NZ708390B2 - Hedgehog antagonists having zinc binding moieties - Google Patents
Hedgehog antagonists having zinc binding moieties Download PDFInfo
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- NZ708390B2 NZ708390B2 NZ708390A NZ70839012A NZ708390B2 NZ 708390 B2 NZ708390 B2 NZ 708390B2 NZ 708390 A NZ708390 A NZ 708390A NZ 70839012 A NZ70839012 A NZ 70839012A NZ 708390 B2 NZ708390 B2 NZ 708390B2
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/86—Hydrazides; Thio or imino analogues thereof
- C07D213/87—Hydrazides; Thio or imino analogues thereof in position 3
-
- C—CHEMISTRY; METALLURGY
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- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- 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
- C07D401/10—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 aromatic rings
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- 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
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Provided are compounds of the general formula (I) or (II), wherein the variables are as defined in the specification. Examples of the compounds include (E)-2-chloro-N-(4-chloro-3-(5-(3-(hydroxyamino)-3-oxoprop-1-enyl)pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and 2-((3-(4-Chloro-3-(5-(dimethylamino)-1H-benzo[d]imidazol-2-yl)phenylcarbamoyl)-5-methoxybenzyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide. The compounds contain zinc binding moieties and can inhibit histone deacetylase (HDAC) and the hedgehog pathway. The compounds may be useful in the treatment of cancer, psoriasis or macular degeneration. amino)-1H-benzo[d]imidazol-2-yl)phenylcarbamoyl)-5-methoxybenzyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide. The compounds contain zinc binding moieties and can inhibit histone deacetylase (HDAC) and the hedgehog pathway. The compounds may be useful in the treatment of cancer, psoriasis or macular degeneration.
Description
/020092
OG NISTS HAVING ZINC BINDING MOIETIES
RELATED APPLICATIONS
This application claims the benefit ofUS. Provisional Application No.
61/429,350, filed on January 3, 2011 and US. Provisional Application No. 61/564,549,
filed on November 29, 2011. The entire teachings of the above applications are
incorporated herein by reference.
BACKGROUND OF THE INVENTION
Hedgehog (Hh) protein was first identified in Drosophila melanogaster as a
segment-polarity gene involved in embryo patterning (Nusslein-Voihard et al., Roux.
Arch. Dev. Biol., 193: 267-282 (1984)). Three ogs of Drosophila hedgehog (Sonic,
Desert and Indian) were later found to occur in all vertebrates, including fish, birds and
mammals. Desert hedgehog (DHh) is expressed principally in the testes, both in mouse
embryonic development and in the adult rodent and human; Indian hedgehog (IHh) is
involved in bone development during embryogenesis and in bone ion in the adult;
and, Sonic hedgehog (SHh) is expressed at high levels in the ord and floor plate of
developing vertebrate embryos. In vitro explant assays as well as ectopic expression of
SHh in transgenic animals have shown that SHh plays a key role in neuronal tube
patterning (Echelard et al., Cell, 75:1417-1430 (1993); Ericson et al., Cell, 81: 747-56
(1995); Marti et al., Nature, 375: 322-5 (1995); Krauss et al., Cell, 75: 1432-44 (1993);
Riddle et al., Cell, 75: 1401-16 ; Roelink et al., Cell, 81: 445-55 (1995); Hynes et
al., Neuron, 19: 15-26 (1997)). Hh also plays a role in the development of limbs (Krauss et
al., Cell, 75: 143-144 (1993); Laufer et al., Cell, 79: 993-1003 (1994)), somites (Fan and
Tessier—Lavigne, Cell, 79: 1175-86 (1994); Johnson et al., Cell, 79: 1165-73 (1994)), lungs
(Bellusci et al., Develop., 124: 53-63 (1997) and skin (Oro et al., Science, 276: 817-21
(1997)).
se, IHh and DHh are involved in bone, gut and germinal cell development
(Apelqvist et al., Curr. Biol., 7: 80 1-4 (1997); ci et al., Development, 124: 53-63
(1997); Bitgood et al., Curr. Biol., 6: 298-304 ; Roberts et al., Development, 121:
3163-74 (1995)).
Human SHh is synthesized as a 45 kDa precursor protein which is autocatalytically
cleaved to yield a 20 kDa inal fragment that is sible for normal hedgehog
signaling activity; and a 25 kDa C- terminal fragment that is responsible for
autoprocessing activity in which the N-terminal fragment is conjugated to a cholesterol
moiety (Lee, J.J., et al. (1994) Science, 266: 1528- 1536; Bumcrot, D.A., et al. (1995),
Mol. Cell Biol., 15 : 2294-2303; Porter, J.A., et al. (1995) Nature, 374: 363-366). The N-
terminal fragment consists of amino acid residues 24-197 of the fiJll-length precursor
sequence which remains membrane- associated through the terol at its C-terminus
(Porter, J.A., et al. (1996) Science, 274: 255-258; Porter, J.A., et al. (1995) Cell, 86(2): 1-
34). Cholesterol conjugation is responsible for the tissue localization of the hedgehog
signal.
At the cell surface, the Hh signal is thought to be relayed by the 12 transmembrane
domain n Patched (Ptc) (Hooper and Scott, Cell, 59: 751-65 ; Nakano et al.,
Nature, 341: 508-13 (1989)) and the G- protein-coupled-like receptor Smoothened (Smo)
(Alcedo et al., Cell, 86(22): 1-232 (1996); van den Heuvel and , Nature, 382: 547-
551 (1996)). Both genetic and biochemical evidence support a receptor model where Ptc
and Smo are part of a multicomponent or complex (Chen and Struhl, Cell, 87: 553-
63 (1996); Marigo et al., Nature, 384: 176-9 (1996); Stone et al., Nature, 384: 129-34
(1996)). Upon binding of Hh to Ptc, the normal tory effect of Ptc on Smo is relieved,
allowing Smo to transduce the Hh signal across the plasma membrane. However, the exact
mechanism by which Ptc controls Smo activity has yet to be clarified.
The signaling e initiated by Smo results in tion of Gli transcription
factors that translocate into the nucleus where they l transcription of target genes.
Gli has been shown to influence transcription of Hh pathway inhibitors such as Ptc and
Hip 1 in a negative ck loop indicating that tight control of Hh y activity is
ed for proper cellular differentiation and organ formation.
Hedgehog pathway signaling has been implicated in tumorigenesis when
reactivated in adult tissues through sporadic mutations or other mechanisms. Three
mechanisms have been proposed for the Hedgehog pathway’s involvement in cancer:
Type 1 cancers are caused by loss-of-function mutations in Patched 1 (PTCH1) or gain-of-
function mutations in Smoothened (SMOH) lead to constitutive Hedgehog (Hh) pathway
tion. Type 2 cancers rely on an autocrine model in which tumor cells themselves
e and respond to Hh ligand. Type 3 is a paracrine model in which tumor cells
produce Hh ligand and surrounding l cells respond by ing additional growth
factors to support tumor growth or survival, for example, IGF (Insulin-Like Growth
Factor) and VEGF (Vascular Endothelial Growth Factor) (Rubin, LL. and de Sauvage,
F.J. Nature Rev. Drug Discovery, 5: 1026-1033 (2006)).
Dysfunctional Ptc gene mutations have also been associated with a large
percentage of sporadic basal cell carcinoma tumors (Chidambaram et al., Cancer
Research, 56: 4599-601 (1996); i et al., Nature Genet, 14: 78- 81 (1996); Haim et
al., Cell, 85: 841-51 (1996); Jolmson et al., Science, 272: 1668-71 (1996); Unden et al.,
Cancer Res., 56: 4562-5; Wickingetal., Am. J. Hum. Genet., 60: 21-6 (1997)). Loss of Ptc
function is thought to cause an uncontrolled Smo signaling in basal cell carcinoma.
Similarly, activating Smo mutations have been identified in ic BCC tumors (Xie et
al., Nature, 391: 90-2 ), emphasizing the role of Smo as the signaling subunit in the
receptor complex for SHh.
The development of resistance to Shh y inhibitors has been ed in
animal tumor models (Buonamici, S. et al., Science Trans. Med., 2010, 2: 51ra70;
Osherovich, L. SciBX 2010, 3(40)) and in humans (Yauch, R. et al, Science, 2009).
Several mechanisms for resistance were identified, including SMO mutations, Gli2
amplification and upregulation of the IGF-lR—PI3K signaling pathway.
Various tors of og signaling have been investigated. The first
Hedgehog ing inhibitor to be discovered was cyclopamine, a natural alkaloid that
has been shown to arrest cell cycle at G0-Gl and to induce apoptosis in SCLC. A number
of synthetic small le Hedgehog pathway inhibitors are currently under development
(Trembley, M.R. et al., Expert Opin. Ther. Patents, 19(8): 1039-56 (2009)). e
advances with these and other compounds, there remains a need for potent inhibitors of the
og signaling pathway.
Histone acetylation is a ible modification, with deacetylation being catalyzed
by a family of enzymes termed histone deacetylases (HDACs). HDAC’s are represented
by 18 genes in humans and are divided into four distinct classes (J. Mol Biol, 2004,
338(1): 17-31). In mammalians class I HDAC’s -3, and HDAC8) are related to
yeast RPD3 HDAC, class 2 HDAC’s (HDAC4-7, HDAC9 and HDAC10) are related to
yeast HDACl, class 4 (HDAC11), and class 3 HDAC’s (a ct class encompassing the
sirtuins) are related to yeast Sir2.
Csordas (Biochem. J., 1990, 286: 23-3 8) teaches that histones are subject to post-
translational acetylation of the s-amino groups ofN-terminal lysine residues, a reaction
that is catalyzed by histone acetyl transferase . Acetylation neutralizes the positive
charge of the lysine side chain, and is thought to impact chromatin structure. Indeed,
access of transcription factors to chromatin templates is enhanced by histone
2012/020092
hyperacetylation, and enrichment in underacetylated histone H4 has been found in
transcriptionally silent regions of the genome (Taunton et al., Science, 1996, 272:408-
411). In the case of tumor suppressor genes, transcriptional silencing due to histone
modification can lead to oncogenic transformation and cancer.
Several classes ofHDAC inhibitors currently are marketed or under evaluation in
clinical trials. Examples include the hydroxamic acid derivatives suberoylanilide
hydroxamic acid (SAHA) and Romidepsin, which are marketed, and PXD101, LH-5 89
and LAQ824, which are currently in clinical development. In the ide class of
HDAC inhibitors, , MGCD0103 and CI-994 are currently being investigated in
clinical . Moume et al. (Abstract #4725, AACR 2005), demonstrate that thiophenyl
modification of benzamides significantly enhances HDAC inhibitory activity against
HDAC 1.
In addition, recent studies have shown that the acetylation of Gli proteins functions
as a key transcriptional checkpoint of og signaling. It was found that an
autoregulatory loop exists whereby Shh increases HDAC1 levels and HDAC1 in turn
enhances Hh-induced signal activation by deacetylation of Glil and Gli2. Moreover,
inhibitors of class 1 HDACs suppress Glil and Gli2 activation, thus ssing Hh-
dependent growth of neural progenitors and tumor cells. (Canettieri, G. et al., Nature Cell
Biology, 2010, 12: 132 -142).
Certain cancers have been ively treated with agents targeting multiple
signaling pathways. A recent study trated that the combined targeting of HDACs
and Hh signaling enhanced cytotoxicity in pancreatic arcinoma. (Chun, S. et al.,
Cancer Biol. & Therapy, 2009, 8(14): 1328-1339). r, treatment regimes using a
cocktail of cytotoxic drugs often are limited by dose limiting toxicities and drug-drug
interactions. More recent advances with molecularly ed drugs have provided some
new approaches to combination treatment for cancer, ng multiple targeted agents to
be used simultaneously, or combining these new therapies with standard
chemotherapeutics or radiation to improve outcome without reaching dose limiting
toxicities. However, in many cases, dose-limiting toxicities are d before
pharmacologically meaningful levels of exposure are ed, and the ability to use such
combinations currently is limited to drugs that show compatible pharmacokinetic and
pharmacodynamic properties. In addition, the regulatory requirements to demonstrate
safety and y of combination therapies can be more costly and lengthy than
corresponding single agent trials. Once approved, combination gies may also be
associated with increased costs to patients, as well as decreased t compliance.
SUMMARY OF THE INVENTION
The present invention relates to hedgehog antagonist compounds having zinc-
binding moieties and their use in the treatment of hedgehog and HDAC d es
and disorders such as cancer and other diseases and disorders characterized by
uncontrolled cell proliferation. The compounds of the present ion act as HDAC
inhibitors by virtue of their ability to bind zinc ions and as inhibitors of the Hedgehog
signaling pathway. Combining hedgehog antagonism and HDAC inhibition into a single
molecule may provide a synergistic effect in therapeutic applications, and in particular, to
the treatment of .
Accordingly, one aspect of the present invention provides a compound of a
(I) or Formula (11):
K O
L—X B D
E
D B X Q n
(11)
or a geometric isomer, enantiomer, diastereomer, racemate, pharmaceutically able
salt or prodrug thereof;
wherein:
Ring A is an aromatic, saturated or partially unsaturated carbocycle; preferably a
monocyclic, bicyclic or polycyclic C3-C12-carbocycle;
E is substituted or unsubstituted aryl or tuted or unsubstituted heteroaryl or
substituted or unsubstituted saturated or lly rated heterocyclyl;
L is tuted or unsubstituted aryl or substituted or unsubstituted heteroaryl or
substituted or unsubstituted saturated or partially unsaturated heterocyclyl;
Q is substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl or substituted
or unsubstituted saturated or partially unsaturated heterocyclyl;
G is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted
or unsubstituted saturated or partially unsaturated heterocyclyl;
K is halogen, preferably Cl;
X is absent, -O-, -N(R2)-, -S-, -S(O)-, -S(O)2-, -C(O)-,-C(O)O-, -OC(O)—, -C(O)N(R2)-, -
N(R2)C(O)-, -S(O)2N(R2)-, or -N(R2)S(O)2-;
R2 is hydrogen or aliphatic, preferably hydrogen or C1-C6-alkyl, and more preferably
hydrogen or ;
n is 0 or 1;
B is a bond or a linker; and
D is selected from:
F503;;31
(a) KJ) ;Where W is O or S; J is O, NH or NCH3; and R31 is
hydrogen or lower alkyl;
R“jib/3
l I
(b) R33 R32
; Where W is O or S; Y2 is absent, N, or CH; Z is N or CH;
R32 and R34 are independently hydrogen, OR’, aliphatic group, provided that
if R32 and R34 are both present, one of R32 or R34 must be OR’ and if Y2 is
absent, R34 must be OR’; R33 is hydrogen or tic group; and R’ is
hydrogen, aliphatic or acyl, ably hydrogen; preferably Y2 and R32 are
absent, Z is N, R34 is hydroxy and R33 is en;
(c) "v”
; Where W is O or S; Y1 and 21 are independently N, C or CH;
(d) R12 ll?“ ; where Z, Y2, and W are as previously defined; R11 and
R12 are independently selected from hydrogen or aliphatic; R21, R22 and R23
are independently selected from hydrogen, hydroxy, amino, halogen, alkoxy,
alkylamino, dialkylamino, CF3, CN, N02, sulfonyl, acyl, aliphatic,
S substituted aliphatic, aryl, substituted aryl, heteroaryl, tuted heteroaryl,
heterocyclic, and substituted heterocyclic.
Another aspect of the invention es methods of inhibiting hedgehog signaling
activity in a cell, by contacting the cell with an effective hedgehog tory amount of a
nd of Formula I or Formula II, or a isomer, geometric isomer, tautomer,
solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof.
Another aspect of the invention es methods of inhibiting HDAC activity in a
cell, by contacting the cell with an effective HDAC inhibitory amount of a compound of
Formula I or Formula II, or a stereoisomer, geometric isomer, tautomer, solvate,
metabolite, or pharmaceutically able salt or prodrug thereof.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides compounds which are
represented by Formula 111 or Formula IV:
L X B D
(111)
D—B—X—Q
(1V),
Where Ring A, K, G, Q, X, B, D, L and E have the meanings given above.
In another embodiment, the compounds of the invention are represented by
Formula V or VI:
D—B—X—Q
(V1)
and stereoisomers, geometric isomers, tautomers, ceutically acceptable salts and
prodrugs thereof, wherein E, K, L, X, B, G, Q and D have the meanings given above.
In an ment, the compounds of the invention are represented by Formula VII
or VIII:
E o
(VII)
D—B—X—Q
(VIII)
and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts and
prodrugs thereof, wherein E, K, L, X, B, G, Q and D have the meanings given above.
Preferably, G and L are each independently substituted or unsubstituted aryl or substituted
or tituted heteroaryl, and more preferably G and L are each independently
substituted or unsubstituted phenyl or substituted or unsubstituted l. Preferably, E
and Q are each independently substituted or unsubstituted heteroaryl.
In an embodiment, the compounds of the invention are represented by Formula IX
or X:
E/\\_\/\
L—X—B—D
(1X)
WO 94328
D—B—X—Q/\\ /\,/
and stereoisomers, ric isomers, tautomers, pharmaceutically acceptable salts and
prodrugs thereof, wherein E, K, L, X, B, G, Q and D have the gs given above.
Preferably, G and L are each independently heterocyclyl, preferably heterocycloalkyl.
In one embodiment, the present invention provides compounds which are
represented by Formula XI:
\XVZ\
(X1)
and stereoisomers, geometric isomers, tautomers, ceutically acceptable salts and
prodrugs thereof;
Wherein
one of Wl-Ws is C(X-B-D) and the others are each independently N or CR3, ed that
no more than three of Wl-WS are N;
each R3 is independently ed from hydrogen, hydroxy, amino, halogen, alkoxy,
alkylamino, dialkylamino, CF3, CN, N02, sulfonyl, acyl, aliphatic, substituted aliphatic,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic; and
X, B and D have the meanings given for these variables above.
In preferred embodiments of the compounds of Formula XI, E is substituted or
unsubstituted pyridyl, such as substituted or unsubstituted pyridyl, pyrid-3 -yl or pyrid-
4-yl, or substituted or unsubstituted benzimidazolyl, such as substituted or unsubstituted
2012/020092
benzimidazolyl. In particularly preferred embodiments, E is selected from the groups
set forth below:
/~ CKN/H (IN/H
In another preferred embodiment of the compounds of Formula XI, the group
/ W\1\W2
\VV =W/
is selected from the groups shown below:
if /B/D f0
\O/X X\B\
55“ \N
X\B\D X\B\D-
In another embodiment, the present invention es compounds which are
represented by Formula XII:
D—B—X—Q
X5/ \\X2
\ /
X4—Xs (XII)
and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts and
prodrugs thereof;
wherein
Xl-Xs are each ndently ed from N and CR3, provided that at least two of X1-
X5 are CR3; and
Q, D, B, X and R3 have the meanings given for these variables above.
In red embodiments of the compounds of Formula XII, Q is substituted or
unsubstituted pyridyl, substituted or unsubstituted pyrimidyl or tuted or
unsubstituted benzimidazolyl. In particularly preferred embodiments, Q is selected from
the groups below,
I{N\H I / \ é
/ n
N
wherein the bond to the benzene ring is denoted by g, and the bond to X is denoted by I .
In other preferred embodiments of the compounds of Formula XII, the group
X5/ \\X2
\ /
X4—X3
is substituted or tituted phenyl, substituted or unsubstituted pyridyl, such as
substituted or unsubstituted pyridyl, 3-yl or pyridyl, or substituted or
unsubstituted pyrimidyl, such as pyrimidyl, pyrimidyl or pyrimid-S -yl. In
particularly preferred embodiments, this group is selected from those set forth below.
O 2
F30 N 02 /
In a preferred ment, the bivalent B is a direct bond or straight- or branched-
substituted or unsubstituted
, alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, arylalkyl, kenyl, arylalkynyl, heteroarylalkyl,
heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, cyclylalkenyl,
heterocyclylalkynyl, aryl, aryl, heterocyclyl, cycloalkyl, cycloalkenyl,
alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl,
alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl,
alkylheteroarylalkyl, alkylheteroarylalkenyl, eteroarylalkynyl,
alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl,
alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl,
alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylhererocyclylalkynyl,
alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl,
alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl,
alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, lheteroaryl, or
alkynylheteroaryl, in which groups one or more methylenes can be interrupted or
terminated by O, S, 8(0), 802, N(R2), C(O), substituted or unsubstituted aryl, substituted
or unsubstituted aryl, or substituted or unsubstituted heterocyclic; such nt B
linkers include but are not limited to alkyl, alkenyl, alkynyl, alkylaryl, alkenylaryl,
WO 94328
alkynylaryl, alkylheterocyclylaryl, alkylheterocyclylarylalkyl, alkylheterocyclylheteroaryl,
alkylheterocyclylheteroarylalkyl, alkoxyaryl, alkylarninoaryl, alkoxyalkyl,
minoalkyl, alkylheterocycloalkyl, alkylheteroarylalkyl, alkylarnino, aryl, heteroaryl,
heterocyclyl, N(R2)alkeny1, N(R2)alkynyl, N(R2)alkoxyalkyl, N(R2)alkylaminoalky1,
N(R2)alkylaminocarbonyl, N(R2)alkylaryl, N(R2)alkenylary1, N(R2)alkynylaryl,
N(R2)alkoxyaryl, N(R2)alkylarninoaryl, N(R2)cycloalky1, N(R2)aryl, N(R2)heteroaryl,
N(R2)heterocycloalkyl, N(R2)alkylheterocycloalkyl, alkoxy, O-alkenyl, O-alkynyl, O-
alkoxyalkyl, O-alkylarninoalkyl, O-alkylarninocarbonyl, O-alkylaryl, O-alkenylaryl, O-
laryl, O-alkoxyaryl, O-alkylaminoaryl, O-cycloalkyl, O-aryl, O-heteroaryl, O-
heterocycloalkyl, O-alkylheterocycloalkyl, C(O)alky1, C(O)—alkenyl, C(O)a1kyny1,
C(O)alky1aryl, C(O)a1kenylaryl, C(O)alkyny1ary1, C(O)alkoxyalkyl, C(O)alkylaminoalkyl,
C(O)alkylarninocarbonyl, C(O)cycloalkyl, C(O)aryl, C(O)heteroaryl,
C(O)heterocycloalky1, CON(R2), CON(R2)alkyl, CON(R2)alkenyl, CON(R2)alkynyl,
)alkylaryl, CON(R2)alkenylary1, CON(R2)alkynylaryl, CON(R2)alkoxyalkyl,
CON(R2)alky1arninoalkyl, )alkylarninocarbonyl, CON(R2)alkoxyaryl,
CON(R2)alkylarninoaryl, )cycloalkyl, )aryl, CON(R2)heteroaryl,
CON(R2)heterocycloalkyl, CON(R2)alkylheterocycloalkyl, N(R2)C(O)alkyl,
N(R2)C(O)alkenyl, N(R2)C(O)- alkynyl, N(R2)C(O)alkylaryl, (O)alkenylaryl,
N(R2)C(O)alkynylaryl, N(R2)C(O)alkoxyalky1, N(R2)C(O)a1ky1arninoalkyl,
N(R2)C(O)a1kylarninocarbony1, (O)alkoxyary1, N(R2)C(O)alky1arninoaryl,
N(R2)C(O)cycloalkyl, N(R2)C(O)aryl, N(R2)C(O)heteroaryl, N(R2)C(O)heterocycloalkyl,
N(R2)C(O)alkylheterocycloalkyl, NHC(O)NH, NHC(O)NH-alkyl, NHC(O)NH-alkenyl,
NHC(O)NH-alkynyl, NHC(O)NH-alkylaryl, NHC(O)NH-alkenylaryl, NH-
alkynylaryl, NHC(O)NH-alkoxyaryl, NHC(O)NH-alkylaminoaryl, NHC(O)NH-
cycloalkyl, NHC(O)NH-aryl, NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl,
NHC(O)NH-alkylheterocycloalkyl, S-alkyl, nyl, S-alkynyl, S-alkoxyalkyl, S-
minoalkyl, S-alkylaryl, S-alkylaminocarbonyl, S-alkylaryl, S-alkynylaryl, S-
alkoxyaryl, S-alkylarninoaryl, S-cycloalkyl, S-aryl, S-heteroaryl, S-heterocycloalkyl, S-
alkylheterocycloalkyl, S(O)a1ky1, S(O)alkenyl, S(O)alkynyl, S(O)alkoxya1kyl,
S(O)alkylarninoalkyl, S(O)alkylarninocarbonyl, S(O)a1kylaryl, S(O)alkenylary1,
S(O)alkynylaryl, k0xyaryl, S(O)a1kylarninoaryl, S(O)cycloalkyl, S(O)ary1,
S(O)heteroaryl, S(O)heterocycloalkyl, S(O)a1kylheterocycloalkyl, S(O)2alky1,
S(O)2alkenyl, S(O)2alkyny1, S(O)2alkoxyalky1, S(O)2alkylarninoalkyl,
lkylarninocarbonyl, S(O)2alkylaryl, S(O)2alkenylaryl, S(O)2alkyny1ary1,
lkoxyaryl, S(O)2alkylaminoaryl, S(O)2cycloalkyl, S(O)2aryl, S(O)2heteroaryl,
S(O)2heterocycloalkyl, S(0)2alkylheterocycloalkyl, S(O)2heterocyclylalkyl,
S(0)2heterocyclylalkenyl, eterocyclylalkynyl, SOZNH, alkyl, SOZNH-
l, SOZNH-alkynyl, SOZNH-alkylaryl, SOZNH-alkenylaryl, SOZNH-alkynylaryl,
cycloalkyl, SOZNH-aryl, SOZNH-heteroaryl, SOZNH-heterocycloalkyl, SOZNH-
eterocycloalkyl, alkylaryloxyalkoxy, alkylaryloxyalkylamino,
alkylarylaminoalkoxy, rylaminoalkylamino, alkylarylalkylaminoalkoxy,
alkylarylalkylaminoalkoxy, alkenylaryloxyalkoxy, alkenylaryloxyalkylamino,
larylaminoalkoxy, alkenylarylaminoalkylamino, alkenylarylalkylaminoalkoxy,
alkenylarylalkylaminoalkylamino.
In a more preferred embodiment, B is a straight chain alkyl, alkenyl, alkynyl,
kyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl,
heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, cyclyl,
cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl,
alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl,
alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl,
alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl,
alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl,
alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl,
alkylhererocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl,
alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl,
alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl,
alkenylheteroaryl, or alkynylhereroaryl. In these linkers, one or more methylenes can be
interrupted or terminated by —O-, -N(R2)-, -C(O)-, -C(O)N(R2)—, or -C(O)O-.
In one embodiment, the linker B is between 1-24 carbon atoms, preferably 4-24
carbon atoms, preferably 4-18 carbon atoms, more preferably 4-12 carbon atoms, and most
preferably about 4-10 carbon atoms.
In a preferred embodiment, B is selected from straight chain C1-C10 alkyl, C1-C10
alkenyl, C1-C10 alkynyl, C1-C10 alkoxy, alkoxyCl-Cloalkoxy, C1-C10 alkylamino,
alkoxyCl-Cloalkylamino, C1-C10 alkylcarbonylamino, C1-C10 alkylaminocarbonyl,
aryloxyCl-Cloalkoxy, aryloxyCl-Cloalkylamino, aryloxyCl-Cloalkylamino yl, C1-
C1o-alkylaminoalkylaminocarbonyl, C1-C10 alkyl(N—alkyl)aminoalkyl-aminocarbonyl,
alkylaminoalkylamino, alkylcarbonylaminoalkylamino, N—alkyl)aminoalkylamino,
(N-alkyl)alkylcarbonylaminoalkylamino, alkylaminoalkyl, alkylaminoalkylaminoalkyl,
alkylpiperazinoalkyl, piperazinoalkyl, alkylpiperazino, alkenylaryloxyCl-C10alkoxy,
alkenylarylaminoCl-C10alkoxy, alkenylaryllalkylaminoC1-C10alkoxy, alkenylaryloxyCl-
Cloalkylamino, alkenylaryloxyCl-C10alkylaminocarbonyl, zinoalkylaryl,
heteroarlel-Cloalkyl, heteroarlez-Cloalkenyl, heteroarlez-Cloalkynyl, heteroarlel-
Cloalkylamino, heteroarlel-Cloalkoxy, heteroaryloxyCl-Cloalkyl, heteroaryloxyCz-
Cloalkenyl, heteroaryloxng-C10alkynyl, heteroaryloxyCl-C10alkylamino,
heteroaryloxyCl-C10alkoxy. In the most preferred embodiments, the D group is attached to
B Via an aliphatic moiety carbon chain, an aryl group or a heteroaryl group Within B.
In another preferred embodiment, B is a direct bond, aryl, heteroaryl, C2-C10-alkyl,
C2-C10-alkenyl, g-Clo-alkyl, aryl-Cg-Clo-alkenyl, aryloxy-Cl-Clo-alkyl,
heterocyclylheteroaryl, C1-C10-alkylheterocyclylheteroaryl, or -
alkylaminoheteroaryl.
It is understood that alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,
heterocyclyl and the like can be r substituted.
In certain embodiments, the compounds of Formulas I and II are represented by
as XIII and XIV, respectively:
HN4< i
L-M1-M2-M3-M4-M5—T2 %_R34
R32 R33
(XIII)
R33 R32
R34—Z Y2_M5'M4'M3'M2'M1—Q
(XIV)
wherein M1 is absent, 0, S, NR2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl,
heteroaryl, heterocyclic, SO, SO2 or C=O; M2 is absent, C1-C6 alkyl, 0, NR2,,
heterocyclic, aryl, heteroaryl, or C=O; M3 is absent, 0, NR2, S, SO, SO2, CO, C1-C6 alkyl,
C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, or heterocyclic; M4 is absent, 0, NR2,
heteroaryl, cyclic or aryl; and M5 is absent, C1-C3 alkyl, C2-C3 alkenyl, C2-
Cgalkynyl, heteroaryl, heterocyclic or aryl; and E, L, Q, G, Z, Y2, R32, R33 and R34 have
the definitions given for these variables above. ably, Y2 and R32 are absent, Z is N,
R33 is H and R34 is hydroxy.
c compounds of the invention are set forth in the Table below.
WO 94328
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2012/020092
37:n=1;38:n=2;39:n=3;40:n=4;41:n=5;42:n=6
43:n=1;44:n=2;45:n=3;46:n=4;47:n=5;48:n=6
/ N
49:n=1;50:n=2;51:n=3;52:n=4;53:n=5;54:n=6
55:n=1;56:n=2;57:n=3;58:n=4;59:n=5;60:n=6
WO 94328
61:n=1;62:n=2;63:n=3;64:n=4;65:n=5;66:n=6
79:n=1;80:n=2;81:n=3;82:n=4;83:n=5;84:n=6
/ \
HN—S//O O
O// \
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107: n=1; 108: n=2; 109: n=3; 110: n=4; 111: n=5; 112: n=6
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131:n=1;132:n=2;133:n=3;134:n=4;135:n=5;136:n=6
137:n=1;138:n=2;139:n=3;140:n=4;141:n=5;142:n=6
149:n=1;150:n=2;151:n=3;152:n=4;153:n=5;154:n=6
WO 94328
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WO 94328
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183: n=1; 184: n=2; 185: n=3; 186: n=4; 187: n=5; 188: n=6
WO 94328
201: n=1; 202: n=2; 203: n=3; 204: n=4; 205: n=5; 206: n=6
/ \
WO 94328
219: n=1; 220: n=2; 221: n=3; 222: n=4; 223: n=5; 224: n=6
WO 94328
237: n=1; 238: n=2; 239: n=3; 240: n=4; 241: n=5; 242: n=6
WO 94328
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256: R=H; 257: R=Me
WO 94328
258: R=H; 259: R=Me
262: R=H; 263: R=Me
/ \
The invention further provides methods for the prevention or treatment of
og-related diseases or disorders, and in particular, diseases or disorders ing
aberrant proliferation, differentiation or survival of cells. In one embodiment, the
2012/020092
ion further provides for the use of one or more compounds of the ion in the
manufacture of a medicament for halting or decreasing diseases involving aberrant
proliferation, differentiation, or survival of cells. In preferred ments, the disease is
cancer. In one embodiment, the invention relates to a method of treating cancer in a
subject in need of treatment comprising administering to said subject a therapeutically
effective amount of a compound of the invention. In another embodiment, the invention
further provides methods for the prevention or treatment of non-cancer hedgehog-related
diseases or disorders, such as psoriasis. The compounds of the invention can also be used
to treat diseases or disorders associated with nt or uncontrolled angiogenesis,
including macular degeneration, diabetic retinopathy, retinopathy of prematurity,
rheumatoid arthritis and obesity. In addition, compounds of the invention may be used to
down-regulate hair growth.
By Virtue of the dual HDAC and Hedgehog inhibitory ties of the compounds
of the present invention, the ion filrther provides a method for ng certain
cancers which are resistant to the action of Hedgehog pathway signaling inhibitors alone.
Such resistance may be characterized by one or more mutations in proteins involved in the
Hedgehog signaling e above the level of Gli transcription activation. The present
compounds having HDAC inhibiting activity may nonetheless be useful for treating
cancers having increased hedgehog levels by inhibiting the deacetylation of the Glil and
Gli2 transcription activators.
The term "cancer" refers to any cancer caused by the proliferation of malignant
stic cells, such as tumors, sms, omas, sarcomas, leukemias, lymphomas
and the like. For example, cancers include, but are not limited to, mesothelioma,
leukemias and lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneous
peripheral T-cell lymphomas, lymphomas associated with human T-cell lymphotrophic
virus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-cell lymphoma, acute
nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic enous
leukemia, acute myelogenous leukemia, lymphomas, and multiple myeloma, non-Hodgkin
lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL),
n’s lymphoma, Burkitt ma, adult T-cell leukemia lymphoma, acute-myeloid
leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Further
examples include myelodisplastic me, childhood solid tumors such as brain ,
neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft-tissue sarcomas,
common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal,
nasopharyngeal and esophageal), genitourinary cancers (e.g., prostate, bladder, renal,
uterine, n, testicular), lung cancer (e. g., cell and non small cell), breast cancer,
pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors
related to ’s syndrome (e.g., medulloblastoma, meningioma, etc.), and liver cancer.
Additional exemplary forms of cancer which may be treated by the subject nds
include, but are not limited to, cancer of skeletal or smooth muscle, stomach cancer,
cancer of the small intestine, rectum carcinoma, cancer of the salivary gland, endometrial
cancer, l cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.
In preferred embodiments, the cancer is ated with aberrant hedgehog
signaling, for example, when Patched fails to, or inadequately, represses Smoothened (Ptc
loss of fianction phenotype) and/or when Smoothened is active regardless of Patched
repression (Smo gain-of on phenotype) and/or when the Hedgehog ligand is
upregulated less of patched or smoothened onal status. Examples of such
cancer types include basal cell carcinoma, neuroectodermal tumors, such as
oblastoma, meningioma, hemangioma, glioblastoma, pancreatic adenocarcinoma,
us lung carcinoma, small cell lung cancer, non-small cell lung cancer, ovarian
cancer, prostate cancer, liver cancer, chondrosarcoma, breast carcinoma,
rhabdomyosarcoma, esophageal cancer, stomach cancer, biliary tract cancer, renal
carcinoma and thyroid carcinoma. Furthermore, compounds of the invention may be
useful in the treatment of hematologic tumors such as leukemias, lymphomas and
myelomas as listed above.
Additional cancers that the compounds described herein may be useful in treating
are, for example, colon carcinoma, familiary adenomatous polyposis carcinoma and
hereditary non-polyposis colorectal cancer, or ma. Further, cancers include, but are
not limited to, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue
carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, thyroid cancer
(medullary and papillary d carcinoma), renal carcinoma, kidney parenchyma
carcinoma, cerVix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion
carcinoma, testis carcinoma, y carcinoma, melanoma, brain tumors such as
astoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal
tumors, gall r oma, bronchial carcinoma, multiple myeloma, basalioma,
teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyosarcoma,
craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma,
f1brosarcoma, Ewing sarcoma, and plasmocytoma.
In one aspect of the invention, the present invention provides for the use of one or
more compounds of the invention in the manufacture of a medicament for the treatment of
cancer.
In one embodiment, the present ion includes the use of one or more
compounds of the ion in the manufacture of a medicament that prevents fiarther
nt proliferation, differentiation, or survival of cells. For example, compounds of the
invention may be useful in preventing tumors from increasing in size or from reaching a
metastatic state. The subject compounds may be administered to halt the progression or
advancement of cancer or to induce tumor apoptosis or to inhibit tumor angiogenesis. In
addition, the instant invention includes use of the subject compounds to prevent a
recurrence of cancer.
This ion filrther embraces the treatment or prevention of cell erative
disorders such as hyperplasias, sias and pre-cancerous lesions. Dysplasia is the
st form of pre-cancerous lesion recognizable in a biopsy by a pathologist. The
subject compounds may be administered for the purpose of preventing said hyperplasias,
dysplasias or pre-cancerous lesions from continuing to expand or from becoming
cancerous. es of pre-cancerous s may occur in skin, esophageal tissue, breast
and cervical intra-epithelial tissue.
"Combination therapy" includes the administration of the subject compounds in
further combination with other biologically active ingredients (such as, but not limited to,
a second and different antineoplastic agent) and non-drug therapies (such as, but not
limited to, surgery or radiation treatment). For instance, the compounds of the invention
can be used in combination with other pharmaceutically active compounds, preferably
compounds that are able to enhance the effect of the compounds of the invention. The
compounds of the invention can be administered simultaneously (as a single preparation or
separate preparation) or sequentially to the other drug therapy. In general, a combination
therapy ons administration of two or more drugs during a single cycle or course of
therapy.
In one aspect of the invention, the subject compounds may be administered in
combination with one or more separate agents that te protein kinases involved in
various disease states or targets downstream f. Examples of such s may
include, but are not limited to: serine/threonine specif1c kinases, receptor tyrosine specific
kinases and ceptor tyrosine specific s. Serine/threonine kinases e
mitogen activated protein kinases (MAPK), s specific kinase (MEK), RAF and
aurora kinase. Examples of receptor kinase families include epidermal growth factor
receptor (EGFR) (e. g., HER2/neu, HER3, HER4, ErbB, ErbB2, ErbB3, ErbB4, erk,
DER, ; last growth factor (FGF) receptor (e.g., FGF-Rl,GFF-R2/BEK/CEK3,
FGF-R3/CEK2, FGF-R4/TKF, KGF-R); hepatocyte growth/scatter factor or
(HGFR) (e. g., MET, RON, SEA, SEX); insulin receptor (e.g., IGFI-R, PI3K, AKT,
mTor); Eph (e.g., CEKS, CEK8, EBK, ECK, EEK, EHK-l, EHK-2, ELK, EPH, ERK,
HEK, MDK2, MDKS, SEK); Axl (e.g., Mer/Nyk, Rse); RET; and platelet-derived growth
factor receptor (PDGFR) (e. g., PDGFu-R, PDGB-R, CSFl-IVFMS, SCF-lVC-KIT, VEGF-
MELT, NEK/FLKl, FLT3/FLK2/STK-l). Non-receptor tyrosine kinase families include,
but are not limited to, BCR—ABL (e. g., p43“, ARG); BTK (e. g., ITK/EMT, TEC); CSK,
FAK, FPS, JAK, SRC, BMX, FER, CDK and SYK.
In another aspect of the invention, the t compounds may be administered in
combination with one or more separate agents that modulate non-kinase biological targets
or processes. Such targets include e deacetylases (HDAC), DNA methyltransferase
(DNMT), heat shock proteins (e.g., HSP90), and proteosomes.
In a preferred embodiment, subject compounds may be combined with
antineoplastic agents (e. g., small molecules, monoclonal antibodies, antisense RNA, and
fusion proteins) that inhibit one or more biological targets such as Zolinza, Tarceva,
Iressa, Tykerb, Gleevec, Sutent, Sprycel, r, CNF2024, RG108, BMS387032,
Affinitak, Avastin, Herceptin, Erbitux, AG24322, 01, ZD6474, PD184322,
Obatodax, ABT737 and AEE788. Such combinations may enhance therapeutic efficacy
over efficacy achieved by any of the agents alone and may prevent or delay the appearance
of resistant mutational variants. For example, the subject compounds may advantageously
be used in combination with a BCL-ABL inhibitor such as Sprycel for the treatment of
hematologic tumors such as leukemias, mas and myelomas.
In certain red embodiments, the compounds of the invention are administered
in combination with a chemotherapeutic agent. Chemotherapeutic agents ass a
wide range of therapeutic treatments in the field of oncology. These agents are
administered at various stages of the disease for the purposes of shrinking ,
ying remaining cancer cells left over after surgery, inducing remission, maintaining
remission and/or alleviating symptoms relating to the cancer or its treatment. Examples of
such agents include, but are not limited to, alkylating agents such as mustard gas
derivatives orethamine, cylophosphamide, mbucil, melphalan, ifosfamide),
ethylenimines (thiotepa, hexamethylmelanine), Alkylsulfonates (Busulfan), Hydrazines
and Triazines (Altretamine, Procarbazine, Dacarbazine and Temozolomide), Nitrosoureas
(Carmustine, Lomustine and Streptozocin), Ifosfamide and metal salts (Carboplatin,
Cisplatin, and latin); plant alkaloids such as Podophyllotoxins (Etoposide and
Tenisopide), Taxanes (Paclitaxel and Docetaxel), Vinca alkaloids (Vincristine,
Vinblastine, Vindesine and Vinorelbine), and Camptothecan analogs (Irinotecan and
can); anti-tumor antibiotics such as Chromomycins (Dactinomycin and
Plicamycin), cyclines (Doxorubicin, Daunorubicin, Epirubicin, Mitoxantrone,
Valrubicin and Idarubicin), and miscellaneous antibiotics such as Mitomycin,
Actinomycin and Bleomycin; anti-metabolites such as folic acid antagonists
(Methotrexate, Pemetrexed, Raltitrexed, Aminopterin), pyrimidine antagonists (5-
Fluorouracil, Floxuridine, Cytarabine, Capecitabine, and Gemcitabine), purine nists
(6-Mercaptopurine and guanine) and adenosine deaminase inhibitors (Cladribine,
abine, Mercaptopurine, Clofarabine, Thioguanine, Nelarabine and Pentostatin);
topoisomerase inhibitors such as topoisomerase I inhibitors (Ironotecan, topotecan) and
topoisomerase II inhibitors (Amsacrine, ide, etoposide phosphate, teniposide);
monoclonal antibodies (Alemtuzumab, Gemtuzumab ozogamicin, Rituximab,
Trastuzumab, momab Tioxetan, Cetuximab, Panitumumab, Tositumomab,
Bevacizumab); and miscellaneous anti-neoplastics such as ribonucleotide reductase
tors (Hydroxyurea); adrenocortical steroid inhibitor (Mitotane); enzymes
aginase and Pegaspargase); anti-microtubule agents (Estramustine); and retinoids
otene, Isotretinoin, Tretinoin (ATRA). For example, the subject compounds may
advantageously be used in combination with a pyrimidine antagonist such as Gemcitabine
for the treatment of solid tumors such as pancreatic cancers such as pancreatic
adenocarcinoma.
In certain preferred ments, the compounds of the invention are administered
in ation with a chemoprotective agent. rotective agents act to protect the
body or minimize the side effects of chemotherapy. es of such agents e, but
are not limited to, amfostine, mesna, and dexrazoxane.
In one aspect of the invention, the subject nds are administered in
combination with radiation therapy. Radiation is commonly delivered internally
(implantation of radioactive material near cancer site) or externally from a machine that
employs photon (x-ray or gamma-ray) or particle radiation. Where the combination
therapy fiarther comprises radiation treatment, the radiation treatment may be conducted at
any suitable time so long as a beneficial effect from the co-action of the combination of
the therapeutic agents and radiation ent is achieved. For example, in appropriate
cases, the beneficial effect is still achieved when the radiation treatment is ally
removed from the stration of the therapeutic agents, perhaps by days or even weeks.
It will be appreciated that compounds of the invention can be used in combination
with an therapeutic agent. One form of immunotherapy is the generation of an
active systemic tumor-specific immune response of host origin by administering a vaccine
composition at a site distant from the tumor. s types of vaccines have been
proposed, including isolated antigen vaccines and anti-idiotype vaccines. Another
approach is to use tumor cells from the subject to be treated, or a derivative of such cells
(reviewed by Schirrmacher et al. (1995) J. Cancer Res. Clin. Oncol., 121 :487). In US.
Pat. No. 5,484,596, Hanna Jr. et al. claim a method for treating a resectable carcinoma to
prevent recurrence or metastases, comprising surgically removing the tumor, dispersing
the cells with collagenase, irradiating the cells, and vaccinating the t with at least
three consecutive doses of about 107 cells.
It will be appreciated that the compounds of the invention may advantageously be
used in conjunction with one or more adjunctive therapeutic agents. Examples of suitable
agents for tive y include a 5HT1 t, such as a triptan (e.g. sumatriptan or
naratriptan); an inhibitor of the phosphoinositolkinase (PI3K) family; an inhibitor of the
mammalian target of rapamycin (mTOR); an inhibitor of Bcr-Abl; an adenosine Al
agonist; an EP ligand; an NMDA modulator, such as a glycine antagonist; a sodium
channel blocker (e.g. igine); a substance P antagonist (e. g. an NK1 antagonist); a
cannabinoid; acetaminophen or phenacetin; a 5-lipoxygenase inhibitor; a leukotriene
receptor antagonist; a DMARD (e. g. methotrexate); gabapentin and d compounds; a
tricyclic pressant (e. g. amitryptilline); a neuron stabilising antiepileptic drug; a
mono-aminergic uptake inhibitor (e.g. venlafaxine); a matrix metalloproteinase inhibitor; a
nitric oxide synthase (NOS) inhibitor, such as an iNOS or an nNOS inhibitor; an inhibitor
of the release, or action, of tumour necrosis factor alpha; an antibody therapy, such as a
monoclonal antibody therapy; an antiViral agent, such as a nucleoside inhibitor (e.g.
lamivudine) or an immune system modulator (e.g. interferon); an opioid analgesic; a local
anaesthetic; a stimulant, including caffeine; an agonist (e.g. ranitidine); a proton
pump tor (e.g. omeprazole); an antacid (e.g. aluminium or magnesium hydroxide; an
antiflatulent (e. g. simethicone); a decongestant (e. g. phenylephrine, phenylpropanolamine,
ephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline,
propylhexedrine, or levo-desoxyephedrine); an antitussive (e. g. codeine, hydrocodone,
carmiphen, carbetapentane, or dextramethorphan); a diuretic; or a ng or dating
stamine.
The compounds may also be used in the treatment of a disorder involving, relating
to or, associated with dysregulation of histone deacetylase (HDAC). There are a number
of ers that have been implicated by or known to be mediated at least in part by
HDAC activity, where HDAC activity is known to play a role in triggering disease onset,
or whose symptoms are known or have been shown to be alleviated by HDAC inhibitors.
Disorders of this type that would be expected to be le to treatment with the
nds of the ion include the following but not d to: Anti-proliferative
disorders (e.g. cancers); Neurodegenerative diseases including Huntington's Disease,
Polyglutamine disease, Parkinson's Disease, Alzheimer's Disease, Seizures, Striatonigral
degeneration, Progressive supranuclear palsy, Torsion dystonia, Spasmodic torticollis and
esis, Familial tremor, Gilles de la Tourette syndrome, Diffuse Lewy body disease,
Progressive supranuclear palsy, Pick's disease, intracerebral hemorrhage, Primary lateral
sclerosis, Spinal muscular atrophy, Amyotrophic lateral sclerosis, Hypertrophic interstitial
polyneuropathy, Retinitis pigmentosa, Hereditary optic atrophy, Hereditary spastic
paraplegia, Progressive ataxia and Shy-Drager syndrome; Metabolic diseases including
Type 2 diabetes; Degenerative es of the Eye including Glaucoma, lated
macular degeneration, Rubeotic glaucoma; Inflammatory diseases and/or Immune system
disorders including Rheumatoid Arthritis (RA), Osteoarthritis, Juvenile chronic arthritis,
Graft versus Host e, Psoriasis, Asthma, Spondyloarthropathy, Crohn's Disease,
inflammatory bowel disease Colitis Ulcerosa, Alcoholic hepatitis, Diabetes, Sjoegrens's
syndrome, Multiple sis, sing litis, Membranous glomerulopathy,
enic pain, Systemic Lupus Erythematosus; Disease involving angiogenesis
including cancer, psoriasis, rheumatoid arthritis; Psychological disorders including bipolar
disease, schizophrenia, mania, sion and dementia; Cardiovascular Diseases
including the prevention and treatment of ischemia-related or reperfusion-related vascular
and myocardial tissue damage, heart failure, restenosis and osclerosis; Fibrotic
diseases including liver fibrosis, cystic fibrosis and angiof1broma; Infectious diseases
including Fungal infections, such as iasis or Candida Albicans, Bacterial infections,
Viral infections, such as Herpes Simplex, poliovirus, rhinovirus and coxsackievirus,
Protozoal infections, such as Malaria, Leishmania infection, Trypanosoma brucei
infection, Toxoplasmosis and coccidlosis and Haematopoietic disorders including
thalassemia, anemia and sickle cell anemia.
nds of the invention inhibit angiongenesis and are therefore useful in the
treatment of diseases or conditions ed by angiogenesis such as tumors, in particular
solid tumors such as colon, lung, pancreatic, ovarian, breast and glioma. Furthermore,
compounds of the invention are useful for treating macular degeneration, e.g., wet age-
related macular degeneration. Compounds of the invention are also useful for ng
inflammatory/immune diseases such as Crohn’s disease, inflammatory bowel disease,
Sjogren’s syndrome, , organ transplant rejection, systemic lupus erythmatoses,
psoriatic tis, psoriasis and multiple sclerosis. The compounds can also be used for the
down-regulation of hair growth or as a depilatory for cosmetic purposes or in the treatment
of hirsutism.
The invention encompasses pharmaceutical compositions comprising
pharmaceutically acceptable salts of the compounds of the invention as described above.
The invention also encompasses solvates of the compounds of the ion and
pharmaceutical compositions comprising such solvates, such as hydrates, methanolates or
ethanolates. The term “solvate” refers to a solid, preferably crystalline, form of a
compound which es the presence of solvent molecules within the crystal e. A
solvate of a compound comprising a given solvent is typically ed by crystallization
of the compound from that solvent. Solvates can include a variety of solvents, including
water, methanol and ethanol. The term "hydrate" refers to a solvate in which the solvent is
water, and includes, but is not limited to, hemihydrate, monohydrate, dihydrate, trihydrate
and the like. The invention r encompasses pharmaceutical compositions comprising
any solid or liquid physical form of the compound of the ion, including crystalline
and crystalline solvate forms. For example, the compounds can be in a crystalline form, in
amorphous form, and have any particle size. The particles may be ized, or may be
agglomerated, particulate granules, powders, oils, oily suspensions or any other -solid or
liquid physical form.
The compounds of the invention, and tives, fragments, analogs, homologs,
pharmaceutically acceptable salts or solvates thereof can be incorporated into
pharmaceutical compositions suitable for administration, together with a pharmaceutically
able carrier or excipient. Such compositions typically se a therapeutically
effective amount of any of the compounds above, and a pharmaceutically acceptable
carrier. Preferably, the effective amount when treating cancer is an amount effective to
selectively induce terminal entiation of suitable neoplastic cells and less than an
amount which causes toxicity in a patient.
nds of the invention may be administered by any suitable means,
ing, without limitation, parenteral, intravenous, intramuscular, subcutaneous,
implantation, oral, sublingual, buccal, nasal, pulmonary, transdermal, topical, l,
rectal, and ucosal administrations or the like. Topical stration can also
involve the use of transdermal administration such as transdermal patches or iontophoresis
devices. Pharmaceutical preparations include a solid, semisolid or liquid preparation
(tablet, pellet, troche, capsule, itory, cream, ointment, aerosol, powder, ,
emulsion, suspension, syrup, ion etc.) containing a compound of the ion as an
active ingredient, which is suitable for selected mode of administration. In one
ment, the pharmaceutical compositions are administered orally, and are thus
formulated in a form suitable for oral administration, i.e., as a solid or a liquid preparation.
Suitable solid oral formulations include tablets, capsules, pills, granules, pellets, sachets
and effervescent, powders, and the like. Suitable liquid oral formulations include
ons, sions, dispersions, emulsions, oils and the like. In one embodiment of the
present invention, the composition is ated in a capsule. In accordance with this
embodiment, the compositions of the present invention se in addition to the active
compound and the inert carrier or diluent, a hard gelatin capsule.
Any inert excipient that is commonly used as a carrier or diluent may be used in
the formulations of the present invention, such as for example, a gum, a starch, a sugar, a
cellulosic material, an acrylate, or mixtures thereof. A preferred diluent is
microcrystalline cellulose. The compositions may filrther comprise a disintegrating agent
(e.g., croscarmellose sodium) and a lubricant (e. g., magnesium stearate), and may
additionally comprise one or more additives selected from a binder, a buffer, a protease
inhibitor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent,
a viscosity increasing agent, a sweetener, a film forming agent, or any combination
thereof. Furthermore, the compositions of the present invention may be in the form of
controlled release or immediate e formulations.
For liquid formulations, pharmaceutically acceptable carriers may be s or
non-aqueous solutions, suspensions, emulsions or oils. Examples of non-aqueous solvents
are propylene , polyethylene , and injectable organic esters such as ethyl
. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or
suspensions, including saline and buffered media. Examples of oils are those of
petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil,
mineral oil, olive oil, sunflower oil, and fish-liver oil. Solutions or suspensions can also
include the following components: a sterile diluent such as water for injection, saline
solution, fixed oils, polyethylene s, glycerine, propylene glycol or other synthetic
solvents; cterial agents such as benzyl alcohol or methyl parabens; antioxidants such
as ascorbic acid or sodium bisulfite; chelating agents such as nediaminetetraacetic
acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the
adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with
acids or bases, such as hydrochloric acid or sodium hydroxide.
In addition, the compositions may further comprise binders (e.g., acacia,
cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, ne), disintegrating agents (e.g., cornstarch, potato
, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum,
sodium starch glycolate, Primogel), buffers (e. g., tris-HCI., acetate, phosphate) of various
pH and ionic strength, additives such as albumin or n to t tion to
es, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease
inhibitors, surfactants (e.g., sodium lauryl sulfate), permeation enhancers, solubilizing
agents (e. g., glycerol, polyethylene glycerol), a glidant (e. g., colloidal silicon dioxide),
anti-oxidants (e. g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole),
stabilizers (e. g., ypropyl cellulose, hydroxypropylmethyl ose), viscosity
increasing agents (e. g., carbomer, colloidal silicon dioxide, ethyl ose, guar gum),
sweeteners (e. g., sucrose, ame, citric acid), flavoring agents (e.g., peppermint,
methyl salicylate, or orange flavoring), preservatives (e. g., Thimerosal, benzyl alcohol,
parabens), ants (e.g., stearic acid, ium stearate, polyethylene glycol, sodium
lauryl sulfate), flow-aids (e. g., colloidal silicon dioxide), plasticizers (e.g., diethyl
phthalate, triethyl citrate), emulsifiers (e.g., carbomer, hydroxypropyl ose, sodium
lauryl sulfate), polymer coatings (e. g., poloxamers or poloxamines), coating and film
forming agents (e.g., ethyl cellulose, acrylates, polymethacrylates) and/or adjuvants.
In one embodiment, the active compounds are prepared with carriers that will
protect the compound against rapid elimination from the body, such as a controlled release
formulation, including implants and microencapsulated delivery systems. Biodegradable,
biocompatible polymers can be used, such as ne vinyl acetate, polyanhydrides,
polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation
of such formulations will be apparent to those skilled in the art. The als can also be
obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal
suspensions (including liposomes targeted to ed cells with monoclonal antibodies to
WO 94328
viral antigens) can also be used as pharmaceutically acceptable carriers. These can be
prepared according to s known to those skilled in the art, for example, as described
in US. Patent No. 4,522,811.
It is especially advantageous to formulate oral compositions in dosage unit form
for ease of administration and mity of dosage. Dosage unit form as used herein
refers to physically discrete units suited as unitary s for the subject to be treated;
each unit containing a predetermined quantity of active compound calculated to produce
the desired therapeutic effect in ation with the required pharmaceutical carrier. The
ication for the dosage unit forms of the invention are dictated by and directly
dependent on the unique characteristics of the active compound and the particular
therapeutic effect to be achieved, and the limitations inherent in the art of compounding
such an active compound for the treatment of indiViduals.
The pharmaceutical itions can be included in a ner, pack, or
dispenser together with instructions for administration.
Daily administration may be repeated continuously for a period of several days to
several years. Oral treatment may continue for between one week and the life of the
patient. Preferably the administration may take place for five consecutive days after
which time the patient can be evaluated to determine if further administration is required.
The administration can be continuous or intermittent, e.g., treatment for a number of
consecutive days followed by a rest period. The compounds of the present invention may
be administered intravenously on the first day of treatment, with oral administration on the
second day and all consecutive days thereafter.
The preparation of ceutical compositions that contain an active component
is well tood in the art, for example, by mixing, granulating, or tablet-forming
processes. The active therapeutic ingredient is often mixed with ents that are
pharmaceutically acceptable and compatible with the active ingredient. For oral
administration, the active agents are mixed with additives customary for this purpose, such
as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable
forms for administration, such as tablets, coated tablets, hard or soft gelatin capsules,
aqueous, alcoholic or oily solutions and the like as ed above.
The amount of the compound stered to the patient is less than an amount
that would cause toxicity in the patient. In certain embodiments, the amount of the
compound that is administered to the patient is less than the amount that causes a
concentration of the compound in the patient's plasma to equal or exceed the toxic level of
the compound. Preferably, the concentration of the compound in the patient's plasma is
maintained at about 10 nM. In one embodiment, the concentration of the nd in the
patient's plasma is maintained at about 25 nM. In one embodiment, the concentration of
the compound in the patient's plasma is maintained at about 50 nM. In one ment,
the concentration of the compound in the patient's plasma is maintained at about 100 nM.
In one embodiment, the concentration of the nd in the patient's plasma is
maintained at about 500 nM. In one embodiment, the concentration of the compound in
the patient's plasma is ined at about 1000 nM. In one embodiment, the
tration of the compound in the patient's plasma is maintained at about 2500 nM. In
one embodiment, the concentration of the compound in the patient's plasma is maintained
at about 5000 nM. The optimal amount of the compound that should be administered to
the patient in the practice of the present invention will depend on the particular compound
used and the type of cancer being treated.
TIONS
Listed below are definitions of various terms used to describe this ion. These
definitions apply to the terms as they are used throughout this specification and claims,
unless otherwise limited in specific instances, either indiVidually or as part of a larger
group.
An “aliphatic group” or “aliphatic” is non-aromatic moiety that may be saturated
(e. g. single bond) or contain one or more units of unsaturation, e.g., double and/or triple
bonds. An aliphatic group may be straight chained, branched or cyclic, contain carbon,
en or, optionally, one or more heteroatoms and may be tuted or unsubstituted.
An aliphatic group, when used as a linker, preferably contains between about 1 and about
24 atoms, more preferably between about 4 to about 24 atoms, more preferably between
about 4-12 atoms, more typically between about 4 and about 8 atoms. An aliphatic group,
when used as a substituent, preferably ns between about 1 and about 24 atoms, more
preferably between about 1 to about 10 atoms, more preferably between about 1-8 atoms,
more typically between about 1 and about 6 atoms. In addition to aliphatic hydrocarbon
groups, aliphatic groups include, for example, koxyalkyls, such as polyalkylene
glycols, polyamines, and polyimines, for example. Such aliphatic groups may be filrther
tuted. It is understood that aliphatic groups may include alkyl, substituted alkyl,
alkenyl, tuted alkenyl, alkynyl, substituted alkynyl groups described herein.
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The term "substituted carbonyl" includes compounds and es which contain a
carbon connected with a double bond to an oxygen atom, and tautomeric forms thereof.
Examples of es that contain a substituted carbonyl include des, ketones,
carboxylic acids, amides, esters, ides, etc. The term "carbonyl " refers to
groups such as "alkylcarbonyl" groups wherein an alkyl group is covalently bound to a
carbonyl group, "alkenylcarbonyl" groups wherein an alkenyl group is covalently bound to
a carbonyl group, ylcarbonyl" groups wherein an alkynyl group is covalently bound
to a yl group, "arylcarbonyl" groups wherein an aryl group is covalently ed to
the carbonyl group. Furthermore, the term also refers to groups wherein one or more
atoms are covalently bonded to the carbonyl moiety. For example, the term includes
moieties such as, for example, aminocarbonyl moieties, (wherein a nitrogen atom is bound
to the carbon of the carbonyl group, e.g., an amide).
The term "acyl" refers to hydrogen, alkyl, partially saturated or fillly saturated
cycloalkyl, partially saturated or fillly saturated heterocycle, aryl, and heteroaryl
substituted carbonyl groups. For example, acyl includes groups such as (C1-C6)alkanoyl
(e.g., formyl, acetyl, nyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.), (C3-
C6)cycloalkylcarbonyl (e. g., cyclopropylcarbonyl, cyclobutylcarbonyl,
cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), cyclic carbonyl (e.g.,
pyrrolidinylcarbonyl, pyrrolidonecarbonyl, piperidinylcarbonyl, piperazinylcarbonyl,
tetrahydrofilranylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl (e. g., thiophenyl
carbonyl, thiophenylcarbonyl, furanylcarbonyl, filranylcarbonyl, lH-pyrroyl
carbonyl, lH-pyrroylcarbonyl, benzo[b]thiophenylcarbonyl, etc.). In addition, the
alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be any
one of the groups described in the respective definitions. When indicated as being
"optionally substituted", the acyl group may be unsubstituted or optionally substituted
with one or more substituents (typically, one to three substituents) independently selected
from the group of substituents listed below in the tion for "substituted" or the alkyl,
cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be substituted as
described above in the preferred and more preferred list of substituents, respectively.
The term "alkyl" embraces linear or ed radicals having one to about twenty
carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl
radicals are "lower alkyl" radicals having one to about ten carbon atoms. Most preferred
are lower alkyl radicals having one to about eight carbon atoms. Examples of such radicals
include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tyl, tert-butyl, pentyl,
iso-amyl, hexyl and the like.
The term "alkenyl" embraces linear or branched radicals having at least one
carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to
about twelve carbon atoms. More preferred alkenyl radicals are "lower alkenyl" radicals
having two to about ten carbon atoms and more preferably about two to about eight carbon
atoms. Examples of alkenyl radicals include ethenyl, allyl, propenyl, butenyl and 4-
methylbutenyl. The terms "alkenyl", and "lower alkenyl", embrace radicals having "cis"
and "trans" orientations, or alternatively, "E" and "Z" ations.
The term "alkynyl" embraces linear or branched radicals having at least one
carbon-carbon triple bond of two to about twenty carbon atoms or, preferably, two to
about twelve carbon atoms. More preferred alkynyl radicals are "lower alkynyl" radicals
having two to about ten carbon atoms and more preferably about two to about eight carbon
atoms. Examples of alkynyl radicals include propargyl, l-propynyl, ynyl, l-butyne,
2-butynyl and l-pentynyl.
The term "cycloalkyl" embraces saturated carbocyclic radicals having three to
about twelve carbon atoms. The term "cycloalkyl" embraces saturated yclic radicals
having three to about twelve carbon atoms. More preferred cycloalkyl radicals are "lower
lkyl" radicals having three to about eight carbon atoms. Examples of such radicals
include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "cycloalkenyl" embraces partially unsaturated carbocyclic ls
having three to twelve carbon atoms. Cycloalkenyl radicals that are lly unsaturated
carbocyclic radicals that contain two double bonds (that may or may not be conjugated)
can be called alkyldienyl". More preferred cycloalkenyl radicals are "lower
cycloalkenyl" radicals having four to about eight carbon atoms. Examples of such radicals
include utenyl, cyclopentenyl and cyclohexenyl.
The term "alkoxy" embraces linear or branched oxy-containing radicals each
having alkyl portions of one to about twenty carbon atoms or, ably, one to about
twelve carbon atoms. More preferred alkoxy radicals are "lower " radicals having
one to about ten carbon atoms and more preferably having one to about eight carbon
atoms. Examples of such ls include methoxy, ethoxy, propoxy, butoxy and tert-
butoxy.
The term "alkoxyalkyl" embraces alkyl radicals having one or more alkoxy
radicals attached to the alkyl radical, that is, to form koxyalkyl and dialkoxyalkyl
The term "aryl", alone or in combination, means a carbocyclic ic system
containing one, two or three rings wherein such rings may be attached together in a
pendent manner or may be fiJsed. The term "aryl" embraces aromatic radicals such as
phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
The terms “heterocyclyl”, “heterocycle” “heterocyclic” or “heterocyclo” embrace
saturated, partially unsaturated and unsaturated heteroatom-containing haped
radicals, which can also be called "heterocyclyl", "heterocycloalkenyl" and "heteroaryl"
correspondingly, where the heteroatoms may be selected from nitrogen, sulfur and
. Examples of saturated heterocyclyl ls include saturated 3 to 6-membered
heteromonocyclic group ning 1 to 4 nitrogen atoms (e. g. pyrrolidinyl,
imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3 to 6-membered monocyclic
group containing 1 to 2 oxygen atoms and l to 3 nitrogen atoms (e. g. linyl, etc.);
saturated 3 to ered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to
3 nitrogen atoms (e. g., thiazolidinyl, etc.). Examples of partially unsaturated heterocyclyl
radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
Heterocyclyl radicals may include a pentavalent nitrogen, such as in tetrazolium and
pyridinium radicals. The term "heterocycle" also embraces radicals where heterocyclyl
radicals are fused with aryl or cycloalkyl radicals. Examples of such fused bicyclic
ls e benzofuran, hiophene, and the like.
The term "heteroaryl" embraces unsaturated heterocyclyl radicals. Examples of
heteroaryl radicals include unsaturated 3 to 6 membered heteromonocyclic group
containing 1 to 4 nitrogen atoms, for example, pyrrolyl, inyl, imidazolyl, pyrazolyl,
pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e. g., 4H-l,2,4-triazolyl, ,3-
triazolyl, 2H-l,2,3-triazolyl, etc.) tetrazolyl (e.g. lH-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms, for example,
indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl,
benzotriazolyl, tetrazolopyridazinyl (e.g., tetrazolo[l ,5-b]pyridazinyl, etc.), etc.;
unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for
example, pyranyl, furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group
containing a sulfur atom, for example, thienyl, etc.; unsaturated 3- to 6-membered
monocyclic group containing 1 to 2 oxygen atoms and l to 3 nitrogen atoms, for
example, oxazolyl, olyl, oxadiazolyl (e.g., l,2,4-oxadiazolyl, l,3,4-oxadiazolyl,
l,2,5-oxadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2
oxygen atoms and l to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl, etc.);
unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1
to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., l,2,4- thiadiazolyl, 1,3,4-
thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc.; unsaturated sed heterocyclyl group
containing 1 to 2 sulfur atoms and l to 3 nitrogen atoms (e. g., benzothiazolyl,
benzothiadiazolyl, etc.) and the like.
The term "heterocycloalkyl" embraces heterocyclo-substituted alkyl ls. More
preferred heterocycloalkyl ls are "lower heterocycloalkyl" radicals haVing one to six
carbon atoms in the heterocyclo radicals.
The term "alkylthio" embraces ls containing a linear or branched alkyl
radical, of one to about ten carbon atoms ed to a divalent sulfur atom. Preferred
hio radicals have alkyl radicals of one to about twenty carbon atoms or, ably,
one to about twelve carbon atoms. More preferred hio radicals have alkyl radicals
are "lower alkylthio" radicals haVing one to about ten carbon atoms. Most preferred are
alkylthio radicals haVing lower alkyl radicals of one to about eight carbon atoms.
Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio
and hexylthio.
The terms "aralkyl" or “arylalkyl” e aryl-substituted alkyl radicals such as
, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl.
The term "aryloxy" embraces aryl radicals attached through an oxygen atom to
other radicals.
The terms "aralkoxy" or “arylalkoxy” embrace aralkyl radicals attached through an
oxygen atom to other radicals.
The term "aminoalkyl" es alkyl radicals tuted with amino radicals.
Preferred aminoalkyl radicals have alkyl radicals haVing about one to about twenty carbon
atoms or, preferably, one to about twelve carbon atoms. More preferred aminoalkyl
radicals are "lower aminoalkyl" that have alkyl radicals haVing one to about ten carbon
atoms. Most preferred are aminoalkyl radicals haVing lower alkyl radicals haVing one to
eight carbon atoms. Examples of such radicals include aminomethyl, aminoethyl, and the
like.
The term "alkylamino" denotes amino groups which are substituted with one or
two alkyl radicals. Preferred alkylamino radicals have alkyl radicals haVing about one to
2012/020092
about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More
preferred alkylamino ls are "lower mino" that have alkyl ls having one
to about ten carbon atoms. Most preferred are alkylamino radicals having lower alkyl
radicals having one to about eight carbon atoms. Suitable lower alkylamino may be
bstituted N—alkylamino or disubstituted N,N—alkylamino, such as N-methylamino,
N—ethylamino, methylamino, ethylamino or the like.
The term "linker" means an organic moiety that connects two parts of a compound.
Linkers typically comprise a direct bond or an atom such as oxygen or sulfur, a unit such
as NR2, C(O), C(O)NH, SO, S02, SOZNH or a chain of atoms, such as substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl,
heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl,
heteroaryl, cyclyl, cycloalkyl, cycloalkenyl, rylalkyl, alkylarylalkenyl,
alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl,
alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl,
alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl,
alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl,
alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl,
alkylheterocyclylalkenyl, alkylhererocyclylalkynyl, alkenylheterocyclylalkyl,
alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl,
alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl,
alkynylaryl, eteroaryl, alkenylheteroaryl, alkynylhereroaryl, which one or more
methylenes can be interrupted or terminated by O, S, S(O), S02, N(R2), C(O), substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl, tuted or tituted
heterocyclic; where R2 is hydrogen, acyl, aliphatic or substituted aliphatic. In one
embodiment, the linker B is between 1-24 atoms in length, preferably 4-24 atoms in
length, preferably 4-18 atoms in length, more preferably 4-12 atoms in length, and most
preferably about 4-10 atoms in length. In some embodiments, the linker is a
C(O)NH(alkyl) chain or an alkoxy chain. It is to be understood that an asymmetric linker,
such as alkylaryl, can connect two structurally distinct moieties in either of its two
possible orientations.
The term "substituted” refers to the replacement of one or more hydrogen radicals
in a given structure with the radical of a specified substituent including, but not limited to:
halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl,
arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy,
aralkoxy, aminocarbonyl, minocarbonyl, arylaminocarbonyl, alkoxycarbonyl,
aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino,
alkylaminoalkyl, arylaminoalkyl, lkylamino, hydroxy, alkoxyalkyl, carboxyalkyl,
alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid,
sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl, heterocyclic, and aliphatic. It is
understood that the substituent may be further substituted.
For simplicity, chemical moieties are defined and referred to throughout can be
univalent chemical moieties (e. g., alkyl, aryl, etc.) or multivalent moieties under the
riate structural circumstances clear to those skilled in the art. For example, an
"alkyl" moiety can be referred to a monovalent radical (e.g. CH3-CH2-), or in other
instances, a bivalent linking moiety can be "alkyl," in which case those skilled in the art
will understand the alkyl to be a divalent radical (e. g., -CH2-CH2-), which is equivalent to
the term ene." Similarly, in circumstances in which divalent moieties are required
and are stated as being “alkoxy3, EC 3) CC 3, H
, alkylamino , aryloxy”, “alkylthio , aryl",
“heteroaryl”, “heterocyclic3, “
, alkyl” “alkenyl”, “alkynyl”, “aliphatic”, or “cycloalkyl”,
those d in the art will understand that the terms alkoxy”, “alkylamino”, “aryloxy”,
“alkylthio”, , “heteroaryl”, “heterocyclic”, “alkyl”, “alkenyl”, “alkynyl”,
“aliphatic”, or “cycloalkyl” refer to the corresponding divalent moiety.
The terms "halogen" or “halo” as used herein, refers to an atom selected from
fluorine, chlorine, bromine and .
As used herein, the term “aberrant eration” refers to abnormal cell growth.
The phrase "adjunctive therapy" asses treatment of a subject with agents
that reduce or avoid side s associated with the combination therapy of the present
invention, ing, but not limited to, those , for example, that reduce the toxic
effect of anticancer drugs, e.g., bone resorption inhibitors, cardioprotective agents; prevent
or reduce the incidence ofnausea and vomiting associated with chemotherapy,
radiotherapy or operation; or reduce the incidence of infection associated with the
administration of myelosuppressive anticancer drugs.
The term “angiogenesis,” as used herein, refers to the formation of blood vessels.
Specifically, enesis is a multi-step process in which elial cells focally
degrade and invade through their own basement membrane, migrate through interstitial
stroma toward an angiogenic stimulus, proliferate proximal to the migrating tip, organize
into blood vessels, and reattach to newly synthesized basement membrane (see Folkman et
al., Adv. Cancer Res., Vol. 43, pp. 175-203 (1985)). Anti-angiogenic agents ere with
this process. Examples of agents that interfere with several of these steps include
thrombospondin-l , angiostatin, endostatin, interferon alpha and compounds such as matrix
metalloproteinase (MMP) inhibitors that block the actions of s that clear and create
paths for newly forming blood vessels to follow; compounds, such as .alpha.v.beta.3
inhibitors, that interfere with molecules that blood vessel cells use to bridge between a
parent blood vessel and a tumor; agents, such as specific COX-2 inhibitors, that prevent
the growth of cells that form new blood vessels; and protein-based nds that
simultaneously interfere with several of these targets.
The term osis” as used herein refers to programmed cell death as signaled
by the nuclei in normally functioning human and animal cells when age or state of cell
health and condition dictates. An “apoptosis inducing agent” triggers the process of
programmed cell death.
The term “cancer” as used herein denotes a class of diseases or disorders
characterized by uncontrolled division of cells and the ability of these cells to invade other
tissues, either by direct grth into adjacent tissue through invasion or by implantation
into distant sites by metastasis.
The term “compound” is defined herein to include pharmaceutically acceptable
salts, solvates, es, polymorphs, enantiomers, reoisomers, racemates and the
like of the compounds having a formula as set forth herein.
The term "device" refers to any appliance, usually mechanical or electrical,
designed to perform a particular function.
As used herein, the term “dysplasia” refers to abnormal cell growth, and lly
refers to the earliest form of ncerous lesion recognizable in a biopsy by a
pathologist.
As used , the term “effective amount of the subject compounds,” with
respect to the subject method of treatment, refers to an amount of the subject compound
which, when delivered as part of desired dose regimen, brings about, e. g. a change in the
rate of cell eration and/or state of differentiation and/or rate of survival of a cell to
clinically acceptable rds. This amount may fiarther relieve to some extent one or
more of the symptoms of a neoplasia disorder, including, but is not limited to: 1) reduction
in the number of cancer cells; 2) reduction in tumor size; 3) inhibition (i.e., slowing to
some extent, preferably stopping) of cancer cell infiltration into peripheral organs; 4)
inhibition (i.e., slowing to some extent, preferably stopping) of tumor metastasis; 5)
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inhibition, to some extent, of tumor growth; 6) relieving or reducing to some extent one or
more of the ms associated with the disorder; and/or 7) relieving or reducing the
side effects associated with the administration of anticancer agents.
The term “hyperplasia,” as used herein, refers to excessive cell division or growth.
The phrase an "immunotherapeutic agent" refers to agents used to transfer the
immunity of an immune donor, e.g., another person or an animal, to a host by inoculation.
The term embraces the use of serum or gamma globulin containing performed antibodies
produced by another individual or an animal; nonspecific systemic stimulation; adjuvants;
active specif1c immunotherapy; and adoptive immunotherapy. Adoptive immunotherapy
refers to the treatment of a disease by therapy or agents that include host inoculation of
sensitized lymphocytes, transfer factor, immune RNA, or antibodies in serum or gamma
globulin.
The term "inhibition," in the context of neoplasia, tumor growth or tumor cell
growth, may be assessed by d appearance of primary or secondary tumors, slowed
development of primary or secondary tumors, decreased occurrence of primary or
secondary tumors, slowed or sed severity of ary effects of disease, arrested
tumor growth and regression of tumors, among . In the extreme, complete inhibition,
is referred to herein as prevention or revention.
The term “metastasis,” as used herein, refers to the migration of cancer cells from
the original tumor site through the blood and lymph vessels to produce cancers in other
tissues. asis also is the term used for a secondary cancer growing at a distant site.
The term “neoplasm,” as used herein, refers to an abnormal mass of tissue that
s from excessive cell division. Neoplasms may be benign (not ous), or
ant (cancerous) and may also be called a tumor. The term asia” is the
pathological process that s in tumor formation.
As used herein, the term “pre-cancerous” refers to a condition that is not
malignant, but is likely to become malignant if left untreated.
The term “proliferation” refers to cells undergoing mitosis.
The phrase "hedgehog related disease or disorder" refers to a disease or disorder
characterized by inappropriate og signaling activity. Such inappropriate hedgehog
signaling activity can occur when Patched fails to, or inadequately, represses Smoothened
(Ptc loss of fianction phenotype) and/or when Smoothened is active regardless of Patched
repression (Smo gain-of function phenotype).
The phrase a "radio eutic agent" refers to the use of electromagnetic or
particulate radiation in the treatment of neoplasia.
The term “recurrence” as used herein refers to the return of cancer after a period of
ion. This may be due to incomplete removal of cells from the l cancer and
may occur y (the same site of initial cancer), regionally (in vicinity of initial cancer,
possibly in the lymph nodes or tissue), and/or distally as a result of metastasis.
The term "treatment" refers to any process, action, application, therapy, or the like,
wherein a mammal, including a human being, is subject to l aid with the object of
improving the mammal's condition, directly or indirectly.
The term "vaccine" includes agents that induce the patient's immune system to
mount an immune response against the tumor by attacking cells that express tumor
associated antigens (Teas).
As used herein, the term aceutically acceptable salt" refers to those salts
which are, within the scope of sound l judgment, suitable for use in contact with
the tissues of humans and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et
al. bes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:
1-19 (1977). The salts can be prepared in situ during the final ion and ation of
the compounds of the invention, or separately by reacting the free base fianction with a
le organic acid or nic acid. Examples of pharmaceutically acceptable
nontoxic acid addition salts include, but are not limited to, salts of an amino group formed
with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid,
sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid,
tartaric acid, citric acid, succinic acid lactobionic acid or malonic acid or by using other
methods used in the art such as ion exchange. Other pharmaceutically acceptable salts
include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate,
benzoate, bisulfate, , butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,
glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, oxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate,
malate, maleate, malonate, methanesulfonate, 2—naphthalenesulfonate, nicotinate, nitrate,
oleate, e, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate,
picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-
2012/020092
toluenesulfonate, undecanoate, te salts, and the like. Representative alkali or
alkaline earth metal salts include sodium, lithium, ium, calcium, magnesium, and
the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic
um, quaternary ammonium, and amine cations formed using counterions such as
halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon
atoms, sulfonate and aryl sulfonate.
As used herein, the term "pharmaceutically acceptable ester" refers to esters which
hydrolyze in vivo and include those that break down readily in the human body to leave
the parent compound or a salt f. Suitable ester groups include, for example, those
derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic,
alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety
advantageously has not more than 6 carbon atoms. Examples of ular esters include,
but are not limited to, formates, acetates, nates, tes, acrylates and
ethylsuccinates.
The term “pharmaceutically acceptable prodrugs” as used herein refers to those
prodrugs of the compounds of the present invention which are, within the scope of sound
l judgment, suitable for use in contact with the tissues of humans and lower s
without undue toxicity, irritation, allergic response, and the like, commensurate with a
reasonable benefit/risk ratio, and effective for their intended use, as well as the
zwitterionic forms, where possible, of the compounds of the present invention.
"Prodrug", as used herein, means a compound which is convertible in vivo by
lic means (e.g. by hydrolysis) to a nd of the invention. Various forms of
prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of
Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic
Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs,
Textbook of Drug Design and Development, Chapter 5, 1 (1991); Bundgaard, et al.,
Journal of Drug Deliver s, 8: 1-38(1992); Bundgaard, J. of Pharmaceutical
Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug
Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim
Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And
Enzymology,” John Wiley and Sons, Ltd. .
As used herein, "pharmaceutically acceptable carrier" is intended to e any
and all solvents, dispersion media, coatings, antibacterial and antifiangal agents, isotonic
and absorption delaying agents, and the like, compatible with pharmaceutical
WO 94328
administration, such as sterile pyrogen-free water. Suitable carriers are described in the
most recent edition of Remington's Pharmaceutical Sciences, a standard nce text in
the field, which is orated herein by reference. Preferred es of such rs
or diluents include, but are not limited to, water, saline, f1nger's solutions, dextrose
solution, and 5% human serum albumin. mes and non-aqueous vehicles such as
fixed oils may also be used. The use of such media and agents for pharmaceutically active
substances is well known in the art. Except insofar as any conventional media or agent is
incompatible with the active compound, use thereof in the compositions is contemplated.
Supplementary active compounds can also be incorporated into the compositions.
As used , the term ancerous” refers to a condition that is not
malignant, but is likely to become malignant if left untreated.
The term “subject” as used herein refers to an animal. Preferably the animal is a
mammal. More preferably the mammal is a human. A subject also refers to, for example,
dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.
The compounds of this invention may be modified by appending appropriate
onalities to e selective biological properties. Such modifications are known in
the art and may include those which increase biological penetration into a given biological
system (e.g., blood, lymphatic system, central nervous system), se oral bility,
increase solubility to allow administration by injection, alter metabolism and alter rate of
excretion.
The synthesized compounds can be separated from a reaction mixture and further
purified by a method such as column chromatography, high pressure liquid
chromatography, or recrystallization. As can be appreciated by the skilled artisan, fiarther
methods of synthesizing the compounds of the formulae herein will be evident to those of
ordinary skill in the art. onally, the various synthetic steps may be performed in an
alternate sequence or order to give the desired compounds. Synthetic chemistry
transformations and protecting group methodologies (protection and deprotection) useful
in sizing the compounds described herein are known in the art and include, for
example, those such as described in R. Larock, Comp_rehensive Organic Transformations,
VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic
Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and
Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette,
ed., opedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and
subsequent editions thereof.
2012/020092
The compounds described herein can contain one or more asymmetric centers and
thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be
defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino
acids. The present invention is meant to include all such possible isomers, as well as their
racemic and optically pure forms. Optical isomers may be ed from their respective
optically active precursors by the procedures described above, or by resolving the racemic
mixtures. The tion can be d out in the presence of a resolving agent, by
chromatography or by repeated crystallization or by some combination of these techniques
which are known to those skilled in the art. Further details regarding resolutions can be
found in Jacques, et al., Enantiomers tes and Resolutions (John Wiley & Sons,
1981). When the compounds described herein contain c double bonds, other
unsaturation, or other centers of geometric asymmetry, and unless specified otherwise, it is
intended that the compounds include both E and Z geometric isomers and/or cis- and
trans- isomers. Likewise, all tautomeric forms are also intended to be included. The
configuration of any carbon-carbon double bond appearing herein is selected for
convenience only and is not intended to designate a particular configuration unless the text
so states; thus a carbon-carbon double bond or carbon-heteroatom double bond depicted
arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.
ceutical sitions
The pharmaceutical compositions of the present ion comprise a
therapeutically ive amount of a compound of the present invention formulated
together with one or more pharmaceutically acceptable rs or ents.
As used herein, the term "pharmaceutically able carrier or excipien " means
a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or
formulation auxiliary of any type. Some examples of materials which can serve as
pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose;
cyclodextrins such as alpha- (0t), beta- ([3) and gamma- (y) cyclodextrins; starches such as
corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc;
excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed
oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene
glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as
ium hydroxide and aluminum ide; alginic acid; pyrogen-free water; isotonic
saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other
non-toxic compatible lubricants such as sodium lauryl e and magnesium stearate, as
well as coloring agents, releasing agents, coating , sweetening, flavoring and
ing agents, preservatives and antioxidants can also be present in the composition,
according to the judgment of the formulator.
The pharmaceutical compositions of this invention may be administered orally,
parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an
implanted oir, ably by oral administration or administration by injection. The
pharmaceutical compositions of this invention may contain any conventional non-toxic
pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the
formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to
enhance the stability of the formulated compound or its delivery form. The term parenteral
as used herein includes subcutaneous, intracutaneous, enous, intramuscular,
intraarticular, intraarterial, intrasynovial, intracistemal, intrathecal, esional and
intracranial injection or infiasion ques.
Liquid dosage forms for oral administration include ceutically acceptable
emulsions, microemulsions, solutions, sions, syrups and elixirs. In on to the
active compounds, the liquid dosage forms may contain inert diluents commonly used in
the art such as, for example, water or other solvents, solubilizing agents and emulsifiers
such as ethyl alcohol, pyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,
benzyl benzoate, propylene glycol, l,3-butylene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfin'yl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and
mixtures thereof. Besides inert diluents, the oral itions can also include adjuvants
such as wetting agents, emulsifying and suspending agents, sweetening, ng, and
perfuming agents.
Inj ectable preparations, for example, sterile inj ectable aqueous or oleaginous
suspensions, may be formulated according to the known art using suitable dispersing or
g agents and suspending agents. The e injectable preparation may also be a
sterile inj ectable solution, sion or emulsion in a nontoxic parenterally acceptable
diluent or t, for example, as a solution in l,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and
isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally
employed as a solvent or suspending medium. For this purpose any bland fixed oil can be
employed including tic mono- or diglycerides. In addition, fatty acids such as oleic
acid are used in the ation of inj ectables.
The inj ectable formulations can be sterilized, for e, by filtration through a
bacterial-retaining filter, or by incorporating izing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water or other sterile inj ectable
medium prior to use.
In order to prolong the effect of a drug, it is often desirable to slow the absorption
of the drug from subcutaneous or intramuscular injection. This may be accomplished by
the use of a liquid suspension of crystalline or amorphous material with poor water
solubility. The rate of absorption of the drug then depends upon its rate of dissolution,
which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally administered drug form is accomplished by dissolving or
suspending the drug in an oil e. Injectable depot forms are made by forming
microencapsule matrices of the drug in biodegradable polymers such as polylactide-
polyglycolide. Depending upon the ratio of drug to polymer and the nature of the
particular polymer employed, the rate of drug e can be controlled. Examples of
other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot
inj e formulations are also prepared by entrapping the drug in mes or
microemulsions that are compatible with body tissues.
itions for rectal or vaginal administration are preferably suppositories
which can be prepared by mixing the compounds of this invention with suitable non-
irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository
wax which are solid at t temperature but liquid at body temperature and therefore
melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, s, pills, powders,
and granules. In such solid dosage forms, the active compound is mixed with at least one
inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium
phosphate and/or: a) fillers or extenders such as starches, lactose, e, glucose,
mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose,
alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as
glycerol, d) disintegrating agents such as gar, calcium carbonate, potato or tapioca
starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents
such as in, f) absorption accelerators such as quaternary ammonium compounds, g)
wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h)
WO 94328
absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium
stearate, magnesium stearate, solid hylene glycols, sodium lauryl sulfate, and
mixtures thereof. In the case of es, tablets and pills, the dosage form may also
comprise buffering .
Solid compositions of a similar type may also be employed as fillers in soft and
hard-filled n capsules using such excipients as lactose or milk sugar as well as high
molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be
prepared with coatings and shells such as enteric gs and other gs well known
in the pharmaceutical formulating art. They may ally contain opacifying agents and
can also be of a composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
Examples of embedding compositions that can be used include polymeric substances and
waxes.
Dosage forms for topical or transdermal administration of a compound of this
invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays,
nts or patches. The active component is admixed under sterile conditions with a
pharmaceutically able carrier and any needed preservatives or buffers as may be
required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are
also contemplated as being within the scope of this invention.
The ointments, pastes, creams and gels may n, in addition to an active
compound of this invention, excipients such as animal and vegetable fats, oils, waxes,
paraffins, starch, tragacanth, ose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of this invention,
excipients such as lactose, talc, silicic acid, aluminum hydroxide, m silicates and
polyamide powder, or mixtures of these substances. Sprays can additionally contain
customary lants such as chlorofluorohydrocarbons.
Transdermal s have the added advantage of providing controlled delivery of
a compound to the body. Such dosage forms can be made by dissolving or dispensing the
compound in the proper medium. Absorption enhancers can also be used to increase the
flux of the compound across the skin. The rate can be controlled by either providing a rate
controlling membrane or by dispersing the compound in a polymer matrix or gel.
WO 94328
For pulmonary delivery, a therapeutic composition of the invention is formulated
and administered to the patient in solid or liquid particulate form by direct administration
e.g., tion into the respiratory . Solid or liquid ulate forms of the active
compound prepared for cing the present invention include les of respirable
size: that is, particles of a size sufficiently small to pass through the mouth and larynx
upon inhalation and into the bronchi and alveoli of the lungs. Delivery of aerosolized
therapeutics, particularly aerosolized antibiotics, is known in the art (see, for example US.
Pat. No. 5,767,068 to VanDevanter et al., US. Pat. No. 5,508,269 to Smith et al., and WO
98/43650 by Montgomery, all of which are incorporated herein by nce). A
discussion of pulmonary delivery of antibiotics is also found in US. Pat. No. 6,014,969,
incorporated herein by reference.
By a "therapeutically effective amount" of a compound of the invention is meant
an amount of the compound which confers a therapeutic effect on the treated subject, at a
reasonable benefit/risk ratio applicable to any medical ent. The therapeutic effect
may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives
an indication of or feels an effect). An effective amount of the compound described above
may range from about 0.1 mg/Kg to about 500 mg/Kg, preferably from about 1 to about
50 mg/Kg. Effective doses will also vary depending on route of administration, as well as
the possibility of co-usage with other agents. It will be understood, however, that the total
daily usage of the compounds and compositions of the present invention will be decided
by the attending physician within the scope of sound l judgment. The specific
therapeutically ive dose level for any particular t will depend upon a variety of
factors including the er being treated and the severity of the disorder; the actiVity of
the specific compound employed; the specific ition ed; the age, body
weight, general health, sex and diet of the patient; the time of administration, route of
administration, and rate of excretion of the specific compound employed; the duration of
the treatment; drugs used in combination or contemporaneously with the specific
compound employed; and like factors well known in the medical arts.
The total daily dose of the compounds of this invention administered to a human or
other animal in single or in divided doses can be in amounts, for e, from 0.01 to 50
mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight. Single dose
compositions may contain such amounts or submultiples thereof to make up the daily
dose. In general, treatment regimens according to the present invention comprise
administration to a t in need of such treatment from about 10 mg to about 1000 mg
of the compound(s) of this ion per day in single or multiple doses.
The compounds of the formulae described herein can, for example, be
administered by injection, enously, intraarterially, subdermally, intraperitoneally,
intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically,
in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.1 to
about 500 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose,
every 4 to 120 hours, or according to the requirements of the particular drug. The s
herein contemplate administration of an effective amount of compound or compound
composition to achieve the desired or stated effect. Typically, the pharmaceutical
compositions of this invention will be stered from about 1 to about 6 times per day
or alternatively, as a continuous infusion. Such administration can be used as a chronic or
acute therapy. The amount of active ingredient that may be combined with
pharmaceutically excipients or rs to produce a single dosage form will vary
depending upon the host treated and the particular mode of administration. A typical
preparation will contain from about 5% to about 95% active compound (w/w).
Alternatively, such preparations may n from about 20% to about 80% active
compound.
Lower or higher doses than those recited above may be required. Specific dosage
and ent regimens for any particular patient will depend upon a variety of factors,
including the activity of the specific compound employed, the age, body weight, general
health status, sex, diet, time of administration, rate of excretion, drug combination, the
severity and course of the e, condition or symptoms, the patient’s disposition to the
disease, condition or symptoms, and the judgment of the treating physician.
Upon improvement of a patient’s condition, a maintenance dose of a compound,
ition or combination of this invention may be stered, if necessary.
Subsequently, the dosage or frequency of administration, or both, may be reduced, as a
function of the symptoms, to a level at which the improved condition is retained when the
symptoms have been alleviated to the desired level. Patients may, however, require
ittent treatment on a long-term basis upon any recurrence of disease symptoms.
Synthetic Methods
The compounds and processes of the present invention will be better understood in
connection with the following synthetic s and es that illustrate the methods
by which the nds of the invention may be prepared, which are intended as an
illustration only and not limiting of the scope of the invention.
General methods for the synthesis of key intermediates
:35-5iii; 0'
Fe/NH4CI PdCI2(dppf) O\BI) (ll—HQ NH2
I NH2 0
N02 trifluoromethane—
sulfonic acid
1-1 1-3
Cl 0
CI 0 CI
I; \
N NOa 2 Kl 1-6
0‘8mN Hem/Q
H2N N02 6 H
l/S\\ 1—
1-9 0 o
E; NH2
0kg; CI
SnCI2/EtOH R
R NH2 N02 N02 N
U —> _) \
R NH
N02 0 H
24 2-3
0 Cl
0 w
o w / / N g\u
/ TU\
+ an
a? _. m
O I / Y
Y (orCl) a/0 3/ IYQo
//\\ 0 Cl
1001 01
1002
NHZOH/MeOH H w s
T \CI/N “WI/QC
0 Cl
Scheme2
/\ AHA N Br
|N\ Br Br 0 Br
HBF4,NaN02 n 0 U —> |N\ —>
/ /
H2N HO AOJLWO
2001 2002 2003
0"S‘b
179 N NHZOH
O \
I [:11 —>
AOJLWO / 8/
n O 0
2004
0 CI
o N
I H
HO\ /
N s/
O ’l\‘
H n O 0
Scheme 3
0 CI
0 CI 0 CI /
Fe 1.NaN02 0
RO —>R0 —>
2. 302, CuCI S/CI
N02 NH2 O’/ \\O
3001 3002 3003
0 CI
N CI
I NH2 0 CI
RO /
(u? H 1-8 N\
S’Nwfifov —> N
/ (I? H 0
o 0 fi’ ”W \/
o o
3005
3004
0 CI
NHgOH N
_, N
/ S? H H
fit W \OH
0 o
WO 94328
Scheme4
K o
O Urea/HCI
\/O\/\[ro\/ Na/E‘OH l 5‘0“ HN O/\
O O I
\\V’ ‘v/’
o HCOOEt 04;\N
O H
4001
4003
4002
o O
N/ o/\ bNBoc
O/\ _ N \ o/\
Br2/H0Ac I POCI3 N \
) A —> —> J'x /
0 N )L / DMF
N (\N
H HN
4004 4005
4005
0 CI
HOfig“
0 Cl |N\ NH2
0 O /
3003 18
HO -
—> 0
II /—‘\
I N—<\
o \__/ /
NNj>—_<o—/O
4007
/ / \
_ o
HN Cl
HN Cl
NHZOH
I/O 5’0
”3‘“l O
O O leN/fi
K/N N
N N
T ‘ T ‘ H
N / N
4008 O\/ ‘OH
O O
Scheme 5
CI HOJKQ CI
R N 0*
NaOH/HZO
\ N~\ O ----+
N ”
H N H
NH2 R‘O/ oJK
5001
5002 5003
NHZOH N
Scheme6
CI CI Cl
Br NBS Br Br
MeNHBoc n—BuLi
—> [I] —>
x O
CCI4 Br
Boc y-Nflo
H \_/
6001 6002 6003
1.THF 0/
0/ Na|O4
2. Nl/YLOA NYN;
6004 cIJ‘N’ 6005
4005
0 CI
1 SOCI2
NYN; CI
N\ NH2
6006 /
1-8 6007
2012/020092
Scheme 7
0 Cl
0 Cl 0 Cl N\
| NH2
30020 /
NH3 RO
RO R0 1-8
NH zN~
Cl , 2 8 Bee
A: O,,S\\O O” \\O
O O
7002
3003 7001
NI \
Cl Cl
0 Cl 0 Cl CIAN/
N 4005
\ N —> \ N
H o H H O
/ gm /
Bee g/NHZ
II ll
0 0
7003 7004
Cl Cl
0 Cl 0 Cl
N NHZOH N
\ N / N
H o H
/ N
8/ gm
7005
WO 94328
Scheme 8
O O
W:S.C
c983
HONOH Pd/C 3003
OZN CHO 02N J 2
8001 8002 8003
0 CI 0 CI
LiOH
RO HO
N o’>
s’ O
o” ‘\o
8004 8005
0 CI
\ N
H O’> —> I2 “O
/’ S/N O
o’ ‘ol \
8006 8007
O 0 CI
[0:51 0 CI
/0 N\\ NHZOH
M H
// S/N
o” ‘\o
8008
0 CI
N\\ N O
/ IS<N \ N,OH
O’ \O H
Scheme 9
0 CI 0 CI
HZNAO LiOH, THF/HZO
NBoc
R0 R0
CI H\/©\JBOC —>N s’ s’
0” ‘\o 0” ‘\o
3003 9001
0 CI CI
N 0 CI
I NHZ
N TFA
HO /
S/N —>
/ S/N
o’ ‘oI \ o” “o
o 0
CI N’YLoA CI /\
0 CI C‘AN/I o
N\ N H\/OH 4005 N\
H I
/ S/N /
o” “o
9004
CI ,OH
0 CI
NHZOH
N X“1%”
\ N \U N H
/ /N
o’s‘b
Scheme 10
HENN0
0 CI 0 0' o N
O\/ \ NH2
O/\ /
HO O HO 1-8
—> H —>
CI /N\/\
s/ ,s\ o
o’ ‘o/ \ / \
3003 1001
0 CI 0
N\ N o/\ NHZOH
H —>
/ O
o” ‘o\
1002
0 CI 0
N\ N N’
H H
/ S/N\/\O
// \\
o o
2012/020092
Scheme11
RCDN
O O H
DMF Jones
Br|\N _>H 2_3
|\N _>HO |\N
/ n-BuLi / /
Br Br
1101 1102 1103
CI CI
\ NBoc \
N O —> N O
H H
HN HN
/ \
N / \N
Br HN
1104 1105
CI bNBoc
RCEN\N o
1) CF3COOH NHZOH
/ \ —>
2) o
N \ o/\ HN
JL /
(:1 N
4005 1106
>/,N\
CI \
\CCN 0
N O
WO 94328
Scheme 12
o o \ O \ O
O o \O
DIBAL-H PBr3 NaNs PPhs
I —> —> —> —>
O OH N3
| —o —o —o
1203
1201 1202 1204
o o O
\O CIJ‘N/NIYLO/
HO HO
1)NaOH 4005
_. N_ o
2)HCI
NH2 NH2 HN_<\ :/>_<
—o —o N o—
1207
1205 1206
CI CI
R N R
NH2 M O
2_3 HN NHZOH
N_ 0
1208 —o MyN o—
_<N— o
HN \ :>—(/
-—O N HN-OH
Scheme 13
CH3NH2/MeOH (Boc)20DMAP NaOH,H20
M80“
TEADCM 1
1203 1301 1302
RUN\CMN B°°1 TFA
DIPEAHATUDMA H
1304
1303
/\o \ N
CI 0/
RUN>_Q
4005
” TEA DCM
1305 1306
CI 0/
NHZOH R N \
, N\
N \6 NHOH
H N /
SIS OF INTERMEDIATES
1) Preparation of 1-chloroiodonitrobenzene (compound 1-3)
2-Chloronitroaniline (40 g, 232.0 mmol) was added to a on of concentrated
sulfuric acid (32 rnL) in water (320 rnL) with mechanical stir. The solution was cooled to -
°C and a solution of sodium nitrite (18.2 g, 0.26 mol) in water (69 rnL) was added
slowly. The mixture was stirred for 0.5 h in ice bath and then a solution of potassium
iodide (69.3 g, 0.41 mol) in water (277 rnL) was added dropwise while keeping the
internal temperature below 5°C. The on was stirred for 3 h at 0°C followed by
tion with ethyl acetate. The combined orangnic layers were washed with saturated
NaZSZOg, dried over Na2S04 and concentrated. The residue was recrystallized from
iPrOH/hexanes (300 mL/100 mL) to afford compound 1-3 as a light tan crystalline solid
(38 g, 58% yield). 1H NMR (400 MHz, CDCl3)C 8 7.61 (d, J=8.8 Hz, 1H), 8.16 (dd, J=8.8
Hz, 2.4 Hz, 1H), 8.70 (d, J=2.8 Hz, 1H).
2) Preparation of 4-chloroiodoaniline (compound 1-4)
A mixture of compound 1-3 (37 g, 0.13 mol), iron powder (29.3 g, 0.52 mol), and
NH4Cl (7g, 0.13 mol) in EtOH/HZO (200 mL / 100 mL) was stirred at 75°C for 3 h. The
reaction mixture was filtered and trated to remove most of EtOH. The remaining
mixture was extracted with ethyl acetate, washed with water and brine, dried over Na2S04.
The titled nd 1-4 was obtained as a yellow solid (32 g, 97% yield) after
cocentration. LCMS: m/z 254.0 . 1H NMR (400 MHz, CDC13): 8 3.65 (br, 2H),
6.58 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.15-7.17 (m, 2H).
3) Preparation of 4-chloro(4,4,5,5,—tetramethyl-1,3,2-dioxaborolanyl)aniline
(compound 1-5)
A mixture of compound 1-4 (10 g, 39.5 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi
(1,3,2-dioxaborolane) (20.0 g, 79.0 mmol), KOAc (11.6 g, 118.5 mmol), and PdC12(dppf )
(960 mg, 1 mmol) in 1,4-di0xane (60 mL) was stirred at 105°C for 8 h under N2. The
reaction mixture was concentrated in vacuo, and the residue was purified by column
tography (hexanes/dichloromethane: 3/1 to 1/ 1) to afford compound 1-5 as a light
yellow solid (6.0 g, 60% yield). LCMS: m/z 295.1 [M+42]+. 1H NMR (400 MHz, CDC13):
8 1.36 (s, 12H), 3.61 (br, 2H), 6.65 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.00 (d, J=2.8 Hz, 1H),
7.11 (d, J=8.8 Hz, 1H).
4) Preparation of 4-chloro(pyridineyl)aniline (compound 1-8)
A mixture of compound 1-5 (1.50 g, 5.9 mmol), opyridine (1.87 g, 11.8 mmol),
sodium bicarbonate (1.49 g, 17.8 mmol), PdC12(Ph3P)2 (100 mg, 0.09 mmol) in 1,4-
dioxane /water (20 mL / 10 mL) was heated at 110°C overnight. After cooling to room
temperature, the mixture was quenched with water and extracted with ethyl e. The
combined organic layers were washed with water and brine, dried over anhydrous sodium
sulfate and evaporated in vacuo. The crude product was purified by column
chromatography (hexanes/ethyl acetate: 3/ 1) to afford compound 1-8 as a yellow solid
(1.38 g, ~100%). LCMS: m/z 205.1 . 1H NMR (400 MHz, DMSO-d6): 5 5.32 (s,
2H), 6.61 (dd, J=8.4 Hz, 2.8 Hz, 1H), 6.77 (d, J=2.8 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.35-
7.39 (m, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.83-7.87 (m, 1H), 8.63-8.65 (m, 1H).
) Preparation of 2-chloro-N-(4-chloro(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenyl)(methylsufonyl)benzamide (compound 1-9)
A mixture of compound 1-5 (1 g, 3.9 mmol), 2-chloro(methylsulf0nyl)benz0ic acid
(1.1 g, 4.7 mmol) and N,N-Diisopropylethylamine (1 g, 7.8 mmol) and O-(Benzotriazol-
1-yl)-N,N,N',N'-tetramethyluroniumtetrafiuoroborate (2.6 g, 7.8 mmol) in
dichloromethane (20 mL) was stirred at room ature overnight. The reaction
mixture was quenched with water, filtered. The solid was collected and dried in vacuo to
afford compound 1-9 as a white solid (1.2 g, 65% . LCMS: m/z 470.1 [M+1]+ .OlH
NMR: (400 MHz, DMSO-d6): 5 1.32 (s, 12H), 3.35 (s, 3H), 7.43 (d, J=8.8 Hz, 1H), 7.81
(dd, J=8.8 Hz, 2.8 Hz,lH), 7.89 (d, J=8.0 Hz, 1H), 7.98-8.01 (m, 2H), 8.12 (d, J=1.6 Hz,
1H), 10.82 (s, 1H).
6) Preparation of 2-chloronitro-N-(2-nitrophenyl)benzamide (compound 2-2)
To a on of 2-nitroaniline (5.0 g, 0.036 mol) in CH3CN (50 mL) was added a
solution of 2-chloronitrobenzoyl chloride (8.0 g, 0.037 mol) in CH3CN (10 mL)
dropwise while keeping the internal temperature below 25°C under N2. When addition was
complete the reaction mixture was heated at 75°C for 1 h. The mixture was cooled to 0°C
and d. The solid was rinsed with cold CH3CN to afford 2-2 as a light yellow solid
(5.3 g, 50%).
7) ation of 3-(1H-benzo[d]imidazol—2-yl)chloroaniline (compound 2-3)
nd 2-2 (5.3 g, 0.017 mol) was taken into EtOH (100 mL) and heated to
40°C.When the internal temperature d 40°C, 1St aliquot SnClz/HCl (3 vol
respectively, divided into 3 portions) was added. The reaction mixture was heated to 60°C
and the 2Ild aliquot of SnClz/HCl was added. The reaction mixture was heated to 80°C and
the 3rd aliquot SnClz/HCl was added and continued to reflux 2 h. The reaction mixture was
cooled to 0°C and NaOH (1N aqueous solution) was added below 10°C to adjust pH to 12-
13. The mixture was diluted with EA and water. The organic layer was washed with brine
and concentrated. The crude product was purified by column chromatography eluted with
dichloromethane/ methanol (60: 1) to afford compound 2-3 as a yellow solid (2.7 g, 68%
yield). LCMS: m/z 244.1[M+1]+. 1H NMR (400 MHz, DMSO-d6): 5 5.48 (s, 2H), 6.71 (d,
z, 1H), 7.13 (s, 1H), 7.21-7.24 (m, 3H), 7.57 (br, 1H), 7.64 (br, 1H), 12.52 (s, 1H).
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EXAMPLE 1: Preparation of (E)—2-chloro-N-(4-chloro(5-(3-(hydroxyamino)—3-
oxopropenyl)pyridinyl)phenyl)(methylsulfonyl)benzamide (compound 1)
Step 1a. (E)-Methyl 3-(6-br0m0pyridin-3 -yl)acrylate (compound 1001-1)
A mixture of 6-br0monicotinaldehyde (500 mg, 2.7 mmol) and methyl
enylphosphoranylidene) (1 g, 3.2 mmol) in romethane (10 mL) was stirred at
room temperature for 1 h. The mixture was concentrated in vacuo and filtered. The solid
was washed with hexanes to afford crude nd 1001-1 as a white solid (1.5 g).
Step 1b. (E)-Methyl(6-(2-chlor0(2-chlor0(methylsulfonyl)benzamido)phenyl)
pyridin-3 -yl)acrylate (1002- 1)
A mixture of 1001 (121 mg, 0.5 mmol), 1-9 (200 mg, 0.4 mmol), Pd(PPh3)2Clz (30
mg) in 1,4-di0xane (6 mL) and aq NaHC03 (2 mL) was stirred at 110 °C for 3 h under N2.
After cooling to room temperature, the reaciton mixture was quenched with water,
extracted with ethyl acetate. The combined organic layers were washed with water and
brine, dried over anhydrous sodium sulfate, evaporated in vacuo. The crude product was
purified by column chromatography nol /dichlor0methane: 1/20) to afford
nd 1002 as a pale yellow solid (160 mg, 74% yield). 1H NMR (400 MHz, CDC13):
8 3.09 (s, 3H), 3.85 (s, 3H), 6.57 (d, J=16.0 Hz, 1H), 7.44-7.48 (m, 1H), 7.52-7.55 (m,
1H), 7.62-7.67 (m, 1H), 7.73 (d, J=16.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.81-7.86 (m,
2H), 7.89 (s, 1H), 7.89-7.95 (m, 2H), 8.03 (d, J=1.2 Hz, 1H), 8.14 (s, 1H), 8.80 (d, J=2.0
Hz, 1H).
Step 1c. (E)Chlor0-N—(4-chlor0(5-(3-(hydr0xyamin0)—3-0x0pr0penyl)pyridin
yl)phenyl)(methylsulfonyl)benzamide (compound 1)
A mixture ofNHZOHHCl (80g, 1.15 mol) in MeOH (400 mL) was heated at 60-65°C
while stirring to form a clear solution. After onal 1 h at reflux, it was cooled to 0 —
10°C. To the reaction mixture a pre-formed solution ofKOH (96 g, purity >85%) in
MeOH (237 mL) (prepared by adding KOH in portion to ol at 0 — 10°C) was added
dropwise while maintaining internal temperature <10°C. The resulting mixture was
continued to stir at 0 - 10°C for 30 min. The suspension was poured into pressure
equalizing addition funnel (1L) pre-packed with anhydrous Na2S04 (700g) and let it sit for
0.5h. The clear filtrate was collected as NHZOH methanolic solution.
A mixture of 1002 (150 mg, 0.3 mmol) in NHZOH methanolic solution (5 mL, 1.79M)
was d at room temperature for 3~4 h. The reaction mixture was adjusted pH to 6-7
with 1.2 M HCl and concentrated. The residue was triturated with water and d, dried
in vacuo to afford compound 1 as an off white solid (90 mg, 60% yield). M.p:185~187°C.
LCMS: m/z 506.1[M+1]+. 1H NMR (400 MHz, DMSO-d6): 5 3.35 (s, 3H), 6.65 (d, J=l6.0
Hz, 1H), 7.55-7.61 (m, 2H), 7.74-7.78 (m, 2H), 7.91 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.4 Hz,
1H), 8.06 (d, J=2.0 Hz, 1H), 8.11-8.13 (m, 2H), 8.90 (s, 1H), 10.90 (br, 1H), 10.96 (s, 1H).
EXAMPLE 2: Preparation of 6-(2-Chloro(2-chloro(methylsulfonyl)
benzamido)phenyl)-N-hydroxynicotinamide (compound 5)
Step 2a. Methyl onicotinate und 1001-5)
To a solution of 6-br0m0nicotinic acid (500 mg, 2.5 mmol) in dichloromethane
(10 mL) and THF (5 mL) was added oxalyl chloride (1.4 mL, 0.016 mol) followed by
addition of one drop of DMF. The e was stirred at room temperature for 1 h. After
removal of solvent, the residue was dissolved in anhydrous methanol (5 mL) and
continued to stir for 10 min. The reaction mixture was quenched with ice water and
filtered to afford 1001-5 as a pale yellow solid (212 mg, 40%). LCMS: m/z 213.1 [M+1]+.
1H NMR (400 MHz, : 8 3.96 (s, 3H), 7.42 (d, J=8.4 Hz, 1H), 8.25 (dd, J=8.0 Hz,
2.0 Hz, 1H), 9.00 (d, J=2.0 Hz, 1H).
Step 2b. Methyl 6-(2-chlor0(2-chlor0(methylsulf0nyl)benzamid0)phenyl)
nicotinate (compound 1002-5)
A mixture of compound 1001-5 (200 mg, 0.9 mmol), 1-9 (367 mg, 0.8 mmol) and
Pd(PPh3)4 (21 mg, 0.018 mmol) in saturated NaHC03 (2 mL) and 1,4-di0xane (6 mL) was
stirred at 100°C for 3 h. To the reaction mixture was added NaOH (37mg, 0.9 mmol) and
stirred for 0.5 h. The reaction mixture was adjusted pH to 6 with 1.2M HCl and extracted
with ethyl acetate. The organic layer was washed with water and brine, dried over
anhydrous sodium sulfate. The methyl ester was hydrolyzed during this reaction condition,
and the obtained crude acid product (365 mg) (LCMS: m/z 465.1 [M+1]+) was used for
the next step without fithher purification. The mixture of the crude acid product (365 mg,
0.8 mmol) in MeOH (15 mL) and H2S04 (0.25 mL) was d at 85°C for 1 h. The
reaction mixture was concentrated. The residue was partitioned between water and ethyl
acetate. The c layers were washed with water and brine, dried over ous
sodium sulfate and concentrated. The residue was d by column chromatography
(dichloromethane/methanol: 20/1) to afford 1002-5 as a white solid (176 mg, 39% yield
via two steps). LCMS: m/z 479.1 [M+1]+. 1H NMR(400 MHz, C 8 3.07 (s, 3H),
3.99 (s, 3H), 7.52 (d, J=8.8Hz,1H), 7.81-7.86 (m, 4H), 7.88 (dd, J=8.8 Hz, 2.8Hz ,1H),
7.97 (d, J=1.2 Hz, 1H) ,8.37 (dd, J=8.4 Hz, 2.4 Hz ,1H), 8.62 (s, 1H), 9.17 (d, J=1.2Hz,
1H).
Step 20. 6-(2-Chloro(2-chloro(methylsulfonyl)benzamido)phenyl)-N-
hydroxynicotinamide (compound 5)
A mixture of 1002-5 (176 mg, 0.4mmol) in NHZOH methanolic solution (5 mL, 1.79
M) was stirred at room temperature for 1 h. The reaction mixture was adjusted pH to 6~7
with 1.2 M HCl. The reaction mixture was filtered, washed with water, dried in vacuo to
afford compound 5 as an off-white solid (120mg 70% yield). M.p.: 190~193°C. LCMS:
m/z 480.2 [M+1]+. HNMR: (400 MHz, DMSO-d6): 5 3.35 (s, 3H), 5 7.61 (d, J=8.4 Hz,
1H), 7.76 (dd, J=8.8 Hz, 2.4 Hz ,1H), 7.82 (d, J=8.0 Hz ,1H), 7.91 (d, J=8.0 Hz ,1H), 8.01
(dd, J=8.0Hz, 1.6Hz, 1H), 8.05 (d, J=2.4 Hz ,1H), 8.13 (d, J=1.6 Hz ,1H), 8.22 (dd, J=8.0
Hz, 2.0 Hz ,1H) 9.02 (d, J=1.6 Hz, 1H), 9.28 (s, 1H), 10.96 (s, 1H), 11.48 (s, 1H).
EXAMPLE 3: Preparation of 2-[2-Chloro(2-chlor0methanesulf0nyl—
benzoylamino)—phenyl]-pyrimidine—5-carboxylic acid hydroxyamide und 7)
Step 3a. 2-Chloro-pyrimidinecarboxylic acid methyl ester und 1001-7)
A e ofNaH (27 g, 60% in mineral oil, 0.675mol) in anhydrous 1,2-
oxyethane (300 mL) was heated to 40-50°C. Methyl 3,3-dimethoxy propionate (100
g, 0.675 mol) was added dropwise. The resulting mixture was d for 0.5 h and
anhydrous methyl formate (81 g, 1.35mol) was added dropwise at 40-50°C. The ing
mixture was stirred at 40-50°C (inner temperature) for 2 h before it was cooled to 0°C. The
reaction mixture was allowed to warm to 25°C slowly and stirred overnight. EtzO (150
mL) was added and stirred for 30 min. The resulting suspension was filtered. The solid
was washed with EtzO (100mL), collected and dried to afford sodium (Z)
(dimethoxymethyl)methoxyoxopropenolate as an off-white solid (82 g, 61%).
LCMS: m/z 130.8 [M+1]+. 1HNMR (400 MHz, CD3OD)I 8 3.36 (s, 6H), 3.60 (s, 3H), 5.34
(s, 1H), 8.92 (s, 1H).
To a mixture of guanidine hydrochloride (42.2 g, 0.44 mol) in DMF (300 mL) was
added above off-white solid (80 g, 0.40 mol). The resulting e was heated at 100°C
for 1 h. The reaction mixture was ed before cooled. The filter cake was washed with
50 mL ofDMF and the combined filtrate was concentrated to leave a residue which was
suspended in cold EtOH and washed with cold EtOH (50 mL) to afford the intermediate 2-
amino-pyrimidinecarboxylic acid methyl ester as a yellow solid (38 g, 61.5%). LCMS:
m/z 154.2 [M+1]+, 195.1[M+42]+. 1HNMR (400 MHz, CDgOD): 5 3.88 (s, 3H), 8.77 (s,
2H).
The obove intermediate (7 g, 0.046 mol) was added to a mixture of concentrated
hydrochloric acid (15.2 mL) and CHzClz (60 mL). After cooling, ZnClz (18.6 g, 0.138
mol) was added at 15-20°C. The mixture was stirred at 15-20°C for 0.5 h and cooled to 5-
°C. NaNOz (9.5 g, 0.138 mol) was added portion wise while keeping the al
temperature 5-10°C. The reaction was continued for ~ 2 h. The reaction mixture was
poured into ter (50 mL). The organic layer was separated and the aqueous phase
was extracted with CHzClz (30 mL x 2). The ed organic extracts were concentrated
to afford crude t (4.2 g). The crude compound was suspended in hexane (20 mL),
heated at 60°C for 30 minutes and ed. The te was concentrated to afford the titled
compound 1001-7 (3.5 g, 44.4 %) as an off-white solid. LCMS: m/z 214.1[M+42]+.
1HNMR (400 MHz, CDClg): 5 4.00 (s, 3H), 9.15 (s, 2H).
Step 3b. 2-[2-Chloro(2-chloromethanesulfonyl-benzoylamino)-phenyl]-pyrimidi
necarboxylic acid methyl ester (compound 1002-7)
A mixture of 1001-7 (200 mg, 1.1 mmol), 1-9 (756 mg, 1.6 mmol) and Pd(PPh3)4 (60
mg, 0.05 mmol) in saturated NaHC03 (2 mL) and DMSO (6 mL) was stirred at 100°C for
3 h. After cooling to room temperature, NaOH (43 mg, 1.1 mmol) was added to reaction
solution and stirred for 0.5 h. The reaction mixture was extracted with ethyl acetate. The
aqueous layer was adjusted pH to 6 with 1.2 M HCl and extracted with ethyl acetate. The
combined organic layers were washed with water and brine, dried over Na2S04,
concentrated to afford crude acid (300 mg) without fiarther purification.
The mixture of the crude acid (300 mg) in MeOH (15 mL) and H2SO4 (0.25 mL) was
d at 85°C for 1 h. After removal of solvent, the residue was partitioned between water
and ethyl acetate. The combined organic layers were washed with water and brine, dried
over Na2S04. The crude product was purified by column chromatography (hexanes/ethyl
e: 1/ 1) to afford compound 1002-7 as a white solid (160 mg, 78% yield Via two
steps). LCMS: m/z M+1]+. 1H NMR: (400 MHz, CDC13)C 8 3.36 (s, 3H), 3.96 (s,
3H), 7.65 (d, J=8.8 Hz, 1H), 7.81 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H),
8.02 (dd, J=8.0 Hz, 1.6 Hz, 1H), 8.14 (d, J=1.2Hz, 1H), 8.30 (d, J=2.4 Hz, 1H), 9.40 (s,
2H), 11.02 (s, 1H).
Step 30. 2-[2-Chloro(2-chloromethanesulfonyl-benzoylamino)-phenyl]-pyrimidi
necarboxylic acid hydroxyamide (compound 7)
A mixture of compound 1002-7 (160 mg, 0.3 mmol) in NHZOH olic solution (5
mL, 1.79 M) was stirred at room temperature for 1 h. The reaction e was adjusted
pH to 6~7 with 1.2 M HCl and concentrated. The residue was triturated with water and
filtered. The crude t was purified by prep-HPLC to afford compound 7 as an off-
white solid (28 mg, 18% yiled). M.p.: 170~172°C. LCMS: m/z 481.1 [M+1]+. 1H NMR:
(400 MHz, DMSO-d6): 8 3.35 (s, 3H), 7.63 (d, J=8.8 Hz, 1H), 7.79 (dd, J=8.8 Hz, 2.4 Hz,
1H), 7.93 (d, J=8.0 Hz, 1H), 8.01 (dd, J=8.0 Hz, 1.6 Hz, 1H), 8.14 (d, J=1.6Hz, 1H), 8.26
(d, J=2.4 Hz, 1H), 9.23 (s, 2H), 11.01 (s, 1H).
EXAMPLE 4: 2-Chlor0-N-{4-chlor0[5-(6-hydr0xycarbamoyl-hexyloxy)-pyridin
yl]-phenyl}methanesulfonyl—benzamide und 23)
Step 43. 6-Bromo-pyridinol und 2002)
3-Aminobromopyridine (1 g, 5.8 mmol) was dissolved in HBF4 (3.6 mL, 40%
aq) and water (3 mL). To the cooled brownish on under an ice-bath was added
dropwise NaNOz (441 mg, 6.4 mmol) solution in water (3 mL). The resulting mixture was
stirried for 1 h at this tempreture. After addition of water (3 mL), the e was stirred at
100°C for 3.5 h. The reaction mixture was neutralized by aqueous NaHC03 (5%) and
extracted with ethyl e. The combined organic layers were washed with water and
brine, dried over anhydrous Na2S04 and evaporated in vacuo. The residue was purified by
column chromatography (hexanes/ethyl acetate: 9/ 1) to afford compound 2002 as a white
solid (270 mg, 27% yield). LCMS: m/z 174.0 [M+1]+. 1H NMR (400 MHz, CDClg): 8
6.65 (br, 1H), 7.13 (dd, J=8.4 Hz, 3.2 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 8.03 (d, J=3.2 Hz,
1H).
Step 4b. 7-(Pyridinyloxy)-heptanoic acid ethyl ester (compound 2003-23)
A mixture of 2002 (270 mg, 1.5 mmol), ethyl 7-bromoheptanoate (736 mg, 3.1
mmol) and K2C03 (430 mg, 3.1 mmol) in DMF (10 mL) was stirred at 75°C for 1 h. The
solution was partitioned between water and ethyl acetate. The combined organic layers
were washed with water and brine, dried over anhydrous Na2S04 and evaporated in vacuo.
The residue was purified by column chromatography (hexanes/ethyl acetate: 20/ 1) to
afford compound 2003-23 as a white solid (440 mg, 86% yield). LCMS: m/z 330.1
[M+1]+. 1H NMR: (400 MHz, CDClg): 5 1.25 (t, J=7.2 Hz, 3H), 1.36-1.52 (m, 4H), 1.62-
1.68 (m, 2H), 1.76-1.83 (m, 2H), 2.31 (t, J=7.2 Hz, 2H), 3.97 (t, J=6.4 Hz, 2H), 4.13 (q,
J=7.2 Hz, 2H), 7.08 (dd, J=8.8 Hz, 3.2 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 8.04 (d, J=2.8 Hz,
1H).
Step 40. 7-{6-[2-Chloro(2-chloromethanesulfonyl-benzoylamino)-phenyl]-pyridi
nyloxy} -heptanoic acid ethyl ester (compound 2004-23)
A mixture of 2003-23 (168 mg, 0.51 mmol), 1-9 (200 mg, 0.43 mmol) and Pd(PPh3)4
(24.6 mg, 0.03 mmol) in saturated NaHC03 (2 mL) and 1,4-dioxane (6 mL) was stirred at
100°C for 3 h. The solution was ioned between water and ethyl acetate. The
combined organic layers were washed with water and brine, dried over anhydrous Na2S04
and evaporated in vacuo. The residue was purified by column chromatography
(dichloromethane/ methanol: 100/1) to afford 2004-23 as a white solid (130 mg, 43%
yield). LCMS: m/z 593.2 [M+1]+. 1H NMR (400 MHz, : 8 1.26 (t, J=7.2 Hz, 3H),
1.37-1.54 (m, 4H), 1.63-1.71 (m, 2H), 1.78-1.85 (m, 2H), 2.32 (t, J=7.2 Hz, 2H), 3.00 (s,
3H), 3.98 (t, J=6.4 Hz, 2H), 4.12 (q, J=7.2 Hz, 2H), 7.19 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.58
(d, J=1.2 Hz, 1H), 7.61 (d, J=1.2Hz, 1H), 7.63 (d, J=1.6Hz, 1H), 7.69 (dd, J=8.0 Hz, 1.6
Hz, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.86 (d, J=1.6 Hz, 1H), 8.02 (dd, J=8.8 Hz, 2.8 Hz, 1H),
8.05 (d, J=2.8 Hz, 1H), 9.88 (s, 1H).
Step 4d. ro-N— {4-chloro[5-(6-hydroxycarbamoyl-hexyloxy)-pyridinyl]-ph
enyl}methanesulfonyl-benzamide (compound 23)
A e of 2004-23 (130 mg, 0.22 mmol) in NHZOH methanolic solution (5 mL,
1.79 M) was stirred at room temperature for 1 h. The reaction mixture was adjusted pH to
6-7 with 1.2 M HCl. The resulting mixture was filtered. The ted solid was purified
by prep-HPLC to afford compound 23 as a white solid (27 mg, 21% yiled). M.p.: 140-
145°C. LCMS: m/z 580.2 [M+1]+. 1H NMR (400 MHz, DMSO-d6): 8 1.29-1.35 (m, 2H),
.47 (m, 2H), 1.49-1.56 (m, 2H), 1.72-1.78 (m, 2H), 1.96 (t, J=7.2 Hz, 2H), 3.35 (s,
3H), 4.10 (t, J=6.4 Hz, 2H), 7.50 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.55 (d, J=8.8Hz, 1H), 7.64
(d, J=8.8Hz, 1H), 7.70 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.99-8.02 (m,
2H), 8.13 (d, J=1.6Hz, 1H), 8.40 (d, J=2.8 Hz, 1H), 8.66 (s, 1H), 10.34(s, 1 H), 10.90 (s,
1H).
EXAMPLE 5: 2-Chloro-N-(4-chlor0(pyridinyl)phenyl)(N-(7-
(hydroxyamino)0x0heptyl)sulfamoyl)benzamide (compound 59)
Step Sa. 4-Aminochlorobenzoic acid (compound 3002)
A mixture of ronitrobenzoic acid (5.0 g, 24.8 mmol), iron powder (8.0 g,
142.9 mmol) and NH4C1 (7.6 g, 142.9 mmol) in EtOH/water (50/50 mL) was heated at
WO 94328
reflux for 2 h. The hot mixture was d through Celite and washed with ethyl acetate.
The mixture was separated and extracted with ethyl acetate. The combined organic layers
were washed with water and brine, dried over anhydrous sodium sulfate. The crude
product was purified by column chromatography (hexanes/ethyl acetate: 5/1, 3/ 1, 1/ 1) to
afford compound 3002 as a white solid (1.0 g, 24% yield). 1H NMR (400 MHz, DMSO-
d6): 5 6.04 (s, 2H), 6.49 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.61 (d, J=2.0 Hz, 1H), 6.63 (d, J=8.8
Hz, 1H), 12.21 (br, 1H).
Step 5b. 2-Chloro(chlorosulfonyl)benzoic acid (compound 3003)
To a solution of 3002 (1 .00g, 5.4 mmol) in HOAc (20 mL) was added conc. HCl (5
mL) at 0°C. After 15 min, NaNOz aqueous on (1.10g, 16.2 mmol in water 4.5 mL)
was added dropwise at -5~-10°C and continued to stir at this ature for 45 min.
The above reaction mixture was added dropwise to cuprous chloride (0.14 g, 1.4 mmol)
and saturated sulfur dioxide in acetic acid (40 mL) at 0°C. After addition was complete the
resulting mixture was warmed to 10°C and stirred for 30 min. The reaction mixture was
quenched with ice water and extracted with ethyl acetate. The combined organic layers
were washed with water and brine, dried over anhydrous sodium sulfate. The crude
product was purified by column chromatography oromethane/methanol: 100/2,
100/5, 100/ 10) to afford compound 3003 as an off-white solid (500 mg, 34% yield).
Step Sc. 2-Chloro(N—(7-ethoxyoxoheptyl)sulfamoyl)benzoic acid (compound 3004-
59)
To a mixture of ethyl 7-aminoheptanoate hydrochloride (777 mg, 3.7 mmol) and N, N-
diisopropylethylamine (4.0 g, 31.2 mmol) in dichloromethane (80 mL) was added
compound 3003 (1.0 g, 3.9 mmol). The ing mixture was stirred at room temperature
overnight. The reaction mixture was adjusted pH to 6~7 with 2M HCl and extracted with
ethyl acetate. The combined organic layers were washed with water and brine, dried over
anhydrous sodium sulfate. The crude t was purified by column chromatography
oromethane/methanol: 100/2, 100/5, 100/ 10) to afford compound 3004-59 as a white
solid (520 mg, 44% yield). LCMS: m/z 392.1 [M+1]+. 1H NMR (400 MHz, CDC13)C 8
1.25-1.33 (m, 7H), 1.44-1.62 (m, 4H), 2.28 (t, J=7.2 Hz, 2H), .02 (m, 2H), 4.13 (q,
J=7.2Hz, 2H), 5.07 (t, J=5.6 Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.97 (s, 1H), 8.08 (d,
J=8.0Hz, 1H).
Step 5d. Ethyl 7-(3-chloro(4-chloro(pyridinyl)phenylcarbamoyl)phenyl
sulfonamido)heptanoate (3005-59)
A mixture of 3004-59 (520 mg, 1.3 mmol), oxalyl chloride (1.59 g, 12.5 mmol) and
DMF (0.05 mL) in dichloromethane was stirred at room temperature for 2 h. After
evaporation, the residue was dissolved in dichloromethane, compound 1-8 (244 mg, 1.2
mmol) and N, N—diisopropylethylamine (325 mg, 2.5 mmol) were added. The reaction
mixture was d at room temperature overnight. The reaction mixture was quenched
with water and extracted with dichloromethane. The combined organic layers were
washed with water and brine, dried over anhydrous sodium sulfate. The crude product was
purified by column chromatography (hexanes/ethyl acetate: 5/1, 3/ 1, 1/ 1) to afford
compound 3005-59 as a white solid (250 mg, 33% . LCMS: m/z 578.2 [M+1]+. 1H
NMR (400 MHz, DMSO-d6): 8 1.13-1.22 (m, 7H), 1.38-1.49 (m, 4H), .27 (m, 2H),
2.76 (t, J=6.8Hz, 2H), 4.03 (q, J=6.8 Hz, 2H), 7.44-7.47 (m, 1H), 7.59 (dd, J=8.4 Hz, 3.2
Hz, 1H), 7.69 (d, J=7.6Hz, 1H), 7.74-7.79 (m, 1H), 7.85 (s, 2H), .95 (m, 3H), 8.02
(d, J=2.0 Hz, 1H), 8.71 (d, J=4.8 Hz, 1H), 10.93 (s, 1H).
Step 5e. 2-Chloro-N-(4-chloro(pyridinyl)phenyl)(N-(7-(hydroxyamino)
oxoheptyl)sulfamoyl)benzamide (compound 59)
A e of 3005-59 (150 mg, 0.2 mmol) in NHZOH methanolic solution (10mL, 1.79
M) was stirred at room temperature for 2.5 h. TLC showed reaction complete. The
reaction e was adjusted pH to 5~6 with 2 M HCl, concentrated. The residue was
triturated with water and filtered, purified by prep-HPLC to afford compound 59 as a
white solid (46 mg, 32%). M.p.: 158.7~159.3°C. LCMS: m/z 565.2 [M+1]+. 1H NMR (400
MHz, DMSO-d6): 8 1.14-1.23 (m, 2H), 1.36-1.46 (m, 4H), 1.91 (t, J=7.2 Hz, 2H), 2.77 (q,
J=6.4Hz, 2H), 3.40-3.47 (m, 2H), 7.44-7.47 (m, 1H), 7.58 (d, J=8.8H, 1H), 7.69 (d, J=7.6
Hz, 1H), 7.75 (dd, J=8.4Hz, 2.4Hz, 1H), .85 (m, 3H), 7.91-7.95 (m, 2H), 8.02 (d,
J=2.4 Hz,1H), 8.71 (d, J=4.8 Hz, 1H), 10.32 (s, 1H), 10.89 (s, 1H).
EXAMPLE 6: 2-{4-[2-Chlor0(4-chlor0pyridinyl—phenylcarbamoyl)—
benzenesulfonyl]-piperazinyl}-pyrimidinecarb0xylic acid hydroxyamide
(compound 86)
Step 63. hyl(ethoxymethyl)methoxyacrylate (Compound 4002)
Sodium (27.6 g, 1.2 mol) was added to hexane (400 mL) and ethanol (27 g, 1.17
mol) was added dropwise at room temperature. The mixture was stirred at room
ature for 1 h. Then ethyl 3-ethoxypropanoate (88.0 g, 602 mmol) was added
dropwise at 0°C followed by ethyl formate (90 g, 1.22 mol). The reaction e was
stirred at 0°C for 2 h. and dimethyl sulfate (160 g, 1.27 mol) was added dropwise at the
2012/020092
same temperature. The resulting mixture was heated at 50°C overnight, filtered, and
washed with hexane (300-500 mL). To the combined filtrate was added triethylammonium
chloride (80 g, 0.58 mol) and sodium hydroxide (14.00 g, 0.35 mol). The e was
stirred at room temperature for 4 h and filtered. The filtrate was washed with water, dried
over Na2S04 and concentrated. The residue was purified by distillation to give the desired
compound 4002 (63.5 g, 56%) as a colorless oil. LCMS: m/z 211 [M+23]+. 1H NMR (400
MHz, : 5 1.20 (t, J: 7.2 Hz, 3H), 1.28 (t, J: 7.2 Hz, 3H), 3.50 (q, J: 7.2 Hz, 2H),
3.88 (s, 3H), 4.20 (m, 4H), 7.45 (s, 1H).
Step 6b. Ethyl 2-oxo-1,2,3,4-tetrahydropyrimidinecarboxylate (Compound 4003)
A mixture of compound 4002 (63.5 g, 337 mmol), urea (18.7 g, 312 mmol) and
trated hydrochloric acid (16 mL) in ethanol (300 mL) was heated at reflux
overnight. After evaporating the most of ethanol (~250 mL), the resulting suspension was
filtered, washed with small amount of ethanol, and dried to give compound 4003 (23.5 g,
44%) as a white solid. LCMS: m/z 171 [M+1]+. 1H NMR (400 MHz, CDC13): 5 1.27 (t, J
= 7.2 Hz 4.19 (m, 4H), 5.28 (s, 1H), 7.21 (d, J: 5.6 Hz, 1H), 7.40 (s, 1H).
, 3H),
Step 60. Ethyl 2-oxo-1,2-dihydropyrimidinecarboxylate (Compound 4004)
To a solution of compound 4003 (23.5 g, 138 mmol) in acetic acid (300 mL) was
added bromine (22.7 g, 142 mmol). The mixture was heated at reflux for 3 h and
concentrated in vacuum to afford the hydrobromide salt of crude compound 4004 as a
yellow solid. The product was used directly in next step without further ation.
LCMS: m/z 169 [M+1]+. 1H NMR (400 MHz, CDC13): 5 1.27 (t, J: 7.2 Hz 4.28 (q,
, 3H),
J: 7.2 Hz 8.85
, 2H), (s, 2H), 12.19 (br, s, 2H).
Step 6d. Ethyl 2-chloropyrimidinecarboxylate (Compound 4005)
A mixture of crude compound 4004 and phosphoryl oride (300 mL) was
heated at reflux for 3 h, cooled to room temperature and concentrated. The residue was
cooled to room temperature and dissolved in ethyl acetate (500 mL). The EtOAc solution
was treated with ice water (300 mL) carefully, washed with ice-water and brine, dried over
NazSO4, evaporated, and purified by column chromatography (eluted with EtOAc/Hexane:
10%) to afford nd 4005 (14 g, 54%, two steps) as a white solid. LCMS: m/z 187
. 1H NMR (300 MHz, CDC13): 5 1.42 (t, J: 7.5 Hz 4.48 (q, J: 7.5 Hz,
, 3H),
2H), 9.15 (s, 2H).
Step 6e. Ethyl 2-(piperazinyl)pyrimidinecarboxylate (compound 4006)
A mixture of tert—butyl piperazine-l-carboxylate (1.1 g, 5.9 mmol) and 4005 (1 g, 5.4
mmol), Et3N (1.1 g, 10.8 mmol) in CHzClz (10 mL) was stirred at room temperature for 2
h. The reaction mixture was washed with H20. The organic layer was trated. The
residue was purified by chromatography eluting with Hexane/EtOAc = 250: 10, then
250:20 to afford the nd ethyl 2-(4-(tert-butoxycarbonyl)piperazinyl)pyrimidine-
-carboxylate (900 mg, 45.4%) as a white solid. 1H NMR (400 MHz, CDC13)C 8 1.37 (t,
3H, J=6.8Hz), 1.49 (s, 9H), 3.51 (t, 4H, J=4.8Hz), 3.92 (t, 4H, J=5.2Hz), 4.35 (q, 2H,
J=7.2 Hz), 8.85 (s, 2H).
A mixture of above t (500 mg, 1.49 mmol) and HCl/dioxane (10 mL) was
stirred at room ature for 2 h. The reaction mixture was concentrated. The residue
was partitioned between EtOAc and saturated aq. NaHC03. The organic layer was washed
with brine, dried over Na2S04 and concentrated to afford the titled compound 4006 (370
mg, 88.2%) as a white solid. 1H NMR (400 MHZ, C 5 1.39 (t, 3H, J=6.8Hz), 2.96 (t,
4H, J=4.8Hz), 3.95 (t, 4H, J=5.2Hz), 4.36 (q, 2H, J=7.2 Hz), 8.86 (s, 2H).
Step 6f. 2-[4-(4-Carboxychloro-benzenesulfonyl)-piperazinyl]-pyrimidine
carboxylic acid methyl ester (compound 4007)
To a mixture of 4006 (1.04g, 4.7mmol) and DIPEA (4.0g, 31.2mmol) in
dicholoromethane (80mL) was added compound 3003 (1.0g, 3.9mmol). The mixture
solution was stirred at room temperature overnight. The reaction mixture was adjusted pH
to 6~7 with 2M HCl and extracted with ethyl acetate. The combined c layers were
washed with water and brine, dried over anhydrous sodium sulfate, evaportated in vacuo.
The crude product was purified by column chromatography (methane/dichloromethane:
1/20) to afford compound 4007 as a white solid (520 mg, 30% yield). LCMS: m/z 455.2
[M+1]+. 1H NMR (400 MHz, 6): 5 1.27 (t, J=7.2 Hz, 3H), 3.08 (br, 4H), 3.96 (br,
4H), 4.25 (q, J=7.2 Hz, 2H), 7.72 (dd, J=8.0Hz, 1.6Hz, 1H), 7.78 (d, J=1.2Hz, 1H), 7.87
(d, J=8.0Hz, 1H), 8.76 (s, 2H).
Step 6g. 2- {4-[2-Chloro(4-chloropyridinyl-phenylcarbamoyl)-benzenesulfonyl]-
piperazinyl}-pyrimidinecarboxylic acid methyl ester (compound 4008)
A mixture of 4007 (500 mg, 1.1 mmol), oxalyl chloride (1.59 g, 12.5 mmol) and
DMF (0.05mL) in dichloromethane (10mL) was d at room ature for 2 h. The
reaction mixture was concentrated and the residue was dissolved in dichloromethane
(15mL). Compound 1-8 (278 mg, 1.2 mmol) and DIPEA (325 mg, 2.5 mmol) were added.
The resulting mixture was stirred at room ature overnight. The reaction mixture was
quenched with water and extracted with dichloromethane. The combined organic layers
were washed with water and brine, dried over anhydrous sodium sulfate and evaporated in
vacuo. The crude product was purified by column chromatography
(methanol/dichloromethane: 1/20) to afford nd 4008 as a white solid (180 mg,
% yield). LCMS: m/z 641.2[M+1]+. 1H NMR (400 MHz, DMSO-d6): 5 1.28 (t,
J=7.2Hz, 3H), 3.11 (br, 4H), 3.99 (br, 4H), 4.26 (q, J=7.2Hz, 2H), 7.43-7.46 (m, 1H), 7.58
(d, J=8.8Hz, 1H), 7.69 (d, J=8.0Hz, 1H), 7.72 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.83 (dd,
z, 1.2Hz, 1H), .91 (m, 2H), 7.93 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.99 (d, J=2.8
Hz, 1H), 8.71 (d, J=4.4 Hz, 1H), 8.78 (s, 2H), 10.84 (s, 1H).
Step 6h. 2- {4-[2-Chloro(4-chloropyridinyl-phenylcarbamoyl)-benzenesulfonyl]-
piperazinyl}-pyrimidinecarboxylic acid hydroxyamide (compound 86)
A mixture of 4008 (180mg, 0.3mmol) and NHZOH (15mL, 1.79M) olic
solution was stirred at room temperature for 2.5 h. The reaction mixture was adjusted pH
to 5~6 with 2M HCl and evaporated. The resulting mixture was filtered. The crude product
was purified by prep-HPLC to afford compound 86 as a white solid (50 mg, 26% yield).
M.p.:158.7-159.3°C LCMS: m/z 628.2 [M+1]+. 1H NMR (400 MHz, 6): 5 3.09
(br, 4H), 3.93 (br, 4H), 7.43-7.46 (m, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.69-7.73 (m, 2H), 7.83
(dd, J=8.0Hz, 1.2Hz, 1H), 7.87-7.90 (m, 2H), 7.93 (dd, J=7.6 Hz, 1.6 Hz, 1H), 7.99 (d,
J=2.4Hz, 1H), 8.66 (s, 2H), 8.70 (d, J=4.0Hz, 1H), 9.02 (s, 1H), 10.84 (s, 1H), 11.09 (s,
1H).
EXAMPLE 7: N-(4-Chlor0(5-(dimethylamin0)—1H-benzo[d]imidazol-Z-yl)phenyl)—
3-(7-(hydroxyamin0)0x0heptyloxy)benzamide (compound 1 1 1)
Step 73. 3-(4-Chloro(5-(dimethylamino)-1H-benzo[d]imidazol
yl)phenylcarbamoyl)phenyl acetate (compound 5001-1 1 l)
3-Acetoxybenzoic acid (2.6 g, 0.015 mol) was added to a mixture of compound 2-3
(3.5 g, 0.012 mol), HATU (6.9 g, 0.018 mol) and Eth (2.5 mL, 0.018 mol) in
dichloromethane (30 mL). The reaction e was stirred at room temperature
overnight. The mixture was quenched with water and extracted with dichloromethane. The
combined c layers were washed with water and brine, dried over anhydrous Na2S04.
The crude product was purified by column chromatography (hexanes/ethyl acetate: 1/ 1) to
afford nd 5001-111 as a white solid (2.6 g, 49% yield). LCMS: m/z 449.2 [M+1]+.
Step 7b. N—(4-Chloro(5-(dimethylamino)-1H-benzo[d]imidazolyl)phenyl)
hydroxybenzamide (compound 5002-1 1 1)
To a solution of compound 5001-111 (1.0 g, 0.002 mol) in MeOH (15 mL) was added
a solution ofNaOH (0.89 g, 0.02 mol) in H20 (15 mL). The reaction mixture was heated
at reflux overnight. After cooling at ice bath, the mixture was adjusted pH to 7~8 with 1M
HCl and extracted with ethyl acetate. The combined organic layers were washed with
water and brine, dried over anhydrous , evaporated in vacuo to afford crude
nd 5.002411 as a yellow solid (0.81 g, 100% yield). LCMS: m/z 407.2 [M+1]+.
Step 7c. Ethyl(3-(4-chloro(5-(dimethylamino)-1H-benzo[d]imidazol
yl)phenylcarbamoyl)phenoxy)heptanoate (compound 5003-1 1 1)
To a mixture of compound 5002-111 (1.40 g, 0.0034 mol), ethyl 7-
hydroxyheptanoate (0.89 g, 0.0052 mol) and PPh3 (1.8 g, 0.0069 mol) in ous THF
(20 mL) was added DIAD (1.39 g, 0.0069 mol) at 0°C under nitrogen atmosphere. The
resulting solution was heated at 65°C overnight. After cooling to room ature, the
on mixture was concentrated in vacuo. The crude product was purified by column
chromatography (dichloromethane/ ethyl acetate: 1:1) to afford compound 5003-111 as a
white solid (0.9 g, 47% yield). LCMS: m/z 563.3 [M+1]+.
Step 7d. N-(4-Chloro(5-(dimethylamino)-1H-benzo[d]imidazolyl)phenyl)(7-
(hydroxyamino)oxoheptyloxy)benzamide (Compound 111)
Compound 5003-111 (120 mg, 0.21 mmol) was taken into NHZOH methanolic
solution (10 mL, 1.79 M). The mixture stirred at room temperature for 40 min. The
reaction mixture was adjusted pH to 8-9 with acetic acid and concentrated in vacuo. The
residue was purified by PLC to afford compound 111 as a white solid (30 mg, 26%
yield). M.p: 140~142°C. LCMS: m/z 550.3 . 1H NMR (400 MHz, DMSO-d6): 5
1.28-1.35 (m, 40-1.56 (m, 4H), 1.72-1.76 (m, 2H), 1.96 (t, J=3.2 Hz, 2H), 2.93 (s,
6H), 4.05 (t, J=6.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 7.16-7.18 (m, 1H), 7.43-7.61 (m, 5H),
7.97 (dd, J=8.8Hz, 2.4Hz, 1H), 8.23 (s, 1H), 8.42 (d, J=2.4 Hz, 1H), 10.36 (s, 1H), 10.47
(s, 1H), 12.23 (br, 1H).
EXAMPLE 8: 2-((3-Chlor0(4-ch10r0(pyridinyl)phenylcarbamoyl)benzyl)
l)amino)-N-hydroxypyrimidinecarb0xamide (compound 263)
Step 83. 1-Bromo(bromomethyl)chlorobenzene (compound 6002)
A mixture of 1-bromochloromethylbenzene (5 g, 24 mmol), NBS (5.19g, 29
mmol), AIBN (0.39g, 2.0 mmol) in CCl4 (50mL) was heated at reflux overnight. The hot
reaction mixture was filtered and rinsed with CCl4. The combined organic layer was
washed with water and brine, dried over NaSO4, evaporated in vacuo to afford compound
WO 94328
6002 as a white solid (5.6g, 82% yield). 1H NMR (400 MHz, CDC13)C 8 4.39 (s, 2H), 7.14
(dd, J=8.0 Hz, 2.0 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H).
Step 8b. tert—Butyl 4-bromochlorobenzyl(methyl)carbamate (compound 6003)
To a stirring solution of MeNHBoc in DMF (10mL) cooled to 0°C was added
sodium hydride (590 mg, 24.6mmol). The resulting mixture was stirred for 10 min
ed by the on of a solution of 6002 (4.67g, 16.0 mmol) in DMF (5 mL). The
reaction mixture was warmed to room temperature and stirred for 8 h. The reaction
e was quenched with ice water and extracted with ethyl acetate. The combined
organic layers were washed with water and brine, dried over anhydrous sodium sulfate and
evaporated in vacuo. The crude product was purified by column chromatography (ethyl
acetate/hexanes: 1/ 10) to afford 6003 as a white solid (1.8 g, 34% yield). 1H NMR (400
MHz, CDClg): 5 1.47 (s, 9H), 2.83 (d, J=18.4 Hz, 3H), 4.35 (s, 2H), 6.99 (s, 1H), 7.32 (s,
1H), 7.56 (d, J=8.4 Hz, 1H).
Step 80. tert-Butyl 3-chloroformylbenzyl(methyl)carbamate (compound 6004)
To a solution of 6003 (2.15 g, 6.4 mmol) in anhydrous THF (20 mL) was added n-
BuLi (3.8 mL, 2.5 M, 9.5 mmol) se at -78°C. The resulting e was continued
to stir for 2 h followed by the addition ofN—formyl morpholine (884 mg, 7.7 mmol) at -
78°C. The resulting mixture was warmed to room temperature and stirred overnight. The
reaction mixture was quenched with water and extracted with ethyl acetate. The combined
organic layers were washed with water and brine, dried over anhydrous sodium sulfate and
evaporated in vacuo. The crude t was purified by column chromatography (ethyl
acetate/hexanes: 1/ 10) to afford compound 6004 as a red oil (570 mg, 25% yield). LCMS:
m/z 282.1 [M-1]'. 1H NMR (400 MHz, CDClg): 8 1.45, 1.50 (two single peaks, 9H), 2.85,
2.90 (two single peaks, 3H), 4.46 (br, 2H), 7.23 (d, J=6.8 Hz, 1H), 7.31 (s, 1H), 7.90 (d,
J=8.0Hz, 1H), 10.45 (s, 1H).
Step 8d. Ethyl 2-((3-chloroformylbenzyl)(methyl)amino)pyrimidinecarboxylate
(compound 6005)
A e of 6004 (570 mg, 2.0 mmol) in TFA (10 mL) was stirred at room
ature for 2 h. The reaction mixture was concentrated. The residue was mixed with
4005 (560 mg, 3.0 mmol) and TEA (10 ml) and the resulting mixture was stirred at room
temperature overnight. The reaction mixture was ed with water and extracted with
ethyl acetate. The combined organic layers were washed with water and brine, dried over
Na2S04. The crude product was purified by column chromatography (ethyl
acetate/hexanes: 1/5) to afford compound 6005 as a yellow solid (425 mg, 65% yield).
LCMS: m/z 334.1 [M+1]+. 1H NMR(400 MHz, 6): 5 1.29 (t, J=7.2 Hz, 3H), 3.22
(s, 3H), 4.27 (q, J=7.2 Hz, 2H), 5.02 (s, 2H), 7.36 (d, J=8.0 Hz, 1H), 7.47 (s, 1H), 7.83 (d,
J=8.0 Hz, 1H), 8.79, 8.86 (two single peaks, 2H), 10.29 (s, 1H).
Step 8e. 2-Chloro(((5-(ethoxycarbonyl)pyrimidinyl)(methyl)amino)methyl)benzc
acid (compound 6006)
A e of compound 6005 (425 mg, 1.27 mmol), NaIO4 (408 mg, 1.9 mmol),
RuC13 (40 mg, 0.2 mmol) in CH3CN (15 mL) was stirred at room temperature for 16 h.
The on mixture was quenched with water and extracted with ethyl acetate. The
combined organic layers were washed with water and brine, dried over Na2S04. The crude
compound 6006 was obtained as a white solid (188 mg) which used directly for the next
step. LCMS: m/z 350.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6): 5 1.29 (t, J=7.2 Hz, 3H),
3.21 (s, 3H), 4.28 (q, J=7.2 Hz, 2H), 4.98 (s, 2H), 7.26 (d, J=8.0 Hz, 1H), 7.40 (s, 1H),
7.76 (d, J=7.6 Hz, 1H), 8.80, 8.86 (two single peaks, 2H).
Step 8f. Ethyl2-((3-chloro(4-chloro(pyridinyl)phenylcarbamoyl)benzyl)
(methyl)amino)pyrimidinecarboxylate (compound 6007)
A mixture of 6006 (118 mg, 0.3 mmol) in DMF (0.10 mL), thionyl chloride (2 mL,
27.5 mmol) was stirred at room temperature overnight. The reaction mixture was
concentrated and the residue was dissolved in ous dichloromethane (5 mL) and
cooled at ice bath. To the mixture was added DIPEA (1.0 mL, 6.0 mmol) and compound
1-8 (83 mg, 0.4 mmol) and the resultuing mixture was warmed to room temperature and
stirred overnight. The reaction was quenched with water and ted with ethyl acetate.
The combined organic layers were washed with water and brine, dried over NaSO4. The
crude t was purified by column chromatography (ethyl acetate/ dichloromethane:
/1) to afford compound 6007 as a white solid (100 mg 50% yield). LCMS: m/z 536.2
[M+1]+. 1H NMR (400 MHz, DMSO-d6): 5 1.29 (t, J=7.2 Hz, 3H), 3.22 (s, 3H), 4.28 (q,
J=7.2 Hz, 2H), 4.99 (s, 2H), 7.31 (d, J=7.6Hz, 1H), 7.43-7.45 (m, 2H), 7.54-7.58 (m, 2H),
7.68 (d, J=7.6 Hz, 1H), 7.75 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.90-7.94 (m, 1H), 8.02 (d, J=2.8
Hz, 1H), 8.70 (d, J: 4.4 Hz, 1H), 8.82-8.86 (m, 2H), 10.71 (s, 1H).
Step 8g. 2-((3-Chloro(4-chloro(pyridinyl)phenylcarbamoyl)benzyl)
(methyl)amino)-N-hydroxypyrimidinecarboxamide (compound 263)
Compound 6007 (100 mg, 0.2 mmol) was taken into NHZOH methanolic solution (10
mL, 1.79 M). The resulting mixture was stirred at room temperature for 2 h. The reaction
mixture was adjusted pH to 7~8 with acetic acid and trated. The residue was
triturated with water and filtered to afford compound 263 as a white solid (60 mg, 60%
yield). LCMS: m/z 523.2 . 1H NMR (400 MHz, DMSO-d6): 3.19 (s, 3H), 4.96 (s,
2H), 7.29 (d, J=8.0Hz, 1H), 7.42-7.46 (m, 2H), 7.54—7.57 (m, 2H), 7.67 (d, J=8.0Hz, 1H),
7.75 (d, J=8.8 Hz, 2.8 Hz, 1H), 7.90—7.94 (m, 1H), 8.01 (d, J=2.4 Hz, 1H), 8.70 (d, J=4.4
Hz, 1H), 8.74 (s, 2H), 9.03 (s, 1H), 10.75 (s, 1H), 11.21 (s, 1H).
EXAMPLE 9: 2-(3-Chloro(4-chloro(pyridin-Z-yl)phenylcarbamoyl)
phenylsulfonamido)—N-hydroxypyrimidine-S-carboxamide (compound 265)
Step 93. Methyl 2-chlorosulfamoylbenzoate (compound 7001)
Compound 3003 (200 mg, 0.7 mmol) was dissolved in dichloromethane (5 mL)
followed by the addition of saturated NH3 methanolic solution (0.5 mL) at 0°C. After
addition, the on mixture was warmed to room temperature and stirred for 5 min.
After evaporation, the residue was purified by column chromatography es/ethyl
acetate: 3/ 1) to afford compound 7001 as a white solid (160 mg, 86% yield). LCMS: m/z
248.0[M-1]'. 1H NMR (400 MHz, DMSO-d6): 5 3.91 (s, 3H), 7.69 (s, 2H), 7.88 (dd, J=8.4
Hz, 1.6 Hz, 1H), 7.97 (d, J=1.2 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H).
Step 9b. 4-(N-(tert-Butoxycarbonyl)sulfamoyl)—2-chlorobenzoic acid (compound 7002)
A e of 7001 (1.44 g, 5.8 mmol), B0020 (2.51g, 11.5 mmol) and DMAP (71 mg)
in dichloromethane (30 mL) was heated at reflux overnight. After cooling to room
temperature, the mixture was quenched with water, extracted with ethyl acetate. The
combined organic layers were washed with water and brine, dried over anhydrous Na2S04.
The crude product was purified by column chromatography (hexanes/ethyl acetate: 2/ 1) to
afford compound methyl 4-(N-(tert-butoxycarbonyl)sulfam0yl)chlorobenz0ate as a
white solid (1.20 g, 60% . LCMS: m/z 350.2 [M+1]+. 1H NMR (400 MHz, DMSO-
d6): 5 1.32 (s, 9H), 3.91 (s, 3H), 7.94 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.97 (d, J=1.6 Hz, 1H),
8.07 (d, J=8.0 Hz, 1H), 12.03 (br, 1H).
A mixture of above product (1.22g, 3.5 mmol), LiOH (1.46g, 34.9 mmol) in O
(10mL /10 mL) was stirred at room temperature overnight. After evaporation, the mixture
was adjusted to pH 1~2 with 1M HCl and extracted with ethyl acetate. The combined
organic layers were washed with water and brine, evaporated in vacuo to afford nd
7002 as a white solid (1.00 g, 85% yield). LCMS: m/z 334.0 [M-1]'.
1H NMR (400 MHz, DMSO-d6): 5 1.32 (s, 1H), 7.90 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.94 (d,
J=1.6 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 11.99 (br, 1H).
Step 9c. tert-Butyl 3-chlor0(4-chlor0(pyridinyl)phenylcarbamoyl)phenyl
sulfonylcarbamate (compound 7003)
A mixture of compound 7002 (328 mg, 1.0 mmol), 1-8 (100 mg, 0.5 mmol), HATU
(559 mg, 1.5 mmol), DIPEA (253 mg, 2.0 mmol) in DMF (5 mL) was stirred at room
temperature overnight. The mixture was quenched with ted sodium bicarbonate and
extracted with ethyl acetate. The combined c layers were washed with water and
brine, dried over anhydrous Na2S04. The crude product was purified by column
chromatography (dichloromethane / ethyl acetate: 2/1) to afford compound 7003 as a
white solid (270 mg, ~100% yield). LCMS: m/z 522.2 [M+1]+. 1H NMR (400 MHz,
DMSO-d6): 5 1.36 (s, 9H), 7.44-7.47 (m, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.0 Hz,
1H), 7.76 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 7.91-7.98 (m, 4H), 8.01 (d, J=2.4 Hz, 1H), 8.71
(d, J=4.4 Hz, 1H), 10.93 (s, 1H), 11.98 (br, 1H).
Step 9d. 2-Chloro-N-(4-chloro(pyridinyl)phenyl)sulfamoylbenzamide
(compound 7004)
A mixture of 7003 (270 mg, 0.5 mmol) in TFA (5 mL) was stirred at room temperature
for 2 h. After evaporation, the mixture was ed with saturated NaHC03 and
extracted with ethyl acetate. The combined organic layers were washed with water and
brine, dried over anhydrous Na2S04, evaporated in vacuo to afford compound 7004 as a
white solid (180 mg, 84% yiled). LCMS: m/z 422.1 . 1H NMR (400 MHz, DMSO-
d6): 5 7.43-7.47 (m, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.64 (s, 2H), 7.69 (d, J=8.0 Hz, 1H), 7.75
(dd, J=8.8 Hz, 2.4 Hz, 1H), 7.82-7.88 (m, 2H), 7.91-7.96 (m, 2H), 8.01 (d, J=2.4 Hz, 1H),
8.71 (d, J=4.8 Hz, 1H), 10.88 (s, 1H).
Step 9e. Ethyl 2-(3-chloro(4-chloro(pyridinyl)phenylcarbamoyl)phenyl
sulfonamido)pyrimidinecarboxylate (compound 7005)
A mixture of compound 7004 (460 mg, 1.1 mmo), 4005 (203 mg, 1.1 mmol), cesium
carbonate (533 mg, 1.6 mmol), Xantphos (20 mg, 0.03 mmol), Pd2(dba)3 (20 mg, 0.02
mmol) in 1,4-dioxane (15 mL) was heated at 85°C overnight. After cooling to room
temperature, the reaction mixture was quenched with water and extracted with ethyl
acetate. The ed organic layers were washed with water and brine, dried over
anhydrous Na2S04. The crude product was purified by column chromatography
oromethane / ethyl acetate: 2/ 1) to afford compound 7005 as a pale yellow solid (300
mg, 48% yield). LCMS: m/z 572.1 [M+1]+. 1H NMR (400 MHz, 6): 5 1.29 (t,
J=7.2 Hz, 3H), 4.29 (q, J=7.2 Hz, 2H), 7.43-7.46 (m ,1H), 7.57 (d, J=8.8 Hz, 1H), 7.67-
7.73 (m, 2H), 7.84 (d, J=8.0 Hz, 1H), 7.90-7.94 (m, 1H), 7.99 (d, J=2.8 Hz, 1H), 8.06 (dd,
J=8.0 Hz, 1.6 Hz, 1H), 8.10 (d, J=1.6 Hz, 1H), 8.69-8.71 (m, 1H), 8.96 (s, 2H), 9.05 (s,
1H).
Step 9f. 2-(3-Chloro(4-chloro(pyridinyl)phenylcarbamoyl)phenylsulfonamido) -
N-hydroxypyrimidinecarboxamide (compound 265)
Compound 7005 (300 mg, 0.5 mmol) was taken into NHZOH methanolic solution (10
mL, 1.79 M). The resulting mixture was stirred at room temperature for 1 h. The reaction
mixture was adjusted pH to 7~8 with acetic acid and concentrated. The residue was
triturated with water and d. The solid was suspended in dichloromethane and stirred
at room temperature overnight and filtered. The collected solid was dried in vacuo to
afford nd 265 as a white solid (60 mg, 21% yield). M.p: 215~220°C.
LCMS: m/z 559.2 [M+1]+. 1H NMR (400 MHz, DMSO-d6): 8 7.42-7.46 (m, 1H), 7.56 (d,
J=8.8 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.73 (dd, J=8.8 Hz, 2.8 Hz,
1H), 7.85 (d, J=8.0 Hz, 1H), 7.90-7.94 (m, 2H), 8.01 (d, J=2.4 Hz, 1H), 8.53 (s, 2H), 8.70
(d, J=4.4 Hz, 1H), 8.93 (s, 1H), 10.79 (s, 1H), 10.96 (br, 1H).
EXAMPLE 10: (E)—2-Chloro-N-(4-chlor0(pyridinyl)phenyl)(N-(3-(3-
xyamin0)0x0pr0penyl)phenyl)sulfamoyl)benzamide (compound 254)
Step 10a. 2-(3-Nitrophenyl)—1,3-dioxolane (compound 8002)
A mixture of 3-nitrobenzaldehyde (7.0 g, 46.3 mmol), ne glycol (14.4 g, 231.5
mmol), enesulfonic acid (0.79 g, 4.6 mmol) in toluene (80 mL) was heated at reflux
overnight. After cooling to room temperature, the reaction mixture was quenched with
aqueous sodium bicarbonate and extracted with ethyl acetate. The combined c
layers were washed with water and brine, dried over anhydrous Na2S04 and evaporated in
vacuo to afford compound 8002 as a yellow oil (8.6 g, 95%). 1H NMR (400 MHz, CDClg):
4.05-4.11 (m, 2H), 4.12-4.16 (m, 2H), 5.89 (s, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.81 (d, J=7.6
Hz, 1H), 8.21-8.24 (m, 1H), 8.35-8.36 (m, 1H).
Step 10b. 3-(1,3-Dioxolanyl)aniline (compound 8003)
A e of 8002 (215 mg, 1.1 mmol), Pd/C (100 mg, 50%) in ethanol (10 mL) was
stirred under hydrogen at room temperature overnight. The mixture was filtered and the
filtrate was ated in vacuo. The crude product was purified by column
chromatography (hexanes/ethyl acetate: 8/ 1) to afford compound 8003 as a yellow solid
(100 mg, 55%). LCMS: m/z 166.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6): 5 3.86-4.03
(m, 4H), 5.10 (s, 1H), 5.55 (s, 1H), 6.54 (d, J=7.6 Hz, 2H), 6.63 (s, 1H), 6.99 (t, J=7.6 Hz,
1H).
Step 10c. Methyl 4-(N-(3-(1,3-dioxolanyl)phenyl)sulfamoyl)chlorobenzoate
(compound 8004)
A mixture of 8003 (1.12 g, 6.8 mmol), 3003 (2.21 g, 8.2 mmol), anhydrous pyridine
(1.3 g, 16.4 mmol) in anhydrous CHzClz (10 mL) was heated at reflux for 30 min. The
mixture was quenched with water and adjusted pH to 2-3 with HCl (1.0M). The resulting
mixture was extracted with ethyl acetate. The combined organic layers were washed with
water and brine, dried over anhydrous sodium e and evaporated in vacuo. The crude
t was purified by column chromatography (hexanes/ethyl acetate: 10/1) to afford
nd 8004 as a yellow oil (2.16 g, 80%). LCMS: m/z 398.1 [M+1]+. 1H NMR (400
MHz, DMSO-d6): 5 3.87 (s, 3H), 3.91-3.93 (m, 2H), 3.94-3.96 (m, 2H), 5.66 (s, 1H), 7.10-
7.17 (m, 3H), 7.29 (t, J=8 Hz, 1H). 7.77 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.85 (d, J=1.6 Hz,
1H), 7.96 (d, J=8.0 Hz, 1H), 10.58 (s, 1H).
Step 10d. 4-(N-(3-(1,3-Dioxolanyl)phenyl)sulfamoyl)chlorobenzoic acid
(compound 8005)
LiOH (264 mg, 6.25 mmol) was added into a solution of 8004 (500 mg, 1.25 mmol) in
THF/HZO (5 mL /5 mL). The mixture was stirred at room temperature overnight. The
mixture was quenched with HCl (1 M) and adjusted pH to 1-2. The resulting mixture was
extracted with ethyl e. The combined organic layers were washed with water and
brine, dried over anhydrous sodium sulfate and evaporated in vacuo to afford compound
8005 as a red solid (450 mg, 94%). LCMS: m/z 384.1 [M+1]+. 1H NMR (400 MHz,
DMSO-d6): 3.91-3.93 (m, 2H), 3.95-3.97 (m, 2H), 5.67 (s, 1H), 7.11-7.18 (m, 3H), 7.30 (t,
J=8.0 Hz, 1H). 7.74 (dd, J=8.4 Hz, 2.0Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.92 (d, J=8.4 Hz,
1H), 10.57 (s, 1H).
Step 10e. 4-(N-(3-(1,3-Dioxolanyl)phenyl)sulfamoyl)chloro-N-(4-chloro(pyridin
yl)phenyl)benzamide (compound 8006)
A mixture of 8005 (284 mg, 0.74 mmol), 1-8 (100 mg, 0.49 mmol), HATU (373 mg,
0.98 mmol), DIPEA (159 mg, 1.23 mmol) in ous DMF (5 mL) was d
overnight. The mixture was quenched with water and extracted with ethyl acetate. The
combined organic layers were washed with water and brine, dried over anhydrous sodium
sulfate and evaporated in vacuo. The crude product was purified by column
chromatography (hexanes/ethyl acetate: 5/ 1) to afford compound 8006 as a yellow solid
(248 g, 88%). LCMS: m/z 570.2 .
Step 10f. 2-chloro-N-(4-chloro(pyridinyl)phenyl)(N-(3-formylphenyl)
sulfamoyl)benzamide (compound 8007)
A mixture of 8006 (120 mg, 0.18 mmol) and HCl (5 mL) in THF/HZO (5 mL/5 mL)
was refluxed for 1 h. The e was quenched with water and extracted with ethyl
WO 94328
acetate. The combined organic layers were washed with water and brine until pH 7. The
organic layer was dried over ous Na2S04 and evaporated in vacuo. The crude
product was purified by column chromatography (hexanes/ethyl acetate: 5/ 1) to afford
compound 8007 as a yellow solid (90 mg, 82%). LCMS: m/z 526.2 [M+1]+. 1H NMR
(400 MHz, DMSO-d6): 7.42-7.50 (m, 2H), 7.53-7.57 (m, 2H), .72 (m, 5H), 7.81-
7.86 (m, 2H), 7.91 (dd, J=7.6Hz, 1.6Hz, 1H), 7.94 (br, 1H), 7.96 (d, J=2.4Hz, 1H), 8.70 (d,
J=4.8 Hz, 2H), 9.94 (s, 1H), 10.84 (s, 1H), 10.91 (s, 1H).
Step 10g. (E)-methyl 3-(3-(3-chloro(4-chloro(pyridinyl)phenylcarbamoyl)
phenylsulfonamido)phenyl)acrylate (compound 8008)
A mixture of 8007 (110 mg, 0.21 mmol), methyl-(dimethoxyphosphoryl) acetate (58
mg, 0.32 mmol) and sodium methoxide (34 mg, 0.63 mmol) in anhydrous DMF was
stirred at room temperature overnight. The mixture was quenched with HCl (1 M) and
extracted with ethyl acetate. The combined organic layers were washed with water and
brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product
was purified by column chromatography (CHzClz/ethyl acetate: 6/ 1) to afford compound
8008 as a yellow solid (45 mg, 37%). LCMS: m/z 582.2[M+1]+. 1H NMR (400 MHz,
DMSO-d6): 3.72 (s, 3H), 6.52 (d, J=16.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.34 (t, J=7.2
Hz, 1H), 7.41-7.49 (m, 3H), 7.55-7.61 (m, 2H), 7.66-7.72 (m, 2H), 7.80-7.86 (m, 2H),
7.90 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.93-7.96 (m, 2H), 8.70 (d, J=4.4 Hz, 1H), 10.71 (s, 1H),
10.83 (s, 1H).
Step 10h. (E)Chloro-N-(4-chloro(pyridinyl)phenyl)(N-(3-(3-
(hydroxyamino)oxopropenyl)phenyl)sulfamoyl)benzamide und 254)
Compound 8008 (45 mg, 0.077 mmol) was taken into NHZOH methanolic on (10
mL, 1.79 M). The resulting mixture was stirred at room temperature for 1 h. The reaction
mixture was adjusted pH to 7~8 with acetic acid and concentrated. The residue was
triturated with water and filtered. The collected solid was ed with prep-HPLC to
afford compound 254 as an off-white solid (13 mg, 31% . M.p.: 217~221°C LCMS:
m/z 583.2 [M+1]+. 1H NMR (400 MHz, DMSO-d6): 6.41 (d, J=15.6 Hz, 1H), 7.12 (d,
J=7.6, 1H), 7.18 (s, 1H), .38 (m, 4H), 7.42-7.45 (m, 1H), 7.56 (d, J=8.8 Hz, 1H),
7.66-7.72 (m, 2H), 7.80-7.90 (m, 1H), 7.90-7.97 (m, 3H), 8.70 (d, J=4.4 Hz, 1H), 10.71 (s,
1H), 10.80 (br, 1H), 10.84 (s, 1H).
EXAMPLE 11: 2-(4-((3-Chloro(4-chloro(pyridin-Z-yl)phenylcarbamoyl)
phenylsulfonamido)methyl)piperidinyl)—N-hydroxypyrimidine—5-carboxamide
(compound 90)
Step lla. tert-Butyl 4-((3-chloro(meth0xycarbonyl)phenylsulfonamido)methyl)
piperidine-l- carboxylate (compound 9001)
To a mixture of tert-butyl 4-(amin0methyl)piperidinecarb0xylate (570 mg, 2.6
mmol) and 3003 (600 mg, 2.2 mmol) in dichloromethane (10 mL) was added
triethylamine (0.6 mL, 4.4 mmol). The e was stirred at room temperature overnight.
The reaction mixture was diluted with ethyl acetate and washed with 1N HCl. The ethyl
acetate layer was concentrated in vacuo and purified by column chromatography (hexanes:
ethyl acetate = 5:1) to give compound 9001 as a white solid (610 mg, 62% yield). LCMS:
m/z 445.1 [M-1]'. 1H NMR (400 MHz, DMSO-d6): 5 0.87-0.98 (m, 2H), 1.37 (s, 9H),
1.49-1.60 (m, 3H), 2.62-2.70 (m, 4H), 3.86 (br, 2H), 3.90 (s, 3H), 7.84 (dd, J=8.0 Hz, 1.6
Hz, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.94 (t, J=5.6 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H).
Step 1 1b. 4-(N-((1-(tert-Butoxycarbonyl)piperidinyl)methyl)sulfam0yl)—2-
chlorobenzoic acid (compound 9002)
To the solution of 9001 (610 mg, 1.4 mmol) in THF (16 mL) and H20 (8 mL) was
added LiOH (286 mg, 12.0 mmol). The e was stirred at room temperature for 3 h.
The on mixture was acidified to pH=5 with 1N HCl and extracted with ethyl e.
The ethyl acetate layer was dried over Na2S04, filtered and trated in vacuo to give
compound 9002 as a white solid (530 mg, 90% yield). 1H NMR (400 MHz, DMSO-d6): 8
0.89-0.98 (m, 2H), 1.37 (s, 9H), 1.52-1.61 (m, 3H), 2.65-2.69 (m, 4H), 3.89 (d, J=12.0 Hz,
2H), 7.80 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.91 (t, J=6.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H).
Step 11c. tert-Butyl 4-((3-chlor0(4-chloro(pyridinyl)phenylcarbamoyl)phenyl
amido)methyl)piperidinecarboxylate (compound 9003)
To a mixture of 9002 (530 mg, 1.2 mmol) and 1-8 (200 mg, 1.0 mmol) in DMF (2.0
mL) was added DIPEA (300 mg, 2.3 mmol) followed by HATU (733 mg, 1.9 mmol). The
resulting solution was stirred at room temperature overnight. The reaction mixture was
poured into water and extracted with ethyl acetate. The organic phase was washed with
NH4C1 solution, water and brine, dried over Na2S04 and tration in vacuo. The
crude solid was purified by column chromatography eluted with ethyl
acetate:dichloromethane = 3:1 to give compound 9003 as a yellow solid (120 mg, 16%).
LCMS: m/z 619.2 . 1H NMR (400 MHz, DMSO-d6): 5 0.90-1.09 (m, 2H), 1.38 (s,
9H), 1.52-1.63 (m, 3H), 2.66-2.69(m, 4H), 3.90 (d, J=10.8Hz, 2H), 7.40-7.47 (m, 1H),
7.58-7.60 (m, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.75 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.84 (s, 2H),
7.90-7.92 (m, 3H), 8.01 (d, J=2.0 Hz, 1H), 8.65, 8.70 (2 doublet peaks, J=5.2Hz, 1H),
.87 (s, 1H).
Step 11d. 2-Chloro-N-(4-chloro(pyridinyl)phenyl)(N-(piperidin
ylmethyl)sulfamoyl)benzamide (compound 9004)
To the solution of 9003 (120 mg, 0.2 mmol) in dichloromethane (1 mL) was added
TFA (1 mL). The mixture was stirred at room temperature for 1h. The reaction solution
was trated. The residue was dissolved with ethyl acetate and washed with NaHC03
solution. The ethyl acetate layer was dried over Na2S04, filtered and concentrated in vacuo
to give compound 9004 as a yellow solid (100 mg, 99% yield).
LCMS: m/z 519.2 [M+1]+. 1H NMR (400 MHz, DMSO-d6): 8 1.10-1.15 (m, 2H), 1.57
(br, 1H), 1.69 (d, J: 13.2Hz, 2H), 2.60-2.69 (m, 4H), 3.10 (d, J=12.0 Hz, 2H), 7.43 (t,
J=6.0 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H),
7.85 (s, 2H), 7.91-7.94 (m, 2H), 8.01 (s, 1H), 8.71 (d, J=4.4 Hz, 1H), 10.88 (s, 1H).
Step 11e. Ethyl 2-(4-((3-chloro(4-chloro(pyridinyl)phenylcarbamoyl)phenyl
amido)methyl)piperidinyl)pyrimidinecarboxylate (compound 9005)
To the solution of 9004 (100 mg, 0.2 mmol) and Eth (0.2 mL, 1.4 mmol) in DCM (2
mL) was added 4005 (39 mg, 0.2 mmol). The resulting mixture was stirred at room
ature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with
1N HCl. The ethyl acetate layer was dried over , filtered and concentrated to give
compound 9005 as a yellow solid (135 mg, 96% yield). LCMS: m/z 669.3 [M+1]+. 1H
NMR (400 MHz, DMSO-d6): 8 1.10-1.18 (m, 2H), 1.29 (t, J=7.2Hz, 3H), 1.76 (d, J-
6.0Hz, 2H), 2.68-2.72 (m, 2H), 2.94-3.00 (m, 2H), 4.27 (q, z, 2H), 4.72 (d, J=12.8
Hz, 2H), 7.45 (t, J=6.0 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.75 (d,
J=8.8 Hz, 1H), 7.86 (s, 2H), 7.92-8.01 (m, 3H), 8.71 (d, J=4.8 Hz, 1H), 8.77 (s, 2H), 9.28
(br, 1H), 10.89 (s, 1H).
Step 11f. 2-(4-((3-Chloro(4-chloro(pyridinyl)phenylcarbamoyl)
phenylsulfonamido)methyl)piperidinyl)-N-hydroxypyrimidinecarboxamide
(compound 90)
nd 9005 (135 mg, 0.2 mmol) was taken into NHZOH methanolic on
(1.79M, 10mL). The resulting mixture was stirred in sealed tube at room temperature for 3
h. TLC showed reaction te. Acetic acid was added to adjust pH to 6~7 followed by
the addition of ice-water. The reaction mixture was filtered, washed with water. The crude
product was purified by prepared HPLC to afford compound 90 as a white solid (30mg,
22% yield). M.p.: 172—17300 LCMS: m/z 656.2 [M+1]+. 1H NMR (400 MHz, DMSO-
d6): 5 1.04—1.07 (m, 2H), 1.73-1.76 (m, 3H), 2.70—2.72 (m, 2H), 2.89—2.95 (m, 2H), 4.69
(d, J=12.8 Hz, 2H), 7.45 (t, J=6.0 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H),
7.75 (d, J=8.4 Hz, 1H), 7.86 (s, 2H), 7.91—7.95 (m, 2H), 8.02 (s, 1H), 8.65 (s, 2H), 8.71 (d,
J=4.4 Hz, 1H), 8.99 (br, 1H), 10.88 (s, 1H), 10.99 (br, 1H).
EXAMPLE 12: ro-N-(4-chloro(pyridinyl)phenyl)(N-(2-(4-
xycarbamoyl)phenoxy)ethyl)sulfamoyl)benzamide (compound 266)
Step 123. 2-Chlor0(N-(2-(4-(ethoxycarbonyl)phen0xy)ethyl)sulfam0yl)benz0ic acid
(compound 1001)
To a mixture of ethyl 4-(2-amin0eth0xy)benzoate (330 mg, 1.6 mmol) and 3003 (400
mg, 1.6 mmol) in dichloromethane (10 mL) was added triethylamine (0.6 mL, 4.4 mmol).
The mixture was stirred at room temperature overnight. The reaction mixture was diluted
with ethyl acetate and washed with 1N HCl. The ethyl acetate layer was concentrated in
vacuo and purified by column tography (dichloromethane: MeOH = 50: 1) to give
nd 1001 as a yellow solid (270 mg, 40% yield). LCMS: m/z 428.0 [M+1]+. 1H
NMR (400 MHz, DMSO-d6): 5 1.30 (t, J=7.2 Hz, 3H), 3.20-3.22 (m, 2H), 4.04 (t, J=4.8
Hz, 2H), 4.27 (q, J=7.2Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.4 Hz, 1H), 7.71 (d,
J=8.0 Hz, 1H), 7.77 (s, 1H), 7.87 (d, J=8.4 Hz, 2H), 8.12 (br, 1H).
Step 12b. Ethyl 4-(2-(3-chloro(4-chlor0(pyridinyl)phenylcarbamoyl)phenyl
sulfonamido)ethoxy)benzoate (compound 1002)
To a mixture of compound 1001 (270 mg, 0.6 mmol) and 1-8 (108 mg, 0.5 mmol) in
DMF (2.0 mL) was added DIPEA (164 mg, 1.3 mmol) followed by HATU (289 mg, 0.8
mmol). The resulting solution was stirred overnight at room temperature. The reaction
mixture was poured into water and extracted with ethyl acetate. The organic phase was
washed with 1N HCl solution, water, brine and dried over Na2S04. The crude solid was
purified by column chromatography eluted with dichloromethane/MeOH = 100/1 to give
compound 1002 as a yellow solid (130 mg, 33%). LCMS: m/z 614.2 [M+1]+. 1H NMR
(400 MHz, DMSO-d6): 5 1.28 (t, J=6.8Hz, 3H), 3.24-3.26 (m, 2H), 4.06- 4.09 (m, 2H),
4.25 (q, J=6.8Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 7.43-7.47 (m, 1H), 7.59 (d, J=8.8 Hz, 1H),
7.70 (d, J=7.6 Hz, 1H), .95 (m, 7H), 8.01 (s, 1H), 8.24-8.27 (m, 1H), 8.70-8.72 (d,
J=4.0 Hz, 1H), 10.86 (s, 1H).
Step 12c. ro-N—(4-chlor0(pyridinyl)phenyl)(N—(2-(4-
(hydroxycarbamoyl)phenoxy)ethyl)sulfamoyl)benzamide (compound 266)
Compound 1002 (130 mg, 0.2 mmol) was taken into NHZOH olic solution
(1.79M, 10mL). The resulting mixture was stirred in sealed tube at room temperature for 3
h. TLC showed reaction complete. 1N HCl was added to adjust pH to 6~7 followed by the
on of ice-water. The reaction mixture was filtered, washed with water. The crude
product was purified by prep-HPLC to afford compound 266 as a yellow solid (41mg,
32% yield). mp: 138-139°C. LCMS: m/z 601.2 [M+1]+. 1H NMR (400 MHz, DMSO-d6):
3.23 (t, J=4.0 Hz, 2H), 4.06 (t, J=4.8 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 7.45 (t, J=6.4 Hz,
1H), 7.58 (d, J=8.8 Hz, 1H), 7.68-7.76 (m, 4H), 7.86-7.96 (m, 4H), 8.02 (s, 1H), 8.19 (d,
J=4.0Hz, 1H), 8.71 (d, J=4.4 Hz, 1H), 8.89 (br, 1H), 10.88 (s, 1H), 11.05 (s, 1H).
E 13: 2-(4-((5-(3-(1H-Benz0[d]imidazol-Z-yl)—4-chlorophenylcarbamoyl)—6-
methylpyridin-Z-ylamin0)methyl)piperidinyl)-N-hydroxypyrimidine—S-
carboxamide (compound 91)
Step 13a. 6-Bromomethylnicotinaldehyde (compound 1102)
To a stirred solution of 3,6-dibromomethylpyridine (2.0 g, 8.0 mmol) in dry THF
(20 mL) was added n-BuLi (1.6M, 6.0 mL) dropwise at -78°C. When the addition was
complete the reaction was continued for 1 h. Dichloromethane (642.4 mg, 8.8 mmol) was
added at -78°C and continued to stir for 1 h. The reaction was allowed to warm to room
temperature followed by addition of HCl (1M, 10 mL) .The mixture was extracted with
ethyl acetate. The organic layer was washed with brine and concentrated. The crude
product was purified by column chromatography eluted with dichloromethane/ methanol
(30:1) to afford nd 1102 as a white solid (1.4 g, 90%).
Step 13b. 6-Bromomethylnicotinic acid (compound 1103)
To a stirred solution of compound 1102 (1.4 g, 6.7 mmol) in acetone (20 mL) was
added Jones reagent (2.67M, 5.2ml) at 0°C. The reaction mixture was warmed to room
temperature and stirred for 30 min. Saturated NaHC03 solution was added to adjust pH=5-
6. The mixture was extracted with ethyl e. The c layer was washed with brine
and concentrated. The crude product was purified by column chromatography eluted with
ethyl acetate/ hexanes (1 :8) to afford compound 1103 as a white solid (1.0 g, 66%). 1H
NMR (400 MHz, CDC13)C 5 2.87 (s, 3H), 7.46 (d, J=8.4Hz, 1H), 8.15 (d, J=8.4Hz, 1H).
Step 13c. N—(3-(1H-benzo[d]imidazolyl)chlorophenyl)bromo
methylnicotinamide und 1104)
Compound 1103 (1.0 g, 4.6 mmol) was added to a mixture of compound 2-3 (1.2 g,
l), HATU (3.5 g, 5.5 mmol) and Eth (19 mL, 13.8 mmol) in dichloromethane (30
mL). The reaction mixture was d at room temperature overnight. The mixture was
quenched with water, extracted with dichloromethane, concentrated. The crude product
was d by column chromatography eluted with hexanes/ethyl acetate (1 :1) to afford
compound 1104 as a white solid (1.0 g, 50%). LCMS: m/z 443.1[M+1]+.
Step 13d. tert-Butyl 4-((5 -(3 -(1H-benzo[d]imidazolyl)chlorophenylcarbamoyl)
methyl pyridinylamino)methyl)piperidinecarboxylate (compound 1105)
To a stirred solution of compound 1104 (500 mg, 1.13 mmol) in i-PiOH (10 mL)
was added tert-butyl 4-(aminomethyl)piperidinecarboxylate (930 mg, 4.4 mmol) and
K2C03 (1.2 g, 8.7 mmol). The mixture was ng under 100°C for 48 h. The mixture was
quenched with water and extracted with dichloromethane. The crude product was d
by column chromatography eluted with hexane/ethyl acetate (1 :1) to afford compound
1105 as a yellow solid (250 mg, 38% yield). LCMS: m/z 575.4[M+1]+ 1H NMR (400
MHz, DMSO-d6): 8 1.06-1.12 (m, 2H),1.45 (s, 9H), 1.73-1.76 (m, 3H), 2.50 (s, 3H) ,2.73-
2.75 (m, 2H), 3.25 (s, 2H), 3.98-4.02 (m, 2H), 6.43 (d, J: 8.8Hz ,1H), .05 (m, 1H),
7.25-7.34 (m, 2H), 7.63-7.66 (m, 3H), 7.76 (d, J: 7.6Hz ,1H), 7.92 (d, J: 8.8Hz, 2H), 8.41
(s, 1H), 10.28 (s, 1H),12.72 (s, 1H).
Step 13e. Methyl 2-(4-((5-(3-(1H-benzo[d]imidazolyl)chlorophenylcarbamoyl)
methyl pyridinylamino)methyl)piperidinyl)pyrimidinecarboxylate (compound
1 106)
To a stirred solution of compound 1105 (70 mg, 0.12 mmol) in dichloromethane was
added TFA (3 mL). The e was stirred for 30 min. The reaction solution was
concentrated and the residue was dissolved in dichloromethane (10 mL). To the solution
was added 4005 (31 mg, 0.14 mmol) and Eth (1mL). The resulting mixture was stirred at
room temperature for 30 min and concentrated. The residue was purified by column
chromatography eluted with hexanes/ethyl acetate (1 :1) to afford compound 1106 as a
yellow solid (70 mg, 94%). LCMS: m/z 611.3 [M+1]+ 1H NMR (400 MHz, DMSO-d6): 8
1.08-1.14 (m, 72-2.02 (m, 4H), 2.45 (s, 3H), 2.94-3.05 (m, 3H), 3.80 (s, 3H), 4.77
(d, J: 13.2Hz, 2H), 6.39 (d, J: 8.8Hz ,1H), 7.03 (d, J: 5.2Hz, 1H), 7.23-7.27 (m, 2H),
7.58-7.60 (m, 2H), 7.71 (d, J: 7.2Hz ,1H), 7.87 (d, J: 7.6Hz, 2H), 8.35 (s, 1H), 8.77 (s,
2H), 10.23 (s, 1H), 12.69 (s, 1H).
Step 13f. 2-(4-((5-(3-(1H-Benzo[d]imidazolyl)chlorophenylcarbamoyl)
methylpyridinylamino)methyl)piperidinyl)-N-hydroxypyrimidinecarboxamide
(compound 91)
Compound 1106 (70 mg, 0.11 mmol) was taken into NHZOH olic solution
(10 mL, 1.79 M). The mixture was stirred at room temperature for 40 min. The reaction
mixture was adjusted pH to 8-9 with acetic acid and concentrated. The residue was
purified by HPLC to afford the titled compound 91 as a white solid (37 mg, 53%).
M.p.: 194-196°C. LCMS: m/z 612.3[M+1]+1H NMR (400 MHz, DMSO-d6): 5 1.13-1.18
(m, 2H), 1.78-2.00 (m, 3H), 2.45 (s, 3H), 2.91- 2.98 (m, 2H), 3.22 (s, 2H), 4.73 (d, J:
12.4Hz, 2H), 6.38 (d, J: 8.4Hz ,1H), 7.00-7.02 (m, 1H), 7.24-7.26 (m, 2H), 7.57-7.60 (m,
3H), 7.69-7.71 (d, J: 7.2Hz ,1H), 7.86 (d, J: 8.8Hz ,1H), 8.35 (s, 1H), 8.65 (s, 2H), 8.97
(br, 1H),10.23 (s, 1H), 10.98 (br, 1H), 12.68 (s, 1H).
EXAMPLE 14: 2-(3-(4-Chloro(5-(dimethylamin0)—1H-benz0[d]imidazol
yl)phenylcarbamoyl)meth0xybenzylamino)—N-hydr0xypyrimidinecarboxamide
(compound 258)
Step 14a. Methyl 3-(hydroxymethyl)methoxybenzoate (compound 1202)
To a d solution of dimethyl 5-methoxyisophthalate (1.0 g, 4.5 mmol) in THF (10
mL) was added H (6.6 mL, 6.6 mmol). The reaction mixture was stirred for
ght at room ature. The reaction mixture was diluted with ethyl acetate and
washed with water and brine. The organic phase was dried over Na2S04 and concentrated.
The crude product was purified by column chromatography eluted with hexanes/EA (2: 1)
to afford compound 1202 as a yellow solid (600 mg, 68% yield).
LCMS: m/z 197.1[M+1]+. 1H NMR (400 MHz, DMSO-d6): 5 3.80 (s, 3H), 3.85 (s, 3H),
4.53 (d, J=6.0 Hz, 2H), 5.35 (t, J=5.8 Hz, 1H), 7.15 (s, 1H), 7.31 (s, 1H), 7.54 (s, 1H).
Step 14b. Methyl 3-(bromomethyl)methoxybenzoate (compound 1203)
To a stirred solution of compound 1202 (800 mg, 4.0 mmol) in dichloromethane (10
mL) was added PBr3 (0.4 mL, 4.3 mmol). The reaction mixture was stirred for 1 h at room
temperature. The reaction was diluted with ethyl acetate and washed with water and brine.
The c phase was dried over Na2S04 and concentrated. The crude product was
purified by column chromatography eluted with hexanes/ethyl acetate (5: 1) to obtain
compound 1203 as a yellow oil. (640 mg, 61% yield). 1H NMR (400 MHz, CDClg): 8 3.85
(s, 3H), 3.92 (s, 3H), 7.12 (br, 1H), 7.49 (br, 1H), 7.65 (br, 1H).
Step 14c. Methyl 3-(azidomethyl)methoxybenzoate (compound 1204)
To a stirred solution of compound 1203 (640 mg, 2.5 mmol) in DMF (5 mL) was
added NaN3 (1.1 g 16.9 mmol). The reaction mixture was stirred at room temperature for 2
h. The reaction on was d with ethyl acetate and washed with water and brine.
The organic phase was dried over NazSO4 and concentrated. The crude product was
purified by column chromatography eluted with hexanes/ethyl acetate (5: 1) to afford
compound 1204 as a yellow oil (500 mg, 91% yield). LCMS: m/z 263.2[M+1+41]+.
Step 14d. Methyl 3-(aminomethyl)methoxybenzoate (compound 1205)
To a stirred solution of nd 1204 (500 mg, 2.3 mmol) in THF (10 mL) was
added PPh3 (650 mg, 2.5 mmol) and stirred for 30 min. Water (100 mg, 5.5 mmol) was
added. The mixture was warmed to 60°C and stirred for 2 h. The reaction mixture was
diluted with ethyl acetate and washed with water and brine. The organic phase was dried
over NazSO4 and concentrated. The crude t was d by column
chromatography eluted with dichloromethane/MeOH (50: 1) to afford compound 1205 as a
yellow oil (300 mg, 68% yield). LCMS: m/z 196.1[M+1]+.
Step 14e. 3-(Aminomethyl)methoxybenzoic acid (compound 1206)
Compound 1205 (300 mg, 1.5 mmol) was added to a mixture of LiOH (180 mg, 7.5
mmol) in EtOH (2 mL) and H20 (2 mL). The reaction mixture was stirred at room
ature for 3 h. The on mixture was adjusted pH to 6 with 2N HCl. The mixture
was concentrated and directly used to next step without fiarther purification.
Step 14f. 3-Methoxy((5-(methoxycarbonyl)pyrimidinylamino)methyl)benzoic acid
(compound 1207)
To a stirred on of 1206 (200 mg, 1.0 mmol) and Eth (300 mg, 3.0 mmol) in
romethane (5 mL) was added 4005 (176 mg, 1.0 mmol). The reaction mixture was
stirred at room temperature for 1 h. The reaction on was diluted with ethyl acetate
and washed with water and brine. The organic phase was dried over Na2S04, then
concentrated. The crude product was purified by column chromatography eluted with
dichloromethane/MeOH (50: 1) to afford compound 1207 as a yellow solid (110 mg, 31%
yield). LCMS: m/z 318.2[M+1]+. 1H NMR (400 MHz, DMSO-d6): 5 3.78 (s, 3H), 3.79 (s,
3H), 4.60 (d, J=6.4 Hz, 2H), 7.13 (s, 1H), 7.31 (s, 1H), 7.49 (s, 1H), 8.67 (t, J=6.0 Hz,
1H), 8.75 (s, 2H).
Step 14g. Methyl 2-(3-(4-chloro(5-(dimethylamino)-1H-benzo[d]imidazolyl)phenyl
carbamoyl)methoxybenzylamino)pyrimidinecarboxylate (compound 1208)
To a stirred solution of compound 1207 (110 mg, 0.3 mmol), 2-3 (90 mg, 0.3 mmol)
and DIPEA (90 mg, 0.7 mmol) in DMF was added HATU (160 mg, 0.4 mmol). The
on mixture was stirred at room temperature overnight. The reaction mixture was
diluted with ethyl acetate and washed with water and brine. The organic phase was dried
over Na2S04 and concentrated. The crude product was purified by column
tography eluted with hexanes/ethyl acetate (1 :1) to afford compound 1208 as a
yellow solid (60 mg, 30% yield). LCMS: m/z 586.3[M+1]+.
Step 14h. 2-(3-(4-Chloro(5-(dimethylamino)-1H-benzo[d]imidazol
yl)phenylcarbamoyl)methoxybenzylamino)-N-hydroxypyrimidinecarboxamide
(compound 258)
Compound 1208 (70 mg, 0.1 mmol) was taken into NHZOH methanolic on (10
mL, 1.79 M). The mixture was stirred at room temperature for 40 min. The reaction
mixture was adjusted pH to 8-9 with acetic acid and concentrated. The residue was
purified by prep-HPLC to afford the titled compound 258 as a yellow solid (35 mg, 50%).
M.p.: 158-159°C. LCMS: m/z 587.3[M+1]+. 1H NMR (400 MHz, DMSO-d6): 5 2.93 (s,
6H), 3.82 (s, 3H), 4.60 (d, J=6.0 Hz, 2H), 6.78-6.97 (m, 2H), 7.10 (s, 1H), 7.41 (s, 1H),
7.49-7.52 (m, 2H), 7.58 (d, J=8.8 Hz, 1H), 7.94 (dd, J=8.8, 2.8 Hz, 1H), 8.30 (t, J=6.2 Hz,
1H), 8.37 (br, 1H), 8.61 (s, 2H), 8.94 (br, 1H), 10.42 (s, 1H), 10.98 (br, 1H), 12.17, 12.30
(two single peaks, 1H).
EXAMPLE 15: 2-((3-(4-Chlor0(5-(dimethylamin0)—1H-benz0[d]imidazol
yl)phenylcarbamoyl)methoxybenzyl)(methyl)amin0)-N-hydr0xypyrimidine
carboxamide (compound 259)
Step 153. Methyl 3-methoxy((methylamino)methyl)benzoate (compound 1301)
To a solution of 1203 (150 mg, 0.6 mmol) in DMF (3 mL) was added methylamine
methanol solution (2.5 mL). The reaction mixture was d at room temperature for 10
min. Water (10 mL) was added to the reaction mixture and the resulting reaction mixture
was extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed
with water. The organic phase was dried over Na2S04, ed and evaporated to give
product 1301 as light yellow oil (100 mg, 83%). LCMS: m/z 210.1 . 1H NMR (400
MHz, CDClg): 5 2.45 (s, 3H), 3.77 (s, 2H), 3.85 (s, 3H), 3.92 (s, 3H), 7.10 (s, 1H), 7.45 (s,
1H), 7.59(s, 1H).
Step 15b. Methyl 3-((tert-butoxycarbonyl(methyl)amino)methyl)methoxybenzoate
(compound 1302)
(Boc)20 (154 mg, 0.7 mmol), NEt3 (101 mg, 1.0 mmol) and DMAP (6 mg, 0.05
mmol) were added to a on of compound 1301 (100 mg, 0.5 mmol) in anhydrous
dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 2 h
until TLC indicated that compound 1301 had been consumed. The reaction mixture was
concentrated and the residue was purified by column chromatography eluted with CHzClz:
MeOH (10: 1) to afford the titled compound 1302 as light yellow oil (110 mg, 75%).
Step 150. 3-((tert-Butoxycarbonyl(methyl)amino)methyl)methoxybenzoic acid
(compound 1303)
NaOH aqueous solution (4.0M, 10 mL) was added to a on of nd
1302 (160 mg, 0.5 mmol) in ol (5 mL). The solution was stirred at room
temperature for 2 h. The reaction mixture was acidified to pH 3~4 with cone. HCl solution
and extracted with ethyl acetate (10 mL x 2) and dried over NaZSO4. The title compound
1303 was obtained as a yellow solid after concentration (100 mg, 66%). 1H NMR (400
MHz, CDC13)C 8 1.42 (s, 9H), 2.78 (s, 3H), 3.78 (s, 3H), 4.37 (s, 2H), 6.96 (s, 1H), 7.44 (s,
1H), 7.50 (s, 1H).
Step 15d. tert-Butyl 3 -(4-chloro-3 -(5 -(dimethylamino)- 1 H-benzo [d]imidazolyl)
carbamoyl)methoxybenzyl(methyl)carbamate (compound 1304)
Compound 2-3 (97 mg, 0.3 mmol) was added to a solution of compound 1303 (100
mg, 0.3 mmol), HATU (137 mg, 0.4 mmol) and DIPEA (78 mg, 0.6 mmol) in DMF (4
mL). The reaction mixture was stirred at room ature overnight. The mixture was
diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic layer
was washed with water and dried over Na2S04. The titled compound 1304 was ed as
yellow solid after concentration (150 mg, 89%). LCMS: m/z 564.3 [M+1]+.
Step 15e. N—(4-Chloro(5-(dimethylamino)-1H-benzo[d]imidazolyl)phenyl)
methoxy((methylamino)methyl)benzamide (compound 1305)
Compound 1304 (150 mg) was dissolved in trifluoroacetic acid (10 mL). The
reaction mixture was stirred at room temperature for 1 h. The reaction was then
concentrated to remove most trifluoroacetic acid. The residue was adjusted to pH 7~8 with
saturated s NaHC03 solution and extracted with ethyl acetate. The organic layer
was washed with brine and dried over Na2S04 and concentrated. The crude product was
purified by column chromatography eluted with CHgClz: MeOH (20: 1) to afford the titled
compound 1305 as a light yellow solid (50 mg, 40%). 1H NMR (400 MHz, CDC13)C 8 2.69
(s, 3H), 3.00 (s, 6H), 3.76 (s, 3H), 3.91 (s, 2H), 6.85 (s, 2H), 6.90 (dd, J=9.2 Hz, 2.4 Hz,
1H), 7.33~7.38 (m, 2H), 7.52 (d, J=8.8Hz, 1H), 7.58 (s, 1H), 8.06~8.11 (m, 2H), 9.03 (br,
1H).
Step 15f. Ethyl 2-((3-(4-chloro(5-(dimethylamino)-1H-benzo[d]imidazolyl)phen
ylcarbamoyl)methoxybenzyl)(methyl)amino)pyrimidinecarboxylate (compound
1306)
To a on of nd 1305 (50 mg, 0.1 mmol) in dichloromethane was added
compound 4005 (19 mg, 0.1 mmol) and NEt3 (30 mg, 0.3 mmol). The reaction mixture
was stirred at room temperature for 2 h. The reaction mixture was washed with water and
concentrated to afford the title compound 1306 (90 mg). LCMS: 614.3 [M+1]+. 1H NMR
(400 MHz, CDC13)C 5 1.36 (t, J=7.2Hz, 3H), 3.00 (s, 6H), 3.24 (s, 3H), 3.85 (s, 3H), 4.34
(q, J=7.2Hz, 2H), 4.99 (s, 2H), 6.87~6.92 (m, 2H), 6.98 (s, 1H), 7.32 (s, 2H), 7.47 (d,
J=9.2 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 8.23~8.24 (m, 3H), 8.90 (s, 2H).
Step 15g. 2-((3-(4-Chloro(5-(dimethylamino)-1H-benzo[d]imidazol
yl)phenylcarbamoyl)methoxybenzyl)(methyl)amino)-N-hydroxypyrimidine
carboxamide (compound 259)
Compound 1306 (90 mg, 0.1 mmol) was ved in NHZOH methanol solution
(20 mL, 1.79M). The mixture was stirred at room temperature for 1h. The reaction mixture
was adjusted pH to 8-9 with 2N HCl and evaporated in vacuo. The residue was triturated
with water to afford the crude t. The crude product was further purified by prep-
HPLC to afford compound 259 as a yellow solid (18 mg, 20%). M.p.: 207-208°C. LCMS:
m/z 601.3 [M+1]+. 1H NMR (400MHz, DMSO-d6): 5 2.93 (s, 6H), 3.18 (s, 3H), 3.82 (s,
3H), 4.96 (s, 2H), 6.78~6.88 (m, 2H), 7.00 (s, 1H), 7.41~7.51 (m, 3H), 7.57 (d, J=8.4 Hz,
1H), 7.94 (d, J=8.4 Hz, 1H), 8.14 (s, 1H), 8.37 (s, 1H), 8.71 (s, 2H), 8.98 (br, 1H), 10.42
(s, 1H), 11.03 (s, 1H), 12.15 (s, 1H).
EXAMPLE 16: An in vitro assay which determines the ability of a test compound to
inhibit HDAC enzymatic activity
HDAC inhibitory activity was assessed using the Biomol Color de Lys system
(AK-500, Biomol, Plymouth g, PA). Briefly, HeLa cell nuclear extracts were used
as a source of HDACs. Different concentrations of test compounds were serially diluted in
dimethylsulfoxide (DMSO) and added to HeLa cell r extracts in the presence of a
colorimetric artificial substrate. Final assay conditions contained 50 mM Tris/Cl, pH 8.0,
137 mM NaCl, 2.7 mM KCl and 1 mM MgC12. Reactions were carried out at room
ature (25°C) for 1 hour before addition of developer for termination. Relative
enzyme activity was measured in the WALLAC Victor II 1420 microplate reader as
fluorescence intensity (excitation: 350-3 80 nm; emission: 440-460 nm). Data were
ed using GraphPad Prism ) with a sigmoidal dose se curve fitting for
IC50 calculation.
EXAMPLE 17: An in vitro assay which determines the ability of a test compound to
inhibit Hedgehog signalling
nds to he tested were dissolved in DMSO to a concentration of l 0 nrlvl,
and stored at $096 To activate the l: edgeliog pathway in the assay cells, an octylated
SHE) was used This Nmtenninal SHH fragment is produced bacterially. See, for example,
Taylor FR, et al, Biochemistry, 2301, 40: 42l59~7l ,
Compounds were tested in the’fllinLuc’assay below using the eell line lGTl/Z
(le), wherein the cells contain a. ehogvresponsive er construct utilizing
Lueiferase as the er gene. in this way, Hedgehog pathway signaling activity is
measured Via. the {jliluc response,
lG'i‘h’Z (.512) cells were plated in a inuwell nricro~titer plate (Mil?) at 2&000
cells/well in firll nrediurn {DMEM with l0% PBS]. Then plates were placed in the
ineuhator for ineuhaticn overnight {til/N), at 37 “C and 5‘34; (702. After 24 hi the medium
was replaced with Luciterase~assay medium (DMEM with 9.5% PBS) est compounds
were thawed and diluted in assay niediun'i at 3: lllllll (about Ill)0~fold) resulting in a
starting concentration of about 30003 ui‘vl to 30 1.1M. Subsequently l 50 ul of each sample
was added to the first wells (in triplicate), The MT? samples were then diluted at 3~tbld
dilutions to a total of seven wells, ately resulting in a regiment of seven dilutions in
triplicate, for each compound. Next, the protein ligand OCT~Sllll was diluted in
Luciferaseuassay rnediunr and added to each well at a final concentration of (.13 .
Plates were then returned to the incubator for further incubation Q/N, at 37"3C and 5%
(.702. Alter about 24 h, plates were removed train the incubator and the mediator was
aspirated/discarded.
Wells were washed once with assay er [PBS l ranl Mg,“ and l ranl Ea‘r’fl’].
Then 56 ill of assay buffer was added to each well. The Lueiferase assay reagent vitas
prepared as hed by the vendor (ilsuclite hit tron-r Paclotrd}, and 51‘) ul was added to
each well. Plates were incubated at room temperature (RT) for about 30 rninutes after
which the signals were read, again at RT, on a Topcount (Packard).
Similar assays were performed using human cell lines (specifically, human
embryonic palatal niesenehynie cells, modified with the Gli—Lue construct as bed
above} in a growth n'iediurn oils/l liil‘v’l/Sodium lrlyruvate w/l 0‘54; PBS, and an assay mediurn
oi‘MEl‘vi/Sodiuni Pyruyate tar/659$.» FEES. OCT—SHE was added to reach a final
tration of l tug/ml,
Resuhs fifths EBAC irfl'ifliitign and hadgaheg inhibition 35.321ij dcscrilicd iii
Examplas 16 and 'E ?, respectiveiy, :11: set fail} in the table below. which indicates the
{€50 incd iii with assay as fafiows: E 100% nM; 1 (309113,? E: ii 1> 39% 11M; 39% HM
2‘: EH > 10 GM; 10 NM ? W > 1 11M; 1 1113/? P: V.
Hh Repmmr
assay
\ Compound A
E 18 An in vitro assa which determines the abilit of a test com ound to
inhibit bindin of Hed eho t0 Smoothened
Smo is transiently overexpressed in 293T cells, the membranes are harvested and a
filtration membrane-competition-binding assay is performed in a 96-well plate with [3H]-
Hh-Ag 1.5 added at 2 nM. Membranes are prepared as follows. Briefly, approximately
108 cells are transfected with pCMV6-XL5 constructs bearing human Smoothened
(OriGene) using Fugene 6 (Roche). After 48 hours cells are harvested by scraping in PBS,
centrifuged at 1,000 X g for 10 minutes, and gently resuspended in around 10 ml of a 50
mM Tris pH 7.5, 250 mM sucrose buffer containing an EDTA-free protease inhibitor
cocktail ). This cell suspension is then placed in a nitrogen cavitation device (Parr
Instrument Co, Moline, USA) and exposed to nitrogen gas (230 psi) for 10 minutes. Lysed
cells are released from the device and centrifuged at 20,000 rpm in an SS34 rotor for 20
s at 4°C. tants are ded and the pellets are resuspended in 10%
sucrose, 50 mM Tris pH 7.5, 5 mM MgC12, 1 mM EDTA solution using three 10-second
pulses with a on (Brinkman; Westbury, USA) at a power setting of 12. Using these
membranes, ion binding assays are performed according to standard protocols.
Briefly, a test compound is incubated for 1 hour at room temperature in the following
binding buffer (50mm Tris 7.5, 5 mM MgC12, 1 mM EDTA, 0.1% BSA) containing cell
membrane , [3H]-Hh-Ag 1.5 and protease tors. After incubation, the reaction is
transferred to a 96-well filter plate, vacuum is applied to pull down the reaction buffer, the
wells are washed twice and scintillation solution is added. The reactions are read on a Top
Count microplate reader to determine the fraction of [3H]-Hh-Ag 1.5 bound to the
smoothened containing membrane preparation.
ZIIIIm- I
/ Hh-Ag 1.5
While this ion has been particularly shown and bed with references to
preferred embodiments thereof, it will be understood by those skilled in the art that various
changes in form and details may be made therein Without departing from the scope of the
invention encompassed by the appended claims.
Claims (28)
1. A compound of Formula (IV): D B X Q (IV) or a pharmaceutically acceptable salt thereof; wherein Ring A is an ic, saturated or partially unsaturated carbocycle; Q is substituted or unsubstituted aryl; substituted or tituted heteroaryl or substituted or unsubstituted saturated or partially unsaturated heterocyclyl; G is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted saturated or partially unsaturated heterocyclyl; K is halogen; X is absent, -O-, -, -S-, , -S(O)2-, -C(O)-,-C(O)O-, -OC(O)-, -C(O)N(R2)-, - N(R2)C(O)-, -S(O)2N(R2)-, or -N(R2)S(O)2-; R2 is hydrogen or aliphatic; B is a direct bond or straight- or branched-, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, arylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, cyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, larylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, lheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylhererocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, lheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, or alkynylheteroaryl, in which groups one or more methylenes can be interrupted or terminated by O, S, S(O), SO2, N(R2), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic; and D is selected from: (a) J ; where W is O or S; J is O, NH or NCH3; and R31 is hydrogen or lower alkyl; Z Y2 (b) R33 R32 ; where W is O or S; Y2 is absent, N, or CH; Z is N or CH; R32 and R34 are independently hydrogen, hydroxy, aliphatic group, provided that if R32 and R34 are both present, one of R32 or R34 must be hydroxy and if Y2 is absent, R34 must be hydroxy; and R33 is hydrogen or tic group; Z1 Y1 (c) ; where W is O or S; Y1 and Z1 are independently N, C or CH; and R21 NH2 Z Y2 (d) R12 R11 ; where Z, Y2, and W are as previously defined; R11 and R12 are ndently selected from hydrogen or aliphatic; R21, R22 and R23 are ndently selected from hydrogen, hydroxy, amino, halogen, alkoxy, alkylamino, dialkylamino, CF3, CN, NO2, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyclic, and substituted heterocyclic.
2. The nd of claim 1 represented by Formula VI: D B X Q (VI) or a pharmaceutically acceptable salt thereof; wherein K, G, Q, X, B, and D have the meanings given for these variables in claim 1.
3. The compound of claim 1 represented by Formula XII: D B X Q X5 X2 X4 X3 (XII) or a pharmaceutically acceptable salt thereof; wherein X1-X5 are each independently selected from N and CR3, ed that at least 2 of X1-X5 are CR3; each R3 is independently ed from hydrogen, y, amino, halogen, alkoxy, alkylamino, dialkylamino, CF3, CN, NO2, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and Q, D, B and X have the meanings given for these variables in claim 1.
4. The compound of claim 3, wherein Q is tuted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl or substituted or tituted benzimidazolyl.
5. The compound of claim 4, wherein Q is selected from the groups below: N N N , wherein the bond to the benzene ring is d by , and the bond to X is denoted by .
6. The compound of claim 3, wherein X5 X2 X4 X3 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, or substituted or unsubstituted pyrimidyl.
7. The compound of claim 6, wherein X5 X2 X4 X3 is selected from the group consisting of S Cl O F3C N , O2 and .
8. The compound of claim 1, wherein B is a direct bond, straight chain C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl.
9. The compound of any of claims 1 to 8, wherein D is Z Y2 R33 R32 .
10. The compound of claim 9, wherein Y2 and R32 are , Z is N, W is O, R33 is H and R34 is hydroxy.
11. A compound represented by Formula XIV: R33 R32 R34 Z Y2 M5 M4 M3 M2 M1 Q (XIV) or a pharmaceutically acceptable salt thereof; wherein M1 is absent, O, S, NR2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, heterocyclic, SO, SO2 or C=O; M2 is absent, C1-C6 alkyl, O, NR2, cyclic, aryl, heteroaryl, or C=O; M3 is absent, O, NR2, S, SO, SO2, CO, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, or heterocyclic; M4 is absent, O, NR2, heteroaryl, heterocyclic or aryl; M5 is absent, C1-C8 alkyl, C2-C8 alkenyl, C2-C8alkynyl, heteroaryl, heterocyclic or aryl; Q is substituted or unsubstituted aryl; substituted or unsubstituted aryl or substituted or unsubstituted saturated or partially unsaturated heterocyclyl; G is substituted or tituted aryl, substituted or tituted heteroaryl or substituted or unsubstituted saturated or partially unsaturated heterocyclyl; Y2 is absent, N, or CH; Z is N or CH; R2 is hydrogen or aliphatic; R32 and R34 are ndently hydrogen, hydroxy, aliphatic group, provided that if R32 and R34 are both present, one of R32 or R34 must be hydroxy and if Y2 is absent, R34 must be hydroxy; and R33 is hydrogen or aliphatic group.
12. The compound of claim 11, wherein Y2 and R32 are absent, Z is N, R33 is H and R34 is hydroxy.
13. The compound of claim 1 ed from the compounds set forth in the table below, or a pharmaceutically acceptable salt thereof: HO NH Cl N O HN Cl S O HO NH Cl N O HO NH Cl N O HO NH N O HO NH O N O HN Cl S O HO NH N O HO NH N O N O HN Cl S O O N HO NH N O O N HO NH N O HO NH Cl N O HO NH Cl N O HO NH N O O HN Cl S O N O N O N O HN Cl S O N O N O HN Cl S O N O HO O HN Cl N O HN Cl S O HO O HN Cl N O HO O HN Cl N O N O N O HN Cl S O N O N O N O N O wherein n is 1 to 6.
14. A pharmaceutical composition comprising a compound of any of claims 1 to 13 and a pharmaceutically able carrier.
15. The pharmaceutical composition of claim 14 for use in ng a hedgehog associated disease or disorder in a subject in need f, the treatment comprising administering to the subject a eutically effective amount of the ceutical composition.
16. The pharmaceutical composition of claim 15, wherein said hedgehog associated disease or disorder is a cell proliferative er.
17. The pharmaceutical composition of claim 16, wherein said cell proliferative disorder is selected from the group consisting of basal cell carcinoma, neuroectodermal tumors, such as medullablastoma, meningioma, hemangioma, glioblastoma, pancreatic arcinoma, squamous lung carcinoma, chondrosarcoma, breast carcinoma, rhabdomyosarcoma, esophageal cancer, stomach cancer, biliary tract cancer, renal carcinoma, leukemia, lymphoma, myeloma and thyroid carcinoma.
18. The pharmaceutical composition of claim 14 for use in treating a disease or disorder selected from inflammatory conditions, conditions associated with angiogenesis and as a depilatory in a subject, comprising the stration to the subject of a therapeutically effective amount of the pharmaceutical composition.
19. The pharmaceutical composition of claim 18, wherein the disease or disorder is selected from psoriasis and macular degeneration.
20. The pharmaceutical composition of claim 14 for use in treating an HDAC-mediated disease comprising the administration of the ceutical composition to a t in need thereof.
21. The ceutical composition of claim 14 for use in treating a disease associated with both hedgehog and HDAC, wherein ent comprises administration of the pharmaceutical composition to a subject in need thereof.
22. The use of a compound of any one of claims 1-13 in the manufacture of a pharmaceutical composition for ng a hedgehog associated disease or er in a subject in need thereof, the treatment comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition.
23. The use of claim 22, wherein said og associated disease or disorder is a cell proliferative disorder.
24. The use of claim 23, wherein said cell proliferative disorder is selected from the group consisting of basal cell carcinoma, neuroectodermal tumors, such as medullablastoma, meningioma, hemangioma, glioblastoma, pancreatic adenocarcinoma, squamous lung carcinoma, chondrosarcoma, breast carcinoma, rhabdomyosarcoma, esophageal cancer, stomach , y tract cancer, renal carcinoma, leukemia, lymphoma, myeloma and thyroid carcinoma.
25. The use of a compound of any one of claims 1-13 in the cture of a pharmaceutical composition for treating a disease or disorder selected from inflammatory conditions, conditions associated with angiogenesis and as a depilatory in a subject, comprising the stration to the subject of a therapeutically effective amount of the pharmaceutical composition.
26. The use of claim 25, wherein the disease or disorder is selected from psoriasis and macular ration.
27. The use of a compound of any one of claims 1-13 in the manufacture of a pharmaceutical composition for treating an HDAC-mediated disease sing administration of the pharmaceutical ition to a subject in need thereof.
28. The use of a compound of any one of claims 1-13 in the manufacture of a pharmaceutical composition for treating a disease associated with both hedgehog and HDAC, wherein treatment comprises administration of the pharmaceutical composition to a subject in need thereof.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161429350P | 2011-01-03 | 2011-01-03 | |
US61/429,350 | 2011-01-03 | ||
US201161564549P | 2011-11-29 | 2011-11-29 | |
US61/564,549 | 2011-11-29 | ||
NZ612477A NZ612477B2 (en) | 2011-01-03 | 2012-01-03 | Hedgehog antagonists having zinc binding moieties |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ708390A NZ708390A (en) | 2016-03-31 |
NZ708390B2 true NZ708390B2 (en) | 2016-07-01 |
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