-3-(tetrahydro-pyran-4-yl)-l,2~dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step a of example 128, except that l-(4-amino-phenyl)-5-cyclohexyl-8-methyl-3- (tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 182, step b) and 2-(4-methoxy-benzyl)-2H-pyrazole-3-carbaldehyde were used in place of l-(4-aminophenyl)- S-benzyl-S-cyclohexyl-l^-dihydro-SH-l^^-benzotriazepin^-one and formalin respectively. 1H NMR (CDCl3) 7.49 (IH5 s), 7.27 (IH, m), 7.24 (2H, d), 7.17 (2H, d), 6.92 (IH, d), 6.85 (2H, d), 6.55-6.49 (3H, m), 6.25 (IH, s), 5.33 (2H, s), 4.21 (2H5 d), 4.02-3.97 (3H, m), 3.78 (3H, s), 3.71 (IH, m), 3.46 (2H5 1), 2.80 (IH, m), 2.22 (3H5 s), 2.10-1.60 (9H, m), 1.35-1.25 (5H5 m).
Step b A solution of 5-cyclohexyl-l-(4-((2-(4-methoxy-benzyl)-2H-pyrazol-3-ylmethyl)- amino)-phenyl)-8-methyl-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one (190mg, 0.30mmol) and anisole (65DL, 0.60mmol) in trifluoroacetic acid (2mL), was heated at reflux for 4 hr. The solvent was removed at reduced pressure, the residue was then taken up in EtOAc (2OmL) and washed with saturated NaHCO3 (3 x 1OmL). The organic layer was separated and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography (EtOAc) to afford the title compound (106mg, 69%). 1H NMR (DMSO-d6) 12.60/12.54 (IH5 2 x s), 7.60 (0.6H5 br s), 7.43 (1.3H5 m), 6.99- 6.94 (3H, m), 6.61 (2H, d), 6.52 (IH, s), 6.17-6.00 (2H5 m), 4.19 (2H, br m), 3.90-3.70 (3H5 m), 3.32 (2H, m), 2.94 (IH5 m)5 2.16 (3H, s)5 2.00-1.50 (8H, m), 1.50-1.10 (6H5 m). The compound was further characterised and tested as the HCl salt. Found: C 60.0O5 H 6.51, N 13.77%; C30H36N6O2^HCl-0.9H2O required C 59.88, H 6.67, N 13.97%.
Example 265 5-Cyclohexyl-8-methyl-l-(4-((3-(lH-imidazol-4-yl)-propylarnino)-phenyl)-3- (tetrahydropyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
Step a 3-(l-trityl-lH-imidazol-4-yl)-propionaldehyde was obtained using steps d and e of example 201, except that 3-(l-trityl-lH-imidazole-4-yl)-propionic acid was used in place of 3- (l-trityl-lH-imidazole-2-yl)-propionic acid. Lelais, G; Micuch, P; et al.5 HeIv. Chim. Acta (2004), 87 (12), 3131-3159.
Step b The title compound was obtained using step a of example 128, except that l-(4-amino- phenyl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3Η-l,354- benzotriazepin-2-one (example 182, step b) and 3-(l-trityl-lH-imidazol-4-yl)-propionaldehyde were used in place of l-(4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,354- benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.47 (IH5 s), 7.23 (IH5 d), 7.13 (2H, d), 6.91 (IH, d), 6.77 (IH, s), 6.54 (3H, m), 4.03-3.95 (3H, m), 3.46 (2H, t), 3.17 (2H, t), 2.80 (IH5 m), 2.72 (2H, t), 2.21 (3H, s), 2.03-1.26 (14H, m). The compound was further characterised and tested as the HCl salt. Found: C 58.90, H 6.77, N 12.62%; C32H4oN60-2.5HCl-lH20 requires C 58.81 H 6.88, N 12.86%.
Example 266 5-Cyclohexyl-8-methyl-l-(4-((3-(lE-imidazol-2-yl)-propylaιnino)-phenyl)-3- (tetrahydropyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- 5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 182, step b) and 3-(l-trityl-lH-imidazol-2-yl)-propionaldehyde were used in place of 1 -(4-amino-phenyl)-3 -benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl- 1 -(4-(4,5 -dihydro- lH-imidazol-2-ylamino)-phenyl)- 1 ,2-dihydro-3H-l ,3 ,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.24 (IH5 d), 7.10 (2H, d), 6.93 (2H, s), 6.91 (IH, d), 6.57 (IH, s), 6.50 (2H, d), 3.98 (3H, m), 3.45 (2H, t), 3.12 (2H, t), 2.79 (3H, m), 2.21 (3H, s), 2.08-1.26 (14H, m). The compound was further characterised and tested as the HCl salt. Found: C 59.69, H 6.89, N 12.67%; C32H40N6O- 2.9HC1 requires C 59.39 H 6.68, N 12.99%.
Example 267 (S)-l-(4-(2-Amino-3-methyl-butylamino)-phenyl)-5-cyclohexyl8-methyl-3- (tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- 5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 182, step b) and ($-(l-formyl-2-methyl-propyl)-carbamic acid tert-butyl ester were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,N-bis-(ter/-butoxycarbonyl)-N/-(4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro- 3H-l,3,4-benzotriazepin-l-yl)-phenyl)-guanidine, according to step f of example 1. 1H NMR (DMSO-d6-D2O) 7.41 (IH, d), 6.99 (3H, m), 6.64 (2H, d), 6.50 (IH, s), 3.80 (3H, m), 3.34- 3.09 (5H, m), 2.93 (IH, m), 2.14 (3H, s), 2.00-1.06 (15H, m), 0.93 (6H, m). Found: C 60.83, H 7.75, N 11.63%; C31H43N5O2-^SHCl requires: C 61.04, H 7.52, N 11.48%.
Example 268 5-Cyclohexyl-8-methyl-l-(4-((lH-l, 2, 4-triazol-3-yl)methyl-amino)-phenyl)-3- (tetrahydropyran-4-yl)-l , 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- 5-cyclohexyl-8-methyl-3 -(tetrahydro-pyran-4-yl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one (example 182, step b) and l-trityl-lH-(l,2,4)triazole-3-carbaldehyde (obtained from IH- (l,2,4)triazole-3-carboxylic acid methyl ester by N-protection with trityl chloride, followed by lithium aluminium hydride reduction and Swern oxidation) were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained in place of 5-cyclohexyl-l-(4-((2-(4- methoxy-benzyl)-2H-pyrazol-3-ylmethyl)-amino)-phenyl)-8-methyl-3-(tetrahydro-pyran-4-yl)- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one according to example 264 step b. 1H NMR (DMSO-de) 13.80 (IH, d), 8.45/7.85 (IH, 2 x s), 7.42 (IH, d), 6.99-6.93 (3H, m), 6.66-6.58 (2H, m), 6.52 (IH, s), 6.36/6.20 (IH, 2 x br m) 4.36/4.24 (2H, 2 x d), 3.82-3.80 (3H, m), 3.30 (2H, t), 2.94 (IH, m), 2.16 (3H, s), 2.10-1.10 (14H, m). The compound was further characterised and tested as the HCl salt. Found: C 57.21, H 6.42, N 15.65%; C29H35N7O2- 1.9HC1-O.4CH2C12 required C 57.24, H 6.16, N 15.89%. Example 269 5-Cyclohexyl-l-(4-((lH-imidazol-2-ylmethyl)-amino)-phenyl)-8-methyl-3- (tetrahydrothiopyran-4-yl)-l ,2-dihydro-3H-l ,3 ,4-benzotriazepin-2-one
Step a δ-CyclohexylS-methyl^- (tetrahydrothiopyran-4-yl)-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step c of example 181, except that (2-amino-4- methyl-phenyl)(cyclohexyl)methanone (Example 11 step a) and iV-(tetrahydrothiopyran-4-yl)- hydrazinecarboxylic acid tert-butyl ester were used in place of (2-amino-4-methyl- phenyl)(tetrahydro-pyran-4-yl)methanone and JV-(3,3,5,5-tetramethyl-cyclohexyl)- hydrazinecarboxylic acid tert-butyl ester respectively. 1H NMR (CDCl3) 7.25-7.22 (2H, m), 6.93-6.91 (IH, m), 6.60 (IH, s), 6.09 (IH, s), 3.94-3.84 (IH, m), 2.87-2.64 (5H, m), 2.33 (3H5 m), 2.15-2.05 (4H, m), 1.84-1.72 (5H, m), 1.56-1.26 (5H, m). Step b l^-Amino-phenylJ-S-cyclohexylS-methylS-ftetrahydrothiopyran^-ylJ-l^-dihydro- 3H-l,3,4-benzotriazepin-2-one was obtained using steps c and d of example 1, except that 5- cyclohexyl-8-methyl-3 -(tetrahydrothiopyran-4-yl)- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one was used in place of S-benzyl-S-cyclohexyl-l^-dihydro-SH-l^^-benzotriazepin^-one in step c. 1H NMR (CDCl3) 7.24-7.14 (3H, m), 6.92 (IH, d), 6.69-6.62 (2H, m), 6.54 (IH, s), 3.81- 3.69 (3H, m), 2.79-2.53 (5H5 m), 2.21-1.27 (17H, m).
Step c The title compound was obtained using step a of example 128, except that l-(4-amino- phenyl)-5-cyclohexyl-8-methyl-3-(tetrahydrothiopyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of 1- (4-amino-phenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl- 1 -(4-(4,5-dihydro- lH-imidazol-2-ylamino)-phenyl)- 1 ,2-dihydro-3H- 1 ,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 9.50-9.00 (IH , br s), 7.26-7.13 (3H, m), 7.00 (2H, s), 6.94-6.91 (IH, m), 6.67-6.53 (3H, m), 4.43 (3H, m), 3.94- 3.71 (IH5 m), 2.79-2.60 (5H5 m), 2.33-1.32 (17H, m). The compound was further characterised and tested as the HCl salt. Found: C 59.89, H 6.30, N 13.85%;
Figure imgf000232_0001
requires C 59.81, H 6.41, N 13.76%.
Example 270 5-Cyclohexyl-l-(4-(2-(lH-bnidazol-2-yl)-ethylamino)-phenyl)3-methanesulfonyl- 8-methyl-l, 2-dihydro-3H-l, 3, 4-benzotriazepin~2-one Step a 5-Cyclohexyl-3-methanesulfonyl-8-rnethyl-l-(4-nitrophenyl)-l,2~dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step c of example 20 except that 5-cyclohexyl-8- methyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 184, step b) and methanesulfonyl chloride were used in place of 5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one and (3-bromopropenyl)-benzene respectively. 1H NMR (CDCl3) 8.27 (2H, d), 7.53-7.44 (3H, m), 7.17 (IH, d), 6.61 (IH, s), 6.53 (IH, s), 3.42 (3H, s), 2.98 (IH, m), 2.29 (3H, s), 2.16-1.19 (1OH, m).
Step b 1 ^-Amino-phenylJ-S-cyclohexyl^-methanesulfonylS-methyl-l^-dihydro-SH-l, 3, 4- benzotriazepin-2-one To a solution of l-(4-amino-phenyl)-5-cyclohexyl-3-methanesulfonyl-8-methyl-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one (0.27g, 0.58mmol) in THF (1OmL) were added palladium on charcoal (10%, 0.05g) and MeOH (1OmL) and the mixture was stirred under an hydrogen atmosphere for 16h. The catalyst was removed by filtration tghrough celite and the filtrate evaporated to afford the product (0.22g, 89%). 1H NMR (CDCl3) 7.36 (IH5 d), 7.04 (3H, m), 6.70 (3H, m), 4.00 (2H, br s), 3.41 (3H, s), 2.91 (IH, m), 2.26 (3H, s), 2.16 (IH, m), 1.94-1.68 (5H, m), 1.44-1.19 (4H, m).
Step c The title compound was obtained using step a of example 128, except that l-(4-amino- pheny^-S-cyclohexyl-S-methanesulfonyl-S-methyl-l^-dihydro-SH-ljS^-benzotriazepin^-one and (l-trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4-aminophenyl)-3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5- dihydro- lH-imidazol-2-ylamino)-phenyl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.35 (IH, d), 7.04-6.97 (5H, m), 6.69 (IH, s), 6.58 (2H, d), 4.50 (IH, br s), 3.51 (2H, t), 3.40 (3H, s), 3.00 (2H, t), 2.93 (IH, m), 2.25 (3H, s), 2.16 (IH, m), 1.95-1.73 (5H, m), 1.42-1.23 (4H m). The compound was further characterised and tested as the HCl salt. Found: C 53.15, H 5.91, N 13.37 %; C27H32N6O3S- 2.5HC1 requires: C 52.85, H 5.68, N 13.70%
Example 271 5~Cyclohexyl-3,8-dimethyl-l-(4-((4-methyl-lH-imidazol-2-ylmethyl)- amino)- phenyl) -1, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- 5-cyclohexyl-3,8-dimethyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 184, step c) and (4-methyl-l-trityl-lH-imidazol-2-yl)-carboxaldehyde (obtained from 4-methyl-lH- imidazole by the method used in the preparation of l-trityl-lH-imidazol-2-yl)-carboxaldehyde (Kirk, K.L., J. Org. Chem., (1978), 43, 4381) were used in place of l-(4-amino-phenyl)-3~ benzyl-S-cyclohexyl-l^-dihydro-SH-l^^-benzotriazepin^-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5- dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.25 (IH, d), 7.11 (2H, d), 6.93 (IH3 d), 6.63 (IH, s), 6.57 (IH, s), 6.52 (2H, d), 4.54 (IH, br s), 4.21 (2H, s), 3.07 (3H, s), 2.77 (IH, m), 2.21 (6H, s), 2.04-1.26 (1OH, m). The compound was further characterised and tested as the HCl salt. Found: C 62.30, H 6.57, N 15.80%; C27H32N6O-1.8HCl requires C 62.06, H 6.52, N 16.08%.
Example 272 5-Cyclohexyl-3,8-dinιethyl-l-(4-(2-(lH-imidazol-2-yl)-ethylamino)-phenyl)-7- propylamino-1 ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that 7-amino-5- cyclohexyl-3,8-dimethyl-l-(4-(2-(l-trityl-lH-imidazol-2-yl)-ethylamino)-ρhenyl)-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one (example 263, step h) and propionaldehyde were used in place of 1 -(4-aminophenyl)-3 -benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and formalin respectively followed by reaction of the product obtained, in place of 3-benzyl-5- cyclohexyl- 1 -(4-(4, 5 -dihydro- 1 H-imidazol-2-ylamino)-phenyl)- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.13 (2H, d), 6.95 (2H, d), 6.55-6.47 (4H, m), 3.46 (3H, m), 3.13 (2H, t), 3.05 (3H, s), 2.82 (IH, m), 1.99 (3H, s), 1.99-1.55 (7H, m), 1.32-1.27 (5H, m), 1.05 (3H, t). The compound was further characterised and tested as the HCl salt. Found: C 55.97, H 6.80, N 14.89%; C30H39N7O-1.8HCl requires C 55.71, H 6.65, N 15.16%.
Example 273 S-CyclohexylS-methyl-l^-fpiperidin^-ylaminoJ-phenylJ-S-ftetrahydropyran- 4-yl)-l ,2-dihydro-3H-l , 3, 4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- 5-cyclohexyl-8-methyl-3 -(tetrahydro-pyran-4-yl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one (example 182, step b) and 4-oxo-piperidine-l-carboxylic acid acid ter/-butyl ester were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,N-bis- (fert-butoxycarbonyl)-JV"-(4-(3 -benzyM-cyclohexyl^-oxo- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-l-yl)-phenyl)-guanidine, according to step f of example 1. 1H ΝMR (DMSO- d6-D2O) 7.38 (IH, d), 7.06-6.99 (3H, m), 6.76 (2H, d), 6.51 (IH, s), 3.79 (3H, m), 3.53 (2H, m), 3.33-3.26 (4H, m), 2.98-2.90 (3H, m), 2.13 (3H, s), 2.05-1.02 (18H, m). Found: C 59.89, H 7.35, Ν 10.51%; C31H41N5O2^-SHCl-O-SC4H8O2 requires: C 59.89, H 7.28, N 10.58%. Example 274 5-Cyclohexyl-3-cyclopropylmethyl-l-(4-(2-(lH-imidazol-2-yl)-ethylamino)~ phenyl)-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
Step a l-(4-Amino-phenyl)-5-cyclohexyl-3-cyclopropymethyl-8-methyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using step c of example 20 except that 5-cyclohexyl-8- methyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 184, step b) and bromomethyl cyclopropane were used in place of 5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one and (3-bromopropenyl)-benzene respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one, according to step d of example 1. 1H NMR (CDCI3) 7.26(1H, d), 7.15 (2H, d), 6.92 (IH, d), 6.67 (2H, d), 6.57 (IH, s), 3.71 (2H, br s), 3.39 (2H, br s), 2.79 (IH, m), 2.22 (3H, s), 1.84-1.24 (1OH, m), 0.98 (IH, m), 0.39 (2H, d), 0.20 (2H, d).
Step b The title compound was obtained using step a of example 128, except l-(4-amino- phenyl)-5-cyclohexyl-3-cyclopropylmethyl-8-methyl ~l,2-dihydro-3H-l,3,4-benzotriazepin-2- one and (l-trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4-aminophenyl)-3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5- dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.26 (IH, d), 7.11 (2H, d), 6.92 (3H, m), 6.58 (IH, s), 6.52 (2H, d), 3.43 (4H, m), 2.87 (2H, t), 2.79 (IH, m), 2.22 (3H, s), 1.84-1.27 (1OH, m), 0.99 (IH, m), 0.41 (2H, d), 0.20 (2H, d). Found: C 61.17, H 6.64, N 13.67 %; C3OH36N6O^OHCI-OJC4H1OO requires: C 61.02, H 6.75, N 13.86%
Example 275 3-(l-Benzylpiperidin-4-yl)-8-methyl-5-cyclohexyl-l-(4-((lH-imidazol-2-yl)- methylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
Step a l-(4-Aminophenyl)-3-(l-berιzylpiperidin-4-yl)-8-methyl-5-cyclohexyl--l,2-dihydro-3H- 1 ,3,4-benzotriazepin-2-one was obtained using step a of example 128, except 5-cyclohexyl-8- methyl-3-(piperidin-4-yl)- 1 -(4-nitrophenyl)- 1 ,2-dihydro-3H-l ,3 ,4-benzotriazepin-2-one (example 249, step d), and benzaldehyde were used in place of l-(4-amino-phenyl)-3-benzyl- 5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one, according to step d of example 1.
Step b The title compound was obtained using step a of example 128, except that l-(4- aminophenyl)-3-(l-benzylpiperidin-4-yl)-8-methyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and (l-trityl-lH-imidazol-2-yl)-carboxaldehyde were used in place of 1- (4-amino-phenyl)-3 -benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3~benzyl-5- cyclohexyl- 1 -(4-(4,5-dihydro- lH-imidazol-2-ylamino)-phenyl)- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 9.50 (IH, br s), 7.32-7.14 (8H, m), 6.98 (2H, s), 6.92-6.89 (IH, m), 6.57-6.53 (3H, m), 4.43 (IH, m), 4.37 (2H5 s), 3.77-3.73 (IH, m), 3.49 (2H5 br s), 2.89-2.74 (3H, m), 2.26 (3H, s), 2.17-1.31 (14H, m). The compound was further characterised and tested as the HCl salt. Found: C 59.83, H 6.67 N 13.03%; C37H43N7O-S-SHCl-O^C4H8O2 requires C 59.90, H 6.44, N 12.94%.
Example 276 3-(l-Benzylpiperidin-4-yl)-8-methyl-5-cyclohexyl-l-(4-(2-(lH-imidazol-2-yl)- ethylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one The title compound was obtained using step a of example 128, except l-(4-aminophenyl)-3-(l- benzylpiperidin-4-yl)-8-methyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one (example 276, step a) and (l-trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl- l-(4-(4,5-dihydro-lH-imidazol-2-ylamino)-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one, according to step b of example 39. 1H NMR (CDCl3) 9.50 (IH, br s), 7.32-7.17 (8H, m), 6.96-6.92 (3H, m), 6.60-6.55 (3H, m), 4.20 (IH, br s), 3.77 (IH, m), 3.53-3.50 (4H, m), 2.99- 2.78 (5H, m), 2.20-1.32 (19H, m). The compound was further characterised and tested as the HCl salt. Found: C 57.48, H 6.73 N 12.12%; C38H45N7O-S^HCWJH2O requires C 57.35, H 6.73, N 12.32%.
Example 277 5-Cyclohexyl-l-{4-[3-(lH-imidazol-2-yl)-propoxy]-phenyl}-8-methyl-3- (tetrahydro-pyran-4-yl)-l, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one step a 4-[5-Cyclohexyl-8-methyl-2-oxo-3- (tetrάhydro-pyran-4-yl)-l , 2~dihydro-3H-l, 3, 4- benzotriazepin-l-ylj-benzaldehyde A mixture of 5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 182, step a) (10.Og, 29mmol), 4-iodobenzaldehyde (7.47g, 32mmol), copper powder (2.05g, 32mmol), copper (II) acetate (5.85g, 32mmol), and K2CO3 (4.45g, 32mmol) in DMF was stirred at 1300C for 16 hr. On cooling, the reaction mixture was diluted with EtOAc (30OmL) and was washed with aqueous ammonia (25%, 2 x 15OmL), brine (2 x 10OmL) and dried (MgSO4). Filtration and evaporation of the solvent was followed by chromatography (EtOAc-Hexane (3:10-1:2) to afford the product (10.76g, 82%). 1H NMR (CDCl3) 9.94 (IH, s), 7.81 (2H, d), 7.53 (2H, d), 7.35 (IH, d), 7.12 (IH, d), 6.72 (IH, s), 4.19- 3.95 (3H, m), 3.47 (2H, m), 2.86 (IH, m), 2.29 (3H, s), 2.10-1.50 (9H, m), 1.50-1.10 (5H, m) step b S-Cyclohexyl-l^-hydroxy-phenyljS-methyl-S-ftetrahydro-pyran^-ylJ-l^-dihydroSH- 1, 3, 4-benzotriazepin-2-one
Concentrated H2SO4 (170DL) was added to a suspension of 4-[5-cyclohexyl-8-methyl-2-oxo-
3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl]-benzaldehyde (500mg, l.lmmol) in MeOH (23mL). Hydrogen peroxide (30%, 382DL) was added to the resulting solution and the mixture was stirred at rt for 16 h. The solvent was evaporated and the residue was taken into EtOAc (10OmL), washed with saturated NaHCO3 solution (2 x 25mL) and dried
(MgSO4). Filtration and evaporation of the solvent was followed by chromatography (MeOH-
DCM (3:100) to afford the product (315mg, 65%). 1H NMR (DMSO-d6) 9.55 (IH, s), 7.45 (IH, d), 7.07 (2H, d), 7.00 (IH, d), 6.77 (2H, d), 6.51 (IH, s), 3.90-3.80 (3H, m), 3.31 (2H, t),
2.97 (IH, m), 2.18 (3H, s), 2.15-1.10 (14H, m) step c 3-(l-Trityl-lH-imidazol-2-yl)-propan-l-ol
Butyl lithium solution (1.1M in hexanes, 9.5mL, 10.5mmol) was added to a solution of 2- methyl-1-trityl-lH-imidazole (3.24g, lO.Ommol) in THF (12OmL) at -78°C. The solution was stirred at -78°C for 50 min then liquefied ethylene oxide (2.5mL, 50mmol) was added. The mixture was allowed to reach rt and was stirred for 16 h. The solvents were evaporated and the residue was partitioned between EtOAc (20OmL) and saturated NH4Cl solution (10OmL). The organic layer was separated, washed with a saturated NH4Cl solution (10OmL), brine (10OmL) and dried (MgSO4). Filtration and evaporation of the solvent was followed by chromatography (MeOH-DCM (1 :25) to afford the product (2.14g, 58%). 1H NMR (CDCl3) 7.38-7.31 (9H, m), 7.16-7.10 (6H, m), 6.92 (IH, s), 6.69 (IH, s), 5.60 (IH, br), 3.51 (2H, t), 2.10 (2H, t), 1.38 (2H, m). step d 5-Cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l-{4-[3-(l-trityl-lH-imidazol-2-yl)- propoxy] -phenyl}-!, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one Diisopropylazodicarboxylate (136DL, 0.69mmol) was added in two portions to an ice-cooled solution of 5-cyclohexyl- 1 -(4-hydroxy-phenyl)-8-methyl-3 -(tetrahydro-pyran-4-yl)- 1 ,2- dihydro-3H-l,3,4-benzotriazepin-2-one (200mg, 0.46mmol), 3-(l-trityl-lH-imidazol-2-yl)- propan-1-ol (255mg, 0.69mmol), and PPh3 (181mg, 0.69mmol) in THF (HmL). The mixture was allowed to reach rt and was stirred for 24 h. Further portions of diisopropylazodicarboxylate (45DL, 0.23mmol), 3-(l-trityl-lH-imidazol-2-yl)-propan-l-ol (85mg, 0.23mmol), and PPH3 (60mg, 0.23mmol) were added and the mixture was stirred at rt for a further 4 days. The solvent was removed at reduced pressure and the residue was purified by chromatography (EtOAc-hexane (1:2) to EtOAc) to afford the product (33mg, 9%). 1H NMR (CDCl3) 7.33-7.20 (12H, m), 7.15-7.11 (6H, m), 7.00-6.95 (2H, m), 6.72-6.67 (3H, m), 6.51 (IH, s), 4.05-3.90 (3H, m), 3.69 (2H, t), 3.46 (2H, t), 2.81 (IH, m), 2.21 (3H, s), 2.15-1.20 (18H, m) step e The title compound was obtained using step b of example 210 except that 5-cyclohexyl- 8-methyl-3 -(tetrahydro-pyran-4-yl)- l-{4-[3-(l -trityl- 1 H-imidazol-2-yl)-propoxy] -phenyl } - 1 ,2- dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 8-chloro-5-cyclohexyl-3-(3,3,5,5- tetramethyl-cyclohexyl)- 1 -(4-(2-( 1 -trityl- 1 H-imidazol-2-yl)-ethylamino)-phenyl)- 1 ,2-dihydro- 3H-l,3,4-benzotriazepin-2-one. The compound was further characterised and tested as the HCl salt. 1H NMR (DMSO-d6) 14.06 (2H, br s), 7.55 (2H, s), 7.47 (IH, d), 7.18 (2H, d), 7.02 (IH, d), 6.86 (2H, d), 6.49 (IH, s), 4.03 (2H, t), 3.85-3.70 (3H, m), 3.31 (2H, t), 3.08 (2H, t), 2.95 (IH, m), 2.25-2.15 (5H, m), 2.15-1.50 (9H, m), 1.50-1.05 (5H, m).
Example 278 5-Cyclohexyl-l-{4-l2-(lH-imidazol-2-yl)-ethoxy]-phenyl}-8-meihyl-3- (tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one step a 2-(l-trityl-lH-imidazol-2-yl)-ethanol
NaBH4 (172mg, 4.6mmol) was added to a solution of (1 -trityl- lH-imidazol-2-yl)-acetaldehyde (Martinez-Perez, J.A., et al, Synlett, (1999), 12, 1875) (800mg, 2.3mmol) in MeOH/THF (1:1, 8mL) and the mixture was stirred at rt for 16 hr. The reaction was quenched with H2O (4OmL), extracted with DCM (3 x 4OmL) and the combined extracts were dried (MgSO4). Filtration and evaporation of the solvent afforded the product (810mg, 100%). 1H NMR (CDCl3) 7.36-7.30 (9H, m), 7.15-7.11 (6H, m), 6.93 (IH, s), 6.74 (IH, s), 5.00 (IH, m), 3.47 (2H, t), 2.02 (2H, m) step b 5-Cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l-{4-[2-(l-trityl-lH-imidazol-2-yl)- ethoxy]-phenyl}-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step d of example 277 except that 2-(l-trityl-lH-imidazol-2-yl)-ethanol was used in place of 3-(l-trityl- lH-imidazol-2-yl)-propan-l-ol. 1H NMR (CDCl3) 7.34-7.15 (18H, m), 6.99 (IH, s), 6.90 (IH, d), 6.76 (IH, s), 6.70 (2H, d), 6.48 (IH, s), 4.09-3.90 (3H, m), 3.88 (2H, t), 3.46 (2H, t), 2.81 (IH, m), 2.41 (2H, t), 2.21 (3H, s), 2.20-1.25 (14H, m). step c The title compound was obtained using step b of example 210 except that 5-cyclohexyl- 8-methyl-3-(tetrahydro-pyran-4-yl)-l-{4-[2-(l-trityl-lH-imidazol-2-yl)-ethoxy]-phenyl}-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 8-chloro-5-cyclohexyl-3-(3,3,5,5- tetramethyl-cyclohexyl)- 1 -(4-(2-( 1 -trityl- 1 H-imidazol-2-yl)-ethylamino)-phenyl)- 1 ,2-dihydro- 3H-l,3,4-benzotriazepin-2-one. 1H NMR (DMSO-d6) 11.76 (IH, br s), 7.45 (IH, d), 7.19 (2H, d), 7.02-6.88 (5H, m), 6.49 (IH, s), 4.27 (2H, t), 3.90-3.70 (3H, m), 3.31 (2H, t), 3.09-2.90 (3H, m), 2.17 (3H, s), 2.10-1.45 (9H, m), 1.45-1.10 (5H, m). The product was further characterised and tested as the HCl salt. Found: C 62.61, H 6.62, N 11.64%; C3iH37N5O3- 1.3HCl-(UCH2Cl2 requires: C 62.60, H 6.53, N 11.66%. Example 279 5-Cyclohexyl-l-[4-(2-dimethylamino-ethoxy)-phenyl]-8-methyl-3-(tetrahydro- pyran-4-yl)-l,2-dihydro-3H~l,3,4-benzotriazepin-2-one
A suspension of 5-cyclohexyl-l-(4-hydroxy-phenyl)-8-methyl-3-(tetrahydro-pyran-4-yl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one (example 277 step b) (325mg, 0.75mmol), (2-chloro- ethyl)-dimethyl-amine HCl (160mg, 1.13mmol), and K4CO3 (520mg, 3.75mmol) in acetone was heated at reflux for 16 hr. The mixture was allowed to cool, was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc (5OmL) and H2O (5OmL), the organic layer was separated, washed with brine (5OmL) and dried (MgSO4). Filtration and evaporation of the solvent followed by chromatography (neat DCM to MeOH-DCM (1 :50)) afforded the title compound (268mg, 71%). 1H NMR (CDCl3) 7.30-7.23 (3H, m), 6.95-6.88 (3H, m), 6.51 (IH, s), 4.08 (2H, t), 4.04-3.97 (3H, m), 3.46 (2H, t), 2.81 (IH, m), 2.74 (2H, t), 2.35 (6H, m), 2.21 (3H, s), 1.85-1.27 (14H, m). The compound was further characterised and tested as the HCl salt. Found: C 64.67, H 7.61, N 9.96%; C30H40N4O3-1.4HCl requires: C 64.76, H 7.50, N 10.06%. Example 280 S-CyclohexylS-methyl-l-^^-pyrrolidin-l-yl-ethoxyJ-phenylJ-S-ftetrahydw- pyran-4-yl) -1, 2-dihydro-3H-l , 3, 4-benzotriazepin-2-one
The title compound was obtained using the method of example 279 except that l-(2-chloro- ethyl)-pyrrolidine HCl was used in place of (2-chloro-ethyl)-dimethyl-amine HCl. 1H NMR (CDCl3) 7.30-7.23 (3H, m), 6.95-6.89 (3H, m), 6.51 (IH, m), 4.13 (IH, t), 4.03-3.97 (3H, m), 3.46 (2H, t), 2.90 (2H, t), 2.81 (IH, m), 2.65 (4H, br s), 2.21 (3H, s), 2.20-1.26 (18H, m). The compound was further characterised and tested as the HCl salt. Found: C 65.76, H 7.67, N 9.59%; C32H42N4O3-I^HCl requires: C 65.90, H 7.51, N 9.61%.
Example 281 S-Cyclohexyl-S-methyl-l-^-fl-morpholin^-yl-ethoxyyphenylJS-^etrahydro- pyran-4-yl)-l ,2-dihydro-3H-l , 3, 4-benzotriazepin-2-one The title compound was obtained using the method of example 279 except that 4-(2-chloro- ethyl)-morpholine HCl was used in place of (2-chloro-ethyl)-dimethyl-amine HCl. 1H NMR (CDCl3) 7.31-7.24 (3H, m), 6.95-6.87 (3H, m), 6.51 (IH, s), 4.12 (2H, t), 4.03-3.97 (3H, m), 3.74 (4H, m), 3.46 (2H, t), 2.81 (3H, t), 2.58 (4H, m), 2.22 (3H, s), 1.86-1.26 (14H, m). The compound was further characterised and tested as the HCl salt. Found: C 64.52, H 7.42, N 9.34%; C32H42N4O4-LSHCl requires: C 64.57, H 7.34, N 9.41%.
Example 282 S-CyclohexylS-methyl-l-^^-piperidin-l-yl-ethoxyyphenylJS-^etrahydro- pyran-4-yl)-l, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one The title compound was obtained using the method of example 279 except that l~(2-chloro- ethyl)-piperidine HCl was used in place of (2-chloro-ethyl)-dimethyl-amine HCl. 1H NMR (CDCl3) 7.31-7.23 (3H, m), 6.94-6.86 (3H, m), 6.51 (IH, s), 4.12 (2H, t), 4.05-3.96 (3H, m), 3.46 (2H, t), 2.79 (3H, m), 2.53 (4H, t), 2.21 (3H, s), 1.85-1.26 (2OH, m). The compound was further characterised and tested as the HCl salt. Found: C 65.99, H 7.77, N 9.22%; C33H44N4O3-LSHCl requires: C 66.08, H 7.65, N 9.34%.
Example 283 S-Cyclohexyl-l-ft-β-diethylamino-ethoxyJ-phenylJS-methyl-S-ftetrahydro- pyran-4-yl)-l, 2-dihydro-3H-l , 3, 4-benzotriazepin-2-one
The title compound was obtained using the method of example 279 except that (2-chloro- ethyl)-diethyl-amine HCl was used in place of (2-chloro-ethyl)-dimethyl-amine HCl. 1H NMR (CDCl3) 7.27-7.23 (3H, m), 6.94-6.87 (3H, m), 6.51 (IH, s), 4.07-3.96 (5H, m), 3.46 (2H, t), 2.89 (2H, t), 2.81 (IH, m), 2.68-2.60 (4H, m), 2.21 (3H, s), 2.14-1.26 (14H,m ), 1.09-1.05 (6H, m). The compound was further characterised and tested as the HCl salt. Found: C 65.11, H 7.84, N 9.34%; C32H44N4O3-LeHCl requires: C 65.03, H 7.78, N 9.48%. Example 284 7-Benzyloxy-5-cyclohexyl-3-isopropyl-8-methyl-l-[4-(3-piperidin-l-yl-propyl)- phenylj-l ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one
Step a N'-Isopropyl-hydrazinecarboxylic acid tert-butyl ester
A mixture of acetone (75mL, 79mmol), tert-butyl carbazate (1Og, 76mmol), MgSO4 (2g) and AcOH (5 drops) in hexane was heated at reflux for 1 hr. On cooling, the mixture was filtered and the filtrate was concentrated at reduced pressure. The residue was taken up in AcOH-H2O (1:1, 8OmL) and NaCNBH3 (4.75g, 82mmol) was added. The mixture was stirred at rt for 2.5 hr, then the solvents were removed at reduced pressure, the residue was taken up in EtOAc (30OmL) and was washed with 10% K2CO3 (15OmL), brine (15OmL) and dried (MgSO4). Filtration and evaporation of the solvent and trituration of the residue with hexane afforded the product as an amorphous white solid. A further crop of product crystallised on standing from the supernatant (6.Og, 46%). 1H NMR (CDCl3) 6.12 (IH, br s), 3.85 (IH, br s), 3.12 (IH, m), 1.46 (9H, s), 1.02 (6H, d)
Step b (2-Amino-5-methoxy-4-methyl-phenyl)-cyclohexyl-methanone was obtained using step b of example 181 except that cyclohexanecarbonitrile and 4-methoxy-3-methyl-phenylamine were used in place of tetrahydro-pyran-4-carbonitrile and m-toluidine respectively. 1H NMR (CDCl3) 7.12 (IH, s), 6.49 (IH, s), 5.98 (2H5 br s), 3.80 (3H5 s), 3.19 (IH, m), 2.19 (3H, s), 1.95-1.20 (1OH, m) Step c 5-Cyclohexyl-S-isopropyl' 7-methoxy-8-methyl-l , 2-dihydro-3H-l, 3, 4-benzotriazepin-2- one was prepared using step c of example 181 except that (2-amino-5-methoxy-4-methyl- phenyl)-cyclohexyl-methanone and isopropyl-hydrazinecarboxylic acid tert-butyl ester were used in place of (2-amino-4-methyl-phenyl)-(tetrahydro-pyran-4-yl)-methanone and N- (3,3,5,5-tetramethyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester respectively. 1H ΝMR (CDCl3) 6.71 (IH, s), 6.58 (IH, s), 5.98 (IH, br s), 4.30 (IH, m), 3.84 (3H, s), 2.69 (IH, m), 2.19 (3H, s), 1.90-1.20 (16H, m).
Step d 4-(5-Cyclohexyl-3-isopropyl- 7-methoxy-8~methyl-2-oxo-l ,2-dihydro-3H-l , 3, 4- benzotriazepin-l-yl)-benzaldehyde was prepared using step a of example 277 except that 5- cyclohexyl-3-isopropyl-7-methoxy-8-methyl-l,2-dihydro-lH-l,3,4-benzotriazepin-2-one was used in place of 5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l52-dihydro-3H-l,3,4- benzotriazepin-2-one. 1H NMR (CDCl3) 9.90 (IH, s), 7.75 (2H, dd), 7.45 (2H, d), 6.79 (2H5 d), 4.34 (IH, m), 3.91 (3H, s), 2.85 (IH, m), 2.17 (3H, s), 2.05-1.03 (16H, m). step e 4-(5-Cyclohexyl-7-hydroxy-3-isopropyl-8-methyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-benzaldehyde
BBr3 (1.0M in DCM / 36mL, 36mmol) was added to an ice-cooled solution of 4-(5-cyclohexyl- 3-isopropyl-7-methoxy-8-methyl-2-oxo- 1 ,2-dihydro-3H-l ,3,4-benzotriazepin- 1 -yl)- benzaldehyde (3.14g, 7.2mmol) in DCM (24mL). The mixture was stirred at 50C for 1 hr, then quenched with H2O (25mL) and diluted with DCM (5OmL). The organic layer was separated, washed with saturated NaHCO3 solution (3 x 5OmL) and dried (MgSO4). Filtration and evaporation of the solvent afforded the product (3.02g, 99%). 1H NMR (CDCl3) 9.90 (IH, s), 7.76 (2H, d), 7.45 (2H, d), 6.86 (IH, s), 6.80 (IH, s), 5.13 (IH, br s), 4.35 (IH, m), 2.78 (IH, m), 2.24 (3H, s), 1.95-0.90 (16H, m) step f 4-(7-Benzyloxy-5-cyclohexyl-3-isopropyl-8-methyl-2-oxo-l,2-dihydro-3H-l, 3, 4- benzotriazepin-l-yl)-benzaldehyde was prepared using step a of example 150 except that 4-(5- cyclohexyl-7-hydroxy-3-isopropyl-8-methyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)- benzaldehyde and benzyl bromide were used in place of phenol and 3-benzyl-5-bromomethyl- l-(4-nitro-ρhenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one respectively. 1H NMR (CDCl3)
9.90 (IH, s), 7.77 (2H, d), 7.48-7.37 (7H, m), 6.82 (2H, d), 5.16 (2H, d), 4.34 (IH5 m), 2.74 (IH5 m), 2.23 (3H, s), 1.96-0.84 (16H, m).
step g 3-[4-(7-Benzyloxy-5-cyclohexyl-3-isopropyl-8-methyl-2-oxo-l,2-dihydro-lH-l,3,4- benzotriazepin-1-yl) -phenyl] -acrylic acid ethyl ester
A solution of 4-(7-benzyloxy-5-cyclohexyl-3-isopropyl-8-methyl-2-oxo-l,2-dihydro-3H-l,354- benzotriazepin-l-yl)-benzaldehyde (l-42g, 2.8mmol) and (carbethoxymethylene)triphenylphosphorane (1.46g, 4.2mmol) in THF (1OmL) was heated at reflux for 4 hr. The solvent was evaporated and the residue purified by chromatography (EtOAc-hexane (1:5)) to afford the product (1.59g, 98%). 1H NMR (CDCl3) 7.64 (IH, d), 7.47- 7.35 (9H, m), 6.80 (IH, s), 6.64 (IH, s), 6.34 (IH, d), 5.14 (2H, s), 4.30-4.22 (3H, m), 2.72 (IH, m), 2.18 (3H, s), 2.00-1.60 (6H, m), 1.50-0.90 (13H, m) step h S- [4- (l-BenzyloxyS-cyclohexyl-S-isopropylS-methyl-l-oxo-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-1-yl) -phenyl] -propionic acid ethyl ester
A solution of 3-[4-(7-benzyloxy-5-cyclohexyl-3-isopropyl-8-methyl-2-oxo-l,2-dihydro-lH- l,3,4-benzotriazepin-l-yl)-phenyl]-acrylic acid ethyl ester (1.58g, 2.7mmol) in THF (9mL) was hydrogenated over 10% Pd-C (160mg) at rt for 5 hr. The solution was filtered through a pad of Celite and the solvent was evaporated. The residue was dissolved in DMF (9mL), benzyl bromide (357DL, 3.0mmol) and K2CO3 (753mg, 5.4mmol) were added and the mixture was stirred at rt overnight. The mixture was diluted with EtOAc (5OmL), washed with 2M HCl (3 x 25mL) and dried (MgSO4). Filtration and evaporation of the solvent was followed by chromatography (EtOAc-hexane (3:10)) to afford the product (1.44g, 91%). 1H NMR (CDCI3) 7.46-7.27 (7H, m), 7.15 (2H, d), 6.76 (IH, s), 6.53 (IH, s), 5.12 (2H, s), 4.14 (3H, m), 2.94 (2H, t), 2.75-2.55 (3H, m), 2.14 (3H, s), 2.10-1.55 (6H, m), 1.50-0.90 (13H, m) step i 3-[4-(7-Benzyloxy-5-cyclohexyl-3-isopropyl-8-methyl-2-oxo-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-1-yl) -phenyl] -propionaldehyde DIBAL (1.5M solution in toluene/ 3.3mL, 5.0mmol) was added to a solution of 3-[4-(7- benzyloxy-S-cyclohexyl-S-isopropyl-δ-methyl^-oxo-l^-dihydro-SH-ljS^-benzotriazepin-l- yl)-phenyl]-propionic acid ethyl ester in toluene at -780C. The solution was stirred at -78°C for 1 hr then MeOH (5mL) slowly added followed by 2M HCl (6OmL). The mixture was allowed to reach rt and extracted with EtOAc (3 x 25mL). The combined organic extracts were washed with brine (25mL) and dried (MgSO4). Filtration and evaporation of the solvent was followed by chromatography (EtOAc-hexane (3:10)) to afford the product (912mg, 69%). 1H NMR (CDCl3) 9.82 (IH, s), 7.46-7.33 (7H, m), 7.16 (2H, d), 6.78 (IH, s), 6.55 (IH, s), 5.13 (2H, s), 4.17 (IH, m), 2.95 (2H, t), 2.80-2.68 (3H, m), 2.16 (3H, s), 2.15-1.55 (5H, m), 1.55- 0.90 (1 IH, m) step j The title compound was obtained using step a of example 128 except that piperidine and 3 -[4-(7-benzyloxy-5 -cyclohexyl-S-isopropyl-δ-methyl^-oxo- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-l-yl)-phenyl]-propionaldehyde were used in place of l-(4-aminophenyl)-3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 7.46-7.27 (7H, m), 7.14 (2H, d), 6.76 (IH, s), 6.54 (IH, s), 5.12 (2H, s), 4.17 (IH, m), 2.70-2.58 (3H, m), 2.45-2.25 (6H, m), 2.14 (3H, s), 2.10-0.90 (24H, m). The compound was further characterised and tested as the HCl salt. Found: C 70.66, H 7.87, N 8.09%; C39H50N4O2-1.1HC1-0.9H20 requires: C 70.63, H 8.04, N 8.45%.
Example 285 7-Benzyloxy-5-cyclohexyl-3-isopropyl~8-methyl-l-[4-(3-morpholin-4-yl-propyl)- phenyl] -1, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
The title compound was obtained using step a of example 128 except that morpholine and 3-[4- (7-benzyloxy-5-cyclohexyl-3-isopropyl-8-methyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin- l-yl)-phenyl]-propionaldehyde (example 284, step i) were used in place of l-(4-aminophenyl)- 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 7.46-7.28 (7H, m), 7.14 (2H, d), 6.76 (IH, s), 6.53 (IH, s), 5.12 (2H, br s), 4.17 (IH, m), 3.73-3.70 (4H, m), 3.45-3.30 (6H, m), 2.75-2.60 (3H, m), 2.14 (3H, s), 2.05-1.55 (8H, m), 1.50-0.90 (1OH, m). The compound was further characterised and tested as the HCl salt. Found: C 68.82, H 7.56, N 8.18%; C3SH48N4O3-O^HCl-IJH2O requires: C 68.63, H 7.81, N 8.42%. Example 286 J-Benzyloxy-S-cyclohexylS-isopropyl-S-methyl-l-^-fi-ø-methyl-piperazin-l- yl)-propyl] -phenyl}-!, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
The title compound was obtained using step a of example 128 except that 1-methylpiperazine and 3-[4-(7-benzyloxy-5-cyclohexyl-3-isopropyl-8-methyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-propionaldehyde (example 284, step i) were used in place of 1- (4-aminophenyl)-3-benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 7.46-7.28 (7H, m), 7.14 (2H, d), 6.76 (IH, s), 6.53 (IH, s), 5.11 (2H, br s), 4.17 (IH, m), 2.70-2.25 (16H, m), 2.14 (3H, s), 2.10-1.60 (8H, m), 1.50-0.90 (1OH, m). The compound was further characterised and tested as the HCl salt. Found: C 64.76, H 7.57, N 9.36%; C39H51N5O2-2.1HCl-0.4CH2Cl2 requires: C 64.61, H 7.42, N 9.56%
Example 287 7-Benzyloxy-5-cyclohexyl-l-[4-(3-dimethylamino-propyl)-phenyl]-3-isopropyl-8~ methyl- 1 ,2-dihydro-3H-l ', 3, 4-benzotriazepin-2-one
The title compound was obtained using step a of example 128 except that dimethylamine and 3-[4-(7-benzyloxy-5-cyclohexyl-3-isopropyl-8-methyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl]-propionaldehyde (example 284, step i) were used in place of 1- (4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 7.45-7.27 (7H, m), 7.14 (2H, d), 6.76 (IH, s), 6.54 (IH, s), 5.12 (2H, s), 4.17 (IH, m), 2.75-2.60 (3H, m), 2.35-2.30 (8H,m), 2.14 (3H, s), 2.00- 1.50 (8H, m), 1.50-1.00 (1OH, m). The compound was further characterised and tested as the HCl salt. Found: C 69.73, H 7.71, N 8.92%; C36H46N4O2-LlHCl-OJH2O requires: C 69.80, H 7.89, N 9.04%.
Example 288 7-Benzyloxy-5-cyclohexyl-3-isopropyl-8-methyl-l-[4-(3-piperazin-l-yl-proρyl)- phenylj-l ,2-dihydro-3H~l ,3,4-benzotriazepin-2-one The title compound was obtained as the HCl salt using step a of example 128 except that piperazine-1-carboxylic acid tert-butyl ester and 3-[4-(7-benzyloxy-5-cyclohexyl~3-isopropyl- 8-methyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin- 1 -yl)-phenyl]-proρionaldehyde (example 284, step i) were used in place of l-(4-aminophenyl)-3~benzyl-5-cyclohexyl-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,iV-bis-(tert-butoxycarbonyl)-N/-(4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl)-guanidine, according to example 1 step f. 1H ΝMR (DMSO-d6) 11.75 (IH, br s), 9.58 (2H, br s), 7.48-7.11 (1OH, m), 6.52 (IH, s), 5.21 (2H, s), 4.02 (IH, m), 3.80-2.90 (HH, m), 2.63 (2H, t), 2.20-1.50 (HH, m), 1.50-0.80 (1OH, m). Found: C 64.55, H 7.53, Ν 9.38%; C38H49Ν5θ2-2.5HCl-0.6dioxane requires: C 64.54, H 7.55, N 9.31%
Example 289 l-{4-[(l-Amino-cyclopentylmethyl)-amino]-phenyl}-5-cyclohexyl-3-isopropyl-8- methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one step a S-Cyclohexyl-S-isopropylS-methyl-l ,2-dihydro-lH-l ,3 ,4-benzotriazepin-2-one was prepared by the method of example 181 step c except that (2-amino-4-methyl-phenyl)- cyclohexyl-methanone (example 11, step a) and N'-isopropyl-hydrazinecarboxylic acid tert- butyl ester (example 284, step a) were used in place of (2-amino-4-methyl-phenyl)-(tetrahydro- pyran-4-yl)-methanone and N -(3,3,5,5-tetramethyl-cyclohexyl)-hydrazinecarboxylic acid tert- butyl ester respectively. 1H ΝMR (CDCl3) 7.25-6.60 (3H, m), 6.14 (IH, br s), 4.32 (IH, m), 2.70 (IH, m), 2.33 (3H, s), 1.86-1.20 (16H, m) step b 5-Cyclohexyl-3-isopropyl-8-methyl-l-(4~nitro-phenyl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one was obtained using step b of example 211 except that 5-cyclohexyl-3- isopropyl-8-methyl-l,2-dihydro-lH-l,3,4-benzotriazepin-2-one was used in place of 5- cyclohexyl-3-cyclooctyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one. 1H ΝMR (CDCl3) 8.14-6.83 (7H, m), 4.35 (IH, m), 2.87 (IH, m), 2.33 (3H, s), 2.05-0.80 (16H, m) step c l-(4-Amino-phenyl)-5-cyclohexyl-3-isopropyl-8-methyl-l,2-dihydro-3H-l,3,4- benzotriazepin'2-one was obtained using step d of example 1 except that 5-cyclohexyl-3- isopropyl-8-methyl-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl- 1 -(4-nitrophenyl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one. 1H NMR (CDCl3) 7.26-6.54 (7H, m), 4.15 (IH, m), 3.71 (2H5 br s), 2.80 (IH, m), 2.21 (3H5 s), 2.00-1.00 (16H, m) step d The title compound was obtained as the HCl salt using step a of example 128 except that l-(4-amino-phenyl)-5-cyclohexyl-3-isopropyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin- 2-one and (l-formyl-cyclopentyl)-carbamic acid tert-butyl ester were used in place of l-(4- aminophenyl)-3 -benzyl-5-cyclohexyl- 152-dihydro-3H- 153,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of
Figure imgf000245_0001
butoxycarbonyl)-N"-(4-(3-benzyl-5 -cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin- 1 - yl)-phenyl)-guanidine, according to example 1 step f. 1H ΝMR (DMSO-d6) 8.20 (3H5 br s), 7.45-7.41 (IH5 m), 7.02-6.96 (3H, m), 6.71-6.68 (2H, m), 6.50 (IH, s), 4.00-3.92 (IH, m), 3.26 (IH, s)5 2.98-2.92 (IH, m), 2.16 (3H5 s), 1.83-0.98 (24H, m). Found: C 63.78, H 7.85, Ν 11.73%; CsoHuΝsO^HCl-O^dioxane requires: C 63.7O5 H 7.82, Ν 11.75%.
Example 290 5-Cyclohexyl-3-isopropyl-8-methyl-l-{4-[(pipeτidm-4-ylmethyl)-amino]- phenyl}-l,2-dihydro-3H-l, 3, 4-benzotriazepin-2-one The title compound was obtained as the HCl salt using step a of example 128 except that l-(4- amino-phenyl)-5-cyclohexyl-3-isopropyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 289, step c) and 4-formyl-piperidine-l-carboxylic acid tert-butyl ester were used in place of 1 -(4-aminophenyl)-3-benzyl-5-cyclohexyl- 1 ,2-dihydro-3H- 153,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,N-bis- (fert-butoxycarbonyl)-N'-(4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3;4- benzotriazepin-l-yl)-phenyl)-guanidine5 according to example 1 step f. 1H ΝMR (CDCI3) 8.87 (IH, m), 8.60 (IH5 m)5 7.44-7.41 (IH5 m)5 7.04-7.00 (3H5 m), 6.69-6.66 (2H, m), 6.53 (IH, s), 3.98-3.94 (IH, m)5 3.34-3.23 (2H5 m)5 2.97-2.79 (5H, m), 2.17 (3H5 s), 1.72-0.98 (20H5 m). Found: C 60.12, H 7.78, Ν 11.28%; C30H41Ν5O-2.9HCl-0.4dioxane requires: C 60.37, H 7.55, N 11.14%.
Example 291 5-Cyclohexyl-3-isopropyl-8-methyl-l-[4-(2-methylamino-ethylamino)-phenylJ- l,2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
The title compound was obtained as the HCl salt using step a of example 128 except that l-(4- amino-phenyl)-5-cyclohexyl-3 -isopropyl-8-m ethyl- 152-dihydro-3H- 1 ,3,4-benzotriazepin-2-one (example 289, step c) and methyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester were used in place of 1 -(4-aminophenyl)-3 -benzyl-5-cyclohexyl- 152-dihydro-3H- 1 ,354-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,N-bis- (tert-butoxycarbonyl)-N"-(4-(3 -benzyl-S-cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1,3,4- benzotriazepin-l-yl)-phenyl)-guanidine, according to example 1 step f. 1H ΝMR (CDCl3) 8.82 (2H5 br s), 7.44-7.41 (IH, m), 7.04-6.97 (3H, m), 6.64-6.61 (2H, m), 6.51 (IH, s), 5.20 (2H, br s), 4.00-3.92 (IH, m), 3.38 (2H5 m), 3.05-2.96 (3H5 m), 2.58-2.55 (3H, m), 2.16 (3H, s), 1.94- 0.98 (16H, m). Found: C 61.28, H 7.6I5 N 12.88%; C27H37N5O-2.2HCl-0.2dioxane requires: C 61.22, H 7.54, N 12.84%. Example 292 l'[4-(2-Amino-ethylωnino)-phenyl]-5-cyclohexyl-3-isopropyl-8-methyl-l,2- dihydro-3H-l, 3, 4-benzotriazepin-2-one step a 2-{2-[4-(5-Cyclohexyl-3-isopropyl-8-methyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenylamino]-ethyl}-isoindole-l,3-dione was obtained using step a of example 128 except that l-(4-amino-phenyl)-5-cyclohexyl-3-isopropyl-8-methyl-l,3-dihydro- 3H-l,3,4-benzotriazepin-2-one (example 289, step c) and (l,3-dioxo-l,2-dihydro-isoindol-2- yl)-acetaldehyde (R. Thayumanavan, F. Tanaka, C. F. Barbas III, Org. Lett., 2004, 6, 3541) were used in place of l~(4-aminophenyl)-3-benzyl~5-cyclohexyl~l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 7.87-7.83 (2H5 m), 7.75- 7.71 (2H, m), 7.27-7.19 (3H, m), 6.90-6.87 (IH, m), 6.62-6.53 (3H, m), 4.18-4.09 (2H5 m), 4.00-3.93 (2H, m), 3.45-3.40 (2H, m), 2.80 (IH, m), 2.19 (3H, s), 1.88-1.24 (16H, m). step b A mixture of 2-{2-[4-(5-cyclohexyl-3-isopropyl-8-methyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenylamino]-ethyl}-isoindole-l,3-dione (877mg5 1.56mmol) and hydrazine hydrate (377OL5 7.77mmol) in EtOH (15mL) was heated at reflux for 1 hr. On cooling, the precipitate was removed by filtration and was washed with CHCl3. The combined filtrate was evaporated, the residue was taken up in EtOAc (5OmL), washed with H2O (5OmL)5 brine (5OmL) and dried (MgSO4). Filtration and evaporation of the solvent afforded the title compound (449mg5 66%). 1H NMR (CDCl3) 7.25-7.17 (3H5 m), 6.91-6.88 (IH5 m), 6.63-6.56 (3H5 m), 4.19-4.11 (2H, m)5 3.21-3.18 (2H5 m)5 2.99-2.95 (2H, m), 2.81 (3H5 s), 1.85-1.23 (18H5 m). The compound was further characterised and tested as the HCl salt. Found: C 60.54, H 7.46, N 12.95%; C26H35N5O^.2HC1-0.3 dioxane requires: C 60.47, H 7.39, N 12.96%
Example 293 l-{4-[(2-Amino-pyridin-3-ylmethyl)-amino]-phenyl}-5-cyclohexyl-3-isopropyl-8- methyl-1 ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one step a (3-{[4-(5-Cyclohexyl-3-isopropyl-8-methyl-2-oxo-l,2-dihydro-3H~l,3,4-benzotriazepin- l-yl)-phenylamino]-methyl}-pyridin-2-yl)-carbamic acid tert-butyl ester was obtained using step a of example 128 except that l-(4-amino-phenyl)-5-cyclohexyl-3-isopropyl-8-methyl-l52- dihydro-3H-l,3,4-benzotriazepin-2-one (example 289, step c) and (3-formyl-pyridin-2-yl)- carbamic acid tert-butyl ester (M.C. Venuti, R. A. Stephenson et al, J. Med. Chem., (1988), 31, 2136) were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 8.35 (IH5 br s)5 7.73 (IH, d), 7.29-7.18 (4H, m), 7.08 (IH, m), 6.89 (IH, d), 6.62 (2H, m), 6.53 (IH, s), 4.35 (2H, s), 4.20 (IH, br s), 4.14 (IH, m), 2.80 (IH, m), 2.21 (3H, s), 2.00-1.00 (16H, m), 1.50 (9H, s) step b A solution of (3-{[4-(5-cyclohexyl-3-isopropyl-8-methyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenylamino] -methyl }-pyridin-2-yl)-carbamic acid tert-butyl ester (120mg, 0.20mmol) in TFA (2mL) was stirred at rt for 2 hr. The solvents were removed at reduced pressure and the residue was suspended in EtO Ac-saturated NaHCO3 solution (1:1 / 4OmL) and the organic layer was separated and dried (MgSO^. Filtration and evaporation of the solvent gave the title compound (80mg, 80%). 1H NMR (CDCl3) 8.00 (IH, m), 7.45 (IH, d), 7.25 (3H, m), 6.90 (IH, d), 6.70 (3H, m), 6.55 (IH, s), 5.30 (2H, br s), 4.20 (2H, s), 3.80 (IH, br s), 2.80 (IH, m), 2.20 (3H, s), 2.00-1.00 (16H, m). The compound was further characterised and tested as the HCl salt. Found: C 60.62, H 6.81, N 14.29%; C30H36N6O^HCl- 1.25H2O requires: C 60.85, H 6.89, N 14.19%
Example 294 l-{4-[(6-Amino-pyridin-3-ylmethyl)-amino]-phenyl}-5-cyclohexyl-3-isopropyl-8- methyl-1 ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one The title compound was obtained using step a of example 128 except that l-(4-amino-ρhenyl)- 5-cyclohexyl-3-isopropyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 289, step c) and (5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (P.G. Nantermet et al, Bioorg. Med. Chem. Lett, 2004, 14, 2141) were used in place of l-(4-aminophenyl)-3-benzyl- 5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of (3-{[4-(5-cyclohexyl-3-isopropyl-8-methyl-2- oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenylamino]-methyl}-pyridin-2-yl)-carbamic acid tert-butyl ester, according to example 293 step b. 1H NMR (CDCl3) 8.06 (IH, s), 7.47 (IH, d), 7.26-7.17 (3H, m), 6.89 (IH, d), 6.61-6.49 (4H, m), 4.55 (2H, br s), 4.15 (3H, m), 3.96 (IH, t), 2.80 (IH, m), 2.21 (3H5 s), 2.00-1.00 (16H, m). The compound was further characterised and tested as the HCl salt. Found: C 61.30, H 6.91, N 14.41%; C30H36N6O-2HCl- H2O requires: C 61.32, H 6.86, N 14.30%
Example 295 5-Cyclohexyl-3-isopropyl-8-methyl-l-{4-[(l-methyl-piperidin-4-ylmethyl)- amino]-phenyl}-l,2-dihydro-lH-l,3,4-benzotriazepin-2-one
The title compound was obtained using step a of example 128 except that l-(4-amino-phenyl)- S-cyclohexyl-S-isopropyl-δ-methyl-l^-dihydro-SH-ljS^-benzotriazepin^-one (example 289, step c) and l-methyl-piperidine-4-carbaldehyde (A. P. Gray, R. D. Platz et al, J. Med. Chem. 1988, 31, 807) were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 7.23-7.15 (3H, m), 6.88 (IH, d), 6.58-6.50 (3H, m), 4.15 (IH, m), 3.75 (IH, br s), 3.02 (2H, d), 3.00-2.75 (3H, m), 2.30 (3H, s), 2.20 (3H, s), 2.00-1.00 (23H, m). The compound was further characterised and tested as the HCl salt. Found: C 58.80, H 7.87, N 10.56%; C3iH43N5O-3.5HCl-0.6dioxane requires: C 58.81, H 7.58, N 10.27%
Example 296 5-CyclohexylA-[4-(2-dimethylamino-ethylamino)-phenyl]-3Asopropyl-8-methyl- 1, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one step a N-[4-(5-CyclohexyI-3-isopropyl-8-methyl-2-oxo-l ,2-dihydro-3H-l ,3,4-benzotria∑epin-l- yl)-phenyl]-2-dimethylamino-acetamide was obtained using step a of example 71 except that 1- (4-amino-phenyl)-5-cyclohexyl-3-isopropyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one (example 289 step c) and dimethylamino-acetic acid were used in place of l-(4- aminopheny^-S-benzyl-S-cyclohexyl-l^-dihydro-SH-ljS^-benzotriazepin^-one and tert- butoxycarbonyl glycine respectively. 1H NMR (CDCl3) 9.10 (IH, s), 7.55 (2H, d), 7.39 (2H, d), 7.24 (IH, d), 6.90 (IH, d), 6.53 (IH, s), 4.20 (IH, m), 3.08 (2H, s), 2.80 (IH, m), 2.39 (6H, s), 2.21 (3H, s), 2.00-1.00 (16H, m) step b Borane-THF complex (1.0M, LOmL, lmmol) was added to a solution of N-[4-(5- cyclohexyl-3-isopropyl-8-methyl-2-oxo-l,2-dihydro-3H-l;,3,4-benzotriazepin-l-yl)-phenyl]-2- dimethylamino-acetamide (237mg, 0.5mmol) in THF (1OmL) and the solution was refluxed for 16 hr. MeOH (5mL) was added and the solution was refluxed for a further 1 hr. On cooling, the solvents were evaporated and the residue was purified by chromatography (MeOH-DCM (1:10) then NH4OH-MeOH-DCM (0.1:1:10)) to afford the title compound (139mg, 57%). 1H NMR (CDCl3) 7.24-7.17 (3H, m), 6.88 (IH, d), 6.61-6.57 (3H, m), 4.30 (IH, br s), 4.15 (IH, m), 3.15 (2H, t), 2.80 (IH, m), 2.56 (2H, t), 2.26 (6H, s), 2.20 (3H, s), 2.00-1.00 (16H, m). The compound was further characterised and tested as the HCl salt. Found: C 60.58, H 7.82, N 12.91%; C28H39N5O^HCl-H2O requires: C 60.86, H 7.84, N 12.67%
Example 297 S-Cyclohexyl-S-methyl-l-ft-β-morpholin^-yl-propylJ-phenylJS-ftetrahydro- pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzofriazepin-2-one step a 3-{4-[5-Cyclohexyl-8-methyl-2-oxo-3-(tetrahydro-pyran-4-yl)-l ,2-dihydro-3H-l ,3 ,4- benzotriazepin-l-yl]-phenyl}-acrylic acid ethyl ester was prepared using step g of example 284, except that 4-[5-cyclohexyI-8~methyl-2-oxo-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl]-benzaldehyde (example 277 step a) was used in place of 4-(7- benzyloxy-S-cyclohexyl-S-isopropyl-δ-methyl^-oxo-l^-dihydro-SH-ljS^-benzotriazepin-l- yl)-benzaldehyde. 1H NMR (CDCl3) 7.66 (IH, d), 7.51-7.41 (4H, m), 7.30 (IH, d), 7.03 (IH3 d), 6.59 (IH, s), 6.39 (IH, d), 4.26 (2H, q), 4.20-3.90 (3H, m), 3.45 (2H, m), 2.84 (IH, m), 2.25 (3H, s), 2.10-1.60 (9H, m), 1.50-1.10 (8H, m). step b 3-{4-[5-Cyclohexyl-8-methyl-2-oxo-3-(tetrahydro-pyran-4-yl)-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-l-yl]-phenyl}-propionic acid ethyl ester was prepared using step c of example 7, except that 3-{4-[5-cyclohexyl-8-methyl-2-oxo-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl]-phenyl}-acrylic acid ethyl ester was used in place of 5-fluoro-2- nitrobenzonitrile. 1H NMR (CDCl3) 7.33-7.25 (3H, m), 7.21-7.18 (2H, m), 6.96 (IH, d), 6.53 (IH, s), 4.13 (2H5 q), 4.03-3.97 (3H, m), 3.46 (2H, t), 2.96 (2H, t), 2.80 (IH, m), 2.62 (2H, t), 2.22 (3H, s), 2.15-1.15 (17H, m). step c 3-{4-[5-Cyclohexyl-8-methyl-2-oxo-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl]-phenyl}-propionaldehyde was prepared using step i of example 284, except that 3-{4-[5-cyclohexyl-8-methyl-2-oxo-3-(tetrahydro-pyran-4-yI)-l,2-dihydro-3H- l,3,4-benzotriazepin-l-yl]-phenyl}-propionic acid ethyl ester was used in place of 3-[4-(7- benzyloxy-S-cyclohexyl-S-isopropyl-δ-methyl^-oxo-l^-dihydro-SH-l^^-benzotriazepin-l- yl)-phenyl]-propionic acid ethyl ester. 1H NMR (CDCl3) 9.83 (IH, s), 7.34-7.25 (3H, m), 7.18 (2H5 d), 6.96 (IH, d), 6.53 (IH, s), 4.05-3.95 (3H5 m), 3.46 (2H, t), 2.97 (2H, t), 2.85-2.75 (3H, m), 2.22 (3H, s), 2.10-1.50 (1OH, m), 1.50-1.20 (4H, m). step d The title compound was obtained using step a of example 128 except that niorpholine and 3-{4-[5-cyclohexyl-8-methyl-2-oxo-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl]-phenyl}-propionaldehyde were used in place of l-(4-aminophenyl)-3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,354-benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 7.31-7.25 (3H, m), 7.17 (2H, d), 6.95 (IH, d), 6.53 (IH, s), 4.10-3.90 (3H, m), 3.72 (4H, t), 3.46 (2H, t), 2.83 (IH, m), 2.65 (2H, t), 2.50-2.30 (6H, m), 2.22 (3H, s), 2.15-1.15 (16H5 m). The compound was further characterised and tested as the HCl salt. Found: C 65.82, H 7.74, N 9.20%; C33H44N4O3-LoHCl requires: C 65.72, H 7.62, N 9.29%
Example 298 S-CyclohexylS-methyl-l-ft-β-piperidin-l-yl-propylJ-phenylJ-S-ftetrahydro- pyran-4-yl)-l ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one
The title compound was obtained using step a of example 128 except that piperidine and 3-{4- [5-cyclohexyl-8-methyl-2-oxo-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin- l-yl]-phenyl}-propionaldehyde (example 297, step c) were used in place of l-(4- aminophenyO-S-benzyl-S-cyclohexyl-l^-dihydro-SH-l^^-benzotriazepin^-one and formalin respectively. 1H NMR (CDCl3) 7.30-7.24 (3H, m), 7.17 (2H, d), 6.95 (IH, d), 6.54 (IH, s), 4.04-3.95 (3H5 m), 3.46 (2H, t), 2.82 (IH, m), 2.63 (2H, t), 2.45-2.25 (6H, m), 2.22 (3H, s), 2.20-1.10 (22H, m). The compound was further characterised and tested as the HCl salt. Found: C 67.87, H 7.93, N 9.27%; C34H46N4O2-LoHCl requires: C 67.94, H 7.98, N 9.32% Example 299 S-Cyclohexyl-l-[4-(lHAmidazol-2-yhnethoxymethyl)-phenyl]-8-methyl-3- (tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one step a 2-Bromomethyl-l-trityl-lH-imidazole
PPI13 (751mg, 2.9mmol) was added to an ice-cooled suspension of (l-trityl-lH-imidazol-2- yl)methanol (J. J. Baldwin, M. E. Christy et al, J. Med. Chem. (1986), 29, 1065) (464mg, 1.4mmol) and CBr4 (904mg, 2.7mmol) in DCM (2OmL). The mixture was allowed to reach rt slowly and was stirred for 16 hr. The solvent was evaporated and the residue purified by chromatography (MeOH-DCM (3:100)) to afford the product (318mg, 58%). 1H NMR (CDCl3) 7.38-7.30 (9H, m), 7.16-7.10 (7H, m), 6.72 (IH, s), 3.82 (2H, s) step b 5-Cyclohexyl-l-(4-hydroxymethyl-phenyl)-8-methyl-3-(tetrahydw-pyran-4-yI)-l,2- dihydro-3H'l,3,4-benzotriazepin-2-one was obtained using step a of example 278 except that 4-[5-cyclohexyl-8-methyl-2-oxo-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl]-benzaldehyde was used in place of (l-trityl-lH-imidazol-2-yl)- acetaldehyde. 1H NMR (CDCl3) 7.41-7.37 (4H, m), 7.29 (IH, m), 6.97 (IH, d), 6.54 (IH, s), 4.70 (2H, d), 4.09-3.97 (3H, m), 3.47 (2H, t), 2.83 (IH, m), 2.22 (3H, s), 2.05-1.20 (15H, m). step c 5-Cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l-[4-(l-trityl-lH-imidazol-2- ylmethoxymethyl)-phenyl]-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step c of example 20 except that 5-cyclohexyl-l~(4-hydroxymethyl-phenyl)-8-methyl-3- (tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and 2-bromomethyl-l- trityl-lH-imidazole were used in place of 5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one and (3-bromopropenyl)-benzene respectively. 1H NMR (CDCI3) 7.32-6.85 (22H, m), 6.72 (IH, s), 6.50 (IH, s), 4.20-3.85 (5H, m), 3.77 (2H, s), 3.47 (2H, t), 2.83 (IH, m), 2.20 (3H, s), 2.18-1.20 (14H, m). step d The title compound was obtained using step b of example 210 except that 5-cyclohexyl- 8-methyl-3-(tetrahydro-pyran-4-yl)-l-[4-(l-trityI-lH-imidazol-2-ylmethoxymethyl)-phenyl]- l52-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of δ-chloro-S-cyclohexyl-S- (3,3,5,5-tetramethyl-cyclohexyl)-l-(4-(2-(l-trityl-lH-imidazol-2-yl)-ethylamino)-phenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (DMSO-d6) 12.07 (IH, br s), 7.49 (IH, d), 7.35 (2H, d), 7.27 (2H, d), 7.10-7.04 (2H, br m), 6.84 (IH, br m), 6.52 (IH, s), 4.58-4.49 (4H, m), 3.93-3.82 (3H, m), 3.31 (2H, t), 2.99 (IH, m), 2.17 (3H, s), 2.10-1.10 (14H5 m). The compound was further characterised and tested as the HCl salt. Found: C 63.84, H 6.69, N 11.37%; C31H37N5O3-1.4HC1-O.4dioxane requires: C 63.78, H 6.83, N 11.41%
Example 300 5-Cyclohexyl-l-{4-[2-(lH-imidazol-2~yl)-ethylamino]-phenyl}-3-isopropyl-8- methyl-1, 2-dihydro~3H-l, 3, 4-benzotriazepin-2-one The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- 5-cyclohexyl-3-isopropyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 289 step c) and (l-trityl-lH-imidazol-2-yl)-acetaldehyde were used in place of l-(4-amino-phenyl)- 3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of 3-benzyl-5-cyclohexyl-l-(4-(4,5- dihydro- 1 H-imidazol-2-ylamino)-phenyl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one, according to step b of example 39. 1H NMR (CDCl3) 7.24-7.16 (3H, m), 6.97 (2H, s), 6.92- 6.86 (IH, m), 6.60-6.53 (3H, m), 4.20-4.11 (2H, m), 3.54-3.46 (2H, m), 3.04-2.96 (2H, m), 2.84-2.77 (IH, m), 2.21 (3H, s), 2.05-1.24 (16H, m). The compound was further characterised and tested as the HCl salt. Found: C 59.20, H 6.77; N 13.95%; C29H36N6O-2.8HCl-0.2dioxane requires: C 59.22, H 6.74, N 13.91%
Example 301 5-Cyclohexyl~3-isopropyl-8-methyl-l-{4-[(pyrrolidin-2~ylmethyl)-amino]- phenyl}-! ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one
The title compound was obtained as the HCl salt using step a of example 128 except that l-(4- amino-pheny^-S-cyclohexyl-S-isopropyl-δ-methyl-l^-dihydro-SH-ljS^-benzotriazepin^-one (example 289 step c) and 2-formyl-pyrrolidine-l-carboxylic acid tert-butyl ester were used in place of 1 -(4-aminophenyl)-3-benzyl-5-cyclohexyl- 1 ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,N-bis- (tert-butoxycarbonyl)-N'-(4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenyl)-guanidine, according to example 1 step f. 1H ΝMR (CDCI3) 9.35 (IH, br s), 8.95 (IH, br s), 7.44-7.41 (IH, m), 7.04-6.96 (3H, m), 6.66-6.63 (2H, m), 6.51 (IH, s), 5.14 (2H, br s), 3.98-3.94 (IH, m), 3.56 (IH, m), 3.39-3.17 (4H, m), 2.90 (IH, m), 2.16- 1.06 (23H, m). Found: C 63.07, H 7.74, Ν 12.17%; C29H39Ν5O-2HCl-0.4dioxane requires: C 63.17, H 7.66, N 12.04% Example 302 S-Cyclohexyl-l-ft-β-ζlH-imidazol^-yty-ethylaminoJ-phenylj-S-isopropyl-S- methoxy-l,2-dihydro-benzotriazepin-2-one step a S-Cyclohexyl-S-isopropylS-methoxy-l^-dihydroSH-l^^-benzotriazepin^-one was prepared by the method of example 181 step c except that (2-amino-4-methoxy- phenyl)cyclohexylmethanone (example 198 step a) and N'-isopropyl-hydrazinecarboxylic acid tert-butyl ester (example 284, step a) were used in place of (2-amino-4-methyl-phenyl)- (tetrahydro-pyran-4-yl)-methanone and N-(3,3,5J5-tetramethyl-cyclohexyl)- hydrazinecarboxylic acid tert-butyl ester respectively. step b 5-Cyclohexyl-3-isopropyl-8-methoxy-l-(4-nitro-pheny!)-l,2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step b of example 211 except that 5-cyclohexyl-3- isoρropyl-8-methoxy-l,2-dihydro-lH-l,3,4-benzotriazepin-2-one was used in place of 5- cyclohexyl-3-cyclooctyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one. step c l-(4-Amino-phenyl)-5-cyclohexyl-3-isopropyl-8-methoxy-l, 2-dihydro-3H-l, 3, 4- benzotriazepin-2-one was obtained using step d of example 1 except that 5-cyclohexyl-3- isopropyl-8-methoxy-l-(4-nitro-phenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was used in place of 3-benzyl-5-cyclohexyl-l-(4-nitrophenyl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2- one. 1H NMR (CDCl3) 7.27-7.25 (1Η, m), 7.19-7.15 (2Η, m), 6.68-6.63 (3H, m), 6.26 (IH, d), 4.21-4.12 (IH, m), 3.67-3.65 (5H, m), 2.81-2.73 (IH, m), 1.88-1.21 (16H, m) step d The title compound was obtained by the method of example 300, except that l-(4- amino-pheny^-S-cyclohexyl-S-isopropyl-δ-methoxy-l ,2-dihydro-3H-l ,3,4-benzotriazepin-2- one was used in place of l-(4-amino-phenyl)-5-cyclohexyl-3-isoρropyl-8-methyl-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one. 1U NMR (CDCl3) 10.00-8.50 (IH, br s), 7.28-7.25 (IH, m), 7.18-7.15 (2H, m), 6.96 (2H, s), 6.67-6.63 (IH, m), 6.57-6.55 (2H, m), 6.27 (IH, d), 4.23-4.09 (2H, m), 3.65 (3H, s), 3.51-3.46 (2H, m), 2.96-2.92 (2H, m), 2.81-2.74 (IH, m), 1.90-1.22 (16H, m). The product was further characterised as the HCl salt. Found: C 57.96, H 6.70, N 13.27%; C29H36N6θ2-2.7HCl-0.4dioxane requires: C 57.94, H 6.66, N 13.25%
Example 303 l-{4-[(l-Aπιino-cyclopentylmethyl)-amino]~phenyl}-5-cyclohexyl-3-isopropyl-8- methoxy-1, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one
The title compound was obtained as the HCl salt using step a of example 128 except that l-(4- amino-phenyl)-5-cyclohexyl-3-isopropyl-8-methoxy- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2- one (example 302, step c) and (l-formyl-cyclopentyl)-carbamic acid tert-butyl ester were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro~3H-l,3,4-benzotriazepin-2- one and formalin respectively, followed by reaction of the product obtained, in place of N1N- bis-(tert-butoxycarbonyl)-N"-(4-(3 -benzyl-5 -cyclohexyl-2-oxo- 1 ,2-dihydro-3H- 1 , 3 ,4- benzotriazepin-l-yl)-phenyl)-guanidine, according to example 1 step f. 1H ΝMR (CDCl3) 8.22 (3H, br s), 7.50 (IH, d), 7.02-7.00 (2H, m), 6.78-6.69 (3H, m), 6.16 (IH, d), 5.52 (2H, br s), 4.01-3.92 (IH, m), 3.62 (3H, s), 3.27 (2H, s), 2.92 (IH, m), 1.83-1.05 (24H, m). Found: C 61.36, H 7.58, Ν 11.22%; C3oH4iΝ5θ2-2.2HCl-0.4dioxane requires: C 61.30, H 7.55, N 11.31%. Example 304 5-Cyclohexyl -l-[4-(2-dhnethylamino-ethylamino)-phenyl]-8-methyl-3- (tetrahydropyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one step a N-{4-(5-Cyclohexyl-8-methyl-2-oxo-3-(tetrahydropyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl]-phenyl}-2-dimethylamino-acetamide was obtained using step a of example 71 except that l-(4-amino-phenyl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 182, step b) and dimethylamino-acetic acid were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H~l,3,4~ benzotriazepin-2-one and tert-butoxycarbonyl glycine respectively. 1H NMR (CDCI3) 9.15 (IH, s), 7.58 (2H, d), 7.36 (2H, d), 7.26 (IH, d), 6.95 (IH, d), 6.53 (IH, s), 4.03 (3H, m), 3.46(2H, t), 3.09 (2H, s), 2.89 (IH, m), 2.40 (6H, s), 2.22 (3H, s), 2.05-1.24 (14H, m) step b The title compound was obtained using step b of example 296 except that N-{4-[5- cyclohexyl-8-methyl-2-oxo-3-(tetrahydropyran-4-yl)- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin- 1 - yl]-phenyl}-2-dimethylamino-acetamide was used in place of N-[4-(5-cyclohexyl-3-isopropyl- 8-methyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl]-2-dimethylamino- acetamide. 1H NMR (CDCl3) 7.25 (IH, d), 7.16 (2H, d), 6.90 (IH3 d), 6.60 (3H, m), 4.34 (IH, br s), 4.04-3.95 (3H, m), 3.46 (2H, t), 3.14 (2H, t), 2.80 (IH, m), 2.55 (2H, t), 2.26 (6H, s), 2.21 (3 H, s), 2.03-1.27 (14H, m). The compound was further characterised and tested as the HCl salt. Found: C 60.29, H 7.60, N 11.55%; C30H41N5O-2.5HCI requires: C 60.50, H 7.37, N 11.76% Example 305 5-Cyclohexyl-8-methyl-l-[4-(2-methylamino-ethylamino)-phenyl]-3-
(tetrahydropyran-4~yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
The title compound was obtained as the HCl salt using step a of example 128, except that l-(4- amino-phenyl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 182, step b) and methyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N'-(4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro- 3H-l53,4-benzotriazepin-l-yl)-phenyl)-guanidine, according to step f of example 1. 1H NMR (DMSOd6-D2O) 7.41 (IH, d), 7.02-6.98 (3H5 m), 6.62 (2H, d), 6.51 (IH5 s), 3.80 (3H, m), 3.31 (4H, m), 3.05 (2H, t), 2.93 (IH, m), 2.56 (3H, s), 2.14 (3H, s), 1.92-1.21 (14H, m). Found: C 62.08, H 7.60, N 11.65%; C29H39N5O2-LSHCl-O-SC4H8O2 requires: C 62.12, H 7.53, N 11.69%.
Example 306 S-Cyclohexyl-S-metiψl-l-ft-fft-methylpiperidin^-ylmethylJ-aminoJ-phenylj-S- (tetrahydropyran-4-yl)-l, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- 5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 182, step b) and l-methyl-piperidine-4-carbaldehyde (Gray A.P. et al: J. Med. Chem., (1988), 807) were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 7.20 (IH, d), 7.13 (2H, d), 6.91 (IH, d), 6.54 (3H, d), 3.99 (3H, m), 3.83 (IH5 m), 3.48 (2H, m), 3.00 (2H, m), 2.88 (4H, m), 2.27 (4H, m), 2.20 (3H, s), 1.95-1.25 (19H, m). The compound was further characterized and tested as the HCl salt. Found: C 59.99, H 7.46, N 10.37%; C33H45N5O2-S^HCl-O1IC4H8O2 requires: C 60.01, H 7.36, N 10.60%. Example 307 5-Cyclohexyl-7-fluoro-8-methyl-l-[4-(2-methylamino-ethylamino)-phenyl]-3- (tetrahydropyran-4~yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
Step a 5-Fluoro-4-methyl-2-nitrobenzonitrile
To an ice-cooled solution of 3-fluoro-4-methylbenzonitrile (21.25g, 157mmol) in concentrated H2SO4 (10OmL) was added drop-wise fuming nitric acid (12mL, 286mmol). After 20min the coolant was removed and the reaction mixture stirred at rt for 2.5h. The reaction mixture was poured into ice and diluted with H2O. The suspension was filtered, the solid was washed with H2O and then dried in vacuo at 700C. 1H NMR (CDCl3) 8.25 (IH, d), 7.55 (IH, d), 2.48 (3H, s)
Step b 2-Amino-5-fluoro-4-methyl-benzonitrilewa.s obtained using step c of example 7 except that 5-fluoro-4-methyl-2-nitrobenzonitrile was used in place of 5-fluoro-2-nitrobenzonitrile. 1H NMR (CDCl3) 7.03 (IH, d), 6.56 (IH, d), 4.20 (2H, br s), 2.24 (3H, s)
Step c (2-Amino-5-fluoro-4-methyl-phenyl)-cyclohexyl-methαnone was obtained using step a of example 5, except that cyclohexylmagnesium chloride and 2-amino-5-fluoro-4- methylbenzonitrile were used in place of isopropylmagnesium chloride and 2- aminobenzonitrile respectively. 1H NMR (CDCl3) 7.36 (IH, d), 6.46 (IH, d), 6.07 (2H, br s), 3.14 (IH, m), 2.23 (3H, s), 1.90-1.70 (5H, m), 1.55-1.10 (5H; m)
Step d 5-Cyclohexyl-7-fluoro~8-methyl-3-(tetrαhydropyrαn-4-yl)A,2-dϊhydro-lH-l,3,4- benzotriαzepin-2-one was obtained using step c of example 181, except that (2-amino-5-fluoro- 4-methyl-phenyl)-cyclohexyl-methanone and N'-(tetrahydro-pyran-4-yl)-hydrazinecarboxylic acid tert-butyl ester (example 61, step a) were used in place of (2-amino-4-methyl-ρhenyl)- (tetrahydro-pyran-4-yl)-methanone and N-(3,3,5,5-tetramethyl-cyclohexyl)- hydrazinecarboxylic acid tert-butyl ester respectively. 1H ΝMR (CDCI3) 7.99 (IH, d), 6.63 (IH, d), 6.19 (IH, s), 4.13 (IH, m), 4.01 (2H, m), 3.47 (2H, t), 2.62 (IH, m), 2.26 (3H, s), 2.20- 2.00 (2H, m), 1.95-1.55 (6H, m), 1.55-1.20 (6H, m)
Step e δ-Cyclohexyl^-βuoroS-methyl-l^-mtro-phenylJ-S-ftetrαhydropyrαn^-yl)- 1,2- dihydro-lH-l,3,4-benzotriazepin-2-one was obtained using step b of example 211 except that 5-cyclohexyl-7-fluoro-8-methyl-3-(tetrahydropyran-4-yl)-l,2-dihydro-lH-l,3,4- benzotriazepin-2-one was used in place of 5-cyclohexyl-3-cyclooctyl-8-methyl-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one. ΝMR (CDCl3) 8.15 (2H, d), 7.46 (2H, d), 7.11 (IH, d), 6.81 (IH, s), 4.18 (IH, m), 4.00 (2H, m), 3.48 (2H5 m), 2.86 (IH, m), 2.30-2.25 (4H, m), 2.15-1.55 (8H, m), 1.50-1.10 (6H, m).
Step f l-(4-Amino~phenyl)-5-cyclohexyl-7-fluoro-8-methyl-3-(tetrahydropyran-4-yl) 1,2- dihydro-lH-l,3,4-benzotriazepin-2-one was obtained using step d of example 1 except that 5- cyclohexyl-7-fluoro-8-methyl-l -(4-nitro-phenyl)-3-(tetrahydropyran-4-yl)- 1,2-dihydro-lH- l,3,4-benzotriazepin-2-one was used in place of 3-benzyl~5-cyclohexyl-l-(4-nitrophenyl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (CDCl3) 7.13 (2Η, d), 6.97 (IH, d), 6.66 (2H, d), 6.57 (IH, d), 4.10-3.96 (3H, m), 3.76 (2H, br s), 3.46 (2H, t), 2.70 (IH, m), 2.14 (3H, s), 2.10-1.20 (14H, m). Step g The title compound was obtained as the HCl salt using step a of example 128, except that 1 -(4-amino-phenyl)-5-cyclohexyl-7-fluoro-8-methyl-3-(tetrahydro-pyran-4-yl)- 1 ,2- dihydro-lH-l,3,4-benzotriazepin-2-one and methyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N//-(4-(3-benzyl-5-cyclohexyl-2-oxo-l,2-dihydro- 3H-l,3,4-benzotriazepin-l-yl)-phenyl)-guanidine, according to step f of example 1. 1H NMR (DMSO-de) 8.81 (2H, br m) 7.41 (IH, d), 7.01 (2H, d), 6.63 (3H, d), 6.07 (3H, br s) 3.90-3.75 (3H, m), 3.35-3.25 (4H, m), 3.10-2.90 (3H, m), 2.55 (3H, br t), 2.10-1.10 (17H, m). Found: C 57.65, H 7.00, N 10.76%; C29H38N5O2F^oHCl-O1SC4H8O2 requires: C 57.59, H 6.95, N 10.83%.
Example 308 l-[4-(2-Amino-ethylamino)-phenyl]- 5-cyclohexyl-8-methyl-3-(tetrahydropyran- 4-yl)-l ,2-dihydro-3H-l , 3, 4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- 5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 182, step b) and (2-oxo-ethyl)-carbamic acid tert-butyl ester (P. Blaney et al Tetrahedron 58, (2002) 1719-1737) were used in place of l-(4-aminophenyl)-3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of ^-{(^-(S-cyclohexyl-S-isopropyl-S-methyl^-oxo- l^-dihydro-SH-ljS^-benzotriazepm-l-yty-phenylaminol-methylJ-pyridin^-y^^ acid tert-butyl ester, according to step b of example 293. 1H NMR (CDCl3) 7.23 (IH, d), 7.16 (2H, d), 6.91 (IH, d), 6.64-6.55 (3H, m), 4.10 (IH, br, s) 4.05-3.96 (3H, m), 3.50-3.41 (3H, m), 3.20 (IH, t), 3.00 (2H, t), 2.80 (IH3 m), 2.21 (3H, s), 2.00-1.26 (16H, m). The compound was further characterized and tested as the HCl salt. Found: C 60.15, H 7.15, N 12.22%; C28H37N5O2^HCl requires: C 60.31, H 7.23, N 12.56%. Example 309 3-Amino-4-(2-{4-[5-cyclohexyl-8-methyl-2-oxo-3-(tetrahydro-pyran-4-yl)-l,2- dihydro-l,3,4-benzotriazepin-l-yl]-phenylamino}-ethylamino)-cyclobut-3-ene-l,2~dione
Step a S-tei't-Butoxycarbonylamino^-tø-^-tS-cyclohexyl-S-methyl^-oxo-S-ftefrahydro- pyran^-ylJ-l^-dihydro-l^^-benzotr'iazepin-l-ylJ-phenylaminoj-ethylaminoj-cyclobutS-ene- 1,2-dione l-[4-(2-Amino-ethylamino)-phenyl]-5-cyclohexyl-8-methyl-3-(tetrahydropyran-4-yl)-l,2- dihydro-3H-l,3,4-benzotriazepin-2-one (example 308) (300mg, 0.63 mmol) and bis-tert- butoxycarbonyl-squarylamide (239mg, O.Tmmol) (Chi- Wan Lee et al. Bioorg. Med. Chem. Letts (2005), 15, 4243) and NEt3 (138 Dl, 1.0 mmol) in EtOH (5 mL) were stirred at rt for lhr. The solvent was evaporated and the residue was purified by chromatography (DCM-EtOAc (4:1)) (120 mg, 28%).
Step b The title compound was obtained using step b of example 293, except that 3-tert- butoxycarbonylamino-4-(2-{4-[5-cyclohexyl-8-methyl-2-oxo-3-(tetrahydro-pyran-4-yl)-l,2- dihydro- 1 ,3,4-benzotriazepin- 1 -yl]-phenylamino } -ethylamino)-cyclobut-3 -ene- 1 ,2-dione was used in place of (3-{[4-(5-cyclohexyl-3-isopropyl-8-methyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenylamino]-methyl}-pyridin-2-yl)-carbamic acid tert-butyl ester. 1H NMR (DMSO-d6) 7.60 (IH, br s), 7.50 (2H, br s), 7.41 (IH, d), 6.97 (3H, d), 6.58 (2H, d), 6.52 (IH, s), 5.88 (IH, br s), 3.82 (3H, m), 3.64 (2H, m), 3.32-3.20 (4H, m), 2.90 (IH, m), 2.17 (3H, s), 2.00-1.20 (14H, m). The compound was further characterized and tested as the HCl salt. Found: C 59.65, H 6.60, N 13.05%; C32H38N6O4^HCl requires: C 59.72, H 6.27, N 13.05%
Example 310 l~{4-[(l-Amino-cyclopentylmethyl)-amino]-phenyl}-8-chloro-5-cyclohexyl-3- (tetrahydropyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that l-(4-amino-phenyl)- 8-chloro-5-cyclohexyl-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 243, step b) and (l-formyl-cyclopentyl)-carbamic acid tert-butyl ester were used in place of 1 -(4-aminophenyl)-3 -benzyl-5 -cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of (3-{[4-(5- cyclohexyl-3 -isopropyl-8-methyI-2-oxo- 1 ,2-dihydro-3H- 1 ,3,4-benzotriazepin- 1 -yl)- phenylamino]-methyl}-pyridin-2-yl)-carbamic acid tert-butyl ester, according to step b of example 293. NMR (CDCl3) 7.28 (IH, d), 7.13 (2H, d), 7.06 (IH, d), 6.76 (IH, s), 6.65 (2H, d), 3.40 (IH, br s), 3.97-4.00 (3H, m), 3.46 (2H, t), 3.12 (2H, s), 2.75 (IH, m) 1.83-1.34 (24H, m). The compound was further characterized and tested as the HCl salt. Found: C 60.96, H 6.92, N 11.07%; C31H40ClN5O2-LeHCl-O-SC4H8O2 requires: C 60.91, H 6.99, N 11.03% Example 311 l-[4-(2-Amino-methyl-propylamino)-phenyl]-5-cyclohexyl-8-methyl-3- (tetrahydropyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
The title compound was obtained as the HCI salt using step a of example 128, except that l-(4- amino-phenyl)-5-cyclohexyl-8-methyl-3-(tetrahydropyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 182, step b) and methyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H- 1,3,4- benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,N-bis-(^^-butoxycarbonyl)-N"-(4-(3-ben2yl-5-cyclohexyl-2-oxo-l,2-dihydro- 3Η-l,3,4-benzotriazepin-l-yI)-phenyl)-guanidine, according to step f of example 1. 1H NMR (DMSO-d6-D2O) 7.39 (IH, d), 6.97 (3H, d), 6.68 (2H, d), 6.50 (IH, s), 3.78 (3H, m), 3.34 (2H, m), 3.17 (2H, s), 2.91(1H, m), 2.13 (3H, s), 1.95-1.14 (20H3 m). Found: C 59.19, H 7.77, N 11.20%; C3oH4iN502-2.7HCl-0.4C4H8θ2 requires: C 59.55, H 7.42, N 10.99%
Example 312 5-Cyclohexyl-8-methyl-l-[4-l-methyl-piperidin-4-ylamino)-phenyl]-3- (tetrahydropyran-4-yl)-l ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one The title compound was obtained using step a of example 128, except that 5-cyclohexyl-8- methyl-l-[4-(piperidin-4-ylamino)-phenyl]-3-(tetrahydropyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 273) was used in place of l-(4-aminophenyl)-3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one. 1H NMR (CDCl3) 7.23 (IH, d), 7.15 (2H, d), 6.91 (IH, d), 6.57 (3H, m), 4.04-3.96 (3H, m), 3.58 (IH, br s), 3.46 (2H, t), 3.29 (IH, m), 2.82 (3H, m), 2.33 (3H, s), 2.21 (3H, s), 2.17-1.26 (2OH, m). The compound was further characterized and tested as the HCl salt. Found: C 59.16, H 7.49, N 10.58%; C32H43N5O2- 3.2HC1 requires: C 59.43, H 7.28, N 10.83%.
Example 313 l-{4-[(l-Amino-cyclopentylmethyl)-amino]-phenyl}-5-cyclohexyl-8-methyl-3- (tetrahydropyran-4-yl)-l ,2-dihydro-3H-l , 3, 4-benzotriazepin-2-one The title compound was obtained using step a of example 128, except that that l-(4-amino- phenyl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 182, step b) and (l-formyl-cyclopentyl)-carbamic acid tert- butyl ester were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of (3-{[4-(5-cyclohexyl-3-isopropyl-8-methyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenylamino]-methyl}-pyridin-2-yI)-carbamic acid tert-butyl ester, according to step b of example 293. NMR (CDCl3) 7.22 (IH, d), 7.15 (2H, d), 6.90 (IH, d), 6.61 (3H, m), 4.36 (IH, br s), 3.99 (3H, m), 3.45 (2H, t), 3.08 (2H, s), 2.80 (IH, m), 2.20 (3H,' s), 2.20-1.26 (24H, m). The compound was further characterized and tested as the HCl salt. Found: C 62.66, H 6.52, N 11.21%; C32H43N5O2-2.2HCl-0.2C4HgO2 requires: C 62.78, H 6.52, N 11.16%.
Example 314 5-Cyclohexyl-8-methyl-l-[4-(2-piperidin-4-yl-ethylamino)-phenyl]-3-
(tetrahydropyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one The title compound was obtained as the HCl salt using step a of example 128, except that l-(4- amino-phenyl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 182, step b) and 4-(2-oxo-ethyl)-piperidine-l-carboxylic acid tert-butyl ester were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,N-bis-(fert-butoxycarbonyl)-N'-(4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl)-guanidine, according to step f of example 1. 1H ΝMR (DMSO-d6-D2O) 7.44 (IH, d), 7.21 (2H, d), 7.09-7.03 (3H, m), 6.52 (IH, s), 3.84-367 (3H, m), 3.41-3.13 (6H, m), 2.94 (IH, m), 2.79 (2H, t), 2.15 (3H, s), 1.92-1.05 (21H, m). Found: C 60.08, H 7.70, Ν 10.05%; C33H45N5O2-SHCl-COC4H8O2 requires: C 60.22, H 7.54, N 9.92%
Example 315 5-Cyclohexyl-8-methylA-{4[(piperidin-4-ylmethyl)-amino)]-phenyl}-3- (tetrahydropyran-4-yl)-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
The title compound was obtained as the HCl salt using step a of example 128, except that l-(4- amino-phenyl)-5-cyclohexyl-8-methyl-3-(tetrahydro-pyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 182, step b) and 4-formyl-ρiperidine-l-carboxylic acid tert- butyl ester were used in place of l-(4-aminophenyl)-3-benzyl-5-cyclohexyl-l,2-dihydro-3H- l,3,4-benzotriazepin-2-one and formalin respectively, followed by reaction of the product obtained, in place of N,N-bis-(tert-butoxycarbonyl)-N/-(4-(3-benzyl-5-cyclohexyl-2-oxo-l,2- dihydro-3H-l,3,4-benzotriazepin-l-yl)-phenyl)-guanidine, according to step f of example 1. 1H ΝMR (DMSO-d6-D2O) 7.40 (IH, d), 7.00 (3H, m), 6.70 (2H, d), 6.51 (IH5 s), 3.74 (3H, m), 3.36-3.26 (4H, m), 3.00-2.80 (5H, m), 2.14 (3H, s), 1.90-1.03 (19H, m). Found: C 59.23, H 7.66, Ν 9.84%; C32H43N5O2-S-IHCl-O^C4H8O2 requires: C 59.22, H 7.44, N 9.70%
Example 316 5-Cyclohexyl-3~isopropyl-8-methyl-l-[4-(2-isopropylamino-ethylamino)- phenylj-l ,2-dihydro-3H-l ,3,4-benzotriazepin-2-one The title compound was obtained using step a of example 128, except that l-[4-(2-amino- ethylamino)-phenyl]-5-cyclohexyl-3-isopropyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin- 2-one (example 292) and acetone were used in place of l-(4-aminophenyl)-3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively. 1H NMR (DMSO-d6-D2O) 7.24-7.17 (3H, m), 6.89 (IH, d), 6.60 (2H, d), 6.56 (IH, s), 4.15 (IH, m), 3.23 (2H, t), 2.88 (2H, t), 2.84-2.80 (2H, m), 2.20 (3H, s), 1.96-1.13 (16H, m), 1.08 (6H, d). The compound was further characterised and tested as the HCl salt. Found: C 61.19, H 7.58, N 11.29%; C29H41N5O^HCl-O-SMeOH requires: C 61.15, H 7.64, N 11.39%
Example 317 5-Cyclohexyl-3-isopropyl-8-methyl-l-[4-(2-(4-tetrahydropyranyl)amino- ethylamino)-phenyl]-l , 2-dihydro-3H-l, 3, 4~benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that l-[4-(2-amino- ethylamino)-phenyl]-5-cyclohexyl-3-isopropyl-8-methyl-l,2-dihydro-3H-l,3,4-benzotriazepin- 2-one (example 292) and tetrahydro-4H-pyran-4-one were used in place of l-(4-aminophenyl)- 3-benzyl-5-cyclohexyl-l,2-dihydro-3Η-l,3,4-benzotriazepin-2-one and formalin respectively. 1H NMR (DMSO-d6-D2O) 7.24-7.17 (3H, m), 6.89 (IH, d), 6.60 (2H, d), 6.56 (IH, s), 4.16 (IH, m), 3.97 (2H, d), 3.40 (2H, t), 3.22 (2H, t), 2.92 (2H, t), 2.81 (IH, t), 2.69 (IH, m), 2.20 (3H, s), 1.86-1.15 (22H, m). The compound was further characterised and tested as the HCl salt. Found: C 61.54, H 7.72, N 12.15%; C31H43N5O2^HCl-CSMeOH requires: C 61.44, H 7.85, N 12.23% Example 318 5-Cyclohexyl-3-(tetrahydropyran-4-yl)-8-methyl-l-[4-(2-(4- tetrahydropyranyl)amino-ethylamino)-phenyl]-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that l-[4-(2-amino- ethylamino)-phenyl]-5-cyclohexyl-8-methyl-3-(tetrahydropyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 308) and tetrahydro-4H-pyran-4-one were used in place of 1- (4-aminophenyl)-3-benzyl-5-cyclohexyl- 1 ,2-dihydro-3Η- 1 ,3,4-benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 7.23 (IH, d), 7.16 (2H, d), 6.91 (IH, d), 6.62-6.57 (3H, s), 4.23 (IH, br s), 4.00 (5H, m), 3.49-3.36 (4H5 m), 3.22 (2H, t), 2.92 (2H, t), 2.80 (IH, m), 2.70 (IH, m), 2.21 (3H, s), 2.14-1.26 (19H, m). The compound was further characterised and tested as the HCl salt. Found: C 61.31, H 7.53, N 10.68%; C33H45N5O3^HCl requires: C 61.27, H 7.38, N 10.83%
Example 319 5-Cyclohexyl-3-(tetrahydropyran-4-yl)-8-methyl-l-[4-(2-isopropyl amino- ethylamino)-phenyl]-l, 2-dihydro-3H-l , 3, 4~benzotriazepin-2-om
The title compound was obtained using step a of example 128, except that l-[4-(2-amino- ethylamino)-phenyl]-5-cyclohexyl-8-methyl-3-(tetrahydropyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 308) and acetone were used in place of l-(4-aminophenyl)-3- benzyl-5-cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 7.23 (IH, d), 7.15 (2H, d), 6.62 (2H, d), 6.56 (IH, s), 4.24 (IH, m), 4.03-3.96 (3H, m), 3.46 (2H, m), 3.22 (2H, br s), 2.90-2.76 (4H, m), 2.21 (3H, s), 2.12-1.32 (15H, m), 1.09 (6H, d). The compound was further characterised and tested as the HCl salt. Example 320 5-Cyclohexyl-3-(tetrahydropyran-4-yI)-8-methyl-J-[4-(2-(4-tetrahydropyranyl)- N-methyl-anιino-ethylamino)-phenyl]-l ,2-dϊhydro-SH-l , 3, 4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that 5-cyclohexyl-8- methyl-l-[4-(2-methylamino-ethylamino)-phenyl]-3-(tetrahydropyran-4-yl)-l,2-dihydro-3H- . l,3,4-benzotriazepin-2-one (example 305) and tetrahydro-4H-pyran-4-one were used in place of 1 -(4-aminoρhenyl)-3-benzyl-5-cyclohexyl- l,2-dihydro-3Η- 1 ,3,4-benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 7.23 (IH, d), 7.16 (2H, d), 6.91 (IH, d), 6.61-6.57 (3H, s), 4.23 (IH, br s), 4.00 (5H, m), 3.50-3.33 (4H5 m), 3.22 (2H, t), 2.80 (IH, m), 2.72 (2H, t), 2.62 (IH, m), 2.27 (3H, s), 2.21 (3H, s), 2.14-1.26 (19H, m).The compound was further characterised and tested as the HCl salt.
Example 321 5-Cyclohexyl-3-(tetrahydropyran-4-yl)-8-methyl-l-[4~(3-(4- tetrahydropyranyl)amino-propylamino)-phenyI]-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one step a 2-{3-[4-(5-Cyclohexyl-3-(tetrahydropyran-4-yl)-8-methyl-2-oxo-l,2-dihydro-3H-l,3,4~ benzotriazepin~l~yl)-phenylamino]-propyl}-i$oindole-l,3-dione was obtained using step a of example 128 except that 1 -(4-amino-phenyl)-5-cyclohexyl-8-methyl-3 -(tetrahydro-pyran-4-yl)- l,2-dihydro-3H-l,3,4-benzotriazepin-2-one (example 182, step b) and (l,3-dioxo-l,2-dihydro~ isoindol-2-yl)-proionaldehyde were used in place of l-(4-aminophenyl)-3-benzyl-5- cyclohexyl-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one and formalin respectively. step b l-[4-(3-Amino-propylamino)-phenyl]-5-cyclohexyl-3-(tetrahydropyran-4-yl)-8-meihyl~ l,2-dihydro-3H-l,3,4-benzotriazepin-2-one was obtained using step b of example 292 except that 2-{3-[4-(5-cyclohexyl-3-(tetrahydropyran-4-yl)-8-methyl-2-oxo-l,2-dihydro-3H-l,3,4- benzotriazepin-l-yl)-phenylamino]-propyl}-isoindole-l,3-dione was used in place of 2-{2~[4- (5-cyclohexyl-3-isopropyl-8-methyl-2-oxo-l,2-dihydro-3H-l,3,4-benzotriazepin-l-yl)- phenylamino]-ethyl}-isoindole-l,3-dione. step c The title compound was obtained using step a of example 128, except that l-[4-(3- amino-propylamino)-phenyl]-5-cyclohexyl-8-methyl-3-(tetrahydropyran-4-yl)-l,2-dihydro- 3H-l,3,4-benzotriazepin-2-one and tetrahydro-4H-pyran-4-one were used in place of l-(4- aminophenyl)-3-benzyl-5-cyclohexyl- 1 ,2-dihydro-3Η- 1 ,3,4-benzotriazepin-2-one and formalin respectively. 1H NMR (CDCl3) 7.25-7.17 (3H, m), 6.91-6.88 (IH, m), 6.63-6.56 (3H, m), 4.19- 4.11 (2H, m), 3.21-3.18 (2H, m), 2.99-2.95 (2H, m), 2.81 (3H, s), 1.85-1.23 (2OH, m). The compound was further characterised and tested as the HCl salt.
Example 322 5-Cyclohexyl-3-(tetrahydropyran-4-yl)-8-metJiyl-l-[4-(2-cyclopentylamino- ethylamino)-phenyl]-l,2-dihydro-3H-l,3,4-benzotriazepin-2-one The title compound was obtained using step a of example 128, except that l-[4-(2-amino- ethylamino)-phenyl]-5-cyclohexyl-8-methyl-3-(tetrahydropyran-4-yl)-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 308) and cyclopentanone were used in place of l-(4- aminophenyty-S-benzyl-S-cyclohexyl-l^-dihydro-SH-l^^-benzotriazepin^-one and formalin respectively.
Example 323 5-Cyclohexyl-3-(tetrahydropyran-4-yl)-8-methyl-l-[4-(3-isopropylamino- propylamino) -phenyl] -1 ,2-dihydro-3H-l , 3, 4-benzotriazepin-2-one
The title compound was obtained using step a of example 128, except that l-[4-(3-amino- propylamino)-phenyl]-5-cyclohexyl-3-(tetrahydropyran-4-yl)-8-methyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 321, step b) and acetone were used in place of l-(4- aminophenyl)-3 -benzyl-5-cycIohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and formalin respectively.
Example 324 5-Cyclohexyl-3-(tetrahydropyran-4-yl)-8-methyl-l~[4-(3-cyclopentylamino- propylamino)-phenyl]-l, 2-dihydro-3H-l, 3, 4-benzotriazepin-2-one The title compound was obtained using step a of example 128, except that l-[4-(3-amino- propylamino)-phenyl]-5-cyclohexyl-3-(tetrahydropyran-4-yl)-8-methyl-l,2-dihydro-3H-l,3,4- benzotriazepin-2-one (example 321, step b) and cyclopentanone were used in place of l-(4- aminophenyl)-3 -benzyl-5 -cyclohexyl- 1 ,2-dihydro-3H- 1 ,3 ,4-benzotriazepin-2-one and formalin respectively.

Claims

Claims
1. A compound of formula (I):
Figure imgf000262_0001
CO or a salt, solvate or pro-drug thereof; wherein: one of the carbon atoms labelled 6, 7, 8 or 9 may be replaced by a nitrogen atom;
R1, R4 and R5 are independently selected from H, COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH, S(C1-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H, SO2(Ci-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(C1-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(C1-6 alkyl), 0(C6-20 aryl), 0(C7-20 alkaryl), 0(C7-20 aralkyl), NH2, NH(C1-6 alkyl), N(Ci-6 alkyl)2, NH(C6-20 aryl), NH(C7-20 alkaryl), NH(C7-20 aralkyl), N(Cj-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-2o alkaryl), N(C1-6 aIkyl)(C7-20 aralkyl), N(C6-20 aryl)2, N(C6-20 aryl)(C7-20 alkaryl), N(C6-20 aryl)(C7-20 aralkyl), NHC(O)(C1-6 alkyl), NHC(O)(C6-20 aryl), NHC(O)(C7-20 alkaryl), NHC(O)(C7-20 aralkyl), N(C-6 alkyl)C(0)(C6-2o aryl), N(C1-6 alkyl)C(O)(C7-20 alkaryl), N(Ci-6 alkyl)C(O)(C7-20 aralkyl), C(O)NH2, C(O)NH(Ci-6 alkyl), C(O)N(Ci-6 alkyl)2, C(O)NH(C6-20 aryl), C(O)N(C6-20 aryl)2, C(O)NH(C7-20 aralkyl), C(O)N(C7-20 aralkyl)2, C(O)NH(C7-20 alkaryl), C(O)N(C7-20 alkaryl)2, C(O)N(Cj-6 alkyl)(C6-20 aryl), C(O)N(Ci-6 alkyl)(C7-20 alkaryl), C(O)N(C1-6 alkyl)(C7-20 aralkyl), C(O)N(C6-20 aryl)(C7-2o alkaryl), C(O)N(C6-20 aryl)(C7-20 aralkyl), NO2, CN, SO2NH2, SO2NH(Ci-6 alkyl), SO2N(Ci-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 8IyI)2, SO2N(C1-6 alkyl)(C6.20 aryl), SO2N(Ci-6 alkyl)(C7-20 alkaryl), SO2N(Ci-6 alkyl)(C7-20 aralkyl), SO2N(C6-20 aryl)(C7-20 alkaryl), SO2N(C6-20 aryl)(C7-20 aralkyl), C(O)H, C(O)(Ci-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl), C(O)(C7-20 aralkyl), OC(O)(Ci-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 aralkyl), OC(O)(C7-20 alkaryl) and C1-30 hydrocarbyl or C1-30 heterocarbyl groups, wherein any of the C1-30 hydrocarbyl or C]-30 heterocarbyl groups are optionally substituted with one or more of the groups, preferably 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (a), (b) and (c): (a) -CH=CH-, -C≡C-, S, N, -N=, Si(C1-6 alkyl)2, Si(OH)2, Si(OCi-6 alkyl)2, C(O)NH, C(O)N(C1-6 alkyl), C(O)O, N(C1-6 alkyl)C(0)N(C1-6 alkyl), NHC(O)N(C1-6 alkyl), N(C1-6 alkyl)C(0)0, NHC(O)NH, NHC(O)O, NH, N(C1-6 alkyl), N(C6-20 aryl), N(C7-20 alkaryl), N(C7-20 aralkyl), O, CO, SO2, NHSO2, NHSO2NH3 N(C1-6 alkyl)SO2NH, N(C1-6 alkyl)SO2N(C1-6 alkyl), N(C6-20 aryl)SO2NH, SO, C(O)N(C6-20 aryl), N(Ci-6 alkyl)SO2,
N(C6-20 aryl)SO2, C(O)NHNHC(O), =N-N- and C(O)NHNH in the backbone;
(b) COOH, COO(Ci-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH, S(C1-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H, SO2(Ci-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(C1-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(Cj-6 alkyl), 0(C6-20 aryl),
0(C7-20 alkaryl), 0(C7-20 aralkyl), =0, NH2, =NH, NH(C1-6 alkyl), N(Ci-6 alkyl)2, NH(C6-20 aryl), NH(C7-20 aralkyl), NH(C7-20 alkaryl), N(C1-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-20 aralkyl), N(Cj-6 alkyl)(C7-2o alkaryl), =N(C1-6 alkyl), =N(C6-2o aryl), =N(C7-20 aralkyl), =N(C7-20 alkaryl), NHC(O)(C1-6 alkyl), NHC(O)(C6-20 aryl), NHC(O)(C7-20 aralkyl), NHC(O)(C7-20 alkaryl), N(C1-6 alkyl)C(O)(C6-20 aryl), N(C1-6 alkyl)C(O)(C7-20 aralkyl),
N(C1-6 alkyl)C(O)(C7-20 alkaryl), NO2, CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(C1-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, SO2NH(C7-20 aralkyl), SO2NH(C7-20 alkaryl), SO2N(C1-6 alkyl)(C6-2o aryl), SO2N(Ci-6 alkyl)(C7-20 aralkyl), SO2N(Ci-6 alkyiχC7-20 alkaryl), NHSO2(Ci-6 alkyl), NHSO2(C6-20 aryl), NHSO2(C7-20 aralkyl), NHSO2(C7-20 alkaryl), N(Cj-6 alkyl)SO2(C1-6 alkyl), N(C1-6 aIkyl)SO2(C6-20 aryl), N(Cj-6 alkyl)SO2(C7-20 aralkyl), N(Ci-6 alkyl)SO2(C7-20 alkaryl), C(O)H, C(O)(Ci-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl), C(O)(C7-20 aralkyl), OC(O)(C1-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 aralkyl), OC(O)(C7-20 alkaryl), C(O)NH(Ci-6 alkyl), C(O)NH(C6-20 aryl), C(O)NH(C7-20 aralkyl), C(O)NH(C7-20 alkaryl), C(O)N(Ci-6 alkyl)2, C(O)N(Ci-6 alkyl)(C6-20 aryl), C(O)N(Ci-6 alkyl)(C7-20 aralkyl) and C(O)N(C1-6 alkyl)(C7-20 alkaryl) on the backbone; and,
(c) groups independently selected from the group consisting of C1-J0 alkyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, C12-20 aryloxyaryl, C7-20 aryloxyalkyl, C1-10 alkoxy, C6-20 aryloxy, C2-10 alkenyl, C2-I0 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl and C6-20 aryl on the backbone;
Rla and R5a are independently selected from H, COOH, COOCH3, COOCH2CH3, halo, OH, OCH3, OCH2CH3, OCF3, CF3, CH3, OCCl3, CCl3, OCF2CF3, CF2CF3, NH2, NH(CH3), N(CH3)2, NHC(O)(CH3), NO2, CN, OC(O)CH3 and C(O)H; or R1 is joined to R5, R5a or Rla to form a 5, 6, 7, 8, 9 or 10-membered saturated, unsaturated or aromatic, heterocyclic or carbocyclic ring which is optionally substituted with one or more of the groups, preferably, I5 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (b) and (c) above; or R5 is joined to R5a or RIa to form a 5, 6, 7, 8, 9 or 10-membered saturated, unsaturated or aromatic, heterocyclic or carbocyclic ring which is optionally substituted with one or more of the groups, preferably, 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (b) and (c) above;
R3 is selected from H, COOH, COO(Ci-20 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SO3H, SO2(Ci-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(C1-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, SO2NH(C7-20 aralkyl), SO2NH(C7-20 alkaryl), SO2N(C1-6 alkyl)(C6-2o aryl), SO2N(Ci-6 alkyl)(C7-20 aralkyl), SO2N(C1-6 alkyl)(C7-20 alkaryl), SO2N(C6-20 aryl)2, SO2N(C6-20 aryl)(C7-20 aralkyl), SO2N(C6-20 aryl)(C7-20 alkaryl), C(O)H, C(O)(Ci-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl), C(O)(C7-20 aralkyl), C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(Ci-6 alkyl)2, C(O)NH(C6-20 aryl), C(O)N(C6-20 aryl)2, C(O)NH(C7-20 aralkyl), C(O)N(C7-20 aralkyl)2, C(O)NH(C7-20 alkaryl), C(O)N(C7-20 alkaryl)2, C(O)N(Cj-6 alkyl)(C6-20 aryl), C(O)N(Cj-6 alkyl)(C7-20 aralkyl), C(O)N(C1-6 alkyl)(C7-20 alkaryl), C(O)N(C6-20 aryl)(C7-2o aralkyl), C(O)N(C6-20 aryl)(C7-20 alkaryl) and Ci-30 hydrocarbyl or C1-30 heterocarbyl groups, wherein any of the Ci-30 hydrocarbyl or C1-30 heterocarbyl groups are optionally substituted with one or more of the groups, preferably 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (d), (e) and (f):
(d) -CH=CH-, -C≡C-, S, N, -N= Si(C1-6 alkyl)2, Si(OH)2, Si(OCj-6 alkyl)2, C(O)NH, C(O)N(C1-6 alkyl), C(O)O, N(C1-6 alkyl)C(O)N(Ci-6 alkyl), NHC(O)N(Ci-6 alkyl), N(C1-6 alkyl)C(O)O, NHC(O)NH, NHC(O)O, NH, N(Ci-6 alkyl), N(C6-20 aryl), N(C7-20 alkaryl), N(C7-20 aralkyl), O, CO, SO2, NHSO2, NHSO2NH, N(Ci-6 alkyl)SO2NH, N(C1-6 alkyl)SO2N(C1-6 alkyl), N(C6-20 aryl)SO2NH, SO, C(O)N(C6-20 aryl), N(C1-6 alkyl)SO2,
N(C6-20 aryl)SO2, C(O)NHNHC(O), =N-N- and C(O)NHNH in the backbone;
(e) COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH, S(C1-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(C1-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(C1-6 alkyl), 0(C6-20 aryl),
0(C7-20 alkaryl), 0(C7-20 aralkyl), =0, NH2, =NH, NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), NH(C7-20 aralkyl), NH(C7-20 alkaryl), N(C-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-20 aralkyl), N(C1-6 alkyl)(C7-20 alkaryl), =N(C1-6 alkyl), =N(C6-20 aryl), =N(C7-20 aralkyl), =N(C7-20 alkaryl), NHC(O)(C1-6 alkyl), NHC(O)(C6-20 aryl), NHC(O)(C7-20 aralkyl), NHC(O)(C7-20 alkaryl), N(C]-6 alkyl)C(0)(C6-2o aryl), N(C1-6 alkyl)C(O)(C7-20 aralkyl), N(C1-6 alkyl)C(O)(C7-20 alkaryl), NO2, CN, SO2NH2, SO2NH(Ci-6 alkyl), SO2N(C1-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, SO2NH(C7-20 aralkyl), SO2NH(C7-20 alkaryl), SO2N(C1-6 alkyl)(C6-2o aryl), SO2N(Ci-6 alkyl)(C7-20 aralkyl), SO2N(Ci-6 alkyl)(C7.20 alkaryl), NHSO2(Ci-6 alkyl), NHSO2(C6-20 aryl), NHSO2(C7-20 aralkyl), NHSO2(C7-20 alkaryl), N(Ci-6 alkyl)SO2(Ci-6 alkyl), N(Ci-6 alkyl) SO2(C6-20 aryl), N(Cj-6 alkyl)SO2(C7-20 aralkyl), N(C1-6 alkyl)SO2(C7-20 alkaryl), C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl), C(O)(C7-20 aralkyl), OC(O)(C3-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 aralkyl), OC(O)(C7-20 alkaryl), C(O)NH(Ci-6 alkyl), C(O)NH(C6-20 aryl), C(O)NH(C7-20 aralkyl), C(O)NH(C7-20 alkaryl), C(O)N(C1-6 alkyl)2, C(O)N(Ci-6 alkyiχC6-2o aryl), C(O)N(C1-6 alkyl)(C7-20 aralkyl) and C(O)N(C1-6 alkyl)(C7-20 alkaryl) on the backbone; and,
(f) groups independently selected from the group consisting of C1-]O alkyl, C2-I0 alkoxyalkyl, C7-20 alkoxyaryl, Ci2-20 aryloxyaryl, C7-20 aryloxyalkyl, C1-I0 alkoxy, C6-20 aryloxy, C2-I0 alkenyl, C2-I0 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl and C6-20 aryl on the backbone;
R2 is a group
Figure imgf000265_0001
wherein: n is an integer of 0, 1, 2, 3, 4 or 5; m is an integer of O, 1, 2, 3, 4 or 5; wherein the group -(CH2)m- is optionally substituted by 1 or more -OH groups on the CH2 backbone, preferably 1 -OH group;
R7 and Rs are independently selected from the group consisting of H, COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH, S(C1-6 alkyl), SO2H, SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(Ci-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, O(d-6 alkyl), NH2, NH(Ci-6 alkyl), N(Ci-6 alkyl)2, NHC(O)(C1-6 alkyl), NO2, CN, SO2NH2, SO2NH(Ci-6 alkyl), SO2N(C1-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, C(O)H5 C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl) and C(O)(C7-20 aralkyl), and hydrocarbyl or heterocarbyl groups selected from C1-2O alkyl, C2-20 alkenyl, C1-20 alkoxy, C2-2O alkoxyalkyl, Cg-3O aryloxy, C7-30 alkoxyaryl, C2-2O alkynyl, C3-3O cycloalkyl, C4-3O (cycloalkyl)alkyl, Cs-30 cycloalkenyl, C7-3O cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, C1-3O heteroaryl, C2-3O heterocyclyl, C2-30 heteroaralkyl and C3-30 heterocyclylalkyl, any of said hydrocarbon groups being optionally substituted with one or more of the groups, preferably 1, 2, 3, 4, 5 or 6 groups, independently selected from the groups defined in (g), (h) and (i):
(g) -CH=CH-, -C≡C-, S, N, -N= Si(C1-6 alkyl)2, Si(OH)2, Si(OC1-6 alkyl)2, C(O)NH, C(O)N(C1-6 alkyl), C(O)O, N(C1-6 alkyl)C(O)N(C1-6 alkyl), NHC(O)N(Ci-6 alkyl), N(Ci-6 alkyl)C(O)O, NHC(O)NH, NHC(O)O, NH, N(C1-6 alkyl), N(C6-20 aryl), N(C7-20 alkaryl), N(C7-20 aralkyl), O, CO, SO2, NHSO2 and C(O)NHNH in the backbone;
(h) COOH, COO(Ci-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), SH, S(C1-6 alkyl), S(C6-20 aryl), S(C7-20 alkaryl), S(C7-20 aralkyl), SO2H, SO3H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), SO2(C7-20 aralkyl), SO(C1-6 alkyl), SO(C6-20 aryl), SO(C7-20 alkaryl), SO(C7-20 aralkyl), P(OH)(O)2, halo, OH, 0(Cj-6 alkyl), 0(C6-20 aryl), 0(C7-20 alkaryl), 0(C7-20 aralkyl), =0, NH2, =NH, NH(C1-6 alkyl), N(C1-6 alkyl)2, =N(Ci-6 alkyl), NHC(O)(C1-6 alkyl), NO2, CN, SO2NH2, SO2NH(C1-6 alkyl), SO2N(C1-6 alkyl)2, SO2NH(C6-20 aryl), SO2N(C6-20 aryl)2, C(O)H, C(O)(C1-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 alkaryl) and C(O)(C7-20 aralkyl) on the backbone; and,
(i) groups independently selected from the group consisting Of C1-I0 alkyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, C12-20 aryloxyaryl, C7-20 aryloxyalkyl, Ci-I0 alkoxy, C6-20 aryloxy, C2-I0 alkenyl, C2-I0 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyL C7-20 aralkyl, C7-20 alkaryl and C6-20 aryl on the backbone; when n is 1 or more, -(CH2)m-R6 is located in the ortho, meta or para position relative to the -(CH2V group; when n is O, -(CH2)m-R6 is located in the meta or para position relative to the to the N1 atom;
R6 is selected from the group consisting of NR9R10, CONR9R10, NR9COR10, OR10, NR9C(=NR15)N(R14)2 and N=C(NR15R9)N(R14)2; wherein
R9 is selected from the group consisting of H and Ci-6 alkyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C6-20 aryl, C7-20 aralkyl, C7-20 alkaryl, C1-20 heteroaryl and C2-20 heterocyclyl;
R10 is selected from the group consisting of, H, Q-20 alkyl, C2-20 alkenyl, C2-20 alkoxyalkyl, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, C1-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl, C3-30 heterocyclylalkyl, Cg-3O heterocyclylalkaryl, C4-30 heterocyclylalkoxyalkyl, C4-30 heterocyclylalkylaminoalkyl, C8-30 heteroarylalkaryl, C3-30 heteroarylalkoxyalkyl, C3-30 heteroarylalkylaminoalkyl, C7-30 aryloxyalkyl, C7-30 arylaminoalkyl, C7-30 alkylaminoaryl, C1-10 aminoalkyl, C7-20 aminoaralkyl, C7-20 aminoalkaryl, C2-20 alkylguanidinylalkyl and ureayl C1-J0 alkyl; or, in the groups NR9R10 and CONR9R10, R9 and R10 may be joined to form a 3, 4, 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring; any of the groups defined as R10 (except H) being optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from C1-10 alkyl, C1-2O haloalkyl, C1-20 perhaloalkyl, Ci-20 hydroxyalkyl, C3-io cycloalkyl, halo, OH, OCi-6 alkyl, NH2, OC(Ci-6 alkyl), OC(C6-20 aryl), OC(C7-20 aralkyl), OC(C7-20 alkaryl), OCO(C1-6 alkyl), OCO(C6-20 aryl), OCO(C7-20 aralkyl), OCO(C7-20 alkaryl), COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), N(C6-20 aryl)2, NH(C7-20 aralkyl), N(C7-20 aralkyl)2, NH(C7-20 alkaryl), N(C7-20 alkaryl)2, N(Ci-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-20 alkaryl), N(C1-6 alkyl)(C7-20 aralkyl), N(C6-20 aryl)(C6-20 aryl), N(C6-20 aryl)(C7-20 alkaryl), N(C6-20 aryl)(C7-20 aralkyl), NO2, CN, C(O)H, C(O)(Ci-6 alkyl), C(O)(C6-20 aryl), C(O)(C7-20 aralkyl) and C(O)(C7-20 alkaryl); any the groups defined as R10 (except H) being optionally substituted in the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from -CH=CH-, -C≡C-, S, N, -N=, Si(C1-6 alkyl)2, Si(OH)2, Si(OC1-6 alkyl)* C(O)NH, C(O)N(C1-6 alkyl), C(O)O, N(C1-6 alkyl)C(O)N(C1-6 alkyl), NHC(O)N(C1-6 alkyl), N(Cj-6 alkyl)C(O)O, NHC(O)NH, NHC(O)O, NH, N(C1-6 alkyl), N(C6-20 aryl), N(C7-20 alkaryl), N(C7-20 aralkyl), O, CO, SO2, NHSO2, NHSO2NH, N(C1-6 alkyl)SO2NH, N(C1-6 alkyl)SO2N(C1-6 alkyl), N(C6-20 aryl)SO2NH, SO, C(O)N(C6-20 aryl), N(C1-6 alkyl)SO2, N(C6-20 aryl)SO2, C(O)NHNHC(O), =N-N- and C(O)NHNH; each R14 is independently selected from the group consisting of H, Ci-20 alkyl, C2-20 alkenyl, C2-20 alkoxyalkyl, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, Cs-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, C1-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl and C3-30 heterocyclylalkyl, Ci-10 aminoalkyl, C6-20 aminoaryl, guanidinyl C1-10 alkyl, C2-20 alkylguanidinylalkyl, ureayl C1-10 alkyl and C2-20 alkylureaylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, OH, OC1-6 alkyl, NH2, COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), OC(O)(C1-6 alkyl), OC(O)(C6-20 aryl), OC(O)(C7-20 aralkyl), OC(O)(C7-20 alkaryl), NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), N(C6-20 aryl)2, NH(C7-20 aralkyl), N(C7-20 aralkyl)2, NH(C7-20 alkaryl), N(C7-20 alkaryl)2, N(C1-6 alkyl)(C6-20 aryl), N(C1-6 alkyl)(C7-20 aralkyl), N(C1-6 alkyl)(C7-20 alkaryl), N(C6-20 aryl)(C7-20 aralkyl), N(C6-20 aryl)(C7-20 alkaryl), NO2, CN, C(O)H and C(O)(C1-6 alkyl), or each R14 is joined to one another to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring; and, R15 is selected from the group consisting of H, CN, C1-20 alkyl, C2-20 alkenyl, C2-20 alkoxyalkyl, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, C1-30 heteroaryl, C2-30 heterocyclyl, C2-30 heteroaralkyl and C3-30 heterocyclylalkyl, C1-10 aminoalkyl, C6-20 aminoaryl, guanidinyl C1-10 alkyl, C2-20 alkylguanidinylalkyl, ureayl C1-10 alkyl and C2-20 alkylureaylalkyl, any of which (except H) are optionally on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, OH, OC1-6 alkyl, NH2, COOH, COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C6-20 aryl), N(C6-20 aryl)2, NH(C7-20 aralkyl), N(C7-20 aralkyl)2, NH(C7-20 alkaryl), N(C7-20 alkaryl)2, NO2, CN, C(O)H and C(O)(C1-6 alkyl); or R15 and one of R14 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R14 not joined to R15 is H or C1-6 alkyl.
2. A compound according to claim 1, wherein R7 and R8 are independently selected from the group consisting of H, C1-6 alkyl, halo, haloC1-6 alkyl, perhaloC1-6 alkyl, OH, NH2, NO2, CN, COOH, C(O)H, C(O)O(C1-6 alkyl) and C(O)(C1-6 alkyl), n is O or 1 and m is O or 1.
3. A compound according to claim 1, wherein n is 1 or more and R7 and/or R8 are located in the ortho or meta position relative to the -(CH2)n- group.
4. A compound according to claim 1, wherein n is O and R7 and/or R8 are located in the ortho or meta position relative to the N1 atom.
5. A compound according to claim 1, wherein n is O.
6. A compound according to claim 1 or claim 5, wherein m is O.
7. A compound according to any preceding claim, wherein R2 is selected from
Figure imgf000268_0001
Figure imgf000269_0001
and
Figure imgf000269_0002
8. A compound according to any preceding claim, wherein R9 is selected from H, methyl, ethyl and propyl, phenyl, phenylethyl, benzyl, tolyl and xylyl, preferably H.
9. A compound according to any preceding claim, wherein R10 is selected from the group consisting of Ci-15 heteroaryl, C2-i5 heterocyclyl, C2-i5 heteroaralkyl, C3-15 heterocyclylalkyl, C1-I5 alkyl, C6-20 aryl, C7-20 aralkyl, C3-15 cycloalkyl, and C4-15 cycloalkylalkyl, any of which are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from NH2, NH(Cj-4 alkyl), N(C1-4 alkyl)2, NH(C6-16 aryl), N(C6-I6 aryl)2, NH(C7-16 aralkyl), N(C7-16 aralkyl)2, NH(C7-16 alkaryl), N(C7-16 alkaryl)2, N(C1-4 alkyl)(C6-16 aryl), N(C1-4 alkyl)(C7-16 alkaryl), N(C1-4 alkyl)(C7-16 aralkyl), N(C6-I6 aryl)(C7-16 alkaryl), N(C6-16 aryl)(C7-16 aralkyl), NO2, CN, OH, SH, Od-6 alkyl, C(O)H and C(O)(C1-6 alkyl).
10. A compound according to any preceding claim, wherein R10 is selected from the group consisting of C1-1O alkyl, C3-15 cycloalkyl, C4-15 cycloalkylalkyl, C7-20 aralkyl, furanyl, furanyl(C1-3 alkyl), pyridyl, pyridyl(C1-3 alkyl), phthalimido, phthalimido(C1-3 alkyl), thienyl, thienyl(C1-3 alkyl), pyrrolyl, pyrrolyl(d.3 alkyl), imidazolyl, imidazolyl(C1-6 alkyl), pyrazolyl, PyTaZoIyI(C1-3 alkyl), thiazolyl, thiazolyl(C1-3 alkyl), isothiazolyl, isothiazolyl(C1-3 alkyl), thiazolylmethyl, isothiazolylmethyl, oxazolyl, oxazolyl(C1-3 alkyl), pyrrolidinyl, pyrrolidinyl(Ci-3 alkyl), pyrrolinyl, pyrrolinyl(C]-3 alkyl), imidazolidinyl, imidazolidinyl(C1-3 alkyl), imidazolinyl, imidazolinyl(C1-3 alkyl), imidazolemethyl, dihydroimidazolyl, dihydroimidazolyl(C1-3 alkyl), dihydroimidazolylmethyl, tetrahydropyrimidinyl, tetrahydropyrimidinyl(C1-3 alkyl), benzimidazolyl, benzimidazolyl(C1-3 alkyl), tetrahydroisoquinolinyl, tetrahydroisoquinolyl(C1-3 alkyl), pyrazolidinyl, pyrazolidinyl(C1-3 alkyl), tetrahydrofuranyl, tetrahyrdofuranyl(C1-3 alkyl), pyranyl, pyranyl(Ci.3 alkyl), pyridonyl, pyridonyl(Ci-3 alkyl), pyronyl, pyronyl(C1-3 alkyl), pyrazinyl, pyrazinyl(C1-3 alkyl), pyridazinyl, pyridazinyl(C1-3 alkyl), piperidinyl, piperidinyl(Ci-3 alkyl), piperazinyl, piperazinyl(C1-3 alkyl), morpholinyl, morpholinyl(C1-3 alkyl), thionaphthyl, thionaphthyl(C1-3 alkyl), benzofuranyl, benzofuranyl(C1-3 alkyl), isobenzofuryl, isobenzofiiryl(C1-3 alkyl), indolyl, indolyl(C1-3 alkyl), oxyindolyl, oxyindonlyl(C1-3 alkyl), isoindolyl, isoindolyl(Cj-3 alkyl), indazolyl, indazolyl(C1-3 alkyl), indolinyl, indolinyl(Ci-3 alkyl), isoindolinyl, isomdolinyl(C1-3 alkyl), isoindazolyl, isoindazolyl(C1-3 alkyl), benzopyranyl, benopyranyl(C1-3 alkyl), coumarinyl, coumarinyl(C1-3 alkyl), isocoumarinyl, isocoumarinyl(C1-3 alkyl), quinolyl, quinolyl(C1-3 alkyl), isoquinolyl, isoquinolyl(C].3 alkyl), napthridinyl, naphthridinyl(C1-3 alkyl), cinnolinyl, cinnolinyl(Ci_3 alkyl), quinazolinyl, quinazolinyl(C1-3 alkyl), pyridopyridyl, pyridoρyridyl(C1-3 alkyl), benzoxazinyl, benzoxazinyl(C1-3 alkyl), quinoxadinyl, quinoxadinyl(Ci-3 alkyl), chromenyl, chromenyl(C]..3 alkyl), chromanyl, chromanyl(C1-3 alkyl), isochromanyl, isochromanyl(C1-3 alkyl), carbolinyl, carbolinyl(Ci-3 alkyl), thiophenyl, thiophenyl(C1-3 alkyl), thiazolyl, thiazolinyl(C1-3 alkyl), isoxazolyl, isooxazolyl(C1-3 alkyl), isoxazolonyl, isoxazolonyl(C],3 alkyl), isothiazolyl, isothiazolyl(C1-3 alkyl), triazolyl, triazolyl(C1-3 alkyl), oxadiazolyl, oxadiazolyl(C1-3 alkyl), thiadiazolyl, thiadiazolyl(C1-3 alkyl), pyridazyl, pyridazyl(C1-3 alkyl), any of which are optionally substituted on the backbone with one or more groups independently selected from =0, COOH, SH, SO2H, P(OH)(O)2, halo, trihalomethyl, OH, NH2, =NH, NH(C1-6 alkyl), =N(C,-6 alkyl), NO2, CN, OCH3, SO2NH2 and C(O)H, C1-6 alkyl, C2-6 alkoxyalkyl, C7-I0 alkoxyaryl, C3-10 cycloalkyl, C4-15 (cycloalkyl)alkyl, C7-12 aralkyl, C7-12 alkaryl, C1-12 heteroaryl and C6-12 aryl.
11. A compound according to claim 10, wherein R10 comprises a lH-imidazol-2-yl(C1-6 alkyl) group which may be substituted with 1 or more groups independently selected from C1-6 alkyl, halo, haloQ.6 alkyl, hydroxyC1-6 alkyl, perhaloC1-6 alkyl, OH, NH2, NO2, CN, COOH, C(O)H, C(O)O(C1-6 alkyl), 0(C1-6 alkyl), OC(O)(C1-6 alkyl) and C(O)(C1-6 alkyl).
12. A compound according to any of claims 1 to 9, wherein R10 represents a natural or synthetic amino acid residue, preferably 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.
13. A compound according to any of claims 1 to 7, wherein each R14 is independently selected from the group consisting of H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, C2-10 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C5-20 cycloalkenyl, C7-20 cycloalkynyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, C1-20 heteroaryl and C2-20 heterocyclyl, C2-20 heteroaralkyl, C3-20 heterocyclylalkyl, C1-10 aminoalkyl, C6-10 aminoaryl, guanidinyl C1-6 alkyl, C2-12 alkylguanidinylalkyl, ureayl C1-6 alkyl and C2-12 alkylureaylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, OH, OCH3, OCH2CH3 and NH2, or each R14 is joined to one another to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring.
14. A compound according to any of claims 1 to 7, wherein R15 is selected from the group consisting of H, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkoxyalkyl, C7-20 alkoxyaryl, C2-10 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C5-20 cycloalkenyl, C7-20 cycloalkynyl, C7-20 aralkyl, C7-2O alkaryl, C6-20 aryl, Ci-20 heteroaryl and C2-20 heterocyclyl, C2-2O heteroaralkyl, C3-20 heterocyclylalkyl, Ci-I0 aminoalkyl, C6-I0 aminoaryl, guanidinyl, guanidinyl C1-6 alkyl, Ci-6 alkylguanidinyl, C2-I2 alkylguanidinylalkyl, ureayl, ureayl Ci-6 alkyl, C1-6 alkylureayl and C2-I2 alkylureaylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from halo, OH, OCH3, OCH2CH3 and NH2.
15. A compound according to any of claims 1 to 7, wherein R15 and one of R14 are joined to form a 5, 6, 1, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R14 not joined to R15 is H or Ci-6 alkyl.
16. A compound according to any of claims 1 to 7, wherein each R14 is independently selected from the group consisting of H and C1-4 alkyl, or R15 and one of R14 are joined to form a 5, 6, 7, 8, 9 or 10-membered, saturated, unsaturated or aromatic heterocyclic ring, and the R14 not joined to R15 is selected from the group consisting of H and C1-4 alkyl.
17. A compound according to claim 1, wherein R6 comprises a guanidinyl moiety.
18. A compound according to claim 1 or claim 17, wherein R6 is a group
Figure imgf000271_0001
where each R14 and R15 are H.
19. A compound according to any preceding claim, wherein R3 is -(CR16R17)m'-X-R18; wherein: m' is O, 1, 2, 3 or 4;
X is a bond, -CH=CH-, -C≡C-, S, N, Si(C1-6 alkyl)2, Si(OH)2, Si(OCi-6 alkyl)2, C(O)NH, C(O)NCi-6 alkyl, C(O)NC6-20 aryl, C(O)NC7-20 aralkyl, C(O)NC7-20 alkaryl, C(O)O, N(Ci-6 alkyl)C(O)N(Ci-6 alkyl), NHC(O)N(Ci-6 alkyl), OC(O)N(Ci-6 alkyl), NHC(O)NH, NHC(O)O, NH, N(C1-6 alkyl), O, CO, SO2, SO2NH, NHSO2, and C(O)NHNH;
R16 and R17 are independently selected from the group consisting of H, Ci-2O alkyl, C2-20 alkenyl, C2-20 alkoxyalkyl, C7-30 alkoxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-3O cycloalkenyl, C7-30 cycloalkynyl, €7.30 aralkyL C7-30 alkaryl, C6-30 aryl, C1-30 heteroaryl, C2-30 heterocyclyl, C2-3O heteroaralkyl, C3-3o heterocyclylalkyl, Ci-10 aminoalkyl and C6-20 aminoaryl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from COOH, COO(C1-6 alkyl), SH, S(C1-6 alkyl), SO2H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), P(OH)(O)2, halo, haloC1-6 alkyl, perhaloC1-6 alkyl, OH, 0(C1-6 alkyl), =0, NH2, =NH, NH(C1-6 alkyl), N(Ci-6 alkyl)2, =N(C]-6 alkyl), NHC(O)(Ci-6 alkyl), NO2, CN, SO2NH2, C(O)H and C(O)(Ci-6 alkyl), Ci-10 alkyl, C2-10 alkoxyalkyl, C7-2O alkoxyaryl, C2-io alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C1-20 heteroaryl and C6-20 aryl; or R16 and R17 are joined to form a 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20-membered, saturated, unsaturated or aromatic ring; and,
R18 is selected from the group consisting of H, Ci-20 alkyl, C2-20 alkenyL C2-20 alkoxyalkyl, C7-30 alkoxyaryl, C12-30 aryloxyaryl, C2-20 alkynyl, C3-30 cycloalkyl, C4-30 (cycloalkyl)alkyl, C5-30 cycloalkenyl, C7-30 cycloalkynyl, C7-30 aralkyl, C7-30 alkaryl, C6-30 aryl, Ci-30 heteroaryl and C2-30 heterocyclyl, C2-30 heteroaralkyl and C3-30 heterocyclylalkyl, C1-I0 aminoalkyl, C6-20 aminoaryl, guanidine Ci-I0 alkyl, C2-20 alkylguanidinylalkyl, urea Ci-I0 alkyl and C2-20 alkylureaylalkyl, any of which (except H) are optionally substituted on the backbone with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from COOH, COO(C1-6 alkyl), SH, S(C1-6 alkyl), SO2H, SO2(C1-6 alkyl), SO2(C6-20 aryl), SO2(C7-20 alkaryl), P(OH)(O)2, halo, haloCi-6 alkyl, perhaloC1-6 alkyl, OH, 0(Ci-6 alkyl), =O, NH2, =NH, NH(C1-6 alkyl), N(Ci-6 alkyl)2, =N(C1-6 alkyl), NHC(O)(Ci-6 alkyl), C(O)NH2, C(O)NH(Ci-6 alkyl), C(O)N(C1-6 alkyl)2, C(O)NH(C6-I2 aryl), C(O)N(C6-I2 aryl)2, C(O)NH(C7-J2 aralkyl), C(O)N(C7-I2 aralkyl)2, C(O)NH(C7-I2 alkaryl), C(O)N(C7-I2 alkaryl)2, NO2, CN, SO2, SO2NH2, C(O)H and C(O)(Ci-6 alkyl), Ci-I0 alkyl, C2-I0 alkoxyalkyl, C7-20 alkoxyaryl, C2-I0 alkynyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, Ci-20 heteroaryl and C6-20 aryl.
20. A compound according to claim 19, wherein m' is 0, 1 or 2.
21. A compound according to claim 19 or claim 20, wherein X is a bond, C(O)NH5 C(O)N(Ci-6 alkyl) or C(O)N(C6-20 aryl).
22. A compound according to any of claims 19, 20 or 21, wherein R18 is selected from the group consisting of methyl, ethyl, propyl, butyl, phenyl, benzyl, biphenyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, quinolinyl, naphthyl, tetramethylcyclohexyl, benzocycloheptyl, benzodioxepinyl, bicyclooctyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetramethyltetrahydropyranyl, cyclohexylmethyl, phenylethylbenzyl, phenoxybenzyl, phenylethynylbenzyl, cyclohexylbenzyl, tolyl, ethylbenzyl, xylyl, isopropylbenzyl, cyclohexylmethyl, methoxyphenyl, diphenylmethyl, phenethyl, pyridylmethyl, butylphenyl, binaphthyl, adamantyl, propylbenzyl, mesitylyl, ethyltolyl, butylbenzyl, indanyl, diethylbenzyl, methylindanyl, dimethylethylbenzyl, phenylpentyl, tetramethylbenzyl, phenylhexyl, dipropylbenzyl, triethylbenzyl, tetrahydronaphthyl, cyclohexylbenzyl, methylnaphthyl, naphthylmethyl, methyltetrahydronaphthyl, ethylnaphthyl, dimethylnaphthyl, diphenylethyl, diphenylmethyl, propylnaphthyl, butylnaphthyl, phenanthryl, fluoryl, stilbyl, methylfluoryl, benzphenanthryl, triphenylmethyl, acenaphthyl, azulenyl, phenylnaphthyl, methylchrysyl, benzfluoryl, pyrenyl, hexamethylbenzyl, perylenyl, picenyl, dihydroisoxazolyl, fiiranyl, pyridyl, phthalimido, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, carbolinyl, thiophenyl, thiazolyl, isoxazolyl, isoxazolonyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and pyridazyl, any of which are optionally substituted with one or more groups, preferably 1, 2, 3 or 4 groups, independently selected from =0, COOH, SH5 SO2H, P(OH)(O)2, halo, trihalomethyl, OH, NH2, =NH, NH(Cj-6 alkyl), =N(Ci-6 alkyl), NO2, CN, OCH3, SO2NH2 and C(O)H, Cj-6 alkyl, C2-6 alkoxyalkyl, C7-io alkoxyaryl, C3-10 cycloalkyl, C4-I5 (cycloalkyl)alkyl, C7-I2 aralkyl, C7-I2 alkaryl, CM2 heteroaryl and Cg-I2 aryl.
23. A compound according to any of claims 1 to 21, wherein R3 comprises a benzyl group, optionally substituted with 1, 2 or 3 groups, independently selected from COO(C1-6 alkyl), COO(C6-20 aryl), COO(C7-20 aralkyl), COO(C7-20 alkaryl), halo, trihalomethyl, OH, NH2, 0(Ci-6 alkyl), 0(C6-20 aryl), 0(C7-20 aralkyl), 0(C7-20 alkaryl), C1-6 alkyl, C6-12 aryl, C7-I2 aralkyl, C7-J2 alkaryl, C7-I2 aralkynyl, C6-J2 aryloxy, Ci-J2 heteroaryl, C5-J2 cycloalkyl and C(O)(C1-6 alkyl) on the backbone.
24. A compound according to any of claims 1 to 21, wherein R3 comprises a methyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, quinolinyl, naphthyl, benzocycloheptyl, tetrahydropyranyl, dihydropyranyl, tetramethyltetrahydropyranyl, or benzodioxepinyl group, optionally substituted with 1, 2, 3 or 4 groups independently selected from COO(Ci-6 alkyl), halo, trihalomethyl, OH, NH2, 0(Ci-6 alkyl), Ci-6 alkyl, C6-12 aryl, C7-12 aralkyl, C7-12 alkaryl, C6-I2 aryloxy, CM2 heteroaryl, C5-I2 cycloalkyl and C(O)(Ci-6 alkyl) on the backbone.
25. A compound according to any preceding claim, wherein R1 and R5 are independently selected from the group consisting of H, COOH, SH, SO2H, P(OH)(O)2, F, Cl, Br, I, OH, NH2, NO2, CN, SO2NH2, C(O)H, and hydrocarbyl or heterocarbyl groups selected from Ci-S alkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, C7-20 alkoxyaryl, C3-2O cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C6-20 aryl, C1-20 heteroaryl and C2-20 heterocyclyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups, preferably 1, 2, 3 or 4 groups, independently selected from the groups defined in (a), (b) and (c):
(a) C(O)NH, C(O)NMe5 C(O)O, NHC(O)NH, NHC(O)O, NH, O, CO, SO2, NHSO2, and C(O)NHNH in the backbone;
(b) =0, COOH5 SH, SO2H5 SO3H, P(OH)(O)2, F, Cl, Br, I, OH, NH2, =NH, NH(C1-6 alkyl), =N(C1-6 alkyl), NO2, CN, SO2NH2, and C(O)H on the backbone; and, (c) groups independently selected from the group consisting Of C1-6 alkyl, C2-6 alkoxyalkyl, C7-10 alkoxyaryl, C3-10 cycloalkyl, C4-12 (cycloalkyl)alkyl, C7-12 aralkyl, C7-12 alkaryl, C1-12 heteroaryl and C6-12 aryl on the backbone.
26. A compound according to any preceding claim, wherein R5 and R1 are both H.
27. A compound according to any of claims 1 to 25, wherein R1 is a methyl group and is located in the 8-position.
28. A compound according to any preceding claim, wherein R4 is selected from the group consisting of H, hydrocarbyl or heterocarbyl groups selected from C1-10 alkyl, C2-10 alkoxyalkyl, C]2-20 aryloxyaryl, C7-20 aryloxyalkyl, C1-10 alkoxy, C7-20 alkoxyaryl, C4-20 alkoxycycloalkyl, C3-20 cycloalkyl, C4-20 (cycloalkyl)alkyl, C7-20 aralkyl, C7-20 alkaryl, C6-2O aryl, C1-20 heteroaryl, C2-20 heteroaralkyl and C2-20 heterocyclyl, any of said hydrocarbyl or heterocarbyl groups being optionally substituted with one or more of the groups, preferably 1, 2 or 3 groups, independently selected from (a), (b) and (c):
(a) S, C(O)NH, C(O)NMe, C(O)O, NHC(O)NH, NHC(O)O, NH, O, CO, SO2, SO2NH, NHSO2 and C(O)NHNH in the backbone; (b) =O, COOH5 SH, SO2H5 P(OH)(O)2, F, Cl, Br, I, OH, NH2, =NH, NH(C1-6 alkyl), =N(C1-6 alkyl), NO2, CN, SO3H5 SO2NH2, C(O)(C1-6 alkyl) and C(O)H on the backbone; and,
(c) groups independently selected from the group consisting of. C1-6 alkyl, C2-6 alkoxyalkyl, C7-10 alkoxyaryl, C3-10 cycloalkyl, C4-12 (cycloalkyl)alkyl, C7-12 aralkyl, C7-12 alkaryl and C6-12 aryl on the backbone.
29. A compound according to any preceding claim, wherein R4 is selected from the group consisting of C1-6 alkyl, C3-I2 cycloalkyl, C6-12 aryl, C1-J2 heteroaryl, C2-12 heterocyclyl, C2-6 alkoxyalkyl, C5-I2 alkoxycycloalkyl, C2-io alkylthioalkyl, C4-J2 alkylthiocycloalkyl, C2-io alkylsulfonylalkyl, C6-I2 alkylsulfonylcycloalkyl and C6-12 alkylaminocycloalkyl.
30. A compound according to any preceding claim, wherein R4 is selected from the group consisting of methyl, tetrahydropyranyl, cyclohexyl, phenyl, isopropyl, fluorophenyl, cyclohexylmethyl, adamantyl, pyranyl, piperidinylmethyl, cyclohexylsulfanylmethyl, cyclohexanesulfonylmethyl, phenoxymethyl, cyclohexylphenoxymethyl, methoxyphenoxymethyl, naphthalenyloxymethyl, ethanoylphenoxymethoxy, aminoacetylaminophenoxymethyl, cyanophenoxymethyl, acetylaminophenoxymethyl and aminoacetylphenoxymethyl.
31. A compound according to any preceding claim, wherein Rla and R5a are independently selected from H, CH3, F, Cl, Br and OH.
32. A pharmaceutical composition comprising a compound, salt, solvate or pro-drug according to any preceding claim and a pharmaceutically acceptable diluent or carrier.
33. A method of making a pharmaceutical composition according to claim 32, comprising mixing said compound, salt, solvate or pro-drug with a pharmaceutically acceptable diluent or carrier.
34. A compound salt, solvate or pro-drug according to any of claims 1 to 31, for use in therapy.
35. A method for the treatment of a disease, selected from the group consisting of cardiovascular diseases, disorders of the peripheral and central nervous system, inflammation, urological diseases, developmental disorders, cancer, metabolic diseases, endocrinological diseases and disorders of the gastroenterology system in a mammal, comprising administering to a patient in need thereof a therapeutically effective amount of a compound, salt, solvate or pro-drug according to any of claims 1 to 31 or a pharmaceutical composition according to claim 32.
36. A method for the treatment of a disease mediated by PTH-I receptors, by administration to a subject of a compound, salt, solvate or pro-drug according to any of claims 1 to 31, or a pharmaceutical composition according to claim 32.
37. A method according to any of claims 35 or 36, wherein the disease is cancer.
38. A method according to any of claims 35 or 36, wherein the disease is osteoporosis.
39. A method according to any of claims 35 or 36, wherein the disease is an inflammatory disease.
40. A method according to any of claims 35 or 36, wherein the disease is an autoimmune disease.
41. A method according to any of claims 35 or 36, wherein the disease is metastases following a primary tumour.
42. A method according to any of claims 35 or 36, wherein the condition is lack of hair eruption.
43. A method according to any of claims 35 or 36, wherein the disease is disease selected from the group consisting of anaemia, renal impairment, ulcers, myopathy, neuropathy, hypercalcemia, hyperparathyroidism, parathyroid gland adenoma, parathyroid gland hyperplasia, parathyroid gland carcinoma, squamous carcinoma, renal carcinoma, breast carcinoma, prostate carcinoma, lung carcinomas, osteosarcomas, clear cell renal carcinoma, prostate cancer, lung cancer, breast cancer, gastric cancer, ovarian cancer, bladder cancer, bone fracture, severe bone pain, spinal cord compression, cachexia, malnutrition, muscle wasting, net protein loss, arthritis, rheumatoid arthritis, diabetes, congestive heart failure and wound healing.
44. Use of a compound, salt, solvate or pro-drug according to any of claims 1 to 31, or a pharmaceutical composition according to claim 32, in the manufacture of a medicament for the prophylaxis or treatment of a disease as defined in any of claims 35 to 43.
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