NZ711592B2 - Histone deacetylase inhibitors - Google Patents
Histone deacetylase inhibitors Download PDFInfo
- Publication number
- NZ711592B2 NZ711592B2 NZ711592A NZ71159214A NZ711592B2 NZ 711592 B2 NZ711592 B2 NZ 711592B2 NZ 711592 A NZ711592 A NZ 711592A NZ 71159214 A NZ71159214 A NZ 71159214A NZ 711592 B2 NZ711592 B2 NZ 711592B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- disease
- alkyl
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Abstract
Provided herein are compounds and methods for inhibiting histone deacetylase ("HDAC") enzymes (e.g., HDACl, HDAC2, and HDAC3). The compounds are benzamide derivatives of formula (II) where Het, RA, RB, and RC are as defined herein. The compounds are useful for treating neurological disorders such as Friedreich's ataxia. Friedreich's ataxia.
Description
HISTONE DEACETYLASE INHIBITORS
CROSS REFERENCE TO RELATED APPLICATIONS
The benefit of US Application No. 13/843,261, filed March 15, 2013, the disclosure
of which is incorporated by reference in its entirety.
TECHNICAL FIELD
Provided herein are compounds and methods of inhibiting histone deacetylase
(“HDAC”) enzymes (e.g., HDAC1, HDAC2, and HDAC3).
BACKGROUND
To date, 18 HDACs have been identified in humans and there is increasing
evidence that the 18 histone deacetylases (HDAC) in humans are not redundant in function.
HDACs are classified into three main groups based on their homology to yeast proteins.
Class I includes HDAC1, HDAC2, HDAC3, and HDAC8 and have homology to yeast RPD3.
HDAC4, HDAC5, HDAC7, and HDAC9 belong to class IIa and have homology to yeast
HDAC1. HDAC6 and HDAC10 contain two catalytic sites and are classified as class IIb,
whereas HDAC11 has conserved residues in its catalytic center that are shared by both class I
and class II deacetylases and is placed in class IV. These HDACs contain zinc in their
catalytic site and are inhibited by compounds like trichostatin A (TSA) and vorinostat
[suberoylanilide hydroxamic acid (SAHA)]. Class III HDACs are known as sirtuins. They
as cofactor, and do not contain zinc in the
have homology to yeast Sir2, require NAD
catalytic site. In general, HDAC inhibitors of zinc-dependent HDACs include a Zn-binding
group, as well as a surface recognition domain.
HDACs are involved in the regulation of a number of cellular processes. Histone
acetyltransferases (HATs) and HDACs acetylate and deacetylate lysine residues on the N
termini of histone proteins thereby affecting transcriptional activity. They have also been
shown to regulate post-translational acetylation of at least 50 non-histone proteins such as α-
tubulin (see for example Kahn, N et al Biochem J 409 (2008) 581, Dokmanovic, M et al Mol
Cancer Res 5 (2007) 981).
Altering gene expression through chromatin modification can be accomplished by
inhibiting histone deacetylase (HDAC) enzymes. There is evidence that histone acetylation
and deacetylation are mechanisms by which transcriptional regulation in a cell – a major
event in cell differentiation, proliferation, and apoptosis – is achieved. It has been
hypothesized that these effects occur through changes in the structure of chromatin by
12354570_1 (GHMatters) P107928.NZ
altering the affinity of histone proteins for coiled DNA in the nucleosome. Hypoacetylation
of histone proteins is believed to increase the interaction of the histone with the DNA
phosphate backbone. Tighter binding between the histone protein and DNA can render the
DNA inaccessible to transcriptional regulatory elements and machinery. HDACs have been
shown to catalyze the removal of acetyl groups from the ε-amino groups of lysine residues
present within the N-terminal extension of core histones, thereby leading to hypoacetylation
of the histones and blocking of the transcriptional machinery and regulatory elements.
Inhibition of HDAC, therefore can lead to histone deacetylase-mediated
transcriptional derepression of tumor suppressor genes. For example, cells treated in culture
with HDAC inhibitors have shown a consistent induction of the kinase inhibitor p21, which
plays an important role in cell cycle arrest. HDAC inhibitors are thought to increase the rate
of transcription of p21 by propagating the hyperacetylated state of histones in the region of
the p21 gene, thereby making the gene accessible to transcriptional machinery. Further, non-
histone proteins involved in the regulation of cell death and cell-cycle also undergo lysine
acetylation and deacetylation by HDACs and histone acetyl transferase (HATs).
This evidence supports the use of HDAC inhibitors in treating various types of
cancers. For example, vorinostat (suberoylanilide hydroxamic acid (SAHA)) has been
approved by the FDA to treat cutaneous T-cell lymphoma and is being investigated for the
treatment of solid and hematological tumors. Further, other HDAC inhibitors are in
development for the treatment of acute myelogenous leukemia, Hodgkin’s disease,
myelodysplastic syndromes and solid tumor cancers.
HDAC inhibitors have also been shown to inhibit pro-inflammatory cytokines, such
as those involved in autoimmune and inflammatory disorders (e.g. TNF-α). For example, the
HDAC inhibitor MS275 was shown to slow disease progression and joint destruction in
collagen-induced arthritis in rat and mouse models. Other HDAC inhibitors have been shown
to have efficacy in treating or ameliorating inflammatory disorders or conditions in in vivo
models or tests for disorders such as Crohn’s disease, colitis, and airway inflammation and
hyper-responsiveness. HDAC inhibitors have also been shown to ameliorate spinal cord
inflammation, demyelination, and neuronal and axonal loss in experimental autoimmune
encephalomyelitis (see for example Wanf L et al, Nat Rev Drug Disc 8 (2009) 969).
Triplet repeat expansion in genomic DNA is associated with many neurological
conditions (e.g., neurodegenerative and neuromuscular diseases) including myotonic
dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington’s disease,
12354570_1 (GHMatters) P107928.NZ
spinocerebellar ataxias, amyotrophic lateral sclerosis, Kennedy’s disease, spinal and bulbar
muscular atrophy, Friedreich’s ataxia and Alzheimer’s disease. Triplet repeat expansion may
cause disease by altering gene expression. For example, in Huntington’s disease,
spinocerebellar ataxias, fragile X syndrome, and myotonic dystrophy, expanded repeats lead
to gene silencing. In Friedreich’s ataxia, the DNA abnormality found in 98% of FRDA
patients is an unstable hyper-expansion of a GAA triplet repeat in the first intron of the
frataxin gene (see Campuzano et al., Science 271:1423 (1996)), which leads to frataxin
insufficiency resulting in a progressive spinocerebellar neurodegeneration. Since they can
affect transcription and potentially correct transcriptional dysregulation, HDAC inhibitors
have been tested and have been shown to positively affect neurodegenerative diseases (see
Herman D et al, Nat Chem Bio 2 551 (2006) for Friedreich’s ataxia, Thomas EA et al, Proc
Natl Acad Sci USA 105 15564 (2008) for Huntington’s disease).
HDAC inhibitors may also play a role in cognition-related conditions and diseases.
It has indeed become increasingly evident that transcription is likely a key element for long-
term memory processes (Alberini CM, Physiol Rev 89 121 (2009)) thus highlighting another
role for CNS-penetrant HDAC inhibitors. Although studies have shown that treatment with
non-specific HDAC inhibitors such as sodium butyrate can lead to long-term memory
formation (Stefanko DP et al, Proc Natl Acad Sci USA 106 9447 (2009)), little is known
about the role of specific isoforms. A limited number of studies have shown that, within class
I HDACs, main target of sodium butyrate, the prototypical inhibitor used in cognition studies,
HDAC2 (Guan J-S et al, Nature 459 55 (2009)) and HDAC3 (McQuown SC et al, J Neurosci
31 764 (2011)) have been shown to regulate memory processes and as such are interesting
targets for memory enhancement or extinction in memory-affecting conditions such as, but
not limited to, Alzheimer’s disease, post-traumatic stress disorder or drug addiction.
HDAC inhibitors may also be useful to treat infectious disease such as viral
infections. For example, treatment of HIV infected cells with HDAC inhibitors and anti-
retroviral drugs can eradicate virus from treated cells (Blazkova j et al J Infect Dis. 2012 Sep
1;206(5):765-9; Archin NM et al Nature 2012 Jul 25, 487(7408):482-5).
12354570_1 (GHMatters) P107928.NZ
SUMMARY
In one aspect, a compound of the formula (I) is featured:
R NH
wherein n = 0 or 1;
I. when n = 1, Z is R -X-Ar/Het wherein:
Ar/Het is:
(i) a 5 membered heteroaryl selected from the group consisting of pyrazolyl,
thiazolyl, oxazolyl, imidazolyl, thienyl, furanyl, isoxazolyl, isothiazolyl, thiadiazolyl,
oxadiazolyl, and 1,2,4-triazolyl (in some embodiments, the definition of Ar/Het can further
include 3,5-dimethylpyrazolyl); or
(ii) a bicyclic 8-, 9-, or 10-membered heteroaryl selected from the group
consisting of benzofuranyl, benzothienyl, benzothiazolyl, indolyl, indazolyl, quinolonyl,
naphtyridinyl, indolizinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl,
imidazopyridazinyl, triazolopyridinyl, imidazothiazolyl, imidazooxazolyl, triazolothiazolyl,
and triazolooxazolyl;
X is:
(i) –Y–[C(R ) ] –A–[C(R ) ] –B–; wherein
2 a 2 b
c d e
Y is bond, CR =CR , O, NR , or S(O) ;
each of A and B is, independently, a bond, O, NR , or S(O) ;
a is 1-3 (e.g., 1 or 2, e.g., 1);
b is 0-3 (e.g., 0, or other than 0, e.g., 1; or 2 or 3);
m is 0-2;
and R is independently selected from H, F, OH,
each occurrence of R
C1-C6 alkyl, C3-C6 cycloalkyl, NH , OCO-(C1-C6 alkyl), OCO-(C3-C6 cycloalkyl), C1-C6
alkoxy, C1-C6 fluoroalkoxy, and cyano; or
one or more of the following can apply with respect to R and R :
any two R , together with the carbons to which each is attached,
together form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the
heterocyclyl ring atoms is selected from O; S(O)m and NR ; in these embodiments, any
remaining occurrences of R and any occurrence of R are each independently defined
12354570_1 (GHMatters) P107928.NZ
according to any one or more of the preceding or following definitions pertaining to R and
R ; or
one R and one R , together with the carbons to which each is
attached, form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of
the heterocyclyl ring atoms is selected from O; S(O)m and NR ; in these embodiments, the
a b a b
other R , the other R , and any other remaining occurrences of R and R are each
independently defined according to any one or more of the preceding or following definitions
pertaining to R and R ; or
any two R , together with the carbons to which each is attached, form
C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the ring atoms is
selected from O; S(O)m and NR ; in these embodiments, each occurrence of R and any other
remaining occurrences of R are each independently defined according to any one or more of
the preceding or following definitions pertaining to R and R ;
each of R and R is, independently, selected from H, F, OH, C1-C6
alkyl, C3-C5 cycloalkyl, NH , OCO-(C1-C6 alkyl), OCO-(C3-C5 cycloalkyl), C1-C6 alkoxy,
C1-C6 fluoroalkoxy, and cyano;
or R and R , together with the carbons to which each is attached form
a C5-C7 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which from 1-2 of the
heterocyclyl ring atoms is/ are independently selected from O; S(O) and NR ;
e f g g’
each occurrence of R , R , R and R is independently selected from
h i h
H, C1-C6 alkyl, -C(=O)H, -C(=O)R , C(=O)O(C1-C6 alkyl), C(=O)N(R ) , SO -R , wherein
R is selected from C1-C6 alkyl, CH -(heteroaryl including 5-10 ring atoms), CH -(C6-C10
aryl), and C6-C10 aryl; and each occurrence of R is independently selected from H, C1-C6
alkyl, CH2-(heteroaryl including 5-10 ring atoms), CH2-(C6-C10 aryl), and C6-C10 aryl (in
embodiments, the aryl and heteroaryl portion in R and R can be optionally substituted, e.g.,
with one or more independently selected substituents such as F, C1-C6 alkyl, fluoro C1-C6
alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, or cyano);
further wherein:
(a) when each of A and B is a bond, and b is 0, then X has the
following formula: –Y–[C(R ) ] –;
(b) when b is 0 or 1 (e.g., 0), then A and B cannot both be heteroatoms
(i.e., as defined in O, NR , or S(O) ); and
(c) when A or B serves as the point of connection of X to Ar/Het, and
the Ar/Het is linked to X via a nitrogen ring atom in Ar/Het, then the A or B connector cannot
12354570_1 (GHMatters) P107928.NZ
be a heteroatom (i.e., as defined in O, NR , or S(O) );
or X is:
(ii) direct bond; or
j j k k k
(iii) C=O, C(R )2-C(=O), or C(=O)-C(R )2, SO2-NR , NR -SO2, C(=O)NR and
NR -C(=O); wherein:
each occurrence of R is independently selected from H, F, OH, C1-C6
alkyl, C3-C6 cycloalkyl, NH , OCO-(C1-C6 alkyl), OCO-(C3-C6 cycloalkyl), C1-C6 alkoxy,
C1-C6 fluoroalkoxy, and cyano;
or R -C-R together form C3-C6 cycloalkyl or heterocyclyl including
3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O)m and
NR ;
j’ k
each occurrence of R and R is independently selected from H, C1-
m n m
C6 alkyl, -C(=O)H, -C(=O)R , C(=O)O(C1-C6 alkyl), C(=O)N(R ) , and SO -R , wherein
R is selected from C1-C6 alkyl, CH2-heteroaryl, CH2-aryl, and aryl; and each occurrence of
R is independently selected from H, C1-C6 alkyl, CH -(heteroaryl including 5-10 ring
atoms), CH -(C6-C10 aryl), and C6-C10 aryl (in embodiments, the aryl and heteroaryl
portion in R and R can be optionally substituted, e.g., with one or more independently
selected substituents such as F, C1-C6 alkyl, fluoro C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6
alkoxy, C1-C6 fluoroalkoxy, or cyano);
each of R4 and R5 is, independently, selected from H, C1-C6 alkyl
and F;
R1 is:
(i) hydrogen; or
(ii) C6-C10 aryl, which is optionally substituted with from 1-3 R ; or
(iii) monocyclic or bicyclic heteroaryl including from 5-10 ring atoms, which
is optionally substituted with from 1-3 R ; wherein from 1-4 of the ring atoms is/are a
heteroatom independently selected from O, N, N-H, N-R , and S; or
(iv) heterocyclyl including from 4-10 ring atoms, which is optionally
substituted with from 1-3 R ; wherein from 1-4 of the ring atoms is/are a heteroatom
independently selected from O, N, N-H, N-R , and S;
(in some embodiments, R1 is other than H); and
each occurrence of R is independently selected from the group consisting of
(beginning with halogen and through and including nitro below):
• halogen;
12354570_1 (GHMatters) P107928.NZ
• C1-C6 alkyl; fluoro(C1-C6)alkyl;
• hydroxyl;
• hydroxy(C1-C4)alkyl;
• C1-C6 alkoxy; fluoro(C1-C6)alkoxy;
• (C1-C6 alkyl)C(O)-;
• (C1-C6 alkyl)NH-; (C1-C6 alkyl) N- (which includes, e.g., -NMe , -
NMe(iPr));
o’ o o
• -N*(R ) , wherein R ’-N*-R ’ together form a saturated ring having 5
or 6 ring atoms, in which 1 or 2 ring atoms (i.e., 1 or 2 ring atoms in addition to the N* ring
atom) is/are optionally a heteroatom independently selected from NH, N(alkyl), O, or S
) includes cyclic amino such as, e.g., pyrrolidinyl and morpholinyl);
(-N*(R 2
• formyl; formyl(C -C ) alkyl; cyano; cyano(C -C ) alkyl;
1 4 1 4
• benzyl; benzyloxy;
• heterocyclyl)-(C0-C6, e.g., C1-C6) alkyl, wherein the heterocyclyl
portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms is/are a heteroatom
independently selected from NH, N(alkyl), O, or S, and when said alkyl portion is present
(i.e., C1-C6), said alkyl portion serves as the point of attachment to R1 (i.e., the
(heterocyclyl)-(C1-C6) alkyl is connected to R1 via the alkyl portion); otherwise in the case
of C0 alkyl (i.e., no alkyl portion is present), a heterocyclyl carbon ring atom serves as the
point of attachment of the heterocyclyl to R1;
• phenyl or heteroaryl including from 5-6 ring atoms, wherein from 1-4
of the ring atoms is/are a heteroatom independently selected from O, N, N-H, N-R , and S,
each of which is optionally substituted with from 1-3 R ;
• SO -(C1-C6)alkyl; SO-(C1-C6)alkyl; and
• nitro;
• in embodiments, R can be any one (or more) of the substituents listed
above and/or R can be any one or more of the subsets of substituents listed above (such as
those bulleted above); e.g., R can be any one (or more) of the substituents that are present,
and/or any one (or more) of the substituents that encompass those that are present, in the
compounds described herein;
each occurrence of R is independently selected from the group consisting of (beginning
with halogen and through and including nitro below):
• halogen;
12354570_1 (GHMatters) P107928.NZ
• C1-C6 alkyl; fluoro(C1-C6)alkyl;
• hydroxyl;
• hydroxy(C1-C4)alkyl;
• C1-C6 alkoxy; fluoro(C1-C6)alkoxy;
• (C1-C6 alkyl)C(O)-;
• (C1-C6 alkyl)NH-; (C1-C6 alkyl) N- (which includes, e.g., -NMe2, -
NMe(iPr));
• - formyl; formyl(C -C ) alkyl; cyano; cyano(C -C ) alkyl;
1 4 1 4
• benzyl; benzyloxy;
• heterocyclyl)-(C0-C6, e.g., C1-C6) alkyl, wherein the heterocyclyl
portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms is/are a heteroatom
independently selected from NH, N(alkyl), O, or S, and when said alkyl portion is present
(i.e., C1-C6), said alkyl portion serves as the point of attachment to R1 (i.e., the
(heterocyclyl)-(C1-C6) alkyl is connected to R1 via the alkyl portion); otherwise in the case
of C0 alkyl (i.e., no alkyl portion is present), a heterocyclyl carbon ring atom serves as the
point of attachment of the heterocyclyl to R1;
• phenyl or heteroaryl including from 5-6 ring atoms, wherein from 1-4 of
the ring atoms is/are a heteroatom independently selected from O, N, N-H, N-(C1-C6 alkyl),
and S;
• SO -(C1-C6)alkyl; SO-(C1-C6)alkyl; and
• nitro;
• in embodiments, R can be any one (or more) of the substituents listed
above and/or R can be any one or more of the subsets of substituents listed above (such as
those bulleted above); e.g., R can be any one (or more) of the substituents that are present,
and/or any one (or more) of the substituents that encompass those that are present, in the
compounds described herein;
II. when n = 0, Z is R -V-Cy-U-Ar’/Het’ wherein:
Ar’/Het’ is:
(i) phenyl, pyridyl, or pyrimidinyl, each of which is optionally substituted with
from 1-3 R ; provided that the point of connection on said phenyl, pyridyl, or pyrimidinyl to
U (i.e., the connection U-Ar’/Het’ in formula I) and the point of connection on said phenyl,
pyridyl, or pyrimidinyl to the amide carbonyl (i.e., the connection Ar’/Het’-C(=O) in formula
I) do not result in 1,2-relation to one another on said phenyl, pyridyl, or pyrimidinyl (i.e., the
points of connection to U and C(O) on said phenyl, pyridyl, or pyrimidinyl are not ortho with
12354570_1 (GHMatters) P107928.NZ
respect to one another); wherein R at each occurrence is, independently, selected from H, F,
chloro, CH , CF , OCH , OCF , and OCHF ; or
3 3 3 3 2
(ii) a 5-membered heteroaryl selected from pyrazolyl, pyrrolyl, thiazolyl,
thienyl, furanyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl, each
of which is optionally substituted with from 1-3 R ; provided that the point of connection on
said 5-membered heteroaryls to U (i.e., the connection U-Ar’/Het’ in formula I) and the point
of connection on said 5-membered heteroaryls to the amide carbonyl (i.e., the connection
Ar’/Het’-C(=O) in formula I) do not result in 1,2-relation to one another on said 5-membered
heteroaryls (i.e., the points of connection to U and C(O) on said 5-membered heteroaryl are
not adjacent to one another); or
(iii) a 8-, 9- or 10-membered bicyclic heteroaryl selected from benzothienyl,
benzofuranyl, benzothioazolyl, benzoxazolyl, indolyl, isoindolonyl, indolizinyl,
pyrrolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyridazinyl,
triazolopyridinyl, imidazothiazolyl, imidazooxazolyl, quinolinyl, and naphthyridinyl; each of
which is optionally substituted with from 1-3 R ;
(in some embodiments, Ar’/Het’ is other than a 8-, 9- or 10-membered
bicyclic heteroaryl selected from benzothienyl, benzofuranyl, benzothioazolyl, benzoxazolyl,
indolyl, isoindolonyl, indolizinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl,
imidazopyridazinyl, triazolopyridinyl, imidazothiazolyl, imidazooxazolyl, quinolinyl, and
naphthyridinyl; each of which is optionally substituted with from 1-3 R ;);
R1 is:
(i) hydrogen; or
(ii) C6-C10 aryl, which is optionally substituted with from 1-3 R ; or
(iii) monocyclic or bicyclic heteroaryl including from 5-10 ring atoms, which
is optionally substituted with from 1-3 R ; wherein from 1-4 of the ring atoms is/are a
heteroatom independently selected from O, N, N-H, N-R , and S; or
(iv) heterocyclyl including from 4-10 ring atoms, which is optionally
substituted with from 1-3 R ; wherein from 1-4 of the ring atoms is/are a heteroatom
independently selected from O, N, N-H, N-R , and S; and
each occurrence of R is independently selected from the group consisting of
(beginning with halogen and through and including nitro below):
• halogen;
• C1-C6 alkyl; fluoro(C1-C6)alkyl;
• hydroxyl;
12354570_1 (GHMatters) P107928.NZ
• hydroxy(C -C )alkyl;
• C1-C6 alkoxy; fluoro(C1-C6)alkoxy;
• (C1-C6 alkyl)C(O)-;
• (C1-C6 alkyl)NH-; (C1-C6 alkyl) N- (which includes, e.g., -NMe , -
NMe(iPr));
q’ q q
• -N*(R ) , wherein R ’-N*-R ’ together form a saturated ring having 5 or
6 ring atoms, in which 1 or 2 ring atoms (i.e., 1 or 2 ring atoms in addition to the N* ring
atom) is/are optionally a heteroatom independently selected from NH, N(alkyl), O, or S (-
N*(R ) includes cyclic amino such as, e.g., pyrrolidinyl and morpholinyl);
• formyl; formyl(C -C ) alkyl; cyano; cyano(C -C ) alkyl;
1 4 1 4
• benzyl; benzyloxy;
• heterocyclyl)-(C0-C6, e.g., C1-C6) alkyl, wherein the heterocyclyl
portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms is/are a heteroatom
independently selected from NH, N(alkyl), O, or S, and when said alkyl portion is present
(i.e., C1-C6), said alkyl portion serves as the point of attachment to R1 (i.e., the
(heterocyclyl)-(C1-C6) alkyl is connected to R1 via the alkyl portion); otherwise in the case
of C0 alkyl (i.e., no alkyl portion is present), a heterocyclyl carbon ring atom serves as the
point of attachment of the heterocyclyl to R1;
• phenyl or heteroaryl including from 5-6 ring atoms, wherein from 1-4 of
the ring atoms is/are a heteroatom independently selected from O, N, N-H, N-R , and S,
each of which is optionally substituted with from 1-3 R ;
• SO -(C1-C6)alkyl; SO-(C1-C6)alkyl; and
• nitro;
• in embodiments, R can be any one (or more) of the substituents listed
above and/or R can be any one or more of the subsets of substituents listed above; e.g., R
can be any one (or more) of the substituents that are present, and/or any one (or more) of the
substituents that encompass those that are present, in the compounds described herein;
each occurrence of R is independently selected from the group consisting of
(beginning with halogen and through and including nitro below):
• halogen;
• C1-C6 alkyl; fluoro(C1-C6)alkyl;
• hydroxyl;
• hydroxy(C -C )alkyl;
12354570_1 (GHMatters) P107928.NZ
• C1-C6 alkoxy; fluoro(C1-C6)alkoxy;
• (C1-C6 alkyl)C(O)-;
• (C1-C6 alkyl)NH-; (C1-C6 alkyl)2N- (which includes, e.g., -NMe2, -
NMe(iPr));
• - formyl; formyl(C -C ) alkyl; cyano; cyano(C -C ) alkyl;
1 4 1 4
• benzyl; benzyloxy;
• heterocyclyl)-(C0-C6, e.g., C1-C6) alkyl, wherein the heterocyclyl
portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms is/are a heteroatom
independently selected from NH, N(alkyl), O, or S, and when said alkyl portion is present
(i.e., C1-C6), said alkyl portion serves as the point of attachment to R1 (i.e., the
(heterocyclyl)-(C1-C6) alkyl is connected to R1 via the alkyl portion); otherwise in the case
of C0 alkyl (i.e., no alkyl portion is present), a heterocyclyl carbon ring atom serves as the
point of attachment of the heterocyclyl to R1;
• phenyl or heteroaryl including from 5-6 ring atoms, wherein from 1-4 of
the ring atoms is/are a heteroatom independently selected from O, N, N-H, N-(C1-C6 alkyl),
and S;
• SO -(C1-C6)alkyl; SO-(C1-C6)alkyl; and
• nitro;
• in embodiments, R can be any one (or more) of the substituents listed
q’’ q’’
above and/or R can be any one or more of the subsets of substituents listed above; e.g., R
can be any one (or more) of the substituents that are present, and/or any one (or more) of the
substituents that encompass those that are present, in the compounds described herein;
U is selected from:
(i) =CR (for purposes of clarification, in these embodiments, the carbon atom
in =CR is doubly bonded to a ring atom (e.g., ring carbon atom) of Cy, thereby forming an
exocyclic double bond, see, e.g., compounds F1-F7); or
(ii) -U’-C(R ) - or -C(R ) -U’-; wherein
R is hydrogen, F, C1-C6 alkyl, fluoro C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6
alkoxy C1-C6 fluoroalkoxy, and cyano;
each occurrence of R is independently selected from H, F, OH, C1-C6 alkyl,
C3-C6 cycloalkyl, NH , OCO-(C1-C6 alkyl), OCO-(C3-C6 cycloalkyl), C1-C6 alkoxy C1-
C6 fluoroalkoxy, and cyano; or
R -C-R together form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring
atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O)m and NR ;
12354570_1 (GHMatters) P107928.NZ
each occurrence of R is independently selected from H, C1-C6 alkyl, -
v w v v
C(=O)H, -C(=O)R , C(=O)O(C1-C6 alkyl), C(=O)N(R ) , SO -R , wherein R is selected
from C1-C6 alkyl, CH -(heteroaryl including 5-10 ring atoms), CH -(C6-C10 aryl), and C6-
C10 aryl; and each occurrence of R is independently selected from H, C1-C6 alkyl, CH2-
(heteroaryl including 5-10 ring atoms), CH -(C6-C10 aryl), and C6-C10 aryl (e.g., in
embodiments, the aryl and heteroaryl portion in R and R can be optionally substituted, e.g.,
with one or more independently selected substituents such as F, C1-C6 alkyl, fluoro C1-C6
alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, or cyano);
U’ is a bond; O; NR ; S(O) (m = 0-2); CH ; and U’’-CH -; wherein U’’ is O;
m 2 2
NR ; S(O) (m = 0-2);
Cy is C4-C10 (e.g., C4-C8, C4-C6) cycloalkyl or saturated heterocyclyl including 4-10
(e.g., 4-8, 4-6) ring atoms, each of which is optionally substituted with from 1-3 R (wherein
each occurrence of R is independently selected from F, OH, C1-C6 alkyl, fluoro C1-C6
alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 fluoroalkoxy, and cyano), in which from 1-3
x’ x’ q’’
heteroatoms are independently selected from O, N-H, NR (wherein R is defined as R ),
and S(O)m (m = 0-2); wherein when the heterocyclyl contains a secondary amine as part of
its structure, then:
(i) V is linked through the nitrogen of the secondary amine portion of the
heterocyclyl; and
(ii) U is linked to Cy via a Cy ring carbon atom; wherein the bond between U
and the Cy ring carbon is a single or double bond; and
(iii) V-Cy and Cy-U do no lead to 1,2 relationship (i.e. the Cy ring carbon
atom that is attached to U is not adjacent to Cy ring nitrogen atom that is attached to V);
for purposes of clarification, the phrases “heterocyclyl contains a secondary
amine as part of its structure” and “heterocyclyl that contains a secondary amine as part of its
structure” as used herein, mean that the parent heterocycle includes as part of its structure a
ring nitrogen atom of the following formula: ; in which the bonds intersected by
the wavy lines indicate bonds between the nitrogen atom and other ring atoms in the parent
heterocycle (the above-shown portion of the parent heterocycle is sometimes referred to
herein as the “secondary amine” portion); other additional heteroatoms (including nitrogens,
including other secondary amine nitrogens) can also be present in such a parent heterocycle,
however, when one (or more) secondary amine(s) is(are) present in the parent heterocycle, it
12354570_1 (GHMatters) P107928.NZ
is the (or one of the) secondary amine nitrogen atom(s) that serves as the point of attachment
of that heterocycle to variable V (i.e., V replaces the H of the N-H in the parent heterocycle;
see, e.g., compounds F1-F7); examples of such parent heterocycles include, without
limitation, azetidine, pyrrolidine, piperidine, azepane, diazepane, isoxazolidine,
thiazolidinone, imidazolidinone, pyrrolidinone, azabicyclooctane (aka. tropane),
azabicycloheptane, azabicyclohexane; accordingly, examples of heterocyclyl that contains a
secondary amine as part of its structure include, without limitation, azetidinyl, pyrrolidinyl,
piperidinyl, azepanyl, diazepanyl, isoxazolidinyl, thiazolidinonyl, imidazolidinonyl,
pyrrolidinonyl, azabicyclooctanyl (aka. tropanyl), azabicycloheptanyl, azabicyclohexanyl;
V is selected from:
) - or -C(R ) -V’-; or
(i) -V’-C(R 2 2
(ii) O, NR , or S(O)m (m = 0-2); or
y y t z
(iii) -CH=CH-, C=O, C(R ) -C(=O), -C(=O)-C(R ) -, -SO NRz , NR SO , -
2 2 2 2
C(=O)NR , and NR C(=O); wherein:
each occurrence of R is independently selected from H, F, OH, C1-C6 alkyl,
C3-C6 cycloalkyl, NH , OCO-(C1-C6 alkyl), OCO-(C3-C6 cycloalkyl), C1-C6 alkoxy C1-
C6 fluoroalkoxy, and cyano; or
R -C-R together form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring
atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O)m and NR ;
z aa
each occurrence of R and R is independently selected from H, C1-C6 alkyl,
v w v
-C(=O)H, -C(=O)R , C(=O)O(C1-C6 alkyl), C(=O)N(R ) , SO -R , wherein R is selected
from C1-C6 alkyl, CH -(heteroaryl including 5-10 ring atoms), CH -(C6-C10 aryl), and C6-
C10 aryl; and each occurrence of R is independently selected from H, C1-C6 alkyl, CH -
(heteroaryl including 5-10 ring atoms), CH2-(C6-C10 aryl), and C6-C10 aryl;
V’ is a bond; O; NR ; S(O) (m = 0-2); -C(O)-O-(CR ) -,
m 2 0-2
y y y y y y
-(CR ) -O-C(O)-, C(R ) , C(R ) -C(R ) ; -(R ) -V’’; and V’’-C(R ) -; wherein V’’ is O;
2 0-2 2 2 2 2 2
NR ; S(O) (m = 0-2); wherein each occurrence of R is independently defined as above;
(in some embodiments, V’ is a bond; O; NR ; S(O)m (m = 0-2); -C(O)-O-
(CH ) -, -(CH ) -O-C(O)-, CH ; -CH -V’’; and V’’-CH -; wherein V’’ is O; NR ; S(O)m
2 0-2 2 0-2 2 2 2
(m = 0-2));
R2 is selected from H, F, Cl, CF , CF CF , CH CF , OCF , OCHF , phenyl; substituted
3 2 3 2 3 3 2
phenyl (e.g., phenyl substituted with from 1-3 substituents independently selected from F,
OH, C1-C6 alkyl, fluoro(C1-C6) alkyl C3-C6 cycloalkyl, NH , C1-C6 alkoxy, C1-C6
fluoroalkoxy, and cyano); thienyl; thiazolyl; and pyrazolyl; and
12354570_1 (GHMatters) P107928.NZ
R3 is H, F, or Cl;
or a salt (e.g., a pharmaceutically acceptable salt) thereof.
In another aspect, a compound of the formula (I) is featured, in which n = 1, and
each of the attendant definitions associated with n =1 (as well as R2 and R3) can be as
defined anywhere herein (in some embodiments, the definition of Ar/Het can further include
3,5-dimethylpyrazolyl).
In another aspect, a compound of the formula (I) is featured, in which n = 0, and
each of the attendant definitions associated with n =0 (as well as R2 and R3) can be as
defined anywhere herein.
In one aspect, the present invention provides a compound of formula (II), or a
pharmaceutically acceptable salt thereof:
(II),
wherein R is H or F; R is H, Cl, or F; Het is piperidinyl, and the ring nitrogen is substituted
with R ; and R is C1-C6alkyl, C1-C6hydroxyalkyl, or C1-C3alkylene-C3-C6cycloalkyl.
In a further aspect, the formula (I) compounds specifically described herein (or a
salt, e.g., a pharmaceutically acceptable salt thereof) are featured (e.g., compounds A1-A12,
B1-B6, C1-C3, D1-D16, E1, E2, F1-F7, F8-F20, G1 and G2).
In one aspect, a composition (e.g., a pharmaceutical composition) is featured, which
includes a compound of formula (I) (e.g., formula (II)) or a salt (e.g., a pharmaceutically
acceptable salt) thereof as defined anywhere herein and a pharmaceutically acceptable carrier.
In some embodiments, the composition can include an effective amount of the compound or
salt. In some embodiments, the composition can further include an additional therapeutic
agent.
In another aspect, a dosage form is featured, which includes from about 0.05
milligrams to about 2,000 milligrams (e.g., from about 0.1 milligrams to about 1,000
milligrams, from about 0.1 milligrams to about 500 milligrams, from about 0.1 milligrams to
about 250 milligrams, from about 0.1 milligrams to about 100 milligrams, from about 0.1
milligrams to about 50 milligrams, or from about 0.1 milligrams to about 25 milligrams) of a
12354570_1 (GHMatters) P107928.NZ
compound of formula (I) (e.g., formula (II)) or a salt (e.g., a pharmaceutically acceptable salt)
thereof as defined anywhere herein. The dosage form can further include a pharmaceutically
acceptable carrier and/or an additional therapeutic agent.
Provided herein are methods of inhibiting one (or more) HDACs (e.g., HDAC1 or
HDAC2; e.g., HDAC3) or more than one HDAC (e.g., HDAC1 and HDAC2; e.g., HDAC1
and HDAC3; e.g., HDAC2 or HDAC3; e.g., HDAC1, HDAC2, and HDAC 3) with a
compound of formula (I) (e.g., formula (II)) or a salt (e.g., a pharmaceutically acceptable salt)
thereof as defined anywhere herein. In some embodiments, the methods can include, e.g.,
contacting one (or more) HDACs (e.g., HDAC1 or HDAC2; e.g., HDAC3) in a sample (e.g.,
a cell or tissue) with a compound of formula (I) (e.g., formula (II)) or a salt (e.g., a
pharmaceutically acceptable salt) thereof as defined anywhere herein. In other embodiments,
the methods can include administering a compound of formula (I) (e.g., formula (II)) or a salt
(e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein to a subject
(e.g., a mammal, such as a human). Accordingly, in yet another aspect, provided are methods
of screening for compounds that inhibit (e.g., selectively inhibit) one or more HDACs (e.g.,
HDAC1 or HDAC2; e.g., HDAC3, e.g., HDAC1 and HDAC2; e.g., HDAC1 and HDAC3;
e.g., HDAC2 or HDAC3; e.g., HDAC1, HDAC2, and HDAC 3).
In one aspect, a method of selectively inhibiting HDAC3 is featured, which
includes contacting an HDAC3 in a sample (e.g., a cell or tissue) with a compound of
formula (I) (e.g., formula (II)) or a salt (e.g., a pharmaceutically acceptable salt) thereof as
defined anywhere herein; or administering a compound of formula (I) (e.g., formula (II)) or a
salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein to a subject
(e.g., a mammal, such as a human).
In one aspect, a method of selectively inhibiting HDAC1 or HDAC2 (e.g., HDAC1)
is featured, which includes contacting HDAC1 or HDAC2 (e.g., HDAC1) in a sample (e.g., a
cell or tissue) with a compound of formula (I) (e.g., formula (II)) or a salt (e.g., a
pharmaceutically acceptable salt) thereof as defined anywhere herein; or administering a
compound of formula (I) (e.g., formula (II)) or a salt (e.g., a pharmaceutically acceptable salt)
thereof as defined anywhere herein to a subject (e.g., a mammal, such as a human).
In one aspect, a method of selectively inhibiting HDAC1, HDAC2, and HDAC3 is
featured, which includes contacting HDAC1, HDAC2, and HDAC3 in one or more samples
(e.g., a cell or tissue) with a compound of formula (I) (e.g., formula (II)) or a salt (e.g., a
pharmaceutically acceptable salt) thereof as defined anywhere herein; or administering a
12354570_1 (GHMatters) P107928.NZ
compound of formula (I) (e.g., formula (II)) or a salt (e.g., a pharmaceutically acceptable salt)
thereof as defined anywhere herein to a subject (e.g., a mammal, such as a human).
In one aspect, methods of treating (e.g., controlling, relieving, ameliorating,
alleviating, or slowing the progression of) or methods for preventing (e.g., delaying the onset
of or reducing the risk of developing) a disease or disorder mediated by HDAC1 or HDAC2
in a subject (e.g., a mammal, such as a human) in need thereof are featured, which include
administering a compound of formula (I) (e.g., formula (II)) or a salt (e.g., a pharmaceutically
acceptable salt) thereof as defined anywhere herein to the subject.
In one aspect, methods of treating (e.g., controlling, relieving, ameliorating,
alleviating, or slowing the progression of) or methods for preventing (e.g., delaying the onset
of or reducing the risk of developing) a disease or disorder mediated by HDAC3 in a subject
(e.g., a mammal, such as a human) in need thereof are featured, which include administering
a compound of formula (I) (e.g., formula (II)) or a salt (e.g., a pharmaceutically acceptable
salt) thereof as defined anywhere herein to the subject.
In one aspect, methods of treating (e.g., controlling, relieving, ameliorating,
alleviating, or slowing the progression of) or methods for preventing (e.g., delaying the onset
of or reducing the risk of developing) a disease or disorder mediated by two or more HDACs
(e.g., HDAC1 and HDAC2; e.g., HDAC1 and HDAC3; e.g., HDAC2 or HDAC3; e.g.,
HDAC1, HDAC2, and HDAC 3) in a subject (e.g., a mammal, such as a human) in need
thereof are featured, which include administering a compound of formula (I) (e.g., formula
(II)) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein to
the subject.
In one aspect, featured are methods of treating (e.g., controlling, relieving,
ameliorating, alleviating, or slowing the progression of) or methods for preventing (e.g.,
delaying the onset of or reducing the risk of developing) a neurological disorder such as
Friedreich’s ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome,
Huntington’s disease, spinocerebellar ataxia, Kennedy’s disease, amyotrophic lateral
sclerosis, spinal and bulbar muscular atrophy, and Alzheimer’s disease; a cancer (e.g.
cutaneous T cell lymphoma, B cell lymphomas, and colorectal cancer); an inflammatory
disease (e.g.,psoriasis, rheumatoid arthritis, and osteoarthritis); a memory impairment
condition; post-traumatic stress disorder; a drug addiction; a Plasmodium falciparum
infection (e.g., malaria) as well as other parasite infections in a subject (e.g., a mammal, such
as a human) in need thereof, which include administering a compound of formula (I) (e.g.,
12354570_1 (GHMatters) P107928.NZ
formula (II)) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere
herein to the subject.
In one aspect, a compound of formula (I) (e.g., formula (II)) or a salt (e.g., a
pharmaceutically acceptable salt) thereof as defined anywhere herein for use in medicine is
featured.
In one aspect, featured is a compound of formula (I) (e.g., formula (II)) or a salt
(e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein for the treatment
of: a disease or disorder mediated by HDAC1 or HDAC2; a disease or disorder mediated by
HDAC3; A disease or disorder mediated by HDAC3 and HDAC1 or HDAC2; A disease or
disorder mediated by HDAC1 and HDAC2 and HDAC3; a neurological disorder such as
Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome,
Huntington's disease, spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis,
spinal and bulbar muscular atrophy, and Alzheimer's disease; a cancer (e.g. cutaneous T cell
lymphoma, B cell lymphomas, and colorectal cancer); an inflammatory disease
(e.g.,psoriasis, rheumatoid arthritis, and osteoarthritis); a memory impairment condition;
post-traumatic stress disorder; a drug addiction; a Plasmodium falciparum infection (e.g.,
malaria) as well as other parasite infections.
In one aspect, featured is a use of a compound of formula (I) (e.g., formula (II)) or a
salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein, in the
preparation of a medicament for the treatment of: a disease or disorder mediated by HDAC1
or HDAC2; a disease or disorder mediated by HDAC3; A disease or disorder mediated by
HDAC3 and HDAC1 or HDAC2; A disease or disorder mediated by HDAC1 and HDAC2
and HDAC3; a neurological disorder such as Friedreich's ataxia, myotonic dystrophy, spinal
muscular atrophy, fragile X syndrome, Huntington's disease, spinocerebellar ataxia,
Kennedy's disease, amyotrophic lateral sclerosis, Niemann Pick disease, Pitt Hopkins disease,
spinal and bulbar muscular atrophy, and Alzheimer's disease; a cancer (e.g. cutaneous T cell
lymphoma, B cell lymphomas, and colorectal cancer); an inflammatory disease
(e.g.,psoriasis, rheumatoid arthritis, and osteoarthritis); a memory impairment condition;
post-traumatic stress disorder; a drug addiction; an infectious disease such as HIV; a
Plasmodium falciparum infection (e.g., malaria) as well as other parasite infections.
In some embodiments, the subject can be a subject in need thereof (e.g., a subject
identified as being in need of such treatment, such as a subject having, or at risk of having,
one or more of the diseases or conditions described herein). Identifying a subject in need of
12354570_1 (GHMatters) P107928.NZ
such treatment can be in the judgment of a subject or a health care professional and can be
subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method). In
some embodiments, the subject can be a mammal. In certain embodiments, the subject can
be a human.
In one aspect, methods of making compounds described herein are featured. In
embodiments, the methods include taking any one of the intermediate compounds described
herein and reacting it with one or more chemical reagents in one or more steps to produce a
compound of formula (I) (e.g., formula (II)) or a salt (e.g., a pharmaceutically acceptable salt)
thereof as defined anywhere herein.
Some of the formula (I) (e.g., formula (II)) compounds described herein have
enhanced (e.g., increased, e.g., increased by a factor of about 2 or more) stabilities in acid. In
some embodiments, the formula (I) (e.g., formula (II)) compounds have enhanced resistances
to degradation, e.g., less than about 25% degradation (e.g., less than about 20% degradation,
less than about 15% degradation, or less than about 10% degradation) when exposed to acidic
pH, e.g., acidic conditions intended to mimic those in the stomach, e.g., incubation (e.g., as
a10 µM solution) at 50ºC and at a pH of about 2.0 for about four hours. The resistance of
compounds to degradation or metabolism at acidic pH can be a useful feature for a
pharmaceutical agent (e.g., a drug). Increased stability at low pH can allow, for example,
process preparation steps, such as salt formation, to occur without significant degradation of
the desired salt. In addition, it is preferable that orally administered pharmaceuticals are
stable to the acidic pH of the stomach. In some embodiments, compounds display enhanced
stability when exposed to acidic pH with stability half-lives greater than e.g. 12h or e.g. 18h
or e.g. 24h at pH 2 and 50°C.
In some embodiments, the formula (I) (e.g., formula (II)) compounds described
herein selectively inhibit HDAC3, e.g., selectively inhibit HDAC3 over HDAC1 and HDAC2
(e.g exhibiting 5-fold or greater selectivity, e.g. exhibiting 25-fold or greater selectivity).
While not wishing to be bound by theory, it is believed that HDAC3-selective inhibitors can
increase expression of frataxin, and could therefore be useful in the treatment of neurological
conditions (e.g., neurological conditions associated with reduced frataxin expression, such as
Friedreich’s ataxia). It is also believed that HDAC3 inhibition plays an important role in
memory consolidation (McQuown SC et al, J Neurosci 31 764 (2011)). Selective inhibitors
of HDAC3 could provide advantages for treatment of neurological conditions over the use of
broad-spectrum HDAC inhibitors by reducing toxicities associated with inhibition of other
12354570_1 (GHMatters) P107928.NZ
HDACs. Such specific HDAC3 inhibitors would provide a higher therapeutic index,
resulting in better tolerance by patients during chronic or long-term treatment.
In some further embodiments, compounds selectively inhibit HDAC1 and/or
HDAC2 (e.g exhibiting 5-fold or greater selectivity, e.g. exhibiting 25-fold or greater
selectivity). Inhibition of HDAC1 and/or 2 can be useful in treating cancer, or another
disease as disclosed herein.
In some embodiments, the formula (I) (e.g., formula (II)) compounds described
herein inhibit HDAC1, HDAC2 and HDAC3. While not wishing to be bound by theory, it is
believed that HDAC3-selective inhibitors can increase expression of frataxin, and could
therefore be useful in the treatment of neurological conditions (e.g., neurological conditions
associated with reduced frataxin expression, such as Friedreich’s ataxia) and in neurons
derived from induced pluripotent stem cells generated from Friedreich’s ataxia patient cell
line.
In some embodiments, the formula (I) (e.g., formula (II)) compounds described
herein have been shown to inhibit class I histone deacetylases and this inhibition has resulted
in an in vitro increased frataxin mRNA expression in Friedreich’s ataxia patient peripheral
blood mononuclear cells (PBMCs). In other embodiments compounds disclosed herein have
been shown to inhibit in vitro proliferation of colorectal cancer cells in a dose-dependent
fashion. In further embodiments compounds disclosed herein have been demonstrated to
increase long term memory in vivo using the novel object recognition paradigm.
In some embodiments, the formula (I) (e.g., formula (II)) compounds described
herein exhibit enhanced brain penetration. For example, brain/plasma ratios of greater than
about 0.25 (e.g., greater than about 0.50, greater than about 1.0, greater than about 1.5, or
greater than about 2.0) are observed when mice are dosed with some of the formula (I) (e.g.,
formula (II)) compounds described herein. Such compounds are therefore expected to be
particularly suitable for therapies targeting the brain (e.g., neurological conditions such as
Friedreich’s ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome,
Huntington’s disease, spinocerebellar ataxia, Kennedy’s disease, amyotrophic lateral
sclerosis, spinal and bulbar muscular atrophy, and Alzheimer’s disease; a memory
impairment condition; post-traumatic stress disorder; a drug addiction).
In some embodiments, the formula (I) (e.g., formula (II)) compounds described
herein selectively inhibit HDAC3, e.g., selectively inhibit HDAC3 over HDAC1 and HDAC2
12354570_1 (GHMatters) P107928.NZ
(e.g exhibiting 5-fold or greater selectivity, e.g. exhibiting 25-fold or greater selectivity) and
exhibit enhanced brain penetration (e.g., as described above).
In some embodiments, the formula (I) (e.g., formula (II)) compounds described
herein selectively inhibit HDAC1 and/or HDAC2, e.g., selectively inhibit HDAC1 and/or
HDAC2 over HDAC3 (e.g exhibiting 5-fold or greater selectivity, e.g. exhibiting 25-fold or
greater selectivity) and exhibit enhanced brain penetration (e.g., as described above).
Embodiments can include one or more of the following features.
[I] n is 1 (i.e., in which Z is R -X-Ar/Het). Embodiments in which n is 1 can
include one or more of the following features described throughout sections [A] through [F]
below.
[A] Variable X
[1] In some embodiments, X is –Y–[C(R ) ] –A–[C(R ) ] –B–. Embodiments
2 a 2 b
can also include one or more of the features described in [a] – [d] below.
A is a bond and/or B is a bond (in some embodiments, each of A and B is a bond;
or one of A and B (e.g., B) is a bond, and the other of A and B (e.g., A) is other than a bond,
e.g., O or NR , e.g., O; in embodiments, each of A and B is other than S(O) ).
Each occurrence of R and R (when present) is independently selected from H, F,
OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH , OCO-(C1-C6 alkyl), OCO-(C3-C6 cycloalkyl),
C1-C6 alkoxy C1-C6 fluoroalkoxy, and cyano.
and R (when present) is independently selected from H, F,
Each occurrence of R
C1-C6 alkyl, and C3-C6 cycloalkyl.
Each occurrence of R and R (when present) is H.
One or more (e.g., one) of the following apply:
any two R , together with the carbons to which each is attached, together form C3-C6
cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring
atoms is selected from O; S(O) and NR ; in these embodiments, any remaining occurrences
of R and any occurrence of R are each independently defined according to any one or more
of the preceding or following definitions pertaining to R and R ; or
one R and one R , together with the carbons to which each is attached, form C3-C6
cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring
12354570_1 (GHMatters) P107928.NZ
g a b
atoms is selected from O; S(O) and NR ; in these embodiments, the other R , the other R ,
and any other remaining occurrences of R and R are each independently defined according
to any one or more of the preceding or following definitions pertaining to R and R ; or
any two R , together with the carbons to which each is attached, form C3-C6
cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the ring atoms is
selected from O; S(O) and NR ; in these embodiments, each occurrence of R and any other
remaining occurrences of R are each independently defined according to any one or more of
the preceding definitions pertaining to R and R .
In some embodiments, Y is CR =CR (in some embodiments, the double bond
between CR and CR has the trans configuration; in other embodiments, the double bond
between CR and CR has the cis configuration). Embodiments can include one or more of
the following features.
The double bond between CR and CR has the trans configuration. Each of R and
R is, independently, selected from H, F, OH, C1-C6 alkyl, C3-C5 cycloalkyl, NH , OCO-
(C1-C6 alkyl), OCO-(C3-C5 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano. In
certain embodiments, each of R and R is H.
A is a bond and/or B is a bond (in some embodiments, each of A and B is a bond).
a b a
Each of R and R can be as defined anywhere herein (see, for example, the R and
R features described above in section [I][A][1][a]).
a is 1 or 2 (e.g., 1). b is 0 or 1 (e.g., 0).
a is 1 or 2, e.g., 1; and b is 0 or 1, e.g., 0 (in further embodiments, each of A and B
is also a bond.
b is 0 (in embodiments, a is 1 or 2, e.g., 1; in further embodiments, each of A and B
is also a bond).
X is –CH=CH-C(R ) -. In certain embodiments, each R is hydrogen. In other
embodiments, each R is a substituent other than hydrogen (e.g., C1-C6 alkyl), and each R
can be the same or different, e.g., the same. For example, each R can be the same C1-C6
alkyl, such as CH .
X is –CH=CH-CH(R )-. In certain embodiments, R is hydrogen; in other
embodiments, R is a substituent other than hydrogen (e.g., as described above).
12354570_1 (GHMatters) P107928.NZ
a a a
X is –CH=CH-C(R ) -C(R ) . In certain embodiments, each R is hydrogen. In
other embodiments, each R is a substituent other than hydrogen (e.g., C1-C6 alkyl), and each
R can be the same or different, e.g., the same. For example, each R can be the same C1-C6
alkyl, such as CH3. In still other embodiments, in one germinal pair of R ’s, each R is
hydrogen; and in the other germinal pair of R ’s, each R is a substituent other than hydrogen
(e.g., as described above).
a a a
X is –CH=CHCH(R )CH(R ). In certain embodiments, each R is hydrogen; in
other embodiments, each R is a substituent other than hydrogen; in still other embodiments,
one R is hydrogen, and the other is a substituent other than hydrogen.
For example, X is –CH=CH-CH - or –CH=CH-CH -CH - (e.g., in the foregoing
2 2 2
embodiments, the double bond can have the trans configuration; and further each of A and B
can be a bond). In certain embodiments, X is –CH=CH-CH - (e.g., trans).
In some embodiments, Y is O, NR , or S(O)m; e.g., Y is O or NR . Embodiments
can include one or more of the following features.
Y is O.
Y is NR (e.g., R is C1-C6 alkyl).
A is a bond and/or B is a bond (in some embodiments, each of A and B is a bond).
a b a
Each of R and R can be as defined anywhere herein (see, for example, the R and
R features described above in section [I][A][1][a]).
a is 2 or 3 (e.g., 2) and b is optionally other than 0 (e.g., 1 or 2); in embodiments, A
is a bond; or A is other than a bond, e.g., O or NR , e.g., O; and B is a bond. Some examples
are provided below:
a is 2 or 3 (e.g., 2), b is 0; and each of A and B is a bond.
a is 2 or 3 (e.g., 2), b is other than 0 (e.g., 1 or 2), and each of A and B is a bond.
a is 2 or 3 (e.g., 2), b is other than 0 (e.g., 2 or 3), A is other than a bond, e.g., O or
NR , e.g., O, and B is a bond.
For example, X is -O-(CH ) or -N(CH )-(CH ) .
2 2-3(e.g., 2) 3 2 2-3(e.g., 2)
In some embodiments, Y is a bond. Embodiments can include one or more of the
following features.
12354570_1 (GHMatters) P107928.NZ
A is a bond, O, or NR (e.g., A is a bond or O, e.g., A is a bond) and/or B is a bond.
In certain embodiments, A is a bond and B is a bond.
a b a
Each of R and R can be as defined anywhere herein (see, for example, the R and
R features described above in section [I][A][1][a]).
b is 0 (in embodiments, a can be 1, 2, or 3 (e.g., 1) and one or more of the following
can apply: A is a bond, A is other than a bond, such as O; B is a bond, each of R is H; e.g., A
is a bond, a is 1, B is a bond; e.g., X is CH ).
b is 1, 2, or 3 (in embodiments, a can be 1, 2, or 3 and one or more of the following
can apply: A is a bond, A is other than a bond, such as O; B is a bond, each of R is H, each
of R is H). In certain of these embodiments, X has a span of not more than 4 atoms.
[2] In some embodiments, X is a bond.
[B] Variables R4 and R5
In some embodiments, each of R4 and R5 is H.
[C] Variable Ar/Het
In some embodiments, Ar/Het is 5 membered heteroaromatic chosen from
pyrazolyl, thiazolyl, oxazolyl, imidazolyl, thienyl, furanyl, isoxazolyl, isothiazolyl,
thiadiazolyl, oxadiazolyl, and 1,2,4-triazolyl (in some embodiments, the definition of Ar/Het
can further include 3,5-dimethylpyrazolyl); or a bicyclic 8-, 9-, or 10-membered
heteroaromatic chosen from benzofuranyl, benzothienyl, benzothiazolyl, indolyl, indazolyl,
quinolonyl, and naphtyridinyl (in some embodiments, Ar/Het is other than furanyl and 1,2,4-
triazolyl. In certain embodiments, Ar/Het is other than furanyl; in certain embodiments,
Ar/Het is other than1,2,4-triazolyl).
In some embodiments, Ar/Het is 5 membered heteroaromatic selected from
pyrazolyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl,
and 1,2,4-triazolyl (in some embodiments, Ar/Het is other than furanyl and 1,2,4-triazolyl. In
certain embodiments, Ar/Het is other than furanyl; in certain embodiments, Ar/Het is other
than1,2,4-triazolyl). In certain embodiments, Ar/Het is pyrazolyl. In some embodiments, the
definition of Ar/Het can further include 3,5-dimethylpyrazolyl.
12354570_1 (GHMatters) P107928.NZ
In some embodiments, Ar/Het is other than furanyl and 1,2,4-triazolyl. In certain
embodiments, Ar/Het is other than furanyl. In certain embodiments, Ar/Het is other
than1,2,4-triazolyl.
In some embodiments, Ar/Het is a bicyclic 8-, 9-, or 10-membered heteroaryl
selected from the group consisting of benzofuranyl, benzothienyl, benzothiazolyl, indolyl,
indazolyl, quinolonyl, naphtyridinyl, indolizinyl, pyrrolopyrimidinyl, pyrazolopyridinyl,
imidazopyridinyl, imidazopyridazinyl, triazolopyridinyl, imidazothiazolyl, imidazooxazolyl,
triazolothiazolyl, and triazolooxazolyl.
In some embodiments, Ar/Het is a bicyclic 8-, 9-, or 10-membered azabridged
heteroaromatic such as indolizinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl,
imidazopyridazinyl, triazolopyridinyl, imidazothiazolyl, imidazooxazolyl, 1,2,4-
triazolothiazolyl, and 1,2,4- triazolooxazolyl.
[D] Variable R1
In some embodiments, R1 is C6-C10 aryl, which is optionally substituted with from
1-3 Ro. In certain embodiments, R1 is phenyl or naphthyl (e.g., phenyl), which is optionally
substituted with from 1-3 R (in embodiments, each Ro is independently selected from F,
OH, C1-C6 alkyl, fluoro(C1-C6) alkyl C3-C6 cycloalkyl, NH2, C1-C6 alkoxy, C1-C6
fluoroalkoxy, and cyano).
In other embodiments, R1 is C8-C10 aryl, which contains a phenyl ring fused to a
non-aromatic ring and which is optionally substituted with from 1-3 R (e.g., optionally
substituted indanyl or tetralinyl).
In some embodiments, R1 is monocyclic or bicyclic heteroaryl including from 5-10
ring atoms, which is optionally substituted with from 1-3 R ; wherein from 1-4 of the ring
atoms is/are a heteroatom independently selected from O, N, N-H, N-Ro, and S.
In certain embodiments, R1 is monocyclic heteroaryl, such as pyridyl.
In other embodiments, R1 is bicyclic heteroaryl, such as those that are fully
aromatic such as indolyl and the like.
12354570_1 (GHMatters) P107928.NZ
In still other embodiments, R1 is bicyclic heteroaryl that contains a bridgehead
nitrogen ring atom and optionally other heteroatom ring atoms, such as indolizinyl,
pyrrolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyriazinyl,
triazolopyridinyl, imidazothiazolyl, imidazooxazolyl.
Other examples of R1 heteroaryl groups include, without limitation, pyrazolyl,
pyrrolyl, 2-oxo-indolyl, quinolinyl, isoquinolinyl, tetrahydro-isoquinolinyl, benzofuranyl,
benzodioxanyl, benzodioxolyl (aka. methylenedioxyphenyl) and corresponding difluoro
(CF2) analog, thiazolyl, 2-oxopyridinyl, pyridinyl N-oxide, pyrimidinyl, thienyl, furanyl,
oxazolyl, isoxazolyl, pyridazinyl, imidazolyl, pyrazinyl, isothiazolyl, 1,2-thiazinyl-1,1-
dioxide, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzotriazolyl,
benzoxazolyl, benzothienyl, oxadiazolyl, triazolyl, tetrazolyl, dioxoindolyl (isatin),
phthalimido, , and the dihydro and tetrahydro congeners of the fully unsaturated ring systems.
In some embodiments, R1 is heterocyclyl including from 4-10 ring atoms, which is
optionally substituted with from 1-3 R ; wherein from 1-4 of the ring atoms is/are a
heteroatom independently selected from O, N, N-H, N-R , and S (e.g., bicyclic heterocyclyl
containing a bridgehead nitrogen ring atom and optionally other heteroatom ring atoms).
Examples of R1 heterocyclyl groups include, without limitation, piperidinyl,
morpholinyl, pyrrolidinyl, azetidinyl, azepanyl, isoxazolidinyl, oxazolidinyl , thiazolidinyl,
imidazolinyl, quinuclidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl,
thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxanyl, tropanyl and
other bridged bicyclic amines, quiniclidinyl.
In some embodiments, R1 is H.
[E] Variables R2 and R3
In some embodiments, R2 is a substituent other than hydrogen (e.g., phenyl,
substituted phenyl, thienyl, thiazolyl, and pyrazolyl), and R3 is hydrogen. In certain
embodiments, the compounds can exhibit selectivity for HDAC 1 and/or 2.
12354570_1 (GHMatters) P107928.NZ
In some embodiments, R2 is hydrogen, and R3 is a substituent other than hydrogen
(e.g., fluoro). In certain embodiments, the compounds can exhibit selectivity for HDAC 3.
In some embodiments, each of R2 and R3 is hydrogen.
[F] Non-Limiting Combinations of [I][A] through [I][E] (i.e., n = 1)
In some embodiments, one or more of the features described in one or more of
[A][1][a], [A][1][b], [A][1][c], and [A][1][d] can be combined with: the features described
in [B], and/or one or more of the features described in one or both of [C][1] and [C][2],
and/or one or more of the features described in one or more of [D][1], [D][2], [D][3], and
[D][4], and/or one or more of the features described in one or more of [E][1], [E][2], and
[E][3].
In some embodiments, one or more of the features described in one or more of
[A][1][a], [A][1][b], [A][1][c], and [A][1][d] can be combined with: the features described
in [B], and one or more of the features described in one or both of [C][1] and [C][2], and one
or more of the features described in one or more of [D][1], [D][2], [D][3], and [D][4], and
one or more of the features described in one or more of [E][1], [E][2], and [E][3].
In some embodiments, one or more of the features described in one or more of
[A][1][a], [A][1][b], [A][1][c], and [A][1][d] can be combined with: the features described
in [B], and one or more of the features described in [C][1], and one or more of the features
described in one or more of [D][1], [D][2], [D][3], and [D][4], and one or more of the
features described in one or more of [E][1], [E][2], and [E][3].
In some embodiments, one or more of the features described in one or more of
[A][1][a], [A][1][b], [A][1][c], and [A][1][d] can be combined with: the features described
in [B], and one or more of the features described in one or both of [C][1] and [C][2], and one
or more of the features described in one or both of [D][1] and [D][4] (e.g., [D][1]), and one
or more of the features described in one or more of [E][1], [E][2], and [E][3].
In some embodiments, one or more of the features described in one or more of
[A][1][a], [A][1][b], [A][1][c], and [A][1][d] can be combined with: the features described
in [B], and one or more of the features described in [C][1], and one or more of the features
described in one or both of [D][1] and [D][4] (e.g., [D][1]), and one or more of the features
described in one or more of [E][1], [E][2], and [E][3].
12354570_1 (GHMatters) P107928.NZ
In some embodiments, one or more of the features described in [A][1][b] can be
combined with: the features described in [B], and one or more of the features described in
one or both of [C][1] and [C][2], and one or more of the features described in one or more of
[D][1], [D][2], [D][3], and [D][4], and one or more of the features described in one or more
of [E][1], [E][2], and [E][3].
In some embodiments, one or more of the features described in [A][1][b] can be
combined with: the features described in [B], and one or more of the features described in
[C][1], and one or more of the features described in one or more of [D][1], [D][2], [D][3],
and [D][4], and one or more of the features described in one or more of [E][1], [E][2], and
[E][3].
In some embodiments, one or more of the features described in [A][1][b] can be
combined with: the features described in [B], and one or more of the features described in
one or both of [C][1] and [C][2], and one or more of the features described in [D][1], and
one or more of the features described in one or more of [E][1], [E][2], and [E][3].
In some embodiments, one or more of the features described in [A][1][b] can be
combined with: the features described in [B], and one or more of the features described in
[C][1], and one or more of the features described in [D][1], and one or more of the features
described in one or more of [E][1], [E][2], and [E][3].
In some embodiments, one or more of the features described in [A][1][d] can be
combined with: the features described in [B], and one or more of the features described in
one or both of [C][1] and [C][2], and one or more of the features described in one or more of
[D][1], [D][2], [D][3], and [D][4], and one or more of the features described in one or more
of [E][1], [E][2], and [E][3].
In some embodiments, one or more of the features described in [A][1][d] can be
combined with: the features described in [B], and one or more of the features described in
[C][1], and one or more of the features described in one or more of [D][1], [D][2], [D][3],
and [D][4], and one or more of the features described in one or more of [E][1], [E][2], and
[E][3].
In some embodiments, one or more of the features described in [A][1][d] can be
combined with: the features described in [B], and one or more of the features described in
one or both of [C][1] and [C][2], and one or more of the features described in one or both of
12354570_1 (GHMatters) P107928.NZ
[D][1] and [D][4], and one or more of the features described in one or more of [E][1], [E][2],
and [E][3].
In some embodiments, one or more of the features described in [A][1][d] can be
combined with: the features described in [B], and one or more of the features described in
[C][1], and one or more of the features described in one or both of [D][1] and [D][4], and one
or more of the features described in one or more of [E][1], [E][2], and [E][3].
In some embodiments, one or more of the features described in one or more of
[A][2] can be combined with: the features described in [B], and/or one or more of the features
described in one or both of [C][1] and [C][2] (e.g., [C][2]) and/or one or more of the features
described in one or more of [D][1], [D][2], [D][3], and [D][4] (e.g., [D][4]) and/or one or
more of the features described in one or more of [E][1], [E][2], and [E][3].
[II] n is 0 (i.e., in which A is Z is R -V-Cy-U-Ar’/Het’). Embodiments in which
n is 0 can include one or more of the following features described throughout sections [AA]
through [GG] below.
[AA] Variable Ar’/Het’
In some embodiments, Ar’/Het’ is phenyl, pyridyl, or pyrimidinyl, each of which is
optionally substituted with from 1-3 R ; provided that the point of connection on said phenyl,
pyridyl, or pyrimidinyl to U (i.e., the connection U-Arʹ/Hetʹ in formula I) and the point of
connection on said phenyl, pyridyl, or pyrimidinyl to the amide carbonyl (i.e., the connection
Arʹ/Hetʹ-C(=O) in formula I) do not result in 1,2-relation to one another on said phenyl,
pyridyl, or pyrimidinyl (i.e., the points of connection to U and C(O) on said phenyl, pyridyl,
or pyrimidinyl are not ortho with respect to one another).
In some embodiments, Ar’/Het’ is phenyl, pyridyl, or pyrimidinyl, each of which is
optionally substituted with from 1-3 R ; wherein the point of connection on said phenyl,
pyridyl, or pyrimidinyl to U (i.e., the connection U-Arʹ/Hetʹ in formula I) and the point of
connection on said phenyl, pyridyl, or pyrimidinyl to the amide carbonyl (i.e., the connection
Arʹ/Hetʹ-C(=O) in formula I) results in a 1,4-relation to one another on said phenyl, pyridyl,
or pyrimidinyl (i.e., the points of connection to U and C(O) on said phenyl, pyridyl, or
pyrimidinyl are para with respect to one another).
In some embodiments, Ar’/Het’ is phenyl, which is optionally substituted with
from 1-3 R ; provided that the point of connection on said phenyl to U (i.e., the connection
12354570_1 (GHMatters) P107928.NZ
U-Arʹ/Hetʹ in formula I) and the point of connection on said phenyl to the amide carbonyl
(i.e., the connection Arʹ/Hetʹ-C(=O) in formula I) does not result in a 1,2-relation to one
another on said phenyl (i.e., the points of connection to U and C(O) on said phenyl are not
ortho with respect to one another).
In some embodiments, Ar’/Het’ is phenyl, which is optionally substituted with
from 1-3 R ; wherein the point of connection on said phenyl to U (i.e., the connection U-
Arʹ/Hetʹ in formula I) and the point of connection on said phenyl to the amide carbonyl (i.e.,
the connection Arʹ/Hetʹ-C(=O) in formula I) results in a 1,4-relation to one another on said
phenyl (i.e., the points of connection to U and C(O) on said phenyl are para with respect to
one another).
In some embodiments, Ar’/Het’ is a 5-membered heteroaryl selected from
pyrazolyl, pyrrolyl, thiazolyl, thienyl, furanyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,
isoxazolyl, isothiazolyl, each of which is optionally substituted with from 1-3 R ; provided
that the point of connection on said 5-membered heteroaryls to U (i.e., the connection U-
Ar’/Het’ in formula I) and the point of connection on said 5-membered heteroaryls to the
amide carbonyl (i.e., the connection Ar’/Het’-C(=O) in formula I) do not result in 1,2-relation
to one another on said 5-membered heteroaryls (i.e., the points of connection to U and C(O)
on said 5-membered heteroaryl are not adjacent to one another).
In some embodiments, Ar’/Het’ is a 8-, 9- or 10-membered bicyclic heteroaryl
selected from benzothienyl, benzofuranyl, benzothioazolyl, benzoxazolyl, indolyl,
isoindolonyl, indolizinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl,
imidazopyridazinyl, triazolopyridinyl, imidazothiazolyl, imidazooxazolyl, quinolinyl, and
naphthyridinyl; each of which is optionally substituted with from 1-3 R .
In certain embodiments, Arʹ/Hetʹ is a 8-, 9- or 10-membered bicyclic heteroaryl
selected from indolizinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl,
imidazopyridazinyl, triazolopyridinyl, imidazothiazolyl, and imidazooxazolyl; each of which
is optionally substituted with from 1-3 R .
[BB] Variable Cy
12354570_1 (GHMatters) P107928.NZ
In some embodiments, Cy is a saturated heterocyclyl including 4-10 (e.g., 4-8, 4-6)
ring atoms, each of which is optionally substituted with from 1-3 R (wherein each
occurrence of R is independently selected from F, OH, C1-C6 alkyl, fluoro C1-C6 alkyl, C3-
C6 cycloalkyl, C1-C6 alkoxy C1-C6 fluoroalkoxy, and cyano), in which from 1-3
x’ x’ q’’
heteroatoms are independently selected from O, N-H, NR (wherein R is defined as R ),
and S(O) (m = 0-2); wherein when the heterocyclyl contains a secondary amine as part of its
structure, then:
(i) V is linked through the nitrogen of the secondary amine portion of the
heterocyclyl; and
(ii) U is linked to Cy via a Cy ring carbon atom; wherein the bond between U and the
Cy ring carbon is a single or double bond; and
(iii) V-Cy and Cy-U do not lead to 1,2 relationship (i.e. the Cy ring carbon atom that
is attached to U is not adjacent to Cy ring nitrogen atom that is attached to V).
In certain embodiments, Cy is a heterocyclyl that contains a secondary amine as
part of its structure.
In certain embodiments, Cy is azetidinyl, pyrrolidinyl, piperidinyl, azepanyl,
diazepanyl, isoxazolidinyl, thiazolidinonyl, imidazolidinonyl, pyrrolidinonyl, azabicyclooctyl
(aka. tropanyl), azabicycloheptanyl, or azabicyclohexanyl.
In certain embodiments, Cy is azetidinyl, pyrrolidinyl or piperidinyl (e.g.,
azetidinyl or piperidinyl).
In some embodiments, Cy is cycloalkyl (e.g., cyclobutyl, cyclopentyl, cyclohexyl).
[CC] Variable V
In some embodiments, V is -V’-C(R )2- or -C(R )2-V’-.
In some embodiments, each occurrence of R is independently selected from H, F,
OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH , OCO-(C1-C6 alkyl), OCO-(C3-C6 cycloalkyl),
C1-C6 alkoxy C1-C6 fluoroalkoxy, and cyano.
In certain embodiments, each occurrence of R is independently selected from H, F,
C1-C6 alkyl, and C3-C6 cycloalkyl.
In certain embodiments, each occurrence of R is H.
In some embodiments, V’ is a bond.
12354570_1 (GHMatters) P107928.NZ
[DD] Variable U
In some embodiments, U is =CR . R is hydrogen.
In certain embodiments, U is -U’-C(R ) - or -C(R ) -U’-.
In certain embodiments, each occurrence of R is independently selected from H, F,
OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH , OCO-(C1-C6 alkyl), OCO-(C3-C6 cycloalkyl),
C1-C6 alkoxy C1-C6 fluoroalkoxy, and cyano.
In certain embodiments, each occurrence of R is independently selected from H, F,
C1-C6 alkyl, and C3-C6 cycloalkyl.
In certain embodiments, each occurrence of R is H.
In some embodiments, U’ is a bond.
[EE] Variable R1
In some embodiments, R1 is C6-C10 aryl, which is optionally substituted with from
1-3 R . In certain embodiments, R1 is phenyl or naphthyl (e.g., phenyl), which is optionally
substituted with from 1-3 R (in embodiments, each R is independently selected from F, OH,
C1-C6 alkyl, fluoro(C1-C6) alkyl C3-C6 cycloalkyl, NH , C1-C6 alkoxy, C1-C6
fluoroalkoxy, and cyano).
In some embodiments, R1 is monocyclic or bicyclic heteroaryl including from 5-10
ring atoms, which is optionally substituted with from 1-3 R ; wherein from 1-4 of the ring
atoms is/are a heteroatom independently selected from O, N, N-H, N-R , and S.
In certain embodiments, R1 is monocyclic heteroaryl, such as pyridyl.
In other embodiments, R1 is bicyclic heteroaryl, such as those that are fully
aromatic such as indolyl and the like.
In still other embodiments, R1 is bicyclic heteroaryl that contains a bridgehead
nitrogen ring atom and optionally other heteroatom ring atoms, such as indolizinyl,
pyrrolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyriazinyl,
triazolopyridinyl, imidazothiazolyl, imidazooxazolyl.
Other examples of R1 heteroaryl groups include, without limitation, pyrazolyl,
pyrrolyl, 2-oxo-indolyl, quinolinyl, isoquinolinyl, tetrahydro-isoquinolinyl, benzofuranyl,
12354570_1 (GHMatters) P107928.NZ
benzodioxanyl, benzodioxolyl (aka. methylenedioxyphenyl) and corresponding difluoro
(CF ) analog, thiazolyl, 2-oxopyridinyl, pyridinyl N-oxide, pyrimidinyl, thienyl, furanyl,
oxazolyl, isoxazolyl, pyridazinyl, imidazolyl, pyrazinyl, isothiazolyl, 1,2-thiazinyl-1,1-
dioxide, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzotriazolyl,
benzoxazolyl, benzothienyl, oxadiazolyl, triazolyl, tetrazolyl, dioxoindolyl (isatin),
phthalimido, , and the dihydro and tetrahydro congeners of the fully unsaturated ring systems.
In some embodiments, R1 is heterocyclyl including from 4-10 ring atoms, which is
optionally substituted with from 1-3 R ; wherein from 1-4 of the ring atoms is/are a
heteroatom independently selected from O, N, N-H, N-R , and S (e.g., bicyclic heterocyclyl
containing a bridgehead nitrogen ring atom and optionally other heteroatom ring atoms).
Examples of R1 heterocyclyl groups include, without limitation, piperidinyl,
morpholinyl, pyrrolidinyl, azetidinyl, azepanyl, isoxazolidinyl, oxazolidinyl , thiazolidinyl,
imidazolinyl, quinuclidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl,
thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxanyl, tropanyl and
other bridged bicyclic amines, quiniclidinyl.
In some embodiments, R1 is H.
[FF] Variables R2 and R3
In some embodiments, R2 is a substituent other than hydrogen (e.g., phenyl,
substituted phenyl, thienyl, thiazolyl, and pyrazolyl), and R3 is hydrogen. In certain
embodiments, the compounds can exhibit selectivity for HDAC 1 and/or 2.
In some embodiments, R2 is hydrogen, and R3 is a substituent other than hydrogen
(e.g., fluoro). In certain embodiments, the compounds can exhibit selectivity for HDAC 3.
In some embodiments, each of R2 and R3 is hydrogen.
[GG] Non-limiting Combinations of [II][AA] through [II][FF] (i.e., n = 0)
12354570_1 (GHMatters) P107928.NZ
In some embodiments, one or more of the features described in one or more of
[AA][1], [AA][2], and [AA][3] can be combined with: one or more of the features described
in [DD], and/or one or more of the features described in [CC], and/or one or more of the
features described in one or both of [BB][1] and [BB][2], and/or one or more of the features
described in one or more of [EE][1], [EE][2], [EE][3], and [EE][4], and/or one or more of
the features described in one or more of [FF][1], [FF][2], and [FF][3].
In some embodiments, one or more of the features described in one or more of
[AA][1], [AA][2], and [AA][3] can be combined with: one or more of the features described
in [DD], and one or more of the features described in [CC], and one or more of the features
described in one or both of [BB][1] and [BB][2], and one or more of the features described
in one or more of [EE][1], [EE][2], [EE][3], and [EE][4], and one or more of the features
described in one or more of [FF][1], [FF][2], and [FF][3].
In some embodiments, one or more of the features described in [AA][1], can be
combined with: one or more of the features described in [DD], and one or more of the
features described in [CC], and one or more of the features described in one or both of
[BB][1] and [BB][2], and one or more of the features described in one or more of [EE][1],
[EE][2], [EE][3], and [EE][4], and one or more of the features described in one or more of
[FF][1], [FF][2], and [FF][3].
In some embodiments, one or more of the features described in one or more of
[AA][1], [AA][2], and [AA][3] can be combined with: one or more of the features described
in [DD], and one or more of the features described in [CC], and one or more of the features
described in [BB][1], and one or more of the features described in one or more of [EE][1],
[EE][2], [EE][3], and [EE][4], and one or more of the features described in one or more of
[FF][1], [FF][2], and [FF][3].
In some embodiments, one or more of the features described in one or more of
[AA][1], [AA][2], and [AA][3] can be combined with: one or more of the features described
in [DD], and one or more of the features described in [CC], and one or more of the features
described in one or both of [BB][1] and [BB][2], and one or more of the features described
in [EE][2], and one or more of the features described in one or more of [FF][1], [FF][2], and
[FF][3].
In some embodiments, one or more of the features described in [AA][1] can be
combined with: one or more of the features described in [DD], and one or more of the
features described in [CC], and one or more of the features described in [BB][1], and one or
12354570_1 (GHMatters) P107928.NZ
more of the features described in [EE][2], and one or more of the features described in one
or more of [FF][1], [FF][2], and [FF][3].
In certain embodiments, n is 1, and X is –Y–[C(R ) ] –A–[C(R ) ] –B–.
2 a 2 b
In certain embodiments, n is 1, and X is –Y–[C(R )2]a –A–[C(R )2]b–B–, and Y is
CR =CR . Embodiments can include any one or more of the features described herein. For
example, one or both of the following: R1 is C6-C10 aryl (e.g., phenyl), which is optionally
substituted with from 1-3 R ; and Ar/Het is 5 membered heteroaromatic selected from
pyrazolyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl,
and 1,2,4-triazolyl (in some embodiments, Ar/Het is other than 1,2,4-triazolyl and/or
furanyl), e.g., Ar/Het is pyrazolyl. In embodiments, each of R4 and R5 is hydrogen; and/or
one or more of the following: (i) R2 is a substituent other than hydrogen (e.g., phenyl,
substituted phenyl, thienyl, thiazolyl, and pyrazolyl), and R3 is hydrogen, in certain
embodiments, the compounds can exhibit selectivity for HDAC 1 and/or 2; (ii) R2 is
hydrogen, and R3 is a substituent other than hydrogen (e.g., fluoro), in certain embodiments,
the compounds can exhibit selectivity for HDAC 3; and (iii) each of R2 and R3 is hydrogen.
In certain embodiments, n is 1, and X is –Y–[C(R ) ] –A–[C(R ) ] –B–, and Y is O
2 a 2 b
or NR (e.g., Y is O). Embodiments can include any one or more of the features described
herein. For example, one or both of the following: R1 is C6-C10 aryl (e.g., phenyl), which is
optionally substituted with from 1-3 R ; and Ar/Het is 5 membered heteroaromatic selected
from pyrazolyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, isothiazolyl, thiadiazolyl,
oxadiazolyl, and 1,2,4-triazolyl (in some embodiments, Ar/Het is other than 1,2,4-triazolyl
and/or furanyl), e.g., Ar/Het is pyrazolyl. In embodiments, each of R4 and R5 is hydrogen;
and/or one or more of the following: (i) R2 is a substituent other than hydrogen (e.g.,
phenyl, substituted phenyl, thienyl, thiazolyl, and pyrazolyl), and R3 is hydrogen, in
certain embodiments, the compounds can exhibit selectivity for HDAC 1 and/or 2; (ii) R2 is
hydrogen, and R3 is a substituent other than hydrogen (e.g., fluoro), in certain embodiments,
the compounds can exhibit selectivity for HDAC 3; and (iii) each of R2 and R3 is hydrogen.
In certain embodiments, n is 1, and Ar/Het is a bicyclic 8-, 9-, or 10-membered
azabridged heteroaromatic such as indolizinyl, pyrrolopyrimidinyl, pyrazolopyridinyl,
imidazopyridinyl, imidazopyridazinyl, triazolopyridinyl, imidazothiazolyl, imidazooxazolyl,
1,2,4- triazolothiazolyl, and 1,2,4- triazolooxazolyl. Embodiments can include any one or
more of the features described herein. For example, X is a bond and R1 is H. In
embodiments, each of R4 and R5 is hydrogen; and/or one or more of the following: (i) R2 is
12354570_1 (GHMatters) P107928.NZ
a substituent other than hydrogen (e.g., phenyl, substituted phenyl, thienyl, thiazolyl, and
pyrazolyl), and R3 is hydrogen, in certain embodiments, the compounds can exhibit
selectivity for HDAC 1 and/or 2; (ii) R2 is hydrogen, and R3 is a substituent other than
hydrogen (e.g., fluoro), in certain embodiments, the compounds can exhibit selectivity for
HDAC 3; and (iii) each of R2 and R3 is hydrogen.
In certain embodiments, n is 0, and U is =CR (e.g., R is hydrogen). Embodiments
can include any one or more of the features described herein. For example, one or both of the
following: Ar’/Het’ is phenyl, which is optionally substituted with from 1-3 R ; and having
the provisions described elsewhere; Cy is a heterocyclyl (e.g., a heterocyclyl that contains a
secondary amine as part of its structure). In embodiments, one or more of the following
apply: (i) R2 is a substituent other than hydrogen (e.g., phenyl, substituted phenyl, thienyl,
thiazolyl, and pyrazolyl), and R3 is hydrogen, in certain embodiments, the compounds can
exhibit selectivity for HDAC 1 and/or 2; (ii) R2 is hydrogen, and R3 is a substituent other
than hydrogen (e.g., fluoro), in certain embodiments, the compounds can exhibit selectivity
for HDAC 3; and (iii) each of R2 and R3 is hydrogen.
Definitions
The term “hepatocyte” refers to commercially available preparations of liver tissue
derived cells that can be obtained from mouse, rat, dog, monkey, or human liver tissue.
The term “mammal” includes organisms, which include mice, rats, cows, sheep,
pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans.
“An effective amount” refers to an amount of a compound that confers a
therapeutic effect (e.g., treats, e.g., controls, relieves, ameliorates, alleviates, or slows the
progression of; or prevents, e.g., delays the onset of or reduces the risk of developing, a
disease, disorder, or condition or symptoms thereof) on the treated subject. 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 0.01 mg/kg to about 1000 mg/kg, (e.g., from about 0.1 mg/kg to
about 100 mg/kg, from about 1 mg/kg to about 100 mg/kg). Effective doses will also vary
depending on route of administration, as well as the possibility of co-usage with other agents.
The term “halo” or “halogen” refers to any radical of fluorine, chlorine, bromine or
iodine.
12354570_1 (GHMatters) P107928.NZ
In general, and unless otherwise indicated, substituent (radical) prefix names are
derived from the parent hydride by either (i) replacing the “ane” in the parent hydride with
the suffix “yl;” or (ii) replacing the “e” in the parent hydride with the suffix “yl;” (here the
atom(s) with the free valence, when specified, is (are) given numbers as low as is consistent
with any established numbering of the parent hydride). Accepted contracted names, e.g.,
furyl, pyridyl, and piperidyl, and trivial names, e.g., phenyl and thienyl are also used herein
throughout. Conventional numbering/lettering systems are also adhered to for substituent
numbering.
The following definitions are used, unless otherwise described. Specific and
general values listed below for radicals, substituents, and ranges, are for illustration only;
they do not exclude other defined values or other values within defined ranges for the radicals
and substituents. Alkyl, alkoxy, and the like denote both straight and branched groups.
As used herein, the term “alkyl,” employed alone or in combination with other
terms, refers to a saturated hydrocarbon group that may be straight-chain or branched. In
some embodiments, the alkyl group contains 1 to 12, 1 to 8, or 1 to 6 carbon atoms.
Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl,
ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-
methylbutyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, n-heptyl, n-octyl, and the
like. In some embodiments, the alkyl moiety is methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, or 2,4,4-trimethylpentyl.
Throughout the definitions, the term “Cy-Cz” (e.g., C1-C6 and the like) is used,
wherein y and z are integers and indicate the number of carbons, wherein y-z indicates a
range which includes the endpoints.
As referred to herein, the term “alkoxy group” refers to a group of formula
O(alkyl). Alkoxy can be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-
butoxy, sec-butoxy, pentoxy, 2-pentoxy, 3-pentoxy, or hexyloxy.
As used herein, the term “aryl,” employed alone or in combination with other
terms, refers to a monocyclic aromatic hydrocarbon moiety or a polycyclic hydrocarbon
moiety (e.g., having 2, 3 or 4 fused linked rings) that includes at least one aromatic ring.
Examples include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, indanyl and
tetralinyl. In some embodiments, aryl groups have from 6 to 10 carbon atoms.
12354570_1 (GHMatters) P107928.NZ
As referred to herein, “heteroaryl” refers to an aromatic monocyclic or fused
bicyclic ring that includes at least one aromatic ring, each of which containing at least one
(typically one to about three) nitrogen, oxygen, or sulfur ring atoms (independently selected
when more than one is present). Examples of heteroaryl groups include, but are not limited
to pyridyl, pyrazolyl, pyrrolyl, 2-oxo-indolyl, quinolinyl, isoquinolinyl, tetrahydro-
isoquinolinyl, benzofuranyl, indolyl, benzodioxanyl, benzodioxolyl (aka.
methylenedioxyphenyl) and corresponding difluoro (CF ) analog, thiazolyl, 2-oxopyridinyl,
pyridinyl N-oxide, pyrimidinyl, thienyl, furanyl, oxazolyl, isoxazolyl, pyridazinyl,
imidazolyl, pyrazinyl, isothiazolyl, 1,2-thiazinyl-1,1-dioxide, benzimidazolyl, thiadiazolyl,
benzopyranyl, benzothiazolyl, benzotriazolyl, benzoxazolyl, benzothienyl, oxadiazolyl,
triazolyl, tetrazolyl, dioxoindolyl (isatin), phthalimido; heteroaryls that contain a bridgehead
nitrogen ring atom and optionally other heteroatom ring atoms, such as indolizinyl,
pyrrolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyriazinyl,
triazolopyridinyl, imidazothiazolyl, imidazooxazolyl); and the dihydro and tetrahydro
congeners of the fully unsaturated ring systems.
As used herein, the phrase “optionally substituted” means unsubstituted (e.g.,
substituted with a H) or substituted. As used herein, the term “substituted” means that a
hydrogen atom is removed and replaced by a substitutent. It is understood that substitution at
a given atom is limited by valency. The use of a substituent (radical) prefix name such as
alkyl without the modifier “optionally substituted” or “substituted” is understood to mean that
the particular substituent is unsubstituted. However, the use of “fluoro Cy-Cz alkyl” without
the modifier “optionally substituted” or “substituted” is still understood to mean an alkyl
group, in which at least one hydrogen atom is replaced by fluoro.
Unless indicated otherwise, the nomenclature of substituents that are not explicitly
defined herein are arrived at by naming the terminal portion of the functionality followed by
the adjacent functionality toward the point of attachment. In generally, the point of
attachment for a substituent is indicated by the last term in the group. For example,
(heterocyclyl)-(C1-C6) alkyl refers to a moiety of heteroaryl-alkylene-, wherein the alkylene
linker has 1 to 6 carbons, and the substituent is attached through the alkylene linker.
As used herein, the term “cycloalkyl,” employed alone or in combination with other
terms, refers to a saturated, cyclic hydrocarbon moiety. Exemplary cycloalkyl groups
include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and
cycloheptyl.
12354570_1 (GHMatters) P107928.NZ
As used herein, the term “cyano,” employed alone or in combination with other
terms, refers to a group of formula –CN, wherein the carbon and nitrogen atoms are bound
together by a triple bond.
As used herein, the term “halo Cy-Cz alkyl” and the like employed alone or in
combination with other terms, refers to an alkyl group having from one halogen atom to 2n+1
halogen atoms which may be the same or different, where “n” is the number of carbon atoms
in the alkyl group. In some embodiments, the halogen atoms are fluoro atoms.
As used herein, “haloalkoxy,” employed alone or in combination with other terms,
refers to a group of formula –O-haloalkyl. An example haloalkoxy group is OCF . In some
embodiments, the halogen atoms are fluoro atoms.
As used herein, the term “heterocyclyl” employed alone or in combination with
other terms, refers to a saturated ring system, which has carbon ring atoms and at least one
heteroatom ring atom selected from nitrogen, sulfur, and oxygen (independently selected
when more than one is present). When the heterocyclyl group contains more than one
heteroatom, the heteroatoms may be the same or different. Heterocyclyl groups can include
mono- or bicyclic (e.g., having 2 fused rings) ring systems. Heterocyclyl groups can also
include bridgehead heterocycloalkyl groups. As used herein, “bridgehead heterocyclyl
group” refers to a heterocyclyl moiety containing at least one bridgehead heteroatom (e.g.,
nitrogen). In some embodiments, the carbon atoms or hetereoatoms in the ring(s) of the
heterocycloalkyl group can be oxidized to form a carbonyl, or sulfonyl group (or other
oxidized linkage) or a nitrogen atom can be quaternized.
As to any of the above groups that contain one or more substituents, it is
understood, of course, that such groups do not contain any substitution or substitution
patterns that are sterically impractical and/or synthetically unfeasible. In addition, the
compounds disclosed herein include all stereochemical isomers arising from the substitution
of these compounds.
Unless otherwise defined, all technical and scientific terms used herein have the
same meaning as commonly understood by one of ordinary skill in the art. Although
methods and materials similar or equivalent to those described herein can be used in practice
or testing, suitable methods and materials are described below. All publications, patent
applications, patents, and other references mentioned herein are incorporated by reference in
their entirety. In case of conflict, the present specification, including definitions, will control.
12354570_1 (GHMatters) P107928.NZ
In addition, the materials, methods, and examples are illustrative only and not intended to be
limiting.
Other features and advantages will be apparent from the following detailed
description, and from the claims.
It is appreciated that certain features of the disclosure, which are, for clarity,
described in the context of separate embodiments, can also be provided in combination in a
single embodiment. Conversely, various features disclosed which are, for brevity, described
in the context of a single embodiment, can also be provided separately or in any suitable sub-
combination.
Thus, for ease of exposition, it is also understood that where in this specification, a
group is defined by “as defined anywhere herein” (or the like), the definitions for that
particular group include the first occurring and broadest generic definition as well as any sub-
generic and specific definitions delineated anywhere in this specification. Also, for ease of
exposition, the definition “substituent other than hydrogen” refers collectively to the non-
hydrogen possibilities for that particular variable.
BRIEF DESCRIPTION OF THE DRAWINGS
is a bar graph shows the effect of compounds on long-term memory for
object recognition. The data is presented as discrimination index between known and novel
object as a function of compound and dose. In the leftmost cluster of bars, the dosages
represented from left to right are (0, 3, 10, 30 mg/kg); in the center and rightmost cluster of
bars, the dosages represented from left to right are (3, 10, 30 mg/kg).
DETAILED DESCRIPTION
Compounds of formula (I) described herein may contain one or more asymmetric
centers and thus occur as racemates and racemic mixtures, single enantiomers, individual
diastereomers and diastereomeric mixtures. While shown without respect to the
stereochemistry in formula (I), the present disclosure includes such optical isomers
(enantiomers) and diastereomers; as well as the racemic and resolved, enantiomerically pure
R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and
pharmaceutically acceptable salts thereof. The use of these compounds is intended to cover
the racemic mixture or either of the chiral enantiomers.
Compounds of formula (I) described herein may also contain linkages (e.g., carbon-
carbon bonds, carbon-nitrogen bonds such as amide bonds) wherein bond rotation is
12354570_1 (GHMatters) P107928.NZ
restricted about that particular linkage, e.g. restriction resulting from the presence of a ring or
double bond. Accordingly, all cis/trans and E/Z isomers and rotational isomers are expressly
included in the present disclosure.
One skilled in the art will also recognize that it is possible for tautomers to exist for
the compounds described herein. The disclosure includes all such tautomers even though not
shown in the formulas herein. All such isomeric forms of such compounds are expressly
included in the present disclosure.
Optical isomers can be obtained in pure form by standard procedures known to
those skilled in the art, and include, but are not limited to, diastereomeric salt formation,
kinetic resolution, and asymmetric synthesis. See, for example, Jacques, et al., Enantiomers,
Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al.,
Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-
Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268
(E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972), each of which is
incorporated herein by reference in their entireties. It is also understood that this disclosure
encompasses all possible regioisomers, and mixtures thereof, which can be obtained in pure
form by standard separation procedures known to those skilled in the art, and include, but are
not limited to, column chromatography, thin-layer chromatography, and high-performance
liquid chromatography.
The compounds described herein also include the various hydrate and solvate forms
of the compounds.
Compounds described herein can also include all isotopes of atoms occurring in the
intermediates or final compounds. Isotopes include those atoms having the same atomic
number but different mass numbers. For example, isotopes of hydrogen include tritium and
deuterium.
In some embodiments, compounds of formula (I) also include compounds of
formula (II):
(II)
wherein R is H or F; R is H, Cl, or F; Het is selected from oxetanyl, azetindinyl,
piperidinyl, and 8-azabicyclo[3.2.1]octanyl, and when Het is azetindinyl, piperidinyl, or 8-
12354570_1 (GHMatters) P107928.NZ
azabicyclo[3.2.1]octanyl, the ring nitrogen is substituted with R ; R is C1-C6alkyl, C1-
C6hydroxyalkyl, C1-C3alkylene-C3-C6cycloalkyl, C1-C3alkylene-phenyl, or C1-
C3alkylene-pyridyl; and the phenyl or pyridyl ring is optionally substituted with methyl. In
various cases, R is H. In some cases, R is F. In various embodiments, Het is oxetanyl. In
some embodiments, Het is azetindinyl. In some cases, when Het is azetindinyl, R can be
C1-C3alkylene-C3-C6cycloalkyl, such as CH cyclopropyl; or C1-C3alkylene-pyridyl, such
as CH pyridyl or CH -methylpyridyl; or C1-C3alkylene-phenyl, such as benzyl; or C1-
C6alkyl or C1-C6hydroxyalkyl, such as CH C(OH)(CH ) . In various embodiments, Het can
2 3 2
be 8-azabicyclo [3.2.1]octanyl, and R can be C1-C6alkyl, such as methyl. In various
embodiments, Het can be piperidinyl, and R can be C1-C6alkyl or C1-C6hydroxyalkyl, such
as CH C(CH ) or CH C(OH)(CH ) ; or C1-C3alkylene-C3-C6cycloalkyl, such as
2 3 3 2 3 2
C C C
CH cyclopropy. In various cases, R is H. In some cases, R is F. In various cases, R is Cl.
In cases where R is F or Cl, R can be ortho or meta to the Het substituent.
The compounds described herein also include pharmaceutically acceptable salts of
the compounds disclosed herein. As used herein, the term “pharmaceutically acceptable salt”
refers to a salt formed by the addition of a pharmaceutically acceptable acid or base to a
compound disclosed herein. As used herein, the phrase “pharmaceutically acceptable” refers
to a substance that is acceptable for use in pharmaceutical applications from a toxicological
perspective and does not adversely interact with the active ingredient. Pharmaceutically
acceptable salts, including mono- and bi- salts, include, but are not limited to, those derived
from organic and inorganic acids such as, but not limited to, acetic, lactic, citric, cinnamic,
tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric,
hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic,
toluenesulfonic, salicylic, benzoic, and similarly known acceptable acids. Lists of suitable
salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing
Company, Easton, Pa., 1985, p. 1418; Journal of Pharmaceutical Science, 66, 2 (1977); and
"Pharmaceutical Salts: Properties, Selection, and Use A Handbook; Wermuth, C. G. and
Stahl, P. H. (eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN 326-8] each
of which is incorporated herein by reference in their entireties.
In some embodiments, the compounds are prodrugs. As used herein, “prodrug”
refers to a moiety that releases a compound described herein when administered to a patient.
Prodrugs can be prepared by modifying functional groups present in the compounds in such a
way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent
12354570_1 (GHMatters) P107928.NZ
compounds. Examples of prodrugs include compounds as described herein that contain one
or more molecular moieties appended to a hydroxyl, amino, sulfhydryl, or carboxyl group of
the compound, and that when administered to a patient, cleave in vivo to form the free
hydroxyl, amino, sulfhydryl, or carboxyl group, respectively. Examples of prodrugs include,
but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine
functional groups in the compounds described herein. Preparation and use of prodrugs is
discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the
A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B.
Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are
incorporated herein by reference in their entireties.
Synthesis of compounds of formula (I)
The compounds described herein can be prepared in a variety of ways known to one
skilled in the art of organic synthesis. The compounds described herein can be synthesized
using the methods as hereinafter described below, together with synthetic methods known in
the art of synthetic organic chemistry or variations thereon as appreciated by those skilled in
the art.
Compounds of the present disclosure can be conveniently prepared in accordance
with the procedures outlined in the Examples section, from commercially available starting
materials, compounds known in the literature, or readily prepared intermediates, by
employing conventional synthetic methods and procedures known to those skilled in the art.
Conventional synthetic methods and procedures for the preparation of organic molecules and
functional group transformations and manipulations can be readily obtained from the relevant
scientific literature or from standard textbooks in the field. It will be appreciated that, where
typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of
reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless
otherwise stated. Optimum reaction conditions may vary with the particular reactants or
solvent used, but such conditions can be determined by one skilled in the art by routine
optimization procedures. Those skilled in the art of organic synthesis will recognize that the
nature and order of the synthetic steps presented may be varied for the purpose of optimizing
the formation of the compounds described herein.
Synthetic chemistry transformations useful in synthesizing the compounds
described herein are known in the art and include, for example, those such as described in
R.C. Larock, Comprehensive Organic Transformations, 2d.ed., Wiley-VCH Publishers
12354570_1 (GHMatters) P107928.NZ
(1999); P.G.M. Wuts and T.W. Greene, Protective Groups in Organic Synthesis, 4th Ed.,
John Wiley and Sons (2007); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for
Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of
Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions
thereof. Preparation of compounds can involve the protection and deprotection of various
chemical groups. The need for protection and deprotection, and the selection of appropriate
protecting groups can be readily determined by one skilled in the art. The chemistry of
protecting groups can be found, for example, in Wuts PGM and Greene TW, 2006, Greene’s
Protective Groups in Organic Synthesis, Fourth Edition, John Wiley & Sons, Inc., Hoboken,
NJ, USA, which is incorporated herein by reference in its entirety. Adjustments to the
protecting groups and formation and cleavage methods described herein may be adjusted as
necessary in light of the various substituents.
The reactions of the processes described herein can be carried out in suitable
solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable
solvents can be substantially nonreactive with the starting materials (reactants), the
intermediates, or products at the temperatures at which the reactions are carried out, i.e.,
temperatures which can range from the solvent freezing temperature to the solvent boiling
temperature. A given reaction can be carried out in one solvent or a mixture of more than
one solvent. Depending on the particular reaction step, suitable solvents for a particular
reaction step can be selected.
The processes described herein can be monitored according to any suitable method
known in the art. For example, product formation can be monitored by spectroscopic means,
such as nuclear magnetic resonance spectroscopy (e.g., 1H and/or 13C NMR) infrared
spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by
chromatography such as high performance liquid chromatography (HPLC) or thin layer
chromatography.
The compounds described herein can be separated from a reaction mixture and
further purified by a method such as column chromatography, high- performance liquid
chromatography (HPLC), or recrystallization.
One of skill in the art will recognize that there are additional methods of producing
the compounds of formula (I) in addition to those described in the Examples section.
12354570_1 (GHMatters) P107928.NZ
A histone deacetylase (HDAC), as described herein, can be any polypeptide having
features characteristic of polypeptides that catalyze the removal of the acetyl group
(deacetylation) from acetylated target proteins. Features characteristic of HDACs are known
in the art (see, for example, Finnin et al., 1999, Nature, 401:188). Thus, an HDAC can be a
polypeptide that represses gene transcription by deacetylating the ε-amino groups of
conserved lysine residues located at the N-termini of histones, e.g., H3, H4, H2A, and H2B,
which form the nucleosome. HDACs also deacetylate other proteins such as p53, E2F, α-
tubulin, and MyoD (see, for example, Annemieke et al., 2003, Biochem. J., 370:737).
HDACs can also be localized to the nucleus and certain HDACs can be found in both the
nucleus and also the cytoplasm.
Compounds of formula (I) described herein, e.g., compounds of formula (II), may
interact with any HDAC. In some embodiments, the compounds of formula (I) described
herein will have at least about 2-fold (e.g., at least about 5-fold, 10-fold, 15-fold, or 20-fold)
greater activity to inhibit one or more class I HDACS (e.g., HDAC1, HDAC2, or HDAC3) as
compared to one or more other HDACs (e.g., one or more HDACs of class IIa, IIb, or IV).
The disclosure features a method of treating a cancer in patient in need thereof,
comprising administering a therapeutically effective amount of an HDAC inhibitor as
described herein, or pharmaceutically, acceptable salt thereof. In some embodiments, the
cancer is a solid tumor, neoplasm, carcinoma, sarcoma, leukemia, or lymphoma. In some
embodiments, leukemias include acute leukemias and chronic leukemias such as acute
lymphocytic leukemia (ALL), acute myeloid leukemia, chronic lymphocytic leukemia (CLL),
chronic myelogenous leukemia (CML) and Hairy Cell Leukemia; lymphomas such as
cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral T-cell lymphomas,
lymphomas associated with human T-cell lymphotrophic virus (fITLV) such as adult T-cell
leukemia/lymphoma (ATLL), Hodgkin's disease and non-Hodgkin's lymphomas, large-cell
lymphomas, diffuse large B-cell lymphoma (DLBCL); Burkitt's lymphoma; primary central
nervous system (CNS) lymphoma; multiple myeloma; childhood solid tumors such as brain
tumors, neuroblastoma, retinoblastoma, Wilm's tumor, bone tumors, and soft-tissue sarcomas,
common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal and
esophageal), genitor-urinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular,
rectal and colon), lung cancer, breast cancer.
12354570_1 (GHMatters) P107928.NZ
In some embodiments, the cancer is (a) Cardiac: sarcoma (angiosarcoma,
fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma
and teratoma; (b) Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell,
undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial
adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; (c)
Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma,
lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal
adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small
bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma,
hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular
adenoma, villous adenoma, hamartoma, leiomyoma); (d) Genitourinary tract: kidney
(adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and
urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate
(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma,
teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,
fibroadenoma, adenomatoid tumors, lipoma); (e) Liver: hepatoma (hepatocellular carcinoma),
cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;
(f) Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,
chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple
myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginous
exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and
giant cell tumors; (g) Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma,
osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain
(astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma
multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord
(neurofibroma, meningioma, glioma, sarcoma); (h) Gynecological: uterus (endometrial
carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian
carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma), unclassified
carcinoma (granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma,
malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,
adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell
carcinoma, botryoid sarcoma), embryonal rhabdomyosarcoma, fallopian tubes (carcinoma);
(i) Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia,
chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma,
12354570_1 (GHMatters) P107928.NZ
myelodysplastic syndrome), Hodgkin's disease, .non-Hodgkin's lymphoma (malignant
lymphoma); (j) Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma,
Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids,
psoriasis; and (k) Adrenal glands: neuroblastoma conditions.
In another aspect, provided is a method of treating a inflammatory disorder in
patient in need thereof, comprising administering a therapeutically effective amount of a
compound of formula (I) (e.g., formula (II)) as described herein, or pharmaceutically,
acceptable salt thereof. In some embodiments, the inflammatory disorder is an acute and
chronic inflammatory disease, autoimmune disease, allergic disease, disease associated with
oxidative stress, and diseases characterized by cellular hyperproliferation. Non-limiting
examples are inflammatory conditions of a joint including rheumatoid arthritis (RA) and
psoriatic arthritis; inflammatory bowel diseases such as Crohn's disease and ulcerative colitis;
spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and
inflammatory dermatoses such an dermatitis, eczema, atopic dermatitis, allergic contact
dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);
eosinophilic myositis, eosinophilic fasciitis; cancers with leukocyte infiltration of the skin or
organs, ischemic injury, including cerebral ischemia (e.g., brain injury as a result of trauma,
epilepsy, hemorrhage or stroke, each of which may lead to neurodegeneration); HIV, heart
failure, chronic, acute or malignant liver disease, autoimmune thyroiditis; systemic lupus
erythematosus, Sjorgren's syndrome, lung diseases (e.g., ARDS); acute pancreatitis;
amyotrophic lateral sclerosis (ALS); Alzheimer's disease; cachexia/anorexia; asthma;
atherosclerosis; chronic fatigue syndrome, fever; diabetes (e.g., insulin diabetes or juvenile
onset diabetes); glomerulonephritis; graft versus host rejection (e.g., in transplantation);
hemorrhagic shock; hyperalgesia: inflammatory bowel disease; multiple sclerosis;
myopathies (e.g., muscle protein metabolism, esp. in sepsis); osteoarthritis; osteoporosis;
Parkinson's disease; pain; pre-term labor; psoriasis; reperfusion injury; cytokine-induced
toxicity (e.g., septic shock, endotoxic shock); side effects from radiation therapy, temporal
mandibular joint disease, tumor metastasis; or an inflammatory condition resulting from
strain, sprain, cartilage damage, trauma such as burn, orthopedic surgery, infection or other
disease processes.
Allergic diseases and conditions, include but are not limited to respiratory allergic
diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity
pneumonitis, eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic
12354570_1 (GHMatters) P107928.NZ
pneumonia), delayed-type hypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathic
pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus
erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis
or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g.,
to penicillin, cephalosporins), insect sting allergies, and the like.
In another aspect, provided is a method of preventing or treating a memory-related
disorder in patient in need thereof, comprising administering a therapeutically effective
amount of a compound of formula (I) (e.g., formula (II)) as described herein, or
pharmaceutically, acceptable salt thereof. Compounds of formula (I) (e.g., formula (II)) can
be used to treat patients with memory impairments associated with direct cognitive disorders
such as amnesia, dementia and delirium; anxiety disorders such as phobias, panic disorders,
psychosocial stress (e.g. as seen in disaster, catastrophe or violence victims), obsessive-
compulsive disorder, generalized anxiety disorder and post-traumatic stress disorder; mood
disorders such as depression and bipolar disorder; and psychotic disorders such as
schizophrenia and delusional disorder. Memory impairment, a hallmark of neurodegenerative
diseases such as, but not limited to, Parkinson’s, Alzheimer’s, Huntington’s, amyotrophic
lateral sclerosis (ALS), spinocerebellar ataxia, as well as aging, can also be treated by using
compounds of formula (I) (e.g., formula (II)). In addition, compounds disclosed can be used
to treat drug addiction through extinction of drug-seeking behavior.
HDAC inhibitors, e.g., HDAC1 and/or HDAC 2 selective inhibitors, may also be
useful to treat sickle cell disease (SCD) and β-thalassemia (bT). They may also be useful in
treating mood disorders or brain disorders with altered chomatin-mediated neuroplasticity
(Schoreder, et al., PLoS ONE 8(8): e71323 (2013)).
In another aspect, provided is a method of preventing or treating a hemoglobin
disorder in patient in need thereof, comprising administering a therapeutically effective
amount of a compound of formula (I) (e.g., formula (II)) as described herein, or
pharmaceutically, acceptable salt thereof. Compounds of formula (I) (e.g., formula (II)) can
be used to treat patients with sickle cell anemia or -thalassemia. In various cases, the
compound is a selective HDAC 1 and/or HDAC 2 inhibitor and is used to prevent or treat the
hemoglobin disorder (e.g., sickle cell anemia or -thalassemia).
Further provided is a method of preventing or treating a mood disorder or brain
disorders with altered chomatin-mediated neuroplasticity in patient in need thereof,
comprising administering a therapeutically effective amount of a compound of formula (I)
12354570_1 (GHMatters) P107928.NZ
(e.g., formula (II)) as described herein, or pharmaceutically, acceptable salt thereof.
Compounds of formula (I) (e.g., formula (II)) can be used to treat patients with a mood
disorder.
In a further aspect, this application features methods of treating a neurological
condition (e.g., Friedreich’s ataxia (FRDA), myotonic dystrophy, spinal muscular atrophy,
fragile X syndrome, Huntington’s disease, a spinocerebellar ataxia, Kennedy’s disease,
amyotrophic lateral sclerosis, Niemann Pick, Pitt Hopkins, spinal and bulbar muscular
atrophy, Alzheimer’s disease or schizophrenia, bipolar disorder, and related diseases) that
include administering a compound of formula (I) (e.g., formula (II)) described herein to a
patient having a neurological condition.
In another aspect, this application features the use of a compound of formula (I)
(e.g., formula (II)) described herein in the preparation of a medicament for the treatment or
prevention of a neurological condition (e.g., Friedreich’s ataxia, myotonic dystrophy, spinal
muscular atrophy, fragile X syndrome, Huntington’s disease, a spinocerebellar ataxia,
Kennedy’s disease, amyotrophic lateral sclerosis, Niemann Pick, Pitt Hopkins, spinal and
bulbar muscular atrophy, or Alzheimer’s disease); a memory-affecting condition or disease, a
cancer; or an inflammatory disorder, or a Plasmodium falciparum infection (e.g., malaria).
In a further aspect, the application provides a kit for the treatment or prevention of a
disorder selected from a neurological disorder (e.g., Friedreich’s ataxia, myotonic dystrophy,
spinal muscular atrophy, fragile X syndrome, Huntington’s disease, a spinocerebellar ataxia,
Kennedy’s disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, or
Alzheimer’s disease), a memory-affecting condition or disease, a cancer, an inflammatory
disorder, or a Plasmodium falciparum infection (e.g., malaria) in a patient in need thereof,
comprising (i) a compound of formula (I) (e.g., formula (II)) described herein or a
pharmaceutically acceptable salt thereof; and (ii) instructions comprising a direction to
administer said compound to said patient.
In some embodiments of the above methods, the methods further include assaying
the activity of the candidate compound to increase expression of one or more genes whose
expression is decreased in the neurological condition (e.g., frataxin, huntingtin, brain derived
neurotrophic factor (BDNF), peroxisome proliferator-activated receptor-gamma, coactivator
1, alpha (PGC1A), ataxin, fragile X mental retardation (FMR1), dystrophia myotonica
protein kinase (DMPK), or androgen receptor). In some embodiments, the activity of the
candidate compound to increase expression of one or more genes whose expression is
12354570_1 (GHMatters) P107928.NZ
decreased in the neurological condition is measured in an animal, e.g., an animal model of the
neurological condition.
In some embodiments of the above methods, the method is repeated for a plurality
of test compounds (e.g., at least 10, 20, 50, 100, 200, 500, or l000 test compounds).
In another aspect, this application features methods of treating a neurological
condition (e.g., Friedreich’s ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X
syndrome, Huntington’s disease, spinocerebellar ataxias, Kennedy’s disease, amyotrophic
lateral sclerosis, spinal and bulbar muscular atrophy, or Alzheimer’s disease) that include
performing any of the above methods, formulating the candidate compound in a
pharmaceutical composition, and administering the pharmaceutical composition to a patient
having a neurological condition.
HDAC inhibitors have been shown to have antimalarial activity (Andrews et al.,
2000, Int. J. Parasitol., 30:761-768; Andrews et al., Antimicrob. Agents Chemother.,
52:1454-61). The present disclosure provides methods of treating a Plasmodium falciparum
infection (e.g., malaria) in a patient in need thereof.
HDAC inhibitors may also be useful to treat infectious disease such as viral
infections. For example, treatment of HIV infected cells with HDAC inhibitors and anti-
retroviral drugs can eradicate virus from treated cells (Blazkova j et al J Infect Dis. 2012 Sep
1;206(5):765-9; Archin NM et al Nature 2012 Jul 25, 487(7408):482-5). The present
disclosure provides methods of treating a HIV infection in need thereof.
Pharmaceutical compositions
HDAC inhibitors can be administered neat or formulated as pharmaceutical
compositions. Pharmaceutical compositions include an appropriate amount of the HDAC
inhibitor in combination with an appropriate carrier and optionally other useful ingredients.
Acceptable salts of the formula (I) (e.g., formula (II)) compounds described herein
include, but are not limited to, those prepared from the following acids: alkyl, alkenyl, aryl,
alkylaryl and alkenylaryl mono-, di- and tricarboxylic acids of 1 to 20 carbon atoms,
optionally substituted by 1 to 4 hydroxyls; alkyl, alkenyl, aryl, alkylaryl and alkenylaryl
mono-, di- and trisulfonic acids of 1 to 20 carbon atoms, optionally substituted by 1 to 4
hydroxyls; dibasic acids and mineral acids. Examples include hydrochloric; hydrobromic;
sulfuric; nitric; phosphoric; lactic (including (+)-L-lactic, (+/-)-DL-lactic); fumaric; glutaric;
maleic; acetic; salicyclic; p- toluenesulfonic; tartaric (including (+)-L-tartaric); citric;
12354570_1 (GHMatters) P107928.NZ
methanesulfonic; formic; malonic; succinic; naphthalenesulfonic; and benzenesulfonic
acids. Also, pharmaceutically-acceptable salts can be prepared as amine salts, ammonium
salts, or alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of
the carboxylic acid group. These are formed from alkaline metal or alkaline earth metal
bases or from amine compounds.
Pharmaceutical compositions of formula (I) (e.g., formula (II)) compounds
described herein suitable for oral administration can be in the form of (1) discrete units such
as capsules, sachets, tablets, or lozenges each containing a predetermined amount of the
HDAC inhibitor; (2) a powder or granules; (3) a bolus, electuary, or paste; (4) a solution or a
suspension in an aqueous liquid or a non-aqueous liquid; or (5) an oil-in-water liquid
emulsion or a water-in-oil liquid emulsion. Compositions suitable for topical administration
in the mouth, for example buccally or sublingually, include lozenges. Compositions suitable
for parenteral administration include aqueous and non-aqueous sterile suspensions or
injection solutions. Compositions suitable for rectal administration can be presented as a
suppository.
Pharmaceutical compositions of formula (I) (e.g., formula (II)) compounds
described herein can be formulated using a solid or liquid carrier. The solid or liquid carrier
should be compatible with the other ingredients of the formulation and not deleterious to the
recipient. If the pharmaceutical composition is in tablet form, then the HDAC inhibitor is
mixed with a carrier having the necessary compression properties in suitable proportions and
compacted in the shape and size desired. If the composition is in powder form, the carrier is
a finely divided solid in admixture with the finely divided active ingredient. The powders
and tablets can contain up to 99% of the active ingredient. Suitable solid carriers include, for
example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,
gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine,
low melting waxes and ion exchange resins. A solid carrier can include one or more
substances that can act as flavoring agents, lubricants, solubilizers, suspending agents, fillers,
glidants, compression aids, binders or tablet-disintegrating agents. A suitable carrier can also
be an encapsulating material.
If the composition is a solution, suspension, emulsion, syrup, elixir, or pressurized
composition, then liquid carriers can be used. In this case, the HDAC inhibitor is dissolved
or suspended in a pharmaceutically acceptable liquid carrier. Suitable examples of liquid
carriers for oral and parenteral administration include (1) water; (2) alcohols, e.g. monohydric
12354570_1 (GHMatters) P107928.NZ
alcohols and polyhydric alcohols such as glycols, and their derivatives; and (3) oils, e.g.
fractionated coconut oil and arachis oil. For parenteral administration, the carrier can also be
an oily ester such as ethyl oleate and isopropyl myristate. Liquid carriers for pressurized
compositions include halogenated hydrocarbon or other pharmaceutically acceptable
propellants. The liquid carrier can contain other suitable pharmaceutical additives such as
solubilizers; emulsifiers; buffers; preservatives; sweeteners; flavoring agents; suspending
agents; thickening agents; colors; viscosity regulators; stabilizers; osmo-regulators; cellulose
derivatives such as sodium carboxymethyl cellulose; antioxidants; and bacteriostatics. Other
carriers include those used for formulating lozenges such as sucrose, acacia, tragacanth,
gelatin and glycerin as well as those used in formulating suppositories such as cocoa butter or
polyethylene glycol.
If the composition is to be administered intravenously or intraperitoneally by
infusion or injection, solutions of the HDAC inhibitor can be prepared in water, optionally
mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid
polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions
of storage and use, these preparations contain a preservative to prevent the growth of
microorganisms. The composition suitable for injection or infusion can include sterile
aqueous solutions or dispersions or sterile powders comprising the active ingredient, which
are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or
dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form
should be sterile, fluid and stable under the conditions of manufacture and storage. The
liquid carrier or vehicle can be a solvent or liquid dispersion medium as described above.
The proper fluidity can be maintained, for example, by the formation of liposomes, by the
maintenance of the required particle size in the case of dispersions or by the use of
surfactants. The prevention of the action of microorganisms can be brought about by various
antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid,
thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for
example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable
compositions can be brought about by the use in the compositions of agents delaying
absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are
prepared by incorporating the HDAC inhibitor in the required amount in the appropriate
solvent with some of the other ingredients enumerated above, as required, followed by filter
sterilization. In the case of sterile powders for the preparation of sterile injectable solutions,
the preferred methods of preparation are vacuum drying and the freeze-drying techniques,
12354570_1 (GHMatters) P107928.NZ
which yield a powder of the HDAC inhibitor, plus any additional desired ingredient present
in the previously sterile-filtered solutions.
Pharmaceutical compositions can be in unit-dose or multi-dose form or in a form
that allows for slow or controlled release of the HDAC inhibitor. Each unit-dose can be in
the form of a tablet, capsule or packaged composition such as, for example, a packeted
powder, vial, ampoule, prefilled syringe or sachet containing liquids. The unit-dose form
also can be the appropriate number of any such compositions in package form.
Pharmaceutical compositions in multi-dose form can be packaged in containers such as
sealed ampoules and vials. In this case, the HDAC inhibitor can be stored in a freeze- dried
(lyophilized) condition requiring only the addition of a sterile liquid carrier immediately prior
to use. In addition, extemporaneous injection solutions and suspensions can be prepared
from sterile powders, granules and tablets of the kind previously described.
EXAMPLES
Method A
O O O 8
R P R 7
+ 7 or
r e O
R X A H t R
/ O O 8
1 4 R
R X A H t
R X A H t H
R X A /H N
R HN
R X A /H t N
R NH
Compounds described herein, where n=1, and where R1, X, Ar/Het, R2, R3, R4, R5
are defined as described anywhere herein, can be obtained by reaction of a mono- or bicyclic
heterocycle aldehyde or ketone, synthesized using methods well known by those skilled in
12354570_1 (GHMatters) P107928.NZ
the art (see for example Joule JA and Mills K, Heterocyclic Chemistry, Fifth Edition, John
Wiley & Sons, Inc., Hoboken, NJ, USA) with a Wittig or Horner-Wadsworth-Emmons
reagent to form a γ-substituted acrylate ester. After saponification, a substituted or
unsubstituted N-(o-aminophenyl)amide is prepared by an amide-forming reaction of the
acrylic acid with a protected or unprotected substituted or unsubstituted o-phenylenediamine,
where P is a protecting group as defined in Wuts PGM and Greene TW, 2006, Greene’s
Protective Groups in Organic Synthesis, Fourth Edition, John Wiley & Sons, Inc., Hoboken,
NJ, USA. Compounds disclosed herein can be obtained after deprotection if required using
methods well known to those skilled in the art and which are described for example in Wuts
PGM and Greene TW, 2006, Greene’s Protective Groups in Organic Synthesis, Fourth
Edition, John Wiley & Sons, Inc., Hoboken, NJ, USA.
Example 1: hydrochloride salt of (E)-N-(2-aminophenyl)(imidazo[1,2-a]pyridin
yl)acrylamide A6
O oc
Et H
COO COO
N N N
N N N
1 2 3
2 H l
(E)-ethyl 3-(imidazo[1,2-a]pyridinyl)acrylate:
(Ethoxycarbonylmethylene)triphenylphosphorane (0.72 g, 2.05 mmol) was added to a
solution of imidazo[1,2-a]pyridinecarbaldehyde (0.25 g, 1.71 mmol) in anhydrous
tetrahydrofuran (THF) (20mL) at room temperature. The reaction mixture was heated
overnight at 65 C. After completion of the reaction as indicated by HPLC, the reaction
mixture was diluted with ethyl acetate (EtOAc) (20mL) and quenched with a saturated
solution of ammonium chloride (10 mL). The organic layer was washed with water (3 x 20
mL) and brine (15 mL). It was dried over anhydrous Na SO , filtered and evaporated to get
the crude product. This crude was purified by silica gel column chromatography using 50-
80% EtOAc in Hexanes to provide pure (E)-ethyl 3-(imidazo[1,2-a]pyridinyl)acrylate
(0.19 g) as a white solid. ES (M+H) 217.
12354570_1 (GHMatters) P107928.NZ
(E)(imidazo[1,2-a]pyridinyl)acrylic acid: A 1M aqueous solution of KOH
(2.2 mL) was added to a solution of (E)-ethyl 3-(imidazo[1,2-a]pyridinyl)acrylate (0.19 g,
0.88 mmol) in EtOH:THF (1:1 v/v) (10 mL). The resulting solution was heated at 50 C for
3h. After completion of the reaction the reaction mixture was evaporated and water (10 mL)
was added to the residue. This solution was carefully acidified to pH 4 with a 3 M HCl
aqueous solution. Since the product, (E)(imidazo[1,2-a]pyridinyl)acrylic acid, was
soluble in water, the solution was concentrated under reduced pressure and the solid residue
was used directly for the next step. ES (M+H) 189.
(E)-tert-butyl (2-(3-(imidazo[1,2-a]pyridinyl)acrylamido)phenyl)carbamate:
Diisopropylethylamine (DIPEA, 0.34 g, 2.63 mmol) was added to a solution of (E)
(imidazo[1,2-a]pyridinyl)acrylic acid (0.17 g, 0.88 mmol) in 20 mL of dichloromethane
(DCM). After addition of tert-butylaminophenylcarbamate (0.22 g, 1.65 mmol) and 2-(1H-
7-azabenzotriazolyl)--1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 0.43 g,
1.14 mmol) the reaction mixture was stirred overnight at room temperature under a nitrogen
atmosphere. After completion of the reaction as indicated by HPLC, the reaction mixture was
washed with saturated sodium bicarbonate (NaHCO ) and brine. It was dried over Na SO ,
3 2 4
filtered and evaporated to give crude (E)-tert-butyl (2-(3-(imidazo[1,2-a]pyridin
yl)acrylamido)phenyl)carbamate. The solid was washed with ethyl acetate (50 mL) and
saturated NaHCO gave pure product as a light colored solid (0.11 g). ES (M+H) 379.
(E)-N-(2-aminophenyl)(imidazo[1,2-a]pyridinyl)acrylamide: A 4 M solution
of HCl in dioxane (2.5 mL) was added to a solution of (E)-tert-butyl (2-(3-(imidazo[1,2-
a]pyridinyl)acrylamido)phenyl)carbamate (0.11 g, 0.29 mmol) in dioxane (2.5 mL). The
mixture was stirred at room temperature for 3 h. Precipitate formation was observed. After
completion of the reaction as indicated by HPLC/MS, the reaction mixture was diluted with
diethyl ether (20 mL) and the salt was filtered, washed with ether and dried overnight to get
the HCl salt of (E)-N-(2-aminophenyl)(imidazo[1,2-a]pyridinyl)acrylamide (80 mg) as
an off-white solid. H NMR (CD3OD) δ: 9.04 - 9.13 (m, 1H), 8.67 (s, 1H), 8.17 (d, J = 15.8
Hz, 1H), 8.00 - 8.13 (m, 2H), 7.66 (td, J = 6.9, 1.4 Hz, 1H), 7.42 - 7.58 (m, 4H), 7.21 (d, J =
.8 Hz, 1H); ES (M+H) 279.2
12354570_1 (GHMatters) P107928.NZ
Table: Method A
Compound Structure aldehyde diamine MS NMR
O NH + + 1
A1 O ES (M+H) H NMR (CD OD) δ: 7.57 (d, J = 15.1
N H N
N 260
H Hz, 1H), 7.52 - 7.62 (m, 1H), 7.20 (dd,
J = 8.0, 1.4 Hz, 1H), 6.99 (d, J = 15.1
Hz, 1H), 7.04 (ddd, J = 8.0, 7.6, 1.4
Hz, 1H), 6.87 (dd, J = 8.0, 1.4 Hz,
1H), 6.74 (td, J = 7.6, 1.4 Hz, 1H),
2.67 - 2.79 (m, 3H)
O NH + + 1
ES (M+H)
A2 H NMR (CD OD) δ: 7.88 (s, 1H),
7.77 (s, 1H), 7.54 (d, J = 15.7 Hz, 1H),
7.17 (dd, J = 7.6, 1.4 Hz, 1H), 7.04 (td,
J = 7.8, 1.4 Hz, 1H), 6.87 (dd, J = 8.0,
1.5 Hz, 1H), 6.74 (td, J = 7.6, 1.4 Hz,
1H), 6.57 (d, J = 15.7 Hz, 1H), 3.90 (s,
N + +
N NH 1
NH 2
ES (M+H)
A3 2 H NMR (CD OD) δ: 7.50 (d, J = 15.7
N H 2
Hz, 1H), 7.21 (dd, J = 7.7, 1.4 Hz,
1H), 7.05 (td, J = 8.1, 1.5 Hz, 1H),
6.98 (d, J = 15.7 Hz, 2H), 6.87 (dd, J =
8.0, 1.4 Hz, 1H), 6.73 (td, J = 8.0, 1.4
Hz, 1H), 6.55 (s, 1H), 2.31 (s, 1H)
O O NH + + 1
NH 2
A4 2 ES (M+H) H NMR (CD OD) δ: 8.01 (s, 1H),
N H 2
7.48 (d, J = 15.4 Hz, 1H), 7.18 (dd, J =
7.7, 1.4 Hz, 1H), 7.04 (ddd, J = 8.0,
7.3, 1.4 Hz, 1H), 6.84 (d, J = 15.4 Hz,
1H), 6.86 (dd, J = 8.0, 1.4 Hz, 1H),
6.73 (td, J = 7.6, 1.4 Hz, 1H), 2.49 (s,
O NH 1
O ES (M+H)
A5 H NMR (CD OD) δ: 7.49 (d, J = 15.7
O 244
H Hz, 1H), 7.21 (dd, J = 8.0, 1.5 Hz,
1H), 7.04 (ddd, J = 8.0, 7.7, 1.5 Hz,
1H), 6.98 (d, J = 15.7 Hz, 1H), 6.86
(dd, J = 8.0, 1.5 Hz, 1H), 6.73 (td, J =
12354570_1 (GHMatters) P107928.NZ
7.7, 1.4 Hz, 1H), 6.55 (s, 1H), 2.31 (s,
O B 1
O ES (M+H)
A6 H NMR (CD OD) δ: 9.09 (dt, J = 7.1,
(salt) 279
H N 0.8 Hz, 1H), 8.67 (s, 1H), 8.17 (d, J =
NH 15.7 Hz, 1H), 8.10 (ddd, J = 9.1, 6.9,
N 1.1 Hz, 1H), 8.03 (dt, J = 9.1, 1.2 Hz,
1H), 7.66 (td, J = 6.9, 1.4 Hz, 1H),
7.43 - 7.60 (m, 4H), 7.21 (d, J = 15.7
Hz, 1H)
NH O NH + +
ES (M+H)
A7 H H NMR (CD OD) δ: 7.59 (d, J = 2.5
N H N
N 243
Hz, 1H), 7.57 (d, J = 15.8 Hz, 1H),
O 7.19 (dd, J = 7.7, 1.4 Hz, 1H), 7.04 (td,
J = 7.6, 1.4 Hz, 1H), 6.86 (dd, J = 8.1,
1.2 Hz, 1H), 6.78 (d, J = 15.8 Hz, 1H),
6.74 (td, J = 7.7, 1.4 Hz, 1H), 6.59 (d,
J = 2.5 Hz, 1H), 3.90 (s, 3H)
H NMR (CD OD) δ: 8.50 (d, J = 6.6
HN 3
H N Hz, 1H), 7.73 (d, J = 15.9 Hz, 1H),
7.64 (d, J = 8.8 Hz, 1H), 7.17 - 7.29
(m, 2H), 7.06 (d, J = 15.7 Hz, 2H),
7.05 (ddd, J = 8.0, 7.5, 1.5 Hz, 1H),
6.83 - 6.97 (m, 3H), 6.75 (td, J = 7.7,
1.4 Hz, 1H)
B + +
A9 ES (M+H)
N H NMR (CD OD) δ: 8.82 (dt, J = 7.0,
HN 3
N NH
(salt) 279 1.1 Hz, 1H), 8.58 (s, 1H), 8.06 (ddd, J
= 9.1, 7.0, 1.1 Hz, 1H), 7.96 (dt, J =
9.1, 0.8 Hz, 1H), 7.84 (d, J = 15.9 Hz,
1H), 7.45 - 7.57 (m, 5H), 7.22 (d, J =
.9 Hz, 1H)
NH + +
A10 ES (M+H)
H NMR (CD OD) δ: 8.11 (s, 1H),
2 H N
7.78 (d, J = 15.4 Hz, 1H), 7.70 (d, J =
1.4 Hz, 1H), 7.30 (d, J = 1.4 Hz, 1H),
O 7.20 (dd, J = 7.8, 1.5 Hz, 1H), 7.04
(ddd, J = 8.2, 7.7, 1.4 Hz, 1H), 6.87
(dd, J = 8.2, 1.4 Hz, 1H), 6.74 (ddd, J
12354570_1 (GHMatters) P107928.NZ
= 7.8, 7.7, 1.4 Hz, 1H), 6.56 (d, J =
.4 Hz, 1H)
N O B 1
O ES (M+H)
A11 H NMR (CD OD) δ: 8.53 (s, 1H),
H N 8.03 (s, 1H), 7.78 (d, J = 8.5 Hz, 2H),
7.64 (d, J = 15.7 Hz, 1H), 7.51 (t, J =
7.8 Hz, 2H), 7.35 (t, J = 7.7 Hz, 1H),
7.19 (d, J = 7.7 Hz, 1H), 7.04 (t, J =
7.6 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H),
6.69 (d, J = 15.7 Hz, 1H), 6.74 (t, J =
7.7 Hz, 1H)
B + +
A12 ES (M+H)
H NMR (CD OD) δ: 7.69 (s, 1H),
HN 3
243 7.51 (d, J = 15.4 Hz, 1H), 7.37 (s, 1H),
N 7.19 (dd, J = 7.8, 1.2 Hz, 1H), 7.03 (dt,
J = 8.1,1.4 Hz, 1H), 6.86 (dd, J = 8,
1.4 Hz, 1H), 6.74 (d, J = 15.4 Hz, 1H),
6.74 (dt, J = 8, 1.2 Hz, 1H), 3.73 (s,
12354570_1 (GHMatters) P107928.NZ
Method B
O O O O R
A /H t R
R P R P
O OH O N
A /H t N
R R HN
R HN
5 5
R X A /H t N
R HN
R X A /H t N
R NH
Compounds described herein, where n=1, and R1, X, R2, R3, R4, R5, Ar/Het are
defined as defined anywhere herein, can be via preparation of the advanced intermediate
Ar/Het-CR4=CR5-CO-NH-C6H2R2R3(NH-P) where P is a protecting group,as defined in,
for example, Wuts PGM and Greene TW, 2006, Greene’s Protective Groups in Organic
Synthesis, Fourth Edition, John Wiley & Sons, Inc., Hoboken, NJ, USA, and NH-P is ortho
to the CO-NH group, i.e. in positions 1 and 2 of the aromatic ring..
Thus a Wittig or Horner-Wadsworth-Emmons carboxylic acid reagent, prepared by
methods well known to those skilled in the art such as the Arbuzov reaction, can be reacted
with a suitably mono-protected substituted or unsubstituted o-phenylenediamine. This
compound is then reacted with a monocyclic or bicyclic heterocyclic aldehyde or ketone to
form the corresponding γ-substituted acrylamide. This advanced intermediate can be
derivatized to generate compounds of the disclosure by reaction with different R1-X-
containing reagents using coupling techniques well known to those skilled in the art such as,
but not limited to, Suzuki coupling, Heck coupling, alkylation, acylation. The same
intermediate can also be simply deprotected to form the compound where R1 is H and X is a
single bond.
12354570_1 (GHMatters) P107928.NZ
Example 2: Advanced intermediate (E)-tert-butyl (2-(3-(1H-pyrazol
yl)acrylamido)phenyl)carbamate
COOH P
Et N
t N H
H HN
, , NHB ,
HATU DIEA DCM N H 1 2 q THF
R T 72h
tert-butyl (2-(2-(diethoxyphosphoryl)acetamido)phenyl)carbamate: DIPEA (5.16
g, 6.90 mL, 40 mmol) and tert-butyl 2-aminophenylcarbamate (2.08g, 10 mmol) were added
to a solution of 2-(diethoxyphosphoryl)acetic acid (2.15g, 11 mmol) in DCM (120 mL). After
the mixture was stirred for ten minutes, HATU (4.56g, 12 mmol) was added to the reaction
and stirring was prolonged for 6h at room temperature under a nitrogen atmosphere. After
completion of the reaction as indicated by HPLC, the reaction mixture was washed with
saturated NaHCO and brine. It was dried over Na SO and filtered. The filtrate was
3 2 4
evaporated in vacuo to get the crude product, which was triturated with 30% v/v hexanes in
EtOAc for 30 min. The solid was filtered, washed with 30% hexanes in EtOAc and dried to
get 2.92g of tert-butyl (2-(2-(diethoxyphosphoryl)acetamido)phenyl)carbamate as an off-
white solid in 76% yield. HNMR (300MHz, CD OD): δ 7.64 (d, 1H, J = 8.4 Hz), 7.37 (dd,
1H, J =1.8 Hz, 8.1 Hz), 7.07-7.24 (m, 2H), 4.20 (m, 4H), 3.15 (d, 2H, J = 21.9 Hz), 1.51 (s,
9H), 1.35 (t, 6H, J = 6.9 Hz), MS: ES (M+Na) : 410
(E)-tert-butyl (2-(3-(1H-pyrazolyl)acrylamido)phenyl)carbamate: A 60%
suspension of NaH in paraffin oil (192mg, 5mmol) was added portionwise to a solution of
tert-butyl (2-(2-(diethoxyphosphoryl)acetamido)phenyl)carbamate (1.93g, 5mmol) in
anhydrous THF (25mL) at 0 C. The reaction mixture was stirred for 30min before being
warmed up to room temperature. 1H-pyrazolecarbaldehyde (400 mg, 4.16mmol) dissolved
in anhydrous THF (5 mL) was then added and the reaction mixture was stirred for 72h under
a nitrogen atmosphere. After completion of the reaction as indicated by HPLC, the mixture
was diluted with EtOAc (80 mL) and quenched with a saturated NH Cl solution (10 mL). The
organic layer was separated and washed with water (40mL) and brine (20mL). It was dried
over anhydrous Na SO and the solid was filtered. The filtrate was evaporated under vacuum.
The isolated crude was purified by silica gel column chromatography using a gradient of 0-
100% EtOAc in hexanes to provide 986mg of (E)-tert-butyl (2-(3-(1H-pyrazol
yl)acrylamido)phenyl)carbamate as a white solid. HNMR (300MHz, CD OD): δ 7.93 (broad
s, 2H), 7.64 (d, 1H, J = 15.6 Hz), 7.56 (d, 1H, J = 7.2 Hz), 7.45 d, 1H, J = 7.8 Hz), 7.11-7.24
(m, 2H), 6.59 (d, 1H, J = 15.6 Hz), 1.50 (s, 9H), MS: ES (M+Na) : 351
12354570_1 (GHMatters) P107928.NZ
Example 3: Hydrochloride salt of (E)-N-(2-aminophenyl)(1-(2-(3-chloro
fluorophenoxy)ethyl)-1H-pyrazolyl)acrylamide B5
. Cl
1 DMF
C CO
NH HCl
oxane
2 HCl di
(E)-tert-butyl (2-(3-(1-(2-(3-chlorofluorophenoxy)ethyl)-1H-pyrazol
yl)acrylamido)phenyl)carbamate: Cesium carbonate (98mg, 0.30mmol) was added to a
solution of (E)-tert-butyl (2-(3-(1H-pyrazolyl)acrylamido)phenyl)carbamate (100mg,
0.30mmol) in anhydrous DMF (4mL). A solution of 1-(2-bromoethoxy)chloro
fluorobenzene (76mg, 0.30mmol) in DMF (1 mL) was then added and the reaction mixture
was stirred overnight at room temperature under a nitrogen atmosphere. It was diluted with
EtOAc (30 mL) and washed with water (2x40mL) and brine (10mL). The organic layer was
dried over anhydrous Na SO and filtered. The evaporated crude was purified by silica gel
column chromatography using a gradient of 0-100% of EtOAc in hexanes to provide 144mg
of (E)-tert-butyl (2-(3-(1-(2-(3-chlorofluorophenoxy)ethyl)-1H-pyrazol
(M+Na) : 523
yl)acrylamido)phenyl)carbamate as a white solid. MS: ES
(E)-N-(2-aminophenyl)(1-(2-(3-chlorofluorophenoxy)ethyl)-1H-pyrazol
yl)acrylamide: A 4 M solution of HCl in dioxane (2 mL) was added to a solution of (E)-tert-
butyl (2-(3-(1-(2-(3-chlorofluorophenoxy)ethyl)-1H-pyrazol
yl)acrylamido)phenyl)carbamate (118mg, 0.23mmol) in dioxane (3 mL) and the mixture was
stirred for 6h at room temperature under a nitrogen atmosphere. The reaction mixture was
then diluted with EtOAc (15 mL). The salt was filtered, washed with EtOAc and dried
overnight to give 99mg of the hydrochloric acid salt of (E)-N-(2-aminophenyl)(1-(2-(3-
chlorofluorophenoxy)ethyl)-1H-pyrazolyl)acrylamide as an off-white solid. MS:
ES (M+Na) : 423
Example 4: hydrochloride salt of (E)-N-(2-aminophenyl)(1-(2-(3,5-difluorophenoxy)
ethyl)-1H-pyrazolyl)acrylamide B3
(E)-tert-butyl (2-(3-(1-(2-(3,5-difluorophenoxy)ethyl)-1H-pyrazol
yl)acrylamido)phenyl)carbamate: As described for the synthesis of B5 above, cesium
carbonate (64mg, 0.27mmol) followed by a solution of 1-(2-bromoethoxy)-3,5-
difluorobenzene (76mg, 0.30mmol) in DMF (1 mL) were added to a solution of (E)-tert-butyl
12354570_1 (GHMatters) P107928.NZ
(2-(3-(1H-pyrazolyl)acrylamido)phenyl)carbamate (90mg, 0.27mmol) in anhydrous DMF
(4mL). The reaction mixture was stirred overnight at room temperature under a nitrogen
atmosphere. It was then diluted with 30 mL EtOAc and washed with water (2x40mL) and
brine (10mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The
concentrated filtrate was purified by silica gel column chromatography using a gradient of 0-
100% of EtOAc in hexanes to provide, after evaporation under reduced pressure of pooled
fractions, 123mg of (E)-tert-butyl (2-(3-(1-(2-(3,5-difluorophenoxy)ethyl)-1H-pyrazol
yl)acrylamido)phenyl)carbamate as a white solid. MS: ES (M+Na) : 507
(E)-N-(2-aminophenyl)(1-(2-(3,5-difluorophenoxy)ethyl)-1H-pyrazol
yl)acrylamide: A solution of (E)-tert-butyl (2-(3-(1-(2-(3,5-difluorophenoxy)ethyl)-1H-
pyrazolyl)acrylamido)phenyl)carbamate (113mg, 0.23mmol) in dioxane (3 mL) was mixed
with a 4 M solution of HCl in dioxane (2 mL). The mixture was stirred for 6h at room
temperature under a nitrogen atmosphere. The reaction mixture was then diluted with
ethylaceate (15 mL). The salt was filtered, washed with EtOAc and dried overnight to 92 mg
of the hydrochloric acid salt of (E)-N-(2-aminophenyl)(1-(2-(3,5-difluorophenoxy)ethyl)-
1H-pyrazolyl)acrylamide as an off-white solid. MS: H NMR (CD OD) δ: 8.07 (s, 1H),
7.86 (s, 1H), 7.70 (d, J = 15.4 Hz, 1H), 7.28 - 7.54 (m, 4H), 6.62 (d, J = 15.7 Hz, 1H), 6.45 -
6.57 (m, 3H), 4.55 (t, J = 5.2 Hz, 2H), 4.37 (t, J = 5.2 Hz, 2H)ES (M+Na) : 407
12354570_1 (GHMatters) P107928.NZ
Table: Method B
Compound Structure R1-X- coupling reagent MS NMR
Cl + + 1
B1 ES (M+H) H NMR (CD OD) δ: 8.13 (s, 1H),
(salt) 283
7.91 (s, 1H), 7.72 (d, J = 15.7 Hz,
1H), 7.30 - 7.62 (m, 4H), 6.65 (d, J
= 15.7 Hz, 1H), 4.05 (d, J = 7.1 Hz,
2H), 1.17 - 1.46 (m, 1H), 0.56 -
0.82 (m, 2H), 0.36 - 0.49 (m, 2H)
F + +
B2 B ES (M+H)
H NMR (CD OD) δ: 8.08 (s, 1H),
(salt) 7.90 (s, 1H), 7.73 (d, J = 15.7 Hz,
1H), 7.34 - 7.58 (m, 6H), 7.05 (t, J
H = 9.1 Hz, 2H), 6.63 (d, J = 15.7 Hz,
1H), 6.63 (dd, J = 15.7, 0.8 Hz, 1H),
6.38 (dt, J = 15.7, 6.3 Hz, 1H), 4.95
(dd, J = 6.3, 0.8 Hz, 2H)
F F O +
B3 r ES (M+Na) H NMR (CD OD) δ: 8.07 (s, 1H),
: 407
(salt) 7.86 (s, 1H), 7.70 (d, J = 15.4 Hz,
1H), 7.28 - 7.54 (m, 4H), 6.62 (d, J
= 15.7 Hz, 1H), 6.45 - 6.57 (m, 3H),
4.55 (t, J = 5.2 Hz, 2H), 4.37 (t, J =
.2 Hz, 2H)
F C O 1
ES (M+Na)
B4 r H NMR (CD OD) δ: 8.09 (s, 1H),
(salt) : 429
7.87 (s, 1H), 7.72 (d, J = 15.7 Hz,
1H), 7.57 (d, J = 8.8 Hz, 2H), 7.40 -
H 7.54 (m, 3H), 7.37 (dd, J = 8.0, 1.5
Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H),
6.61 (d, J = 15.7 Hz, 1H), 4.59 (t, J
= 5.2 Hz, 2H), 4.45 (t, J = 5.2 Hz,
12354570_1 (GHMatters) P107928.NZ
Cl O + 1
B5 r ES (M+Na) H NMR (CD OD) δ: 8.07 (s, 1H),
: 423
(salt) 7.87 (s, 1H), 7.71 (d, J = 15.7 Hz,
1H), 7.32 - 7.57 (m, 4H), 6.77 (dt, J
= 8.2, 2.2 Hz, 1H), 6.78 (d, J = 2.2
Hz, 1H), 6.61 (d, J = 15.9 Hz, 1H),
6.66 (dt, J = 10.7, 2.2 Hz, 1H), 4.55
(t, J = 5.2 Hz, 2H), 4.38 (t, J = 5.2
Hz, 2H)
F O 1
B6 ES (M+Na)
r H NMR (CD OD) δ: 8.00 (s, 1H),
: 367
7.82 (s, 1H), 7.55 (d, J = 15.7 Hz,
1H), 7.17 (dd, J = 8.0, 1.4 Hz, 1H),
6.92 - 7.07 (m, 3H), 6.82 - 6.92 (m,
3H), 6.73 (td, J = 7.6, 1.4 Hz, 1H),
6.58 (d, J = 15.7 Hz, 1H), 4.51 (t, J
= 5.2 Hz, 1H), 4.31 (t, J = 5.2 Hz,
12354570_1 (GHMatters) P107928.NZ
Method C
R P R
A /H t R
6 7 O
A /H O
6 O N
A /H t OH
R HN
A /H
R HN
A H t N
R NH
Compounds described herein, where n =1 and R2, R3, R4, R5 are defined as
anywhere herein, where Ar/Het is a mono or bicyclic heterocycle with a free amino group,
and R6 stands for R1-X, can be prepared using a Horner Wadsworth Emmons approach
where the corresponding heterocyclic aldehyde or ketone, such as, but not limited to, 1H-
pyrazolecarbaldehyde, 1H-pyrazolecarbaldehyde, 1-(1H-pyrazolyl)ethanone, 1H-
imidazolecarbaldehyde, is reacted with a dialkoxyphosphono acetic acid ester to give the
corresponding γ-(N-alkylheterocycle)acrylate ester. The ester can be hydrolyzed and the acid
reacted with a protected or unprotected substituted or unsubstituted o-phenylenediamine to
give compounds of the disclosure after deprotection if required using methods well known to
those skilled in the art and which are described for example in P.G.M. Wuts and T.W.
Greene, 2006, Greene’s Protective Groups in Organic Synthesis, Fourth Edition, John Wiley
& Sons, Inc., Hoboken, NJ, USA.
12354570_1 (GHMatters) P107928.NZ
Example 5: (E)-N-(2-aminofluorophenyl)(1-methyl-1H-pyrazolyl)acrylamide
P COOM
HN , ,
s oxane
C CO di 42
DMSO
KOH EtOH H O
60 C 6h
HATU DIEA
DCM 16h
oc OH
n oxane
i 4NHCl i di
HATU DIEA
a a ,
ii S t N HCO
) DCM 16h
N 2 N
n oxane
i 4NHCl i di
ii S t N HCO
(E)-methyl 3-(1-methyl-1H-pyrazolyl)acrylate: Cs CO (1.304g, 4 mmol) was
added to a solution of 1H-pyrazolecarbaldehyde (0.192 g, 2 mmol) in dioxane (8 mL) at
room temperature. Trimethylphosphonoacetate (0.364g, 0.40 mmol) was added to this
suspension, followed by DMSO (2 mL). The reaction mixture was heated to 100 C overnight.
It was then diluted with EtOAc (40 mL), and washed with water (40 mL) and brine (20 mL).
The organic layer was concentrated under vacuum. The crude was purified by silica gel
column chromatography using a 0-100% gradient of EtOAc in hexanes to provide (E)-methyl
3-(1-methyl-1H-pyrazolyl)acrylate (0.278 g). ES (M+H) 167
(E)(1-methyl-1H-pyrazolyl)acrylic acid: (E)-methyl 3-(1-methyl-1H-pyrazol-
4-yl)acrylate (0.24 g, 1.45 mmol) was dissolved in MeOH (10 mL). A 1M solution of KOH
(5.8 mL) was added and the mixture was heated at 70 C overnight. The reaction mixture was
then evaporated under reduced pressure and water (10 mL) was added to the residue. This
solution was carefully acidified to pH 4 with a 3M aqueous solution of HCl. The carboxylic
acid precipitated and was extracted with ethyl acetate. The EtOAc layer was washed with
water (2 x 10 mL) and brine (1 x 15 mL). It was dried over sodium sulfate, filtered and
12354570_1 (GHMatters) P107928.NZ
evaporated under vacuum to give (E)(1-methyl-1H-pyrazolyl)acrylic acid as a white
solid (160 mg). ES (M+H) 153
(E)-tert-butyl (5-fluoro(3-(1-methyl-1H-pyrazolyl)acrylamido)
phenyl)carbamate: DIPEA (0.16 g, 1.20 mmol), 4-fluoro-tert-butyl
aminophenylcarbamate (0.14 g, 0.64 mmol) and HATU (0.20 g, 0.52 mmol) were added to a
solution of (E)(1-methyl-1H-pyrazolyl)acrylic acid (0.061 g, 0.401 mmol) in DCM (10
mL). The reaction mixture was stirred overnight at room temperature under nitrogen. After
completion of the reaction as indicated by HPLC, the organic solution was washed with
saturated NaHCO then brine. It was dried over Na SO and the solvent was evaporated.
3 2 4
Crude (E)-tert-butyl (5-fluoro(3-(1-methyl-1H-pyrazolyl)acrylamido)phenyl)carbamate
was purified by column chromatography using a 20-80% gradient of EtOAc in hexanes to
give the title compound (0.15 g) as an off-white solid. ES (M+H) 361.
(E)-N-(2-aminofluorophenyl)(1-methyl-1H-pyrazolyl)acrylamide: (E)-tert-
butyl (5-fluoro(3-(1-methyl-1H-pyrazolyl)acrylamido)phenyl)carbamate (0.15 g, 0.42
mmol) was dissolved in dioxane (4 mL). A 4M solution of HCl in dioxane (4 mL) was added
and the mixture was stirred at room temperature for 3 h. Salt precipitation was observed. The
reaction mixture was then diluted with diethyl ether (20 mL) and the crude hydrochloride salt
was filtered. It was stirred with saturated sodium bicarbonate (excess) and filtered. The
precipitate was washed with water and vacuum dried. (E)-N-(2-aminofluorophenyl)(1-
methyl-1H-pyrazolyl)acrylamide (73 mg) was obtained as an off-white solid. H NMR
(CD OD) δ: 7.88 (s, 1H), 7.77 (s, 1H), 7.53 (d, J = 15.7 Hz, 1H), 7.12 (dd, J = 8.5, 5.9 Hz,
1H), 6.54 (d, J = 15.9 Hz, 1H), 6.55 (dd, J = 10.5, 3.0 Hz, 1H), 6.39 (td, J = 8.5, 2.7 Hz, 1H),
3.90 (s, 4H); ES (M+H) 261.
Example 6: (E)-N-(2-aminofluorophenyl)(1-methyl-1H-pyrazolyl)acrylamide
(E)-tert-butyl (4-fluoro(3-(1-methyl-1H-pyrazolyl)acrylamido)
phenyl)carbamate: The protocol described above for the synthesis of (E)-tert-butyl (4-fluoro-
2-(3-(1-methyl-1H-pyrazolyl)acrylamido)phenyl)carbamate was used substituting 4-
fluoro-tert-butylaminophenylcarbamate (0.14 g, 0.64 mmol) for the 5-fluoro analog. Thus
starting from (E)(1-methyl-1H-pyrazolyl)acrylic acid (0.061 g, 0.401 mmol) in DCM
(10 mL), 0.10 g of pure (E)-tert-butyl (4-fluoro(3-(1-methyl-1H-pyrazolyl)acrylamido)
phenyl)carbamate were obtained as an off-white solid after silica gel chromatography. ES
(M+H) 361.
12354570_1 (GHMatters) P107928.NZ
(E)-N-(2-aminofluorophenyl)(1-methyl-1H-pyrazolyl)acrylamide:
Protecting group removal was effected by addition of a 4M solution of HCl in dioxane
(2.5mL) to a solution of (E)-tert-butyl (4-fluoro(3-(1-methyl-1H-pyrazolyl)acrylamido)
phenyl)carbamate (0.10 g, 0.28 mmol) in dioxane (2.5 mL). The mixture was stirred at room
temperature for 3 h. The reaction mixture was diluted with diethyl ether (20 mL) and the
hydrochloride salt of (E)-N-(2-aminofluorophenyl)(1-methyl-1H-pyrazol
yl)acrylamide precipitated was filtered. It was suspended in a saturated sodium bicarbonate
solution and the mixture was stirred. The solid was filtered and washed with water then dried
under vacuum to give the pure product (58 mg) as an off-white solid. ES (M+H) 261.
12354570_1 (GHMatters) P107928.NZ
Table: Method C
Compound Structure R- (RO)2P(O)CH2CO2R diamine MS NMR
C1 CH -CH - HN ES (M+H) 257
3 2 H NMR (CD3OD) δ: 7.94 (s, 1H), 7.79
(s, 1H), 7.55 (d, J = 15.7 Hz, 1H), 7.17
(dd, J = 8.0, 1.1 Hz, 1H), 7.04 (td, J =
7.7, 1.4 Hz, 1H), 6.87 (dd, J = 8.0, 1.4
Hz, 1H), 6.74 (td, J = 7.7, 1.4 Hz, 1H),
6.57 (d, J = 15.7 Hz, 1H), 4.20 (q, J = 7.4
Hz, 2H), 1.47 (t, J = 7.4 Hz, 3H)
+ + 1
C2 N CH - HN ES (M+H) 261 H NMR (CD OD) δ: 7.88 (s, 1H), 7.77
(s, 1H), 7.53 (d, J = 15.7 Hz, 1H), 7.12
(dd, J = 8.5, 5.9 Hz, 1H), 6.54 (d, J =
.7 Hz, 1H), 6.55 (dd, J = 10.5, 3.0 Hz,
1H), 6.39 (td, J = 8.5, 2.7 Hz, 1H), 3.90
(s, 3H)
C3 CH - ES (M+H) 261
N 3 H NMR (CD OD) δ: 7.89 (s, 1H), 7.77
(s, 1H), 7.56 (d, J = 15.7 Hz, 1H), 7.13
O (dd, J = 9.9, 2.7 Hz, 1H), 6.78 (td, J =
8.5, 2.7 Hz, 1H), 6.84 (dd, J = 8.8, 5.8
Hz, 1H), 6.56 (d, J = 15.7 Hz, 1H), 3.90
(s, 3H)
12354570_1 (GHMatters) P107928.NZ
Method D
R O O
O 8 8 R O
O O R O
R P R 7 R
R P R 7 R
+ 6 7 7
6 7 7
or R O r e
+ R O
O O 8 A /H t O
r e O O or 8 Ar/Het O
A /H t R R
Ar/Het 4 8
4 O 8
6 R 5 R
R5 R
5 5
O R O R O
O R O R O
O O 8 4 4
O O 8
P R R
- - - -
R P R P R7 R7
+ R P R7 7
r e 6 6 7 r e
R X A /H t R or R O R X A /H t O
R -X-Ar/Het R + R O R -X-Ar/Het O
1 4 O O 8 1
1 4 or 8 1
O O R
R R R
6 6 R R
R 5 5 5 5
R X A /H t OH
R1-X-Ar/Het OH
R X A H t N
R -X-Ar//Het N
R HN
R HN
R X A /H t N
R -X-Ar/Het N
R NH
R5 NH
2 2
Compounds described herein, where n =1, and R1, X, R2, R3, R4, R5, and Ar/Het
are defined as defined anywhere herein, can be prepared by reaction of a mono or bicyclic
heterocycle aldehyde or ketone, which can be prepared by methods well known to those
skilled in the art and detailed in, for example, Joule JA and Mills K, Heterocyclic Chemistry,
Fifth Edition, John Wiley & Sons, Inc., Hoboken, NJ, USA, with a dialkoxyphosphoryl acetic
acid ester or a trialkyl, or triphenyl phosphoranylidene acetic acid ester to give the
corresponding γ-(heterocycle)acrylate ester Ar/Het-CR4=CR5-COOR7. The R1-X- moiety
can then be added to this intermediate by synthetic methods well known to those skilled in
the art, including but not limited to Heck coupling, Suzuki reaction, alkylation, acylation.
Alternatively the R1-X- substituent can be coupled to the aldehyde or ketone prior to the
Wittig or Horner-Wadsworth-Emmons reaction to give the same intermediate ester. The ester
can then be hydrolyzed and the acid reacted with a protected or unprotected substituted or
12354570_1 (GHMatters) P107928.NZ
unsubstituted o-phenylenediamine to give compounds of the disclosure after deprotection if
required using methods well known to those skilled in the art and which are described for
example in P.G.M. Wuts and T.W. Greene, 2006, Greene’s Protective Groups in Organic
Synthesis, Fourth Edition, John Wiley & Sons, Inc., Hoboken, NJ, USA.
Example 7: (E)-N-(2-aminophenyl)(1-(2-phenoxyethyl)-1H-pyrazolyl)acrylamide
Ph B
ACN CS CO
80 C 14h
KOH EtOH H O
60 C 6h
, , N
HATU DIEA
D M 1 h
Or alternatively
CO M
B P 2 e
CHO CO M
N O N
H N H DMF ,
N M THF
N OH
CO H
2 H N
HATU DIEA
(E)-ethyl 3-(1-(2-phenoxyethyl)-1H-pyrazolyl)acrylate: Cesium carbonate
(0.490g, 1.5 mmol) and 1-(2-bromoethoxy)benzene (0.261 g, 1.30 mmol) were added to a
solution of (E)-ethyl 3-(1H-pyrazolyl)acrylate (0.167 g, 1 mmol) in ACN (8 mL) at room
temperature. The suspension was stirred overnight at 80°C. The reaction mixture was then
12354570_1 (GHMatters) P107928.NZ
cooled down to room temperature and the precipitated solids were filtered off. The filtrate
was concentrated and purified by silica gel column chromatography using a gradient of 0-
60% of EtOAc in hexanes to provide the title compound (0.203g, 71%) as a colorless oil. ES
(M+H) 287
(E)(1-(2-phenoxyethyl)-1H-pyrazolyl)acrylic acid: To a solution of (E)-ethyl
3-(1-(2-phenoxyethyl)-1H-pyrazolyl)acrylate (0.143 g, 0.5 mmol) in EtOH (6 mL) was
added KOH (0.168g, 3mmol) in water (2 mL) and the solution was heated at 60°C for 6h.
The reaction mixture was then evaporated under vacuum and water (10 mL) was added to the
residue. This solution was acidified to pH 4 with aqueous 3N HCl and extracted with EtOAc.
The organic extracts were washed with water and brine, dried over Na SO and evaporated in
vacuo to get the acid (0.117g, 91%) as a white solid. ES (M+H) 259
Alternate synthesis: 1-(2-phenoxyethyl)-1H-pyrazolecarbaldehyde: Sodium
hydride (60%, 6.3 g, 1.0 eq) was added to a solution of 1H-pyrazolecarbaldehyde (15 g,
156 mmol) in DMF (150 ml) at 0°C. The mixture was allowed to warm and was stirred at
room temperature. (2-Bromoethoxy)benzene (30.2 g, 1 eq) was then added and the resulting
mixture was stirred overnight at room temperature. It was quenched by addition of aqueous
ammonium chloride, diluted with water and extracted with EtOAc. The combined organic
layers were dried over Na SO , filtered, and concentrated. The residue was purified by
column chromatography using a hexane/EtOAc gradient (10:1 to 0:100). Pure fractions were
combined and evaporated under reduced pressure to yield 1-(2-phenoxyethyl)-1H-pyrazole
carbaldehyde (24 g, 71%).
Alternate synthesis: (E)-methyl 3-(1-(2-phenoxyethyl)-1H-pyrazolyl)acrylate:
Trimethyl phosphonoacetate (20.6 g, 112 mmol) was dissolved in 350 mL THF. A 25% w/w
NaOMe solution (25 mL) was then added at room temperature and the resulting mixture was
stirred for 30 min. 1-(2-Phenoxyethyl)-1H-pyrazolecarbaldehyde (24 g, 111 mmol)
dissolved in 150 mL THF was added and the reaction mixture was stirred for 5h before being
quenched with aqueous ammonium chloride and extracted with EtOAc. The combined
organic layers were dried over Na SO , filtered, and concentrated under vacuum. The residue
was purified by column chromatography using a gradient of hexane/EtOAc (30:1 to 1:2) to
yield (E)-methyl 3-(1-(2-phenoxyethyl)-1H-pyrazolyl)acrylate (22 g, 72.7%).
Alternate synthesis: (E)(1-(2-phenoxyethyl)-1H-pyrazolyl)acrylic acid: A 3M
aqueous solution of NaOH (80mL) was added to a solution of (E)-methyl 3-(1-(2-
phenoxyethyl)-1H-pyrazolyl)acrylate (22 g, 81 mmol) in MeOH (150 mL) at room
12354570_1 (GHMatters) P107928.NZ
temperature and the mixture was stirred overnight. The solvent was evaporated under reduced
pressure. The concentrated solution was washed with diethylether, acidified to pH = 2 with
dilute HCl, and extracted with dichloromethane. The combined organic extracts were washed
with water and brine, before being dried over Na2SO4. Salts were filtered and washed and the
filtrate was evaporated under reduced pressure. The product precipitated from the
concentrated solution upon standing. It was filtered and dried under vacuum to give the
corresponding (E)(1-(2-phenoxyethyl)-1H-pyrazolyl)acrylic acid (18 g, 86%).
(E)-N-(2-aminophenyl)(1-(2-phenoxyethyl)-1H-pyrazolyl)acrylamide, D3:
HATU (0.228g, 0.60 mmol), DIPEA (0.258g, 2.00 mmol) and o-phenylenediamine (0.129g,
1.20 mmol) were added to a solution of ((E)(1-(2-phenoxyethyl)-1H-pyrazolyl)acrylic
acid (0.103g, 0.40 mmol) in DCM (25 mL). The solution was stirred overnight at room
temperature. Solvents were evaporated in vacuo and the residue was taken up in EtOAc (40
mL). This solution was washed with saturated NaHCO and brine, dried (Na SO ) and
3 2 4
evaporated. The crude product was purified by silica gel column chromatography (gradient of
0-80% EtOAc in hexanes) to get D3 as an off-white solid (0.094g, 68%). H NMR (CD OD)
δ: 8.01 (s, 1H), 7.82 (s, 1H), 7.55 (d, J = 15.8 Hz, 1H), 7.21 - 7.31 (m, 2H), 7.17 (dd, J = 8.0,
1.1 Hz, 1H), 7.03 (td, J = 7.8, 1.2 Hz, 1H), 6.81 - 6.97 (m, 4H), 6.73 (td, J = 7.6, 1.4 Hz, 1H),
6.58 (d, J = 15.7 Hz, 1H), 4.53 (t, J = 5.1 Hz, 2H), 4.34 (t, J = 5.0 Hz, 2H); ES (M+H) 349.
12354570_1 (GHMatters) P107928.NZ
Example 8: hydrochloride salt of (E)-N-(2-aminofluorophenyl)(1-cinnamyl-1H-
pyrazolyl)acrylamide D2
Ph OEt
Ph OEt
Ph OEt
C O Ph B
CHO Ph O
Ph Ph Br
HN , o , HN
HN o C CS CO
ACN, CS CO ,
THF 70 C 8h 2 3
THF, 70 C, 8h 2 3
40 C 14h
40 C, 14h
KOH EtOH H O
KOH, EtOH, H O
60 C 6h
60 C, 6h
HATU DIEA
HATU, DIEA,
DCM 16h
DCM, 16h
NHBoc
n x n
o a e
4NHCl i Di
4NHCl in Dioxane
oxane
Dioxane
NH HCl
NH HCl
(E)-ethyl 3-(1H-pyrazolyl)acrylate:
[(Ethoxycarbonyl)methylene]triphenylphosphorane (0.836g, 2.4 mmol) was added to a
solution of 1H-pyrazolecarbaldehyde (0.192 g, 2 mmol) in THF (6 mL) at room
temperature. This solution was heated at 70 C under anitrogen atmosphere for 8h. HPLC/MS
analysis indicated completion of the reaction and both E and Z isomers of product were
observed. The reaction mixture was cooled down to room temperature and evaporated in
vacuo to get the crude product. This crude was purified by silica gel column chromatography
using 0-80% EtOAc in hexanes as eluent to provide, after evaporation of pooled fractions,
pure (E)-ethyl 3-(1H-pyrazolyl)acrylate (0.198g, 60%) as a white solid. ES (M+H) 167
(E)-ethyl 3-(1-cinnamyl-1H-pyrazolyl)acrylate: Cesium carbonate (0.490g, 1.5
mmol) was added to a solution of (E)-ethyl 3-(1H-pyrazolyl)acrylate (0.167 g, 1 mmol) in
ACN (8 mL) at room temperature. The suspension was stirred and 1-((E)bromoprop
enyl)benzene (0.256 g, 1.30 mmol) was added. The mixture was heated at 40°C overnight.
After cooling down to room temperature, the precipitated solids were filtered off. The filtrate
was concentrated and purified by silica gel column chromatography using a 0-60% gradient
12354570_1 (GHMatters) P107928.NZ
of EtOAc in hexanes to provide the title compound as a colorless oil (0.214g, 76%). ES
(M+H) 283
(E)(1-cinnamyl-1H-pyrazolyl)acrylic acid: The ethyl ester of (E)(1-
cinnamyl-1H-pyrazolyl)acrylic acid (0.141 g, 0.5 mmol) dissolved in ethanol (EtOH, 6
mL) was hydrolyzed by addition of a solution of KOH (0.168g, 3mmol) in water (2mL). The
mixture was heated to 60°C and the temperature was maintained for 6h. Solvents were then
evaporated under vacuum and water (10 mL) was added to the residue. This solution was
carefully acidified to pH 4 with a 3M solution of HCl in water and extracted with EtOAc. The
organic layer was washed with water and brine. It was dried (Na SO ), filtered and
evaporated to give the acid as a white solid (0.118g, 93%). ES (M+H) 255
tert-Butyl (2-((E)(1-cinnamyl-1H-pyrazolyl)acrylamido)fluorophenyl)
carbamate: (E)(1-cinnamyl-1H-pyrazolyl)acrylic acid (0.110g, 0.43 mmol) was
dissolved in DCM (25 mL). HATU (0.246g, 0.65 mmol), DIPEA (0.278 g, 2.15 mmol) and
tert-butyl 2-aminofluorophenylcarbamate (0.147g, 0.65 mmol) were added and the
mixture was stirred overnight at room temperature under nitrogen. Slovents were evaporated
and the residue was taken up in EtOAc (40 mL). It was then washed with saturated NaHCO
and brine, dried over Na SO , filtered and evaporated in vacuo to get the crude. The product
was purified by silica gel column chromatography using a gradient of 0-70% EtOAc in
hexanes to get tert-butyl (2-((E)(1-cinnamyl-1H-pyrazolyl)acrylamido)
fluorophenyl)carbamate5 (0.138g, 76%) as an off-white solid. ES (M+Na) 485.
Hydrochloride salt of (E)-N-(2-aminofluorophenyl)(1-cinnamyl-1H-pyrazol-
4-yl)acrylamide: A 4M solution of HCl in dioxane (4 mL) was mixed under nitrogen with a
solution of tert-butyl (2-((E)(1-cinnamyl-1H-pyrazolyl)acrylamido)
fluorophenyl)carbamate (0.138g, 0.30 mmol) in dioxane (12 mL). The mixture was stirred
for 4h at room temperature under nitrogen. Salt precipitation was observed. The
heterogeneous mixture was diluted with EtOAc (12 mL) and the precipitate was filtered,
washed with solvent and dried overnight under vacuum to get the pure hydrochloride salt of
(E)-N-(2-aminofluorophenyl)(1-cinnamyl-1H-pyrazolyl)acrylamide (0.110g, 92%)
as an off-white solid. H NMR (CD OD) δ: 8.08 (s, 1H), 7.90 (s, 1H), 7.71 (d, J = 15.5 Hz,
1H), 7.37 - 7.46 (m, 2H), 7.21 - 7.37 (m, 4H), 6.63 (d, J = 15.7 Hz, 1H), 6.56 - 6.71 (m, 1H),
6.43 (dt, J = 15.8, 6.2 Hz, 1H), 4.96 (dd, J = 6.3, 1.1 Hz, 2H); ES (M+H) 363
12354570_1 (GHMatters) P107928.NZ
Table: Method D
Compound Structure R1-X- coupling diamine MS NMR
reagent
NH + +
D1 ES (M+H)
H NMR (CD OD) δ: 7.98 (s, 1H),
7.83 (s, 1H), 7.56 (d, J = 15.8 Hz,
1H), 7.36 - 7.46 (m, 2H), 7.20 -
7.36 (m, 3H), 7.17 (dd, J = 8.1, 1.1
Hz, 1H), 7.03 (td, J = 7.7, 1.2 Hz,
1H), 6.86 (dd, J = 8.4, 1.2 Hz, 1H),
6.73 (td, J = 7.7, 1.4 Hz, 1H), 6.62
(d, J = 15.8 Hz, 1H), 6.59 (d, J =
.7 Hz, 1H), 6.42 (dt, J = 15.8, 6.2
Hz, 1H), 4.93 (d, J = 6.2 Hz, 2H)
B + +
D2 ES (M+H)
H NMR (CD OD) – HCl salt – δ:
8.08 (s, 1H), 7.90 (s, 1H), 7.71 (d, J
N = 15.5 Hz, 1H), 7.37 - 7.46 (m, 2H),
F 7.21 - 7.37 (m, 4H), 6.63 (d, J =
.7 Hz, 1H), 6.56 - 6.71 (m, 1H),
6.43 (dt, J = 15.8, 6.2 Hz, 1H), 4.96
(dd, J = 6.3, 1.1 Hz, 2H)
O NH + +
D3 r ES (M+H)
B H NMR (CD OD) δ: 8.01 (s, 1H),
349 7.82 (s, 1H), 7.55 (d, J = 15.8 Hz,
N 1H), 7.21 - 7.31 (m, 2H), 7.17 (dd, J
= 8.0, 1.1 Hz, 1H), 7.03 (td, J = 7.8,
1.2 Hz, 1H), 6.81 - 6.97 (m, 4H),
6.73 (td, J = 7.6, 1.4 Hz, 1H), 6.58
(d, J = 15.7 Hz, 1H), 4.53 (t, J = 5.1
Hz, 2H), 4.34 (t, J = 5.0 Hz, 2H)
NH + + 1
B ES (M+H)
D4 H NMR (CD OD) δ: 7.98 (s, 1H),
NH 319
7.82 (s, 1H), 7.55 (d, J = 15.7 Hz,
1H), 7.21 - 7.41 (m, 5H), 7.17 (dd, J
= 7.8, 1.2 Hz, 1H), 7.03 (ddd, J =
8.0, 7.8, 1.1 Hz, 1H), 6.86 (dd, J =
8.0, 1.4 Hz, 1H), 6.73 (td, J = 7.7,
12354570_1 (GHMatters) P107928.NZ
1.1 Hz, 1H), 6.58 (d, J = 15.7 Hz,
1H), 5.35 (s, 2H)
F + +
NH 1
ES (M+H)
D5 H NMR (CD OD) δ: 7.99 (s, 1H),
7.82 (s, 1H), 7.54 (d, J = 15.7 Hz,
H 1H), 7.24 - 7.38 (m, 2H), 7.17 (dd, J
= 8.0, 1.4 Hz, 1H), 6.99 - 7.13 (m,
2H), 7.03 (td, J = 7.6, 1.6 Hz, 1H),
6.86 (dd, J = 8.0, 1.4 Hz, 1H), 6.73
(td, J = 7.6, 1.4 Hz, 1H), 6.58 (d, J
= 15.7 Hz, 1H), 5.33 (s, 2H)
NH + +
D6 ES (M+H)
H NMR (CD OD) δ: 8.07 (s, 1H),
333 7.85 (s, 1H), 7.68 (t, J = 7.7 Hz,
1H), 7.57 (d, J = 15.8 Hz, 1H), 7.22
N (d, J = 7.7 Hz, 2H), 7.18 (dd, J =
7.7, 1.2 Hz, 1H), 7.04 (td, J = 7.7,
1.8 Hz, 1H), 6.87 (dd, J = 8.1, 1.4
Hz, 2H), 6.91 (d, J = 7.7 Hz, 1H),
6.74 (td, J = 7.6, 1.5 Hz, 1H), 6.60
(d, J = 15.7 Hz, 1H), 5.42 (s, 2H),
2.53 (s, 3H)
B NH + +
D7 ES (M+H)
NH H NMR (CD OD) δ: 7.80 (s, 1H),
7.62 - 7.71 (m, 1H), 7.47 (d, J =
.7 Hz, 1H), 7.13 - 7.26 (m, 4H),
7.07 - 7.13 (m, 2H), 7.03 (td, J =
7.7, 1.5 Hz, 1H), 6.86 (dd, J = 8.1,
1.5 Hz, 1H), 6.73 (td, J = 7.6, 1.5
Hz, 1H), 6.51 (d, J = 15.7 Hz, 1H),
4.38 (t, J = 7.0 Hz, 2H), 3.14 (t, J =
7.0 Hz, 2H)
NH + +
ES (M+H)
D8 H NMR (CD OD) δ: 7.92 (s, 1H),
347 7.81 (s, 1H), 7.55 (d, J = 15.7 Hz,
1H), 7.23 - 7.35 (m, 2H), 7.12 -
7.22 (m, 4H), 7.04 (td, J = 7.8, 1.5
Hz, 1H), 6.87 (dd, J = 8.0, 1.4 Hz,
1H), 6.74 (td, J = 7.6, 1.4 Hz, 1H),
12354570_1 (GHMatters) P107928.NZ
6.57 (d, J = 15.7 Hz, 1H), 4.16 (t, J
= 7.0 Hz, 3H), 2.60 (t, J = 7.7 Hz,
3H), 2.18 (tt, J = 7.7, 7.0 Hz, 3H)
B NH + +
D9 ES (M+H)
H NMR (CD OD) δ: 7.90 (s, 1H),
NH 2
2 361
7.79 (s, 1H), 7.54 (d, J = 15.7 Hz,
1H), 7.20 - 7.31 (m, 2H), 7.09 -
7.20 (m, 4H), 7.03 (td, J = 7.5, 1.4
Hz, 1H), 6.87 (dd, J = 8.1, 1.2 Hz,
1H), 6.74 (td, J = 7.5, 1.5 Hz, 1H),
6.56 (d, J = 15.7 Hz, 1H), 4.17 (t, J
= 7.0 Hz, 2H), 2.63 (t, J = 7.6 Hz,
2H), 1.88 (quin, J = 7.0 Hz, 2H),
1.59 (tt, J = 7.6, 7.0 Hz, 2H)
F F NH + +
D10 ES (M+H)
H NMR (CD OD) δ: 7.85 (s, 1H),
369 7.78 (s, 1H), 7.5 (d, J = 15.6 Hz,
1H), 7.46 - 7.40 (m, 5H), 7.17 (dd, J
= 8.1, 1.5 Hz, 1H), 7.04 (td, J = 7.2,
1.5 Hz, 1H), 6.86 (dd, J = 8.1, 1.2
Hz, 1H), 6.73 (td, J = 8.1, 1.2 Hz,
1H), 6.57 (d, J = 15.6 Hz, 1H), 4.84
(t, J = 13.5 Hz, 2H)
Cl NH 1
ES (M+H)
D11 H NMR (CD OD) δ: 7.94 (s, 1H),
7.81 (s, 1H), 7.53 (d, J = 15.7 Hz,
1H), 7.21 - 7.39 (m, 4H), 7.11 -
7.21 (m, 2H), 7.03 (td, J = 7.7, 1.4
Hz, 1H), 6.86 (dd, J = 8.0, 1.2 Hz,
1H), 6.73 (td, J = 7.6, 1.2 Hz, 1H),
6.56 (d, J = 15.5 Hz, 1H), 6.39 (d, J
= 16.1 Hz, 1H), 6.18 (dt, J = 15.9,
7.0 Hz, 1H), 4.30 (t, J = 6.9 Hz,
2H), 2.75 (q, J = 6.8 Hz, 2H)
12354570_1 (GHMatters) P107928.NZ
B + + 1
D12 ES (M+H) H NMR (CD OD) δ: 7.90 (s, 1H),
N Cl
NH 378
7.83 (s, 1H), 7.55 (d, J = 15.7 Hz,
2 H N
1H), 7.09 - 7.23 (m, 3H), 7.03 (td, J
= 7.7, 1.2 Hz, 1H), 6.87 (dd, J =
8.0, 1.4 Hz, 1H), 6.74 (td, J = 7.7,
1.2 Hz, 1H), 6.61 - 6.70 (m, 3H),
6.57 (d, J = 15.8 Hz, 1H), 4.21 (t, J
= 6.9 Hz, 2H), 3.33 (t, J = 7.1 Hz,
2H), 2.89 (s, 3H), 2.13 (quin, J =
7.1 Hz, 2H)
ES (M+H)
D13 H NMR (CD OD) δ: 7.81 (s, 1H),
7.63 (s, 1H), 7.48 (br. d, J = 7.7 Hz,
1H), 7.46 (d, J = 15.7 Hz, 1H), 7.32
(br. d, J = 8.2 Hz, 1H), 7.16 (dd, J =
7.9, 1.3 Hz, 1H), 7.08 (m, 3H), 6.88
(s, 1H), 6.86 (dd, J = 8.1, 1.4 Hz,
1H), 6.73 (td, J = 7.6, 1.5 Hz, 1H),
6.49 (d, J = 15.5 Hz, 1H), 4.42 (t, J
= 7.0 Hz, 2H), 3.29 (t, J = 7.0 Hz,
r oc
B + +
D14 ES (M+H)
H NMR (CD OD) δ: 7.94 (s, 1H),
7.80 (s, 1H), 7.56 (d, J = 15.7 Hz,
H H N
1H), 7.12 - 7.35 (m, 6H), 7.04 (td, J
= 7.7, 1.2 Hz, 1H), 6.87 (dd, J =
8.1, 1.2 Hz, 1H), 6.74 (td, J = 7.6,
1.4 Hz, 1H), 6.58 (d, J = 15.7 Hz,
1H), 4.48 (s, 2H), 4.34 (t, J = 5.1
Hz, 2H), 3.82 (t, J = 5.1 Hz, 2H)
O B B + +
D15 ES (M+H)
H NMR (CD OD) δ: 7.96 (s, 1H),
O HN 3
2 363
7.83 (s, 1H), 7.62 (d, J = 15.7 Hz,
1H), 7.08 - 7.37 (m, 6H), 6.81 -
6.99 (m, 3H), 6.57 (d, J = 15.5 Hz,
1H), 4.38 (t, J = 6.7 Hz, 2H), 3.95
(t, J = 5.8 Hz, 2H), 2.32 (quin, J =
6.4 Hz, 2H)
12354570_1 (GHMatters) P107928.NZ
NH O
12354570_1 (GHMatters) P107928.NZ
Method E
reac reac
R X t
1 1 2 4
R X A H t R
R O R O
- - - -
R X A /H t O R X A /H t N
if P
R X A H t N
R NH
- - -
reac
or reac reac or
R R X t R t t R R R
O HN
8 1 2 9
8 1 3 9 7
R HN
R A /H t R
R - -
= = =
reac an
if R t if R R X d R O R
8 3 8 1 9 7
- - -
reac =
R X Y t
1 4 if R R X
if R NH C H R R NHP
9 6 2 2 3
R O R O
if R O R
- - - -
r e r e
R X A /H t R R X A /H t N
1 9 1
R R HN
5 ,
if P
R X A /H t N
R NH
Compounds described herein, where n = 1, and R1, X, R2, R3, R4, R5 are as
defined anywhere herein, can be prepared by heterocycle ring formation using methods well
known to those skilled in the art, examples of which can be found in, for example, Joule JA
and Mills K, Heterocyclic Chemistry, Fifth Edition, John Wiley & Sons, Inc., Hoboken, NJ,
USA. This methodology allows for synthesis of both monocyclic and bicyclic heterocyclic
12354570_1 (GHMatters) P107928.NZ
systems. As compared to previous methods described in this disclosure, method 5 consists in
building a mono or bicyclic system bearing R1-X and/or C(R4)=C(R5)-
CONH(C H R2R3(NH )) or a protected or unprotected synthetic precursor (see schemes
6 2 2
above for generic examples). Thus adequately substituted reagents are coupled to form
heterocyclic ring systems using methods such as the Hantsch thiazole synthesis, the Fisher
indole synthesis, the Davidson or Robinson-Gabriel oxazole syntheses, as well as other
annulation reactions using complementary bifunctional reagents to effect ring closure and
aromatization. Similar techniques can be used to prepare bicyclic heterocycles by expanding
monocyclic analogs. For example, azabridged triazolothiazoles and triazolooxazoles can be
obtained by methods described in, for example, Pilla M et al, Bioorg Med Chem Lett 20
(2010) 7521; pyrazolopyridines can be prepared as detailed in, for example, Riether D et al, J
Med Chem 53 (2010) 6681. The synthesis of substituted indolazines has also been detailed in
many articles.
Example 9: (E)-N-(2-aminophenyl)(6-(ethoxymethyl)imidazo[2,1-b]thiazol
yl)acrylamide E1
2 OEt
EtO N
(E)-ethyl 3-(2-aminothiazolyl)acrylate: 2-Aminothiazolecarbaldehyde (0.25
g, 2 mmol) was dissolved in anhydrous THF (20mL). (Ethoxycarbonylmethylene)
triphenylphosphorane (0.790 g, 2.2 mmol) was added at room temperature and the reaction
mixture was heated overnight at 65 C. The reaction mixture was then evaporated under
reduced pressure. The residue was purified by silica gel column chromatography using a
12354570_1 (GHMatters) P107928.NZ
gradient of 50-80% EtOAc in Hexanes to provide pure (E)-ethyl 3-(2-aminothiazol
yl)acrylate (0.24g) as a white solid. ES (M+H) 199.
(E)-ethyl 3-(6-(ethoxymethyl)imidazo[2,1-b]thiazolyl)acrylate: 1,3-
Dichloroacetone (0.252g, 2mmol) was added to a solution of (E)-ethyl 3-(2-aminothiazol
yl)acrylate (0.199g, 1mmol) in EtOH (5mL). The solution was heated at 80 C overnight in a
closed vial. The reaction mixture was then evaporated and the residue was treated with a
saturated NaHCO solution (20 mL). It was extracted with EtOAc (30 mL). The organic layer
was separated, dried over Na SO , filtered and evaporated. The crude was purified by silica
gel column chromatography (50-100% gradient of EtOAc in Hexanes) to provide pure (E)-
ethyl 3-(6-(ethoxymethyl)imidazo[2,1-b]thiazolyl)acrylate (0.080g) as a tan solid. ES
(M+H) 281.
(E)(6-(ethoxymethyl)imidazo[2,1-b]thiazolyl)acrylic acid: A solution of (E)-
ethyl 3-(6-(ethoxymethyl)imidazo[2,1-b]thiazolyl)acrylate (0.080 g, 0.28 mmol) in EtOH
(5 mL) was treated with a 1M aqueous solution of KOH (1 mL). The mixture was heated to
50 C for 6h. The reaction mixture was then evaporated under reduced pressure and water (10
mL) was added to the residue. This solution was carefully acidified to pH 4 with 3M aqueous
HCl. Since the product was soluble in water, the acidified solution was evaporated in vacuo
to get (E)(6-(ethoxymethyl)imidazo[2,1-b]thiazolyl)acrylic acid as an HCl salt along
with inorganic solids, which was used for the next step without further purification. ES
(M+H) 253.
(E)-tert-butyl (2-(3-(6-(ethoxymethyl)imidazo[2,1-b]thiazolyl)acrylamido)
phenyl) carbamate: The crude HCl salt of (E)(6-(ethoxymethyl)imidazo[2,1-b]thiazol
yl)acrylic acid (0.080 g, 0.28 mmol, based on (E)-ethyl 3-(6-(ethoxymethyl)imidazo[2,1-
b]thiazolyl)acrylate) was suspended in DCM (10 mL. DIPEA (0.22 g, 1.68 mmol), tert-
butylaminophenylcarbamate (0.087 g, 0.42 mmol) and HATU (0.160 g, 0.42 mmol) were
added and the reaction mixture was stirred overnight at room temperature under nitrogen.
After completion of the reaction as indicated by HPLC, the reaction mixture was washed with
saturated NaHCO and brine. The organic layer was then dried (Na SO ), filtered and
3 2 4
evaporated under reduced pressure. The crude product was purified by silica gel column
chromatography using a gradient of 0 to 8% MeOH in DCM to provide pure (E)-tert-butyl
(2-(3-(6-(ethoxymethyl)imidazo[2,1-b]thiazolyl)acrylamido)phenyl) carbamate (0.033g)
as a tan solid. ES (M+Na) 465.
12354570_1 (GHMatters) P107928.NZ
(E)-N-(2-aminophenyl)(6-(ethoxymethyl)imidazo[2,1-b]thiazolyl) acrylamide:
(E)-tert-butyl (2-(3-(6-(ethoxymethyl)imidazo[2,1-b]thiazolyl)acrylamido)phenyl)
carbamate (0.033 g, 0.071 mmol) was dissolved in dioxane (2mL). A 4M solution of HCl in
dioxane (2. mL) was then added and the mixture stirred at room temperature for 3 h. Salt
precipitation was observed. The reaction mixture was then filtered and washed with DCM (3
mL). The white solid was treated with a saturated NaHCO3 solution to neutralize the acid.
After washing with water and drying under vacuum, pure (E)-N-(2-aminophenyl)(6-
(ethoxymethyl)imidazo[2,1-b]thiazolyl)acrylamide (14mg) was obtained as a tan solid.
ES (M+H) 343.
Example 10: (E)-N-(2-aminophenyl)(2-cinnamylthiazolyl)acrylamide, E2
l D M O
COC C O
2 THF
NH OH
awesson s rea en
L g t
o uene re ux
T l fl
THF O
EtOH
COOH
Ph P
NH NH
ou n
C pli g
(E)phenylbutenamide: A solution of (E)phenylbutenoic acid (1.5 g,
9.25 mmol) in dichloromethane (100 mL) was cooled to 0°C. Oxalyl chloride (1.76 g, 13.86
mmol) was then added dropwise. After addition of three drops of anhydrous DMF, the
reaction mixture was brought to room temperature and stirred for 2h. Dichloromethane was
evaporated under vacuum. The crude residue was dissolved in toluene (25 mL) and
concentrated in-vacuo. This operation was repeated two times to give the acid chloride,
which was dissolved in THF(30 mL) and treated with aqueous ammonium hydroxide (30%)
(20 mL) to give the corresponding amide. Purification by silica gel column chromatography
using a 20-100% gradient of EtOAc in hexane gave pure (E)phenylbutenamide (1.3 g)
as a white solid.
12354570_1 (GHMatters) P107928.NZ
(E)phenylbutenethioamide: Lawesson’s reagent (1.88 g, 4.65 mmol) was
added to (E)phenylbutenamide (500 mg, 3.10 mmol) in toluene (25 mL). The reaction
mixture was refluxed for 24 h then cooled to room temperature. The solvent was then
removed under reduced pressure. The crude residue was purified twice by column
chromatography to give > 90% pure (E)phenylbutenethioamide (320 mg).
(E)(2-cinnamylthiazolyl)acrylic acid: (E)phenylbutenethioamide (120
mg, 0.68 mmol) was dissolved in ethanol (20 mL). (E)bromooxopentenoic acid (290
mg, 1.50 mmol) was then added at room temperature and the reaction mixture was stirred for
1h. The solution was concentrated and the crude residue was purified by column
chromatography to give (E)(2-cinnamylthiazolyl)acrylic acid (90 mg). ES+ (M+H)+
272. [Note: (E)bromooxopentenoic acid was synthesized from commercially
available (E)oxopentenoic acid using (2-carboxyethyl)triphenylphosphonium
tribromide in THF]
(E)-N-(2-aminophenyl)(2-cinnamylthiazolyl)acrylamide: DIPEA (0.21 g,
0.54 mmol), o-phenylene diamine (39 mg, 0.36 mmol) and HATU (89 mg, 0.23 mmol) were
added to a solution of (E)(2-cinnamylthiazolyl)acrylic acid (50 mg, 0.18 mmol) in
DCM (20 mL) and the reaction mixture was stirred overnight at room temperature under
nitrogen. After completion of the reaction as indicated by HPLC, the reaction mixture was
washed with saturated NaHCO and brine. The organic layer was then dried (Na SO ) and
3 2 4
evaporated to give the crude product. Repeated silica gel column chromatography using a 0-
in DCM gave pure (E)-N-(2-aminophenyl)
% gradient of MeOH, containing 0.1% NH3
+ + 1
(2-cinnamylthiazolyl)acrylamide (26 mg) as a tan-colored solid. ES (M+H) 362. H
NMR (CD OD) δ: 7.66 (s, 1H), 7.60 (d, J = 15.4 Hz, 1H), 7.39 - 7.45 (m, 2H), 7.27 - 7.35 (m,
2H), 7.20 (dd, J = 8.0, 1.4 Hz, 1H), 7.17 - 7.26 (m, 1H), 7.04 (ddd, J = 8.0, 7.7, 1.4 Hz, 1H),
7.05 (d, J = 15.3 Hz, 1H), 6.87 (dd, J = 8.0, 1.4 Hz, 1H), 6.74 (td, J = 7.7, 1.4 Hz, 1H), 6.66
(dt, J = 15.9, 1.1 Hz, 1H), 6.47 (dt, J = 15.9, 6.9 Hz, 1H), 3.95 (dd, J = 6.9, 1.1 Hz, 2H)
12354570_1 (GHMatters) P107928.NZ
Method F
R R R
R
9 3
O -
- -
, , =
= or w ere or
or + h R R HN
R V P H Cy O O
11 O
R O R R HN
9 7 9
R R V
12 1
or e ro ec on rs or e ro ec on rs
R H P d p t ti fi t R H P d p t ti fi t
12 ( )
12 ( )
R R R
5 - 5
R R V
12 1
V V V P
R Cy R Cy R Cy HN
1 1 1
OH O N
O O O
V P V
R Cy HN R Cy NH
1 1 2
Compounds described herein, where n =0, Cy is a mono or bicyclic heterocyclic
amine, can be prepared, amongst other potential approaches, by Wittig or Horner Wadsworth
Emmons coupling of an N-protected mono or bicyclic amino heterocyclic ketone with a 4-α-
phosphoranylidenemethyl or phosphonate-substituted or unsubstituted 4-alkyl or aralkyl
benzoic acid derivative, such as, but not limited to, an ester or amide. The exocyclic alkene
substituted protected heterocyclic amine derivative can be deprotected by methods well
known to those skilled in the art and which can be found, for example, in P.G.M. Wuts and
T.W. Greene, 2006, Greene’s Protective Groups in Organic Synthesis, Fourth Edition, John
Wiley & Sons, Inc., Hoboken, NJ, USA. The amine can then be derivatized by R1-V
substituents using methods as diverse as, but not limited to, acylation, alkylation, reductive
amination. Saponification of the benzoate ester, if present, allows for reaction of the acid with
a protected or unprotected substituted or unsubstituted o-phenylenediamine. Alternatively,
the protected or unprotected substituted or unsubstituted o-phenylenediamine can be
introduced at an earlier step in the synthesis. Compounds of the disclosure, R1-V-Cy-U-
Ar/Het-CO-NH-C H R2R3-NH , are obtained after deprotection of the amino group using
6 2 2
12354570_1 (GHMatters) P107928.NZ
methodologies well known to those skilled in the art. The double bond between Cy and U can
also be reduced by hydrogenation to give saturated analogs.
Example 11: 4-((1-((1H-indolyl)methyl)azetidinylidene)methyl)-N-(2-
aminophenyl)chlorobenzamide F5
COOCH
COOCH
Cl HN
B Ph P
COOCH
COOC
COOH
B HN
(2-Chloro(methoxycarbonyl)benzyl)triphenylphosphonium bromide: Methyl 3-
chloromethylbenzoate (2.20 g, 11.96 mmol) was dissolved in carbon tetrachloride (30 mL)
and N-bromosuccinimide (2.10 g, 11.80 mmol) was added followed by a catalytic amount of
benzoyl peroxide (25 mg). The reaction mixture was refluxed for 6h. (ca. 90% conversion).
After cooling to room temperature, a precipitate was filtered. The filtrate was concentrated to
give crude brominated intermediate (3.20 g), which was used for the next step without further
purification.
The brominated intermediate from above (3.20 g, 12.17 mmol) was dissolved in
toluene (100 mL) and triphenylphosphine (6.50 g, 12.17 mmol) was added. The reaction
mixture was heated at 70 C for 6h. Precipitation was observed right away. On completion as
monitored by TLC the reaction mixture was cooled to room temperature and diluted with
toluene (100 mL). The precipitate was filtered, washed with hexanes and air dried to give
4.68 g of (2-chloro(methoxycarbonyl)benzyl)triphenylphosphonium bromide as a white
solid. ES (M+H) 445.1
tert-Butyl 3-(2-chloro(methoxycarbonyl)benzylidene)azetidinecarboxylate:
(2-Chloro(methoxycarbonyl)benzyl)triphenylphosphonium bromide ( 1.04 g, 1.98 mmol)
12354570_1 (GHMatters) P107928.NZ
was dissolved in N,N-dimethylformamide (DMF, 20 mL) and the solution was cooled to 0 C.
A 60% suspension of NaH in paraffin oil (80 mg, 2.00 mmol) was added and the reaction
mixture was stirred at 0 C for 15 mins. A solution of tert-butyl 3-oxoazetidinecarboxylate
(0.32 g, 1.87 mmol) in anhydrous DMF (5 mL) was added and the reaction mixture was
heated overnight at 65 C. After completion of the reaction as indicated by HPLC/MS, the
cooled reaction mixture was diluted with EtOAC (20mL) and quenched with a saturated
NH Cl solution (10 mL). The organic layer was washed with water (3 x 20 mL) and brine (15
mL). It was then dried over anhydrous Na SO , filtered and evaporated to get the crude
product. This crude was purified by silica gel column chromatography using 50-80% EtOAc
in Hexanes as eluent to provide tert-butyl 3-(2-chloro
(methoxycarbonyl)benzylidene)azetidinecarboxylate (0.27 g) as a white solid. ES
(M+Na) 360.
Methyl 4-(azetidinylidenemethyl)chlorobenzoate: A 4 M solution of HCl in
dioxane (5 mL) was added to a solution of tert-butyl 3-(2-chloro(methoxycarbonyl)
benzylidene)azetidinecarboxylate (0.27 g, 0.66 mmol) in dioxane:DCM (1:1 v/v,10 mL)
and the mixture was stirred at room temperature for 3 h. Salt precipitation was observed. The
reaction mixture was diluted with diethyl ether (20 mL). The precipitate was filtered, washed
with ether and dried overnight to get the HCl salt of methyl 4-(azetidinylidenemethyl)
chlorobenzoate (0.12 g) as an off-white solid. ES (M+H) 238
Methyl 4-((1-((1H-indolyl)methyl)azetidinylidene)methyl)chlorobenzoate:
A solution of the hydrochloride salt of methyl 4-(azetidinylidenemethyl)chlorobenzoate
(0.20 g, 0.73 mmol) in THF:DCM (2:1) (25 mL) was neutralized by addition of triethylamine
(0.14 mL, 0.88 mmol). After stirring at room temperature for 20 mins, indole
carboxaldehyde (0.16 g, 1.00 mmol) and sodium triacetoxyborohydride (0.50 g, 2.37 mmol)
were added and the reaction mixture was heated at 50 C overnight. It was then diluted with
DCM (50 mL) and washed with saturated sodium bicarbonate (3 x 25 mL) and brine (1 x 15
mL). The organic layer was separated, dried (Na SO ) and filtered. The filtrate was
concentrated under vacuum to give the crude product which was purified by silica gel column
chromatography using 10-40% EtOAc in hexanes as eluent. Fractions containing the pure
product were pooled and evaporated to give 0.3 g of methyl 4-((1-((1H-indol
yl)methyl)azetidinylidene)methyl)chlorobenzoate (0.30 g) as a colorless oil. ES
(M+H) 367
12354570_1 (GHMatters) P107928.NZ
4-((1-((1H-Indolyl)methyl)azetidinylidene)methyl)chlorobenzoic acid: A 2
M aqueous solution of KOH (1.5 mL) was added to a solution of methyl 4-((1-((1H-indol
yl)methyl)azetidinylidene)methyl)chlorobenzoate (0.3 g, 0.82 mmol) in MeOH (7 mL)
and the mixture was stirred at room temperature overnight. The mixture was then evaporated
under reduced pressur and water (10 mL) was added to the residue. The solution was
carefully acidified to pH 5 with a 3 M aqueous solution of HCl . The precipitated solid was
extracted with ethyl acetate. The EtOAc layer was washed with water (2 x 10 mL) and brine
(1 x 15 mL). It was dried (Na SO ), filtered, and concentrated in vacuo to give 4-((1-((1H-
indolyl)methyl)azetidinylidene)methyl)chlorobenzoic acid as a white solid (0.26 g).
ES (M+H) 353.
tert-Butyl (2-(4-((1-((1H-indolyl)methyl)azetidinylidene)methyl)
chlorobenzamido)phenyl)carbamate: To a solution of 4-((1-((1H-indolyl)methyl)azetidin-
3-ylidene)methyl)chlorobenzoic acid (0.26 g, 0.74 mmol) in DCM (25 mL) was added
DIPEA (0.29 g, 2.22 mmol), tert-butylaminophenylcarbamate (0.27 g, 1.18 mmol) and
HATU (0.37 g, 0.96 mmol). The reaction mixture was stirred overnight at room temperature
under a nitrogen atmosphere. After completion of the reaction as indicated by HPLC, the
mixture was washed with saturated sodium bicarbonate (2 x 20 mL) and brine (1 x 15 mL). It
was dried (Na SO ), filtered and evaporated to give the crude product which was purified by
column chromatography (10% MeOH: 90% DCM). After evaporation of pooled fractions of
pure product, tert-butyl (2-(4-((1-((1H-indolyl)methyl)azetidinylidene)methyl)
(M+H)
chlorobenzamido)phenyl)carbamate (0.2 g) was isolated as an off-white solid. ES
543.
4-((1-((1H-Indolyl)methyl)azetidinylidene)methyl)-N-(2-aminophenyl)
chlorobenzamide: A 4 M solution of HCl in dioxane (5 mL) was added to a solution of tert-
butyl (2-(4-((1-((1H-indolyl)methyl)azetidinylidene)methyl)
chlorobenzamido)phenyl)carbamate (0.20 g, 0.37 mmol) in dioxane (5 mL) and the mixture
was stirred at room temperature for 3 h. Salt precipitation was observed. After completion of
the reaction as indicated by HPLC/MS, the mixture was diluted with diethyl ether (20 mL)
and the salt was filtered to give 110 mg of ca. 85% pure product. 45 mg were purified by
mass-triggered reverse phase auto-purification (0.1% NH OH as additive) to give 8 mg of
pure 4-((1-((1H-indolyl)methyl)azetidinylidene)methyl)-N-(2-aminophenyl)
chlorobenzamide. H H NMR (CD OD) δ: 8.03 (d, J = 1.8 Hz, 1H), 7.85 (dd, J = 8.2, 1.8 Hz,
1H), 7.52 (d, J = 8.1 Hz, 1H), 7.38 (s, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 3.2 Hz, 1H),
12354570_1 (GHMatters) P107928.NZ
7.16 (dd, J = 7.8, 1.3 Hz, 1H), 7.07 (ddd, J = 8.1, 7.3, 1.5 Hz, 1H), 7.02 (dd, J = 8.1, 1.5 Hz,
1H), 6.89 (dd, J = 8.1, 1.4 Hz, 1H), 6.76 (td, J = 7.7, 1.4 Hz, 1H), 6.68 (quin, J = 2.3 Hz, 1H),
6.41 (dd, J = 3.2, 1.0 Hz, 1H), 4.23 - 4.34 (m, 2H), 4.10 - 4.19 (m, 2H), 3.93 (s, 2H); ES
(M+H) 443.
12354570_1 (GHMatters) P107928.NZ
Table: Method F
Compound Structure R-X or aldehyde diamine MS NMR
NH + + 1
F1 ES (M+H) H NMR (CD OD) δ: 8.02 (d, J =
O Cl
8.2 Hz, 1H), 7.21 - 7.52 (m, 10H),
O N N
NH 6.85 - 7.15 (m, 2H), 6.50 (s, 1H),
.14 (s, 2H), 3.44 - 3.71 (m, 4H),
2.32 - 2.61 (m, 4H)
O NH + +
F2 O ES (M+H)
H NMR (CD OD) δ: 8.52 (d, J =
1.8 Hz, 1H), 8.45 (dd, J = 4.9, 1.6
Hz, 1H), 7.93 (d, J = 8.1 Hz, 2H),
7.86 (dt, J = 7.8, 1.9 Hz, 1H), 7.42
(ddd, J = 7.8, 4.9, 0.7 Hz, 1H), 7.33
(d, J = 8.1 Hz, 2H), 7.18 (dd, J =
7.8, 1.3 Hz, 1H), 7.07 (ddd, J = 8.0,
7.3, 1.4 Hz, 1H), 6.90 (dd, J = 8.1,
1.2 Hz, 1H), 6.76 (td, J = 7.6, 1.4
Hz, 1H), 6.39 (s, 1H), 3.60 (s, 2H),
2.40 - 2.65 (m, 8H)
NH + + 1
F3 ES (M+H) H NMR (CD OD) δ: 7.92 (d, J =
H H N
8.0 Hz, 2H), 7.53 (d, J = 8.4 Hz,
1H), 7.33 - 7.43 (br. s, 1H), 7.24 (d,
J = 8.0 Hz, 2H), 7.22 (d, J = 3.2 Hz,
1H), 7.17 (dd, J = 7.6, 1.5 Hz, 1H),
7.07 (td, J = 7.9, 1.5 Hz, 1H), 7.03
(dd, J = 8.5, 1.5 Hz, 3H), 6.89 (dd, J
= 8.0, 1.3 Hz, 1H), 6.76 (td, J = 7.7,
1.4 Hz, 1H), 6.42 (dd, J = 3.2, 0.9
Hz, 1H), 6.34 (quin, J = 1.8 Hz,
1H), 4.36 (br. s., 2H), 4.17 (br. s.,
2H), 3.95 (s, 2H)
NH + +
F4 ES (M+H)
H NMR (CD3OD) δ: 7.91 (d, J =
H H N
8.0 Hz, 2H), 7.55 (d, J = 8.2 Hz,
1H), 7.39 (br. s., 1H), 7.32 (d, J =
8.0 Hz, 2H), 7.26 (t, J = 1.6 Hz,
12354570_1 (GHMatters) P107928.NZ
1H), 7.17 (d, J = 8.2 Hz, 1H), 7.07
(td, J = 8.0, 1.4 Hz, 1H), 7.00 (dd, J
= 8.2, 1.4 Hz, 1H), 6.90 (dd, J =
8.0, 1.4 Hz, 1H), 6.76 (td, J = 7.0,
1.9 Hz, 1H), 6.44 (d, J = 3.3 Hz,
1H), 4.02 (s, 2H), 3.73 (m, 2H),
3.36 - 3.52 (m, 2H), 2.87 - 3.03 (m,
Cl B 1
ES (M+H)
F5 H NMR (CD OD) δ: 8.03 (d, J =
HN 3
N H N 1.8 Hz, 1H), 7.85 (dd, J = 8.2, 1.8
Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H),
7.38 (s, 1H), 7.30 (d, J = 8.2 Hz,
1H), 7.22 (d, J = 3.2 Hz, 1H), 7.16
(dd, J = 7.8, 1.3 Hz, 1H), 7.07 (ddd,
J = 8.1, 7.3, 1.5 Hz, 1H), 7.02 (dd, J
= 8.1, 1.5 Hz, 1H), 6.89 (dd, J =
8.1, 1.4 Hz, 1H), 6.76 (td, J = 7.7,
1.4 Hz, 1H), 6.68 (quin, J = 2.3 Hz,
1H), 6.41 (dd, J = 3.2, 1.0 Hz, 1H),
4.29 (q, J = 1.9 Hz, 2H), 4.16 (t, J =
1.9 Hz, 2H), 3.93 (s, 2H)
O B + +
Cl 1
F6 ES (M+H)
H NMR (CD OD) δ: 8.56 (dd, J =
HN 3
H N 2.2, 0.7 Hz, 1H), 8.48 (dd, J = 4.8,
1.5 Hz, 1H), 8.04 (d, J = 1.6 Hz,
1H), 7.82 - 7.91 (m, 2H), 7.45 (ddd,
J = 7.7, 4.9, 0.8 Hz, 1H), 7.30 (d, J
= 8.2 Hz, 1H), 7.16 (dd, J = 8.0, 1.4
Hz, 1H), 7.08 (ddd, J = 8.1, 7.3, 1.5
Hz, 1H), 6.89 (dd, J = 8.1, 1.2 Hz,
1H), 6.76 (td, J = 7.6, 1.5 Hz, 1H),
6.70 (quin, J = 2.0 Hz, 1H), 4.31 -
4.41 (m, 2H), 4.17 - 4.27 (m, 2H),
3.95 (s, 2H)
12354570_1 (GHMatters) P107928.NZ
Cl O B + + 1
F7 ES (M+H) H NMR (CD OD) δ: 8.53 (d, J =
1.9 Hz, 1H), 8.45 (dd, J = 4.9, 1.4
NH H N
Hz, 1H), 8.04 (br. s, 1H), 7.87 (d, J
= 8.0 Hz, 1H), 7.86 (d, J = 8.3 Hz,
1H), 7.43 (dd, J = 8.3, 4.9 Hz, 1H),
7.39 (d, J = 8.0 Hz, 1H), 7.18 (d, J
= 8.0 Hz, 1H), 7.08 (t, J = 7.4 Hz,
1H), 6.90 (d, J = 8.0 Hz, 1H), 6.76
(t, J = 7.7 Hz, 1H), 6.37 (s, 1H),
3.62 (s, 2H), 2.62 (t, J = 5.5 Hz,
2H), 2.46 - 2.55 (m, 4H), 2.43 (t, J
= 5.5 Hz, 2H)
B + +
F8 ES (M+H)
N/A H NMR (CD OD) δ: 8.17 (s, 1H),
HN 3
382, 384
8.02 (dd, J = 8.4 Hz, 1H), 7.48 (br.
m, 4H), 7.43 (dd, J = 8.4 Hz, 1H),
6.74 (br. s, 1H), 4.06 (br., 1H),
3.92 (br., 1H), 3.15-3.0 (m, 2H),
2.84 (s, 3H), 2.8-2.5 (m., 2H), 2.30
(br. m, 2H), 2.05 (dd, 1H), 1.70 (dd,
B + +
F9 ES (M+H)
O N/A H NMR (DMSO-d ) δ: 9.50 (s,
HN 6
H N 1H), 7.70 (t, 1H), 7.30 (d, 1H), 7.1-
6.9 (3 m, 3H), 6.75 (d, 1H), 6.58 (t,
1H), 6.30 (br. s, 1H), 5.55 (br. m,
2H), 5.35 (br.m, 2H), 4.95 (br. s,
r oc
B + + 1
O ES (M+H)
F10 H NMR (CD OD) δ: 8.21 (s, 1H),
H N 8.02 (d, J = 8.4 Hz, 1H), 7.43 (br. s,
1H), 7.42 (d, J = 8.4 Hz, 1H), 7.27
(br. m, 3H), 6.82 (br. s, 1H), 5.18
(br. s, 2H), 4.94 (2 d, AB system,
2H), 3.19 (br. m, 2H), 1.05 (br. m,
1H), 0.56 (br. d, J = 7.8 Hz, 2H),
0.41 (br. m, 2H)
12354570_1 (GHMatters) P107928.NZ
B + + 1
F11 O ES (M+H) H NMR (DMSO-d ) δ: 9.72 (s,
N/A 6
315, 317
Cl 1H), 8.08 (s, 1H), 7.87 (d, J = 8.1
Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H),
7.11 (d, J = 7.8 Hz, 1H), 6.96 (ddd,
J = 7, 7, 1.5 Hz, 1H), 6.74 (dd, J =
8, 8, 1.2, 1H), 6.60-6.53 (2 m, 2H),
.51 (br.m, 2H), 5.33 (br. m, 2H),
4.93 (s, 2H)
B B + +
F12 O ES (M+H)
H NMR (CD OD) δ: 8.09 (d, J =
HN 3
H N 8.4 Hz, 2H), 7.48 (br. m, 4H), 7.38
(d, J = 8.4 Hz, 2H), 6.65 (br. m,
1H), 5.30 (dd, 2H), 5.05 (dd, 2H),
4.95 (br. m, 2H), 1.12 (br. m, 1H),
0.74 (br. m, 2H), 0.47 (br. m, 2H)
r oc
B + +
ES (M+H)
F13 H NMR (CD OD) δ: 8.08 (d, J =
HN 3
H N 8.4 Hz, 2H), 7.50 (br. m, 4H), 7.45
(d, J = 8.4 Hz, 2H), 6.65 (br. s, 1H),
3.77 (m, 2H), 3.2-2.9 (br. m, 4H),
2.9-2.5 (br. m, 4H), 1.17 (m, 1H),
0.79 (m, 2H), 0.47 (m, 2H)
B + + 1
F14 ES (M+H) H NMR (CD OD) δ: 8.08 (d, J =
l HN
H N 8.4 Hz, 2H), 7.51 (br. m, 4H), 7.44
NH (d, J = 8.4 Hz, 2H), 6.65 (br. s, 1H),
3.72-3.56 (br. m, 2H), 3.3-3.1 (br.
m, 2H), 3.05-2.7 (br. m, 6H), 1.17
(s, 9H)
B + +
F15 O ES (M+H)
N B + +
O r ES (M+H)
F16 H NMR (CD OD) δ: 8.10 (d, J =
B HN 3
N H N 8.4 Hz, 2H), 8.0 (br. m, 1H), 7.51
(br. m, 7H), 7.39 (d, J = 8.4 Hz,
2H), 6.67 (br. m, 1H), 5.39 (br. s,
2H), 5.14 (br. s, 2H), 4.9 (br. under
12354570_1 (GHMatters) P107928.NZ
solvent peak), 2.67 (br. s, 3H)
B + +
F17 ES (M+H)
H NMR (CD OD) δ: 8.09 (d, J =
HN 3
8.4 Hz, 2H), 7.51 (br. m, 9H), 7.37
(d, J = 8.4 Hz, 2H), 6.66 (br. m,
1H), 5.24 (m, AB system, 2H), 4.95
(m, under solvent peak), 4.59 (s,
B + +
F18 O ES (M+H)
B + +
F19 ES (M+H)
O H NMR (CD OD) δ: 8.09 (d, J =
HN 3
352 8.4 Hz, 2H), 7.48 (br. m, 4H), 7.37
(d, J = 8.4 Hz, 2H), 6.61 (br. m,
1H), 5.35 (br. m, 2H), 5.05 (m,
under solvent peak), 3.44 (s, 2H),
1.33 (s, 2H)
B B + +
F20 ES (M+H)
H NMR (CD OD) δ: 8.08 (d, J =
HN 3
H N 8.4 Hz, 2H), 7.46 (m, 1H), 7.38 (d,
J = 8.4 Hz, 2H), 7.22 (m, 2H), 6.64
(br. m, 1H), 5.31 (m, 2H), 5.09 (m,
2H), 3.30 (m, 2H), 1.13 (m, 1H),
0.73 (m, 2H), 0.47 (m, 2H)
12354570_1 (GHMatters) P107928.NZ
Method G
- - - -
= , ', =
r e reac + r
or reac eac or
R R X P t R A /H t t t R R O R
1 7 10 5 6 9 7
R A /H t R
9
- - - -
= = =
reac reac an
if R t R X t if R R X d R O
7 1 8 10 1 9
= ', -
e ro ec en reac =
i R P t t th R X t R
f d p
1 8 if R R X 7
if R NH C H R R NHP
9 6 2 2 3
R O = R O
if R O R
- - - -
r e r e
R X A /H t R R X A /H t N
1 9 1
R R HN
5 ,
if P
R X A /H t N
R NH
Compounds described hererin, where n =1, and R1, X, R2, R3, R4, R5, and Ar/Het
are defined as defined anywhere herein, can be prepared by cross-coupling reactions well
known to those skilled in the art such as the Mizoroki-Heck reaction, the Suzuki-Miyaura
coupling, the Negishi coupling, and other such methods as described in, for example, Alonso
DA and Najera C, Science of Synthesis, 47 (2010), 439-482 and presented in the generic
scheme above, where react (i = 5-8) are reactive moieties selected as appropriate for the
different coupling strategies mentioned above, and where P and P’ are adequate protecting
groups that can be introduced using methods well known to those skilled in the art and which
are described for example in P.G.M. Wuts and T.W. Greene, 2006, Greene’s Protective
Groups in Organic Synthesis, Fourth Edition, John Wiley & Sons, Inc., Hoboken, NJ, USA.
For example, one can prepare compounds of the disclosure using the Mizoroki-Heck reaction
of a mono or bicyclic halogenated heterocycle, or a mono or bicyclic heterocycle triflate
(react = halogen, OTf, where Tf stands for trifuloromethylsulfonyl or triflyl), which can be
prepared by methods well known to those skilled in the art and detailed in, for example, Joule
JA and Mills K, Heterocyclic Chemistry, Fifth Edition, John Wiley & Sons, Inc., Hoboken,
NJ, USA, with an activated alkene, i.e. substituted or unsubstituted acrylic ester (react = H),
to give the corresponding γ-(heterocycle)acrylate ester Ar/Het-CR4=CR5-COOR7, using
protecting groups on the heterocycle when necessary. The R1-X moiety can then be added to
this intermediate by synthetic methods well known to those skilled in the art, including but
12354570_1 (GHMatters) P107928.NZ
not limited to Heck coupling, Suzuki reaction, alkylation, acylation. Alternatively the R1-X
substituent can be coupled to the mono or bicyclic heterocycle prior to the Heck reaction to
give the same intermediate ester. In all cases the R1-X moiety can be built onto the scaffold
in several steps using synthetic chemistry methodologies well known to those skilled in the
art. The ester can then be hydrolyzed and the acid reacted with a protected or unprotected
substituted or unsubstituted o-phenylenediamine to give compounds of the disclosure after
deprotection if required using methods well known to those skilled in the art and which are
described for example in P.G.M. Wuts and T.W. Greene, 2006, Greene’s Protective Groups
in Organic Synthesis, Fourth Edition, John Wiley & Sons, Inc., Hoboken, NJ, USA.
Alternatively, the ester of the intermediate protected or unprotected γ-(heterocycle)acrylate
ester Ar/Het-CR4=CR5-COOR7 described above could be hydrolyzed and the acid reacted
with a protected or unprotected substituted or unsubstituted o-phenylenediamine to give
compounds of the disclosure after deprotection if required using methods well known to
those skilled in the art. Finally, the Heck coupling of the protected or unprotected
halogenated mono or bicyclic heterocycle or mono or bicyclic heterocycle triflate could be
performed using a substituted or unsubstituted acrylamide prepared by reaction of the
corresponding substituted or unsubstituted acrylic acid, prepared by methods well known to
those skilled in the art, with a protected substituted or unsubstituted o-phenylenediamine. The
R1-X moiety can then be added to the intermediate amide Ar/Het-CR4=CR5-CONH(o-
N(R8R9)C H R2R3), after deprotection of Ar/Het when required, by synthetic methods well
known to those skilled in the art, including but not limited to Heck coupling, Suzuki reaction,
alkylation, acylation. Alternatively the R1-X substituent can be coupled to the mono or
bicyclic heterocycle prior to the Heck reaction. As mentioned above, the R1-X moiety can be
built onto the molecule in several steps using synthetic chemistry methodologies well known
to those skilled in the art and which can include, but are not limited to, oxidation, reduction,
coupling, protection, and deprotection. Compounds of the disclosure can be obtained by
deprotection of the ortho-amine on the amide using methods well known to those skilled in
the art.
12354570_1 (GHMatters) P107928.NZ
Example 12: (E)-N-(2-aminophenyl)(1-((1-methylpiperidinyl)methyl)-1H-pyrazol-
4-yl)acrylamide G1
CO M CO M
CO M
N N N
H c c
B HN
CO H CO M
H NH
oc H
1-(4-iodo-1H-pyrazolyl)ethanone: Acetyl chloride (38.2 mL, 1.07 equiv) and
triethylamine (86 mL, 1.2 equiv) were added at 0°C to a solution of 4-iodo-1H-pyrazole
(100g, 0.515 mol) in dichloromethane (1 L). The mixture was stirred overnight at room
temperature. The reaction mixture was poured into water. The aqueous layer was extracted
with dichloromethane. The combined organic layers were washed with brine, dried over
SO ), and filtered. The residue obtained by concentration was
anhydrous sodium sulfate (Na2 4
purified by silica gel column chromatography (Hexane/EtOAc 20:1 to 1:1) to give N-acetyl
4-iodo-1H-pyrazole as a solid (110g, 91%).
(E)-methyl 3-(1-acetyl-1H-pyrazolyl)acrylate: A 5-L multineck flask was fitted
with a mechanical stirrer, a gas inlet adapter, and a thermometer and cooled in a salt-ice bath
to between -10 and -15°C. The system was purged with dry nitrogen for a few minutes. A
solution of 1-(4-iodo-1H-pyrazolyl)ethanone (100 g, 0.425 mol) 1.2 L of N,N-
dimethylformamide (DMF) was added followed by methyl acrylate (110 g, 1.275 mol),
triethylamine (64 mL, 0.458 mol), trimethyl phosphite (5.27 g, 42.5 mmol), and palladium
acetate (4.76 g, 21.25 mmol). The mixture was then warmed to 110°C under dry nitrogen
atmosphere and stirred for 1 hour. LC/MS analysis of an aliquot showed only 10% product
formation. Trimethyl phosphite (5.27 g, 42.5 mmol), and palladium acetate (4.76 g, 21.25
mmol) were then added to the reaction mixture. The reaction went to completion after
another 1.5h as monitored by LC/MS. The mixture was allowed to cool to room temperature
and the DMF was removed under reduced pressure. The residue was stirred with 1.5 L of
methylene chloride, and the suspension was filtered through a plug of silica gel. The filtrate
12354570_1 (GHMatters) P107928.NZ
was collected and washed with 1 L of 3% hydrochloric acid, 1 L of water, and 1 L of
saturated brine. The solution was dried over magnesium sulfate and filtered. The solvent was
removed under reduced pressure and the residue was purified by silica gel column
chromatography (Hexane/EtOAc 10:1 to 1:1) to give (E)-methyl 3-(1-acetyl-1H-pyrazol
yl)acrylate as a solid (70g, 84%).
(E)-methyl 3-(1H-pyrazolyl)acrylate: Sodium hydrogenocarbonate, NaHCO
(32 g, 1.15 equiv), was added to a suspension of protected compound, (E)-methyl 3-(1-acetyl-
1H-pyrazolyl)acrylate (65 g, 0.33 mol), in MeOH (600 mL). The mixture was stirred for
7h at room temperature. The solids were then filtered and washed with dichloromethane. The
filtrate was concentrated under reduced pressure and the residue was purified by silica gel
column chromatography (Hexane/EtOAc 8:1 to 1:2) to give the title compound as a solid
(47g, 92%).
(E)-methyl 3-(1-((1-methylpiperidinyl)methyl)-1H-pyrazolyl)acrylate:
Triphenylphosphine (393 mg, 1.5 mmol) and (E)-methyl 3-(1H-pyrazolyl)acrylate,
prepared as described above, (12 mg, 1 mmol) were added to a solution of N-methyl
hydroxymethyl-piperidine (165 mg, 1.25 mmol) in tetrahydrofuran (THF, 2 mL). After
addition of di-tert-butyl azodicarboxylate (345 mg, 1.5 mmol), the reaction was stirred
overnight at room temperature. Solvents were evaporated under reduced pressure and the
residue was purified by silica gel chromatography using a gradient of Hexane in EtOAc from
1:1 to 0:100 v/v. Fractions containing product were pooled and evaporated to give 220 mg of
pure material (0.84 mmol, 84%).
(E)(1-((1-methylpiperidinyl)methyl)-1H-pyrazolyl)acrylic acid: An
aqueous 3N sodium hydroxide solution (2 mL) was added to a solution of (E)-methyl 3-(1-
((1-methylpiperidinyl)methyl)-1H-pyrazolyl)acrylate (220 mg) in MeOH (5 mL) and
THF (3 mL) was added aq NaOH (3N, 2mL) to saponify the methyl ester. Workup was
performed as described in Example 12 to generate 209 mg of pure product (0.84 mmol,
100%).
(E)-N-(2-aminophenyl)(1-((1-methylpiperidinyl)methyl)-1H-pyrazol
yl)acrylamide G1: A solution of the acrylic acid prepared above (130 mg, 0.52 mmol) in
DMF (2 mL) was treated with tert-butyl-(2-aminophenyl)carbamate (114 mg, 0.55 mmol),
HATU (262 mg, 1.2 eq), and diisopropylethylamine (DIPEA, 0.34 mL) at 0°C. The solution
was allowed to warm up. After stirring 16h at room temperature, the reaction mixture was
quenched with aqueous ammonium chloride. The mixture was diluted with water, extracted
12354570_1 (GHMatters) P107928.NZ
with dichloromethane. The organic phase was washed with saturated NaHCO , and brine. It
was dried over Na SO , filtered, and concentrated. The residue was purified by preparative
HPLC to afford pure tert-butyloxycarbonyl G1 (56 mg, 0.13 mmol, 25%).
Deprotection of the amino group was achieved as described above by overnight
treatment of a solution in dioxane (1 mL) and MeOH (1 mL) with 4 M HCl in dioxane (0.5
mL). Purification by preparative HPLC gave compound G1 as a HCl salt. This product was
neutralized with a solution of NaHCO and repurified by preparative HPLC to give pure G1
(18 mg, 0.053 mmol, 41%).
H NMR (CD OD) δ: 7.97 (s, 1H), 7.84 (s, 1H), 7.55 (d, J = 15.6 Hz, 1H), 7.17 (dd,
J =8.0, 4.5 Hz, 1H), 7.05 (dt, 1H), 6.88 (dd, J =8.0, 4.5 Hz, 1H), 6.75 (dt, 1H), 6.60 (d, J =
.6 Hz, 1H), 4.14 (d, J = 6.6 Hz, 2H), 3.6-3.4 (br, 2H), 3.1-2.9 (br, 2H), 2.84 (s, 3H); 2.22
(br, 1H), 1.95-1.80 (br, 2H), 1.7-1.45 (br, 2H); ES (M+H) 340.
Example 13: (E)-N-(2-aminophenyl)(1-cinnamyl-3,5-dimethyl-1H-pyrazol
yl)acrylamide G2
CO M CO M
CO M
N N N N
N N N N
CO H CO M
B HN
NH NH
NHB NH
(E)-methyl 3-(3,5-dimethyl-1H-pyrazolyl)acrylate: The preparation of the
dimethylpyrazolyl acrylate was performed using a similar protocol as described for the
synthesis of (E)-methyl 3-(1H-pyrazolyl)acrylate (example 12). Thus, from 1.1 g of 4-
iodo-3,5-dimethyl-1H-pyrazole (5 mmol), 440 mg of (E)-methyl 3-(3,5-dimethyl-1H-pyrazol-
4-yl)acrylate were isolated (2.44 mmol, 49% over 3 steps).
12354570_1 (GHMatters) P107928.NZ
(E)-methyl 3-(1-cinnamyl-3,5-dimethyl-1H-pyrazolyl)acrylate: (E)-methyl 3-
(3,5-dimethyl-1H-pyrazolyl)acrylate (360 mg, 2 mmol) was dissolved in DMF (6 mL).
Sodium hydride, (NaH 60% dispersion, 80 mg, 1 equiv) was added in small portions while
maintaining the temperature at 0°C. The mixture was then stirred at room temperature for 1h.
The mixture was cooled to 0°C and cinnamyl bromide (394 mg, 1 equiv) was added. The
mixture was then stirred overnight at room temperature. It was quenched with aqueous
ammonium chloride, diluted with water, and extracted with EtOAc. The combined organic
layers were dried over Na SO , filtered, and concentrated. The residue was purified by
column chromatography using a gradient of hexane/EtOAc (10:1 to 0:100 v/v). Fractions
containing pure product were combined and the solvents were removed under reduced
pressure to yield (E)-methyl 3-(1-cinnamyl-3,5-dimethyl-1H-pyrazolyl)acrylate (401 mg,
68%).
(E)(1-cinnamyl-3,5-dimethyl-1H-pyrazolyl)acrylic acid: The acid was
obtained as described above in examples 12 and 13. Thus 44 mg of pure acid (0.16 mmol)
were obtained by base hydrolysis of 124 mg (0.42 mmol) for a yield of 38%.
(E)-N-(2-aminophenyl)(1-cinnamyl-3,5-dimethyl-1H-pyrazolyl)acrylamide
G2: Title compound G2 was obtained in two steps as described above by coupling of the
acid (44 mg, 0.16 mmol) with tert-butyl (2-aminophenyl) carbamate followed by acid
deprotection. Purification by preparative HPLC of the neutralized hydrochloride salt gave
pure G2 (25 mg, 0.065 mmol, 42%). H NMR (CD OD) δ: 7.65 (d, J = 15.6 Hz, 1H), 7.38
(br d, J = 8.4 Hz, 2H), 7.29 (br dt, J = 8.4, 1.5 Hz, 2H), 7.25-7.23 (m, 1H), 7.17 (dd, J =8.0,
4.5 Hz, 1H), 7.04 (dt, J = 7.8, 1.5 Hz, 1H), 6.88 (dd, J = 7.8, 1.5 Hz, 1H), 6.75 (dt, J = 7.8, 1.5
Hz, 1H), 6.53 (d, J = 15.6 Hz, 1H), 6.4-6.3 (2 multiplets, 2H), 4.80 (d, J = 4.2 Hz, 2H), 2.43
(s, 3H), 2.41 (s, 3H); ES (M+H) 373.
12354570_1 (GHMatters) P107928.NZ
Table: Method G
Compound Structure coupling R1-X-Y-react MS NMR
H NMR (CD OD) δ: 7.97 (s, 1H),
7.84 (s, 1H), 7.55 (d, J = 15.6 Hz,
1H), 7.17 (dd, J =8.0, 4.5 Hz, 1H),
7.05 (dt, 1H), 6.88 (dd, J =8.0, 4.5
N N + +
G1 ES (M+H) 340 Hz, 1H), 6.75 (dt, 1H), 6.60 (d, J =
CO M
c 15.6 Hz, 1H), 4.14 (d, J = 6.6 Hz,
2H), 3.6-3.4 (br, 2H), 3.1-2.9 (br,
2H), 2.84 (s, 3H); 2.22 (br, 1H),
1.95-1.80 (br, 2H), 1.7-1.45 (br, 2H)
H NMR (CD3OD) δ: 7.65 (d, J =
.6 Hz, 1H), 7.38 (br d, J = 8.4 Hz,
2H), 7.29 (br dt, J = 8.4, 1.5 Hz, 2H),
7.25-7.23 (m, 1H), 7.17 (dd, J =8.0,
NH 4.5 Hz, 1H), 7.04 (dt, J = 7.8, 1.5 Hz,
NH N
G2 ES (M+H) 373
1H), 6.88 (dd, J = 7.8, 1.5 Hz, 1H),
c CO M
N 6.75 (dt, J = 7.8, 1.5 Hz, 1H), 6.53 (d,
J = 15.6 Hz, 1H), 6.4-6.3 (2
multiplets, 2H), 4.80 (d, J = 4.2 Hz,
2H), 2.43 (s, 3H), 2.41 (s, 3H)
1H NMR (CD OD) – HCl salt – δ:
NH 7.94 (s, 1H), 7.83 (s, 1H), 7.67 (d, J =
N + +
ES (M+H) 369
G3 = D10 15.6 Hz, 1H), 7.56 – 7.42 (m, 8H),
N CF
CO M 7.41 - 7.36 (m, 1H), 6.63 (d, J = 15.6
Hz, 1H), 4.90 (t, J = 13.5 Hz, 2H)
1H NMR (CD OD) – HCl salt – δ:
8.08 (s, 1H), 7.90 (s, 1H), 7.71 (d, J =
.5 Hz, 1H), 7.37 - 7.46 (m, 2H),
N ES (M+H) 363
G4 = D2 7.21 - 7.37 (m, 4H), 6.63 (d, J = 15.7
CO M
c Hz, 1H), 6.56 - 6.71 (m, 1H), 6.43
F (dt, J = 15.8, 6.2 Hz, 1H), 4.96 (dd, J
= 6.3, 1.1 Hz, 2H)
12354570_1 (GHMatters) P107928.NZ
HDAC enzyme inhibition
The HDAC activity inhibition assay was performed as follows to determine the
ability of a test compound to inhibit HDAC enzymatic activity. Serial dilutions of HDAC
inhibitors were prepared in HDAC assay buffer (25 mM Tris/HCl, pH 8.0, 137 mM NaCl, 2.7
mM KCl, 1 mM MgCl , pH 8) in 96-well assay plates (Fisher scientific, #07309) and
were pre-incubated for 2 hours at room temperature in the presence of 125µg/ml BSA and
purified HDAC1 (BPS Bioscience, San Diego, CA, #50051), HDAC2 (BPS Bioscience,
#50053), or HDAC3/NcoR2 (BPS Bioscience, #50003) at concentrations of 1.25, 1.32, and
0.167 µg/mL, respectively. Following pre-incubation, Fluor-de-Lys substrate (Enzo Life
Sciences, Plymouth Meeting, PA, BML-KI104-0050) was added to a final concentration of
µM and plates were further incubated for 30 minutes at room temperature. The enzymatic
reaction was stopped by addition of Trichostatin A (Sigma-Aldrich, St Louis, MO, #T8552,
final concentration: 100 nM) and trypsin (MP Biomedicals, Solon, OH, #02101179) was
added to reach a final concentration of 100µg/mL. After a 15 minute incubation at room
temperature, fluorescence was recorded using a Spectramax M2 fluorometer (Molecular
Devices, Sunnyvale, CA) with excitation at 365nm and emission at 460 nm. IC50 values
were calculated by using a sigmoidal dose-response (variable slope) equation in GraphPad
Prism® 5 for Windows (GraphPad Software, La Jolla, CA). Results for selected compounds
of the disclosure in the HDAC activity inhibition assay are presented in Tables 1 and 4 (IC50
ranges: IA > 20µM, A < 1µM, 1 < B < 5µM, 5 < C < 10µM, 10 < D < 20µM, ND: not
determined)
Table 1: IC for inhibition of HDAC1, 2, and 3 isoforms
compound HDAC1 HDAC2 HDAC3
A A A
B B A
A A A
D9 A A A
A A A
A B A
B4 A B A
A A A
B B A
A A A
B C A
A B A
A B A
D8 A A A
12354570_1 (GHMatters) P107928.NZ
D14 A A A
D11 A A A
D5 A B A
D12 A A A
D13 A A A
D15 A A A
D10 A B A
B B A
C C A
A B A
A9 B B A
A10 B B A
B C A
C D A
A7 B B A
C2 IA IA B
C3 B B A
B B A
B B A
B1 B C A
A1 B C A
A3 C C A
A4 IA IA B
A5 D D A
A B A
A B A
A A A
A A A
F4 A ND A
F5 A B A
F6 A B A
F7 A A A
G1 B B A
G2 B B A
Acid stability determination
A 100µM solution of test compound was prepared by dilution of a 10 mM DMSO
stock solution in a 0.01 M solution of HCl in deionized water. Immediately after mixing, an
aliquot (100 µL) was sampled and analyzed by HPLC/UV. The area under the compound
peak was determined and used as the time zero reference point. The remainder of the acid
sample was incubated at 50°C and samples were taken after 2, 4, and 24 hours of incubation.
On a few occasions, samples were taken at 30 rather than 24 hours. These were analyzed by
the same HPLC/UV method and the area of the peak corresponding to the test compound was
12354570_1 (GHMatters) P107928.NZ
measured. Percent remaining at a given time point was then calculated as the ratio of the area
under the peak after incubation to that at time zero times 100. In those cases where a 30 hour
time point was recorded, the percent remaining at 24 hours was obtained by interpolation of
the percent remaining versus time curve assuming a unimolecular process, i.e. a
monoexponential decay. Percent remaining after 24 hours incubation are presented in Tables
2 and 4 below, where A corresponds to more than 60%, B is between 40 and 60%, C covers
to 40% and D means less than 20%.
Brain penetration studies
Test compounds were prepared at either 0.5 mg/ml or 5 mg/ml in 30%
hydroxypropyl-β-cyclodextrin, 100 mM sodium acetate pH 5.5, 5% DMSO. C57/BL6/J
mice were dosed s.c. at 5 mg/kg or 50 mg/kg, or i.v. at 5 mg/kg. Animals were euthanized at
pre-dose, 5, 15, 30 min, 1, 2 and 4 hours post-dose and plasma and brain obtained. Three
animals per dose per time points were used. The levels of compound in the plasma and brain
were determined by standard LC/MS/MS methods. Brain/plasma ratio (BPR) was calculated
as the ratio of the C (brain)/C (plasma). The results are shown in Tables 2 and 4, where
max max
IA corresponds to a BPR less than 0.1, D is between 0.1 and 0.2, C is 0.2 to 0.5, B comprises
0.5 to 1 and A is greater than 1.
In-cell deacetylase inhibition assay (DAC assay)
GM 15850(lymphoblastoid cells line) cells were seeded in 96-well plates at an
appropriate density (100,000 cells/well) in 90 µL RPMI1640 medium containing 10% v/v
fetal bovine serum (FBS), 1% v/v penicillin/streptomycin, and 1% v/v L-glutamine.
Compound dilutions were made in 100% DMSO followed by parallel dilution in media with
2% DMSO. 10 µl of the compound dilutions were added to the cells to achieve the desired
concentrations. The final concentration of DMSO in each well was 0.2%. The cells were
incubated for 4h at 37°C with 5% CO . After incubation, the cells were centrifuged down and
the supernatant was removed. The cell pellets were washed with 100 µL phosphate-buffered
saline (PBS) and then lysed with 45 µL lysis buffer (HDAC assay buffer at pH 8.0 (25 mM
Tris/HCl, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl ) + 1% v/v Igepal CA-630). To initiate
the reaction, the HDAC substrate KI-104 (Enzo Life Sciences, Farmingdale, NY) was added
to a final concentration of 50 µM. The reaction was stopped after 30 min incubation by
addition of 50 µL developer (6 mg/mL trypsin in HDAC assay buffer). The reaction was
allowed to develop for 30 min at room temperature and the fluorescence signal was detected
using a fluorometer (Spectramax M2, Molecular Devices, Sunnyvale, CA) with excitation
12354570_1 (GHMatters) P107928.NZ
and emission wavelengths of 360 nm and 470 nm respectively. The data was fitted to a
sigmoidal dose response equation with variable slope in GraphPad Prism 5.0 (GraphPad
Software, La Jolla, CA) to determine IC50. Bottom and top of the curve were fixed to the
average fluorescence response of control wells with no cells and cells but no compound
respectively. IC50’s are reported in Table 2 and 4, where A stands for IC50 less than 1 µM,
B between 1 and 5 µM, C from 5 to 10 µM, D from 10 to 20 µM, and IA for IC50 above 20
Cell proliferation assay
HCT116 cells (5000 cells/well) in 80 µL McCoy’s 5A medium containing 10% v/v
FBS, 1% v/v penicillin/streptomycin and 1% v/v L-glutamine were incubated in 96-well
plates with compounds at various concentrations for 72h at 37°C in a 5% CO atmosphere.
The compound dilutions were made in 100% DMSO followed by parallel dilutions in media.
The final concentration of DMSO in each well was 0.05%. After 72h, 20µL of Cell titer 96
aqueous one solution (Promega Corporation, Madison, WI) were added to the cells and the
plate was incubated at 37°C for another 4h. The absorbance at 490nm was then recorded on a
96-well plate reader (Spectramax M2, Molecular Devices, Sunnyvale, CA). Data analysis
was performed in Microsoft Excel (Microsoft Corp, Redmond, WA).( (O.D. sample –
average O.D. positive control)/(average O.D. negative control - average O.D. positive
control))*100, where O.D. is the measured absorbance, O.D. positive control is the
absorbance from cells incubated with trichostatin A at 5 µM and O.D. negative control is the
absorbance measured from cells incubated without any compound, was plotted against
compound concentration and an IC50 was determined by graphical interpolation of the
concentration required for 50% inhibition of cell growth. IC50’s are presented in Table 2,
where A stands for IC50 less than 5 µM, B covers the range between 5 and 10 µM, C is from
to 20 µM, and IA is used for IC50 greater than 20 µM.
Effect of HDAC inhibitors on frataxin (FXN) mRNA expression
Blood is collected from Friedreich’s ataxia patient donors into tubes containing the
anti-coagulant EDTA. Primary lymphocytes are isolated using Lymphocyte Separation
Medium (MP Biomedicals, Solon, OH) following the manufacturer’s instructions and
including a few modifications made by Repligen. After a final wash in Phosphate Buffered
Saline (PBS), the cells are distributed into a 6-well cell culture plate in cell growth medium.
The test HDAC inhibitor compound is added to cells in a dose escalating manner (usually
concentrations range from 1 to 10 µM) and 0.1% DMSO is added to one well of cells as a no
12354570_1 (GHMatters) P107928.NZ
treatment control. Cells are incubated for 48 hours at 37°C in a CO incubator; cell counts
are taken using a Countess automated cell counter (Invitrogen, Carlsbad, CA). Equivalent
numbers of cells for all treatment conditions are pelleted by centrifugation and resuspended
in cell lysis buffer. Total RNA is isolated from approximately 1x10 primary lymphocytes
using a RNeasy Mini Kit (Qiagen, Valencia, CA), following the manufacturer’s instructions
and including an optional on-column DNAse digestion step. The isolation is performed
either manually or using the QIAcube (Qiagen, Valencia, CA), an instrument that automates
much of the isolation procedure. The RNA yield and concentration is determined using a
Nanodrop spectrophotometer (Thermo Fisher Scientific, Waltham, MA) and depending on
the RNA concentration, one of two protocols is used to measure frataxin (FXN) transcript
levels. For samples containing at least 15 ng/µL RNA a TaqMan Probe-based (Applied
Biosystems, Carlsbad, CA) qRT-PCR method is used, while for samples containing less than
ng/µL RNA a SYBR Green qRT-PCR method is used. In the TaqMan Probe-based
method specific primer/probe pairs for FXN and GAPDH are multi-plexed in each reaction.
In the SYBR Green method FXN and GAPDH are amplified in separate reactions. In both
methods each RNA sample is analyzed in triplicate (preferably) or duplicate (minimally)
using a one-step qRT-PCR master mix that contains all the components necessary for cDNA
synthesis and PCR amplification in a single, continuous reaction. After cycling is complete,
MxPro Software (Agilent Technologies, Santa Clara, CA) is used to analyze the collected
data and determine the relative amount of FXN mRNA compared to a control sample. An
adaptive baseline method is used for baseline correction whereby an algorithm automatically
selects the appropriate baseline cycles for each well and each dye. An amplification-based
threshold is set and the corresponding threshold cycle, or Ct, is obtained for calculating target
concentration. The Ct values for each target gene (FXN and GAPDH) for each replicate
series are averaged. The amount of FXN (or GAPDH) in the sample is determined as the
relative quantity to the calibrator where the calibrator sample is assigned an arbitrary quantity
-∆Ct
of 1. The following equation is used: Relative quantity to the calibrator = 2 where ∆Ct =
(Ct_gene)unknown – (Ct_gene)calibrator , gene is either FXN or GAPDH, calibrator is a
DMSO control sample, and unknown is a HDACi treated sample. The relative quantity of
FXN is normalized to cell number and RNA input. Data is reported in Tables 2 and 4 below,
where the concentration required for a 2-fold increase in FXN mRNA is reported as A if less
than 5 µM, B if between 5 and 10 µM, C if greater than 10 µM.
12354570_1 (GHMatters) P107928.NZ
Table 2: Acid stability, DAC, anti-proliferation, frataxin mRNA expression and tissue
distribution assay results
compound acid stability 850 DAC Hct-116 FXN 2x BPR
F1 B IA IA
B D A A A
B B A A C
F4 B B A A B
A1 IA B
A2 B D IA B
A5 B C
D1 A B B A B
D2 IA IA C C
A B A B C
D10 C IA C B
D4 A C IA C C
D7 B C A B B
D9 A B B A B
D8 B A C C
D5 C IA D
D6 D IA C IA
A6 IA C D
E2 A D IA A
A7 IA B
A8 B D B
A9 IA
G1 B IA
D14 B C B
D11 B B A
D12 A B B
D13 B IA
A10 D C
A11 A A
C1 IA B
E1 IA
D15 B
B1 D
F5 C
12354570_1 (GHMatters) P107928.NZ
F6 D
C3 IA
B6 C
B2 C
D C
B3 B C
G2 D IA
B5 C C
A12 IA
Protocol for compound stability in hepatocytes
To assess the stability and metabolism of RGFP compounds in hepatocytes. This
assay was designed to evaluate the metabolism of RGFP compounds, following their
incubation with human, monkey, dog and rat hepatocytes by monitoring either parent drug
disappearance or metabolite appearance using HPLC. The results are shown in Table 4 ((%
Left in Hep: IA < 10%, 50% < A, 50% > B > 30%, 30% > C > 10%, ND: not determined).
Equipment: Applied Biosystem Triple Quadrupole LC/MS/MS; Ice bucker, timer;
96 well plates; Falcon, Cat# 353072; 96 well plates shaker; Various pipettes: 10µL, 20 µL,
200 µL, and 1000 µL; Test tubes: Catalog # VWR 47729-572, 13x 100 mm
Table 3: Materials and Reagents
Item Vendor Catalog #
Human Hepatocytes Celsis X008001
Monkey Hepatocytes Celsis M00350
Dog Hepatocytes Celsis M00205
Rat Hepatocytes Celsis M00005
Torpedo Antibiotix Mix Invitro Technologies Z99000
In VitroGRO HT Medium Celsis Z99019
In VitroGRO KHB Celsis Z99074
Acetonitrile Fisher A-9981
Methanol Fisher A-4521
Trypan Blue Solution Sigma Chemical T-8154
Procedure: Turn on the water-bath heater to 37°C. Take out the KHB buffer and
make sure it is at room temp before use. Prepare 2.5 mM concentration of RGFP compound
in DMSO stock. Add 10 µL of above DMSO stock to 2490 µL KHB buffer; final
concentration of RGFP compound will be 10 µM. Pre-warm 45ml InVitro HT Medium to
12354570_1 (GHMatters) P107928.NZ
37°C in a sterile 50 ml conical tube. Add 1.0 mL Torpedo Antibiotic Mix per 45 mL InVitro
HT medium. Transfer 13 mL of warm HT medium with Antibiotic Mix into a 15 mL conical
tube. Carefully remove the hepatocyte vials from liquid nitrogen (liquid phase).
Immediately immerse the vial into a 37°C water bath. Shake gently until the ice melts
entirely. Do not keep the cells in 37°C water bath longer than necessary. Immediately empty
contents of the vial into 13ml of pre-warmed InVitro HT Medium with antibiotics. Rinse the
vial with the HT media that you have just transferred the hepatocytes to, in order to ensure
complete transfer. Centrifuge the cell suspension at 600 RPM for 5 minutes at room
temperature. Discard the supernatant by either pouring in one motion (do not pour partially
and re-invert centrifuge tube) or aspirating using a vacuum pump. Add 1.0 ml of KHB (at
room temperature) buffer to the tube of hepatocyte pellet. Loosen the cell pellet by gently
swirling the centrifuge tube. Transfer 100 µL of above solution to a different tube and add
900 µL of KHB buffer to count the cells. Determine the total cell count and the number of
viable cells using the Trypan Blue exclusion method. Once you obtain the cell count,
multiply the number by 10 (attributing to the dilution factor). Now add required volume of
KHB buffer to the tube containing hepatocytes such that the final count will be 2 million
cells/mL. Dispense 50µL of 2 million cells/ml to a 96 well plate and then add 50 µl of
DMSO stock to respective wells (such that, the concentration of RGFP compounds is 5 µM
and number of cells are 100000 in each well). Place the plates on a shaker in a 37°C
incubator with 5% CO . Separate plates for each time point are advisable (Time points: 0h,
1h, 2h, and 6 h). After each time point, add 100 µL of quenching solution.
Quenching solution is an acetonitrile solution containing RGFP531 (10 µM)
internal standard, 0.1% formic acid and phenylglyoxol (400 µM). The formic acid and
phenylglyoxal is used for the identification and quantification of OPD as mentioned above.
Pipette up and down a few times to ensure a complete stop of reaction. Transfer all the
solution into a 1.5ml tube, vortex thoroughly, and centrifuge at 14000 RPM at 4°C for 5
minutes to precipitate cell debris. Transfer the 150 µL of supernatant to vials for analysis
using HPLC.
12354570_1 (GHMatters) P107928.NZ
Table 4
HDAC1 HDAC2 HDAC3 Cmax DAC Fxn % left
Coding Structure MW clogPtPSA IC50 IC50 IC50 BPR brain IC50 >2X 6h
(uM) (uM) (uM) (ng/m (uM) (uM) Hum
IA 3.50 71 A A A ND ND C ND C
C H ClN O
25 4
A 3.52 58 A A A C C A ND A
C H ClN O
22 24 3
H B 1.09 64 A ND A ND ND A ND IA
C H FN O
17 15 2 2
F10 N
A 3.29 58 A ND A A A C ND B
C H ClN O
21 22 3
F11 A 2.07 64 A B A A A A ND C
C H ClN O
17 15 2 2
N A 2.38 58 A A A A A A A A
C H N O
21 23 3
A 3.10 58 A A A A A ND ND B
C H N O
23 27 3
A 4.15 58 A A A A A B A C
C H N O
24 31 3
HO N N
F15 A 2.43 79 A A A A A B A A
C H N O
23 29 3 2
F16 N N ND ND ND ND
A 2.37 70.7 A A A C
N NH H
C H N O
24 24 4
F17 A 3.37 58.4 A A A ND ND ND ND C
C H N O
24 23 3
F18 A 1.87 70.7 A A A ND ND ND ND C
C H N O
23 22 4
F19 A 1.71 78.6 A B A ND ND ND ND A
C H N O
21 25 3 2
F20 A 2.88 58.3 B B A ND ND ND ND A
C H FN O
21 22 3
Effect of compounds on long term memory for object recognition
C57BL/6J male mice were handled 1-2 min for 5 days and were habituated to the
experimental apparatus 5 min a day for 4 consecutive days in the absence of objects. During
the training trial, mice were placed in the experimental apparatus with two identical objects
and were allowed to explore these objects for 3 min, which does not result in short- or long-
term memory (Stefanko et al., 2009). Immediately following training, mice received
subcutaneous injections of either vehicle (20% glycerol, 20% PEG 400, 20% propylene
glycol, and 100 mM sodium acetate, pH 5.4), reference compound 1, RGFP109, class I
12354570_1 (GHMatters) P107928.NZ
HDAC inhibitor, (3, 10, 30 mg/kg), reference compound 2, RGFP136 (3, 10, 30 mg/kg), or
compound D2 (3, 10, 30 mg/kg). 24-h later mice were tested for memory retention (5 min)
using the object recognition memory task (ORM), in which a familiar object was replaced
with a novel one. All training and testing trials were videotaped and analyzed by individuals
blind to the treatment condition and the genotype of subjects. A mouse was scored as
exploring an object when its head was oriented toward the object within a distance of 1 cm or
when the nose was touching the object. The relative exploration time was recorded and
expressed by a discrimination index [DI = (tnovel – tfamiliar)/(tnovel + tfamiliar) × 100].
All doses of the compounds significantly enhanced long-term memory formation
compared to vehicle-treated mice (Figure 1). Dose dependent effects were seen with RGFP
109 and 136, but there was no effect of dose for D2. The lack of an observed dose effect for
D2 is likely due to its enhanced brain penetration, such that 3 mg/kg is sufficient to produce
the full behavioral effect. See
A number of embodiments have been described. Nevertheless, it will be
understood that various modifications may be made without departing from the spirit and
scope of the disclosure. Accordingly, other embodiments are within the scope of the
following claims.
12354570_1 (GHMatters) P107928.NZ
Claims (35)
1. A compound having a structure of formula (II), or a pharmaceutically acceptable salt thereof (II) wherein R is H or F; R is H, Cl, or F; Het is piperidinyl, and the ring nitrogen is substituted with R ; and R is C1-C6alkyl, C1-C6hydroxyalkyl, or C1-C3alkylene-C3-C6cycloalkyl.
2. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein R is H.
3. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein R is F.
4. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 3, wherein R is C1-C6alkyl or C1-C6hydroxyalkyl.
5. The compound or pharmaceutically acceptable salt thereof of claim 4, wherein R is CH C(CH ) or CH C(OH)(CH ) . 2 3 3 2 3 2
6. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 3, wherein R is C1-C3alkylene-C3-C6cycloalkyl.
7. The compound or pharmaceutically acceptable salt thereof of claim 6, wherein R is CH cyclopropyl.
8. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 7, wherein R is H. 12354570_1 (GHMatters) P107928.NZ
9. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 7, wherein R is F.
10. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 7, wherein R is Cl.
11. The compound or pharmaceutically acceptable salt thereof of claim 9 or claim 10, wherein R is ortho to the Het substituent.
12. The compound or pharmaceutically acceptable salt thereof of claim 9 or claim 10, wherein R is meta to the Het substituent.
13. A compound selected from the group consisting of N N N N NH NH Me Me Me HO N N N N Me NH Me NH 2 NH , , and or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 13 and a pharmaceutically acceptable carrier. 12354570_1 (GHMatters) P107928.NZ
15. An in vitro method of selectively inhibiting HDAC3, the method comprising contacting a cell with an effective amount of a compound, or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 13 or the composition of claim 14.
16. An in vitro method of selectively inhibiting HDAC1 or HDAC2, the method comprising contacting a cell with an effective amount of a compound, or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 13 or the composition of claim
17. An in vitro method of inhibiting HDAC1, HDAC2, and HDAC3, the method comprising contacting a cell with an effective amount of a compound, or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 13 or the composition of claim
18. Use of a compound, or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 13 or the composition of claim 14, in the preparation of a medicament for treating a disease or disorder mediated by HDAC1 or HDAC2.
19. Use of a compound, or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 13 or the composition of claim 14, in the preparation of a medicament for treating a disease or disorder mediated by HDAC3.
20. Use of a compound, or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 13 or the composition of claim 14, in the preparation of a medicament for treating a disease or disorder mediated by HDAC1, HDAC2, and HDAC3.
21. Use of a compound, or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 13 or the composition of claim 14, in the manufacture of a medicament for treating a neurological disorder, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington’s disease, spinocerebellar ataxia, Kennedy’s disease, amyotrophic lateral sclerosis, Niemann Pick, Pitt Hopkins, spinal and bulbar muscular atrophy, and Alzheimer’s disease; a cancer; an inflammatory disease; a memory impairment condition or a drug addiction. 12354570_1 (GHMatters) P107928.NZ
22. The use of claim 21, wherein the neurological disorder is Friedreich’s ataxia.
23. Use of a compound or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 13 or the composition of claim 14, in the preparation of a medicament for treating an infection.
24. The method of any one of claims 15 to 17 or the use of any one of claims 18 to 23, wherein the compound is a compound as claimed in claim 13, or a pharmaceutically acceptable salt thereof.
25. A compound, or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 13 for use in medicine.
26. The compound of claim 25, wherein the compound is a compound as claimed in claim 13, or a pharmaceutically acceptable salt thereof.
27. A compound, or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 13 for the treatment of a disease or disorder mediated by HDAC1 or HDAC2, a disease or disorder mediated by HDAC3, a neurological disorder such as Friedreich’s ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington’s disease, spinocerebellar ataxia, Kennedy’s disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, and Alzheimer’s disease; an infection including viral infection;a cancer; an inflammatory disease; a memory impairment condition or a drug addiction.
28. The compound or salt of claim 13, having a structure:
29. The compound or salt of claim 13, having a structure: 12354570_1 (GHMatters) P107928.NZ
30. The compound or salt of claim 13, having a structure:
31. The compound or salt of claim 13, having a structure: Me NH
32. The compound or salt of claim 13, having a structure: Me NH
33. The compound or salt of claim 13, having a structure:
34. The compound or salt of claim 13, having a structure:
35. A compound, or a pharmaceutically acceptable salt thereof according to claim 1, substantially as herein described, with reference to any one of the Examples.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/843,261 US8957066B2 (en) | 2011-02-28 | 2013-03-15 | Histone deacetylase inhibitors |
US13/843,261 | 2013-03-15 | ||
PCT/US2014/027347 WO2014152444A1 (en) | 2013-03-15 | 2014-03-14 | Histone deacetylase inhibitors |
Publications (2)
Publication Number | Publication Date |
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NZ711592A NZ711592A (en) | 2020-11-27 |
NZ711592B2 true NZ711592B2 (en) | 2021-03-02 |
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