CROSS REFERENCE TO RELATED APPLICATION
[1] This application claims the priority benefit of INDIAN Provisional
Patent Application No. 201811049920, filed Dec. 31, 2018, the disclosures of
which is incorporated herein by reference in its entireties.
5
FIELD OF THE INVENTION
[2] The present invention generally relates to compounds possessing
inhibitory activity of mutant isocitrate dehydrogenase (mt-IDH) proteins with
neomorphic activity useful in the treatment of proliferative disorders, such as
10 cancer. The invention also provides method of synthesis of said compounds,
method of using said compounds, pharmaceutical compositions comprising said
compounds and method of using thereof.
BACKGROUND OF THE INVENTION
15 [3] Isocitrate dehydrogenase (IDH) is a family of enzymes found in
cellular metabolism. They are NADP+
/NAD+
and metal dependent
oxidoreductases of the enzyme class EC 1.1.1.42. IDH catalyzes the oxidative
decarboxylation of isocitrate, producing alpha-ketoglutarate (α-ketoglutarate) and
CO2. IDH exists in three isoforms in humans i.e. IDH1, IDH2 and IDH3, wherein
IDH3 catalyzes the third step of the citric acid cycle while converting NAD+
20 to
NADH in the mitochondria. The isoforms IDHl and IDH2 catalyze the same
reaction outside the context of the citric acid cycle and use NADP+
as a cofactor
instead of NAD+
. IDHs localize to the cytosol as well as the mitochondrion and
peroxisome.
25 [4] The wild type proteins catalyze the oxidative decarboxylation of
isocitrate to α-ketoglutarate, generating carbon dioxide and NADPH/NADH in the
process. They are also known to convert oxalosuccinate into α-ketoglutarate.
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[5] Mutations in IDH1 (cytosolic) and IDH2 (mitochondrial) have been
identified in multiple cancer types including, but not limited to glioma,
glioblastoma multiforme, paraganglioma, supratentorial primordial
neuroectodermal tumors, acute myeloid leukemia (AML), prostate cancer, thyroid
5 cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell
lymphoma, and melanoma. (L. Dang et al., Trends Mol. Med., 2010, 16, 387; T.
Shibata et al., Am. J. Pathol., 2011, 178(3), 1395; Gaal et al., J. Clin. Endocrinol.
Metab. 2010, 95(3), 1274; Balss et al., Acta Neuropathol., 2008, 116, 597) The
mutations have been found at or near key residues in the active site: G97D,
10 R100Q, R132H, H133Q, and A134D for IDH1, and R140 and R172 for IDH2. (L.
Dang et al., Nature, 2009, 462, 739; L. Sellner et al., Eur. J. Haematol., 2010, 85,
457)
[6] These mutant forms of IDH are believed to have a neomorphic activity,
reducing α-ketoglutarate to 2-hydroxyglutarate (2-HG). (P. S. Ward et al., Cancer
15 Cell, 2010, 17, 225) In general, production of 2-HG is enantiospecific, resulting in
generation of the D-enantiomer (also known as the R enantiomer or R-2-HG).
Normal cells generally have low native levels of 2-HG, whereas cells harboring
these mutations in IDH1 or IDH2 show significantly elevated levels of 2-HG. 2-
HG production is believed to contribute to the formation and progression of
20 cancer. (Dang, et al. 2009 Nature 462:739-44.) High levels of 2-HG have also
been detected in tumors harboring the mutations. High levels of 2-HG have been
detected in the plasma of patients with mutant IDH containing AML. (S. Gross et
al., J. Exp. Med., 2010, 207(2), 339)
[7] Mutations in IDH1 have been associated with multiple cancers and
25 patients having these disorders often have increased levels of 2-HG in their urine,
plasma or cerebrospinal fluid. (M. Kranendijk et al., Science, 2010, 330, 336)
[8] There is a an urgent and growing need for small molecule inhibitors of
mutant IDH enzymes, or more specifically mutant IDH1 enzymes, for the
treatment of diseases and disorders associated with this enzymes. Therefore, the
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present invention provides inhibitors of mutant isocitrate dehydrogenase (mtIDH1).
SUMMARY OF THE INVENTION
5 [9] In one aspect, the present invention provides a compound of formula
(IA):
formula (IA),
or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof,
wherein X, A, B, L, R
1
, R2
, R3
, R4
, R5
, R6a
, R6b
, R
7
, R
7’ 10 , m and n are as detailed
herein.
[10] In some aspects, the compound of formula (IA) or a salt, polymorph,
solvate, enantiomer, stereoisomer or tautomer thereof, is any of the compounds of
formula (I), (Ia-1) to (Ia-14), (Ib-1) to (Ib-11) or a salt, polymorph, solvate,
15 enantiomer, stereoisomer or tautomer thereof, as detailed herein.
[11] In some aspects, the compound of formula (IA) or a salt, polymorph,
solvate, enantiomer, stereoisomer or tautomer thereof, is a compound of formula
(II), (IIa-1) to (IIa-8) or a salt, polymorph, solvate, enantiomer, stereoisomer or
tautomer thereof, as detailed herein.
20 [12] In some aspects, the compound of formula (IA) or a salt, polymorph,
solvate, enantiomer, stereoisomer or tautomer thereof, is a compound of formula
(III), (IIIa-1) to (IIIa-8) or a salt, polymorph, solvate, enantiomer, stereoisomer or
tautomer thereof, as detailed herein.
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[13] In some aspects, the compound of formula (IA) or a salt, polymorph,
solvate, enantiomer, stereoisomer or tautomer thereof, is any of the compounds of
formula (IV), (IVa-1) to (IVa-7) or a salt, polymorph, solvate, enantiomer,
stereoisomer or tautomer thereof, as detailed herein.
5 [14] In some aspects, the compound of formula (IA) or a salt, polymorph,
solvate, enantiomer, stereoisomer or tautomer thereof, is a compound of formula
(V) or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof, as
detailed herein.
[15] In some aspects, the compound of formula (IA) or a salt, polymorph,
10 solvate, enantiomer, stereoisomer or tautomer thereof, is a compound of formula
(VI) or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof,
as detailed herein.
[16] In some aspects, the present invention provides method of treating a
disease or disorder associated with this mutant IDH enzymes, more specifically
15 mutant IDH1 enzymes in an individual in need thereof, wherein the method
comprises administering to the individual an effective amount of a compound of
the present invention (collectively, a compound of formula (IA), (I), (Ia-1) to (Ia14), (Ib-1) to (Ib-11), (II) , (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (IVa-1)
to (IVa-7), (V) or (VI)), or a salt, polymorph, solvate, enantiomer, stereoisomer or
20 tautomer thereof.
[17] In some aspects, the present invention provides method of treating
cancer in an individual in need thereof, wherein the method comprises
administering to the individual an effective amount of a compound of the present
invention (collectively, a compound of formula (IA), (I), (Ia-1) to (Ia-14), (Ib-1) to
25 (Ib-11), (II) , (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (IVa-1) to (IVa-7),
(V) or (VI)), or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer
thereof.
[18] In some aspects, the present invention provides method of inhibiting
mutant IDH1 in an individual in need thereof, wherein the method comprises
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administering to the individual an effective amount of a compound of the present
invention (collectively, a compound of formula (IA), (I), (Ia-1) to (Ia-14), (Ib-1) to
(Ib-11), (II) , (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (IVa-1) to (IVa-7),
(V) or (VI)), or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer
5 thereof.
[19] In some aspects, the present invention provides method of treating a
disease or disorder associated with this mutant IDH enzymes, or more specifically
mutant IDH1 enzymes in an individual in need thereof, wherein the method
comprises administering to the individual an effective amount of a compound of
10 the present invention (collectively, a compound of formula (IA), (I), (Ia-1) to (Ia14), (Ib-1) to (Ib-11), (II) , (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (IVa-1)
to (IVa-7), (V) or (VI)), or a salt, polymorph, solvate, enantiomer, stereoisomer or
tautomer thereof in combination with other therapeutic agents.
[20] In some aspects, the present invention also provides pharmaceutical
15 compositions, comprising a compound of the present invention (collectively, a
compound of formula (IA), (I), (Ia-1) to (Ia-14), (Ib-1) to (Ib-11), (II) , (IIa-1) to
(IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (IVa-1) to (IVa-7), (V) or (VI)) and at least
one pharmaceutically acceptable excipient.
[21] In some aspects, the present invention provides method of treating a
20 disease or disorder associated with this mutant IDH enzymes, or more specifically
mutant IDH1 enzymes in an individual in need thereof, wherein the method
comprises administering to the individual a pharmaceutical composition
comprising an effective amount of a compound of the present invention
(collectively, a compound of formula (IA), (I), (Ia-1) to (Ia-14), (Ib-1) to (Ib-11),
25 (II) , (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (IVa-1) to (IVa-7), (V) or
(VI) ), or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof.
[22] In some aspects, the present invention provides uses of the compound
of the present invention (collectively, a compound of formula (IA), (I), (Ia-1) to
(Ia-14), (Ib-1) to (Ib-11), (II) , (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV),
30 (IVa-1) to (IVa-7), (V) or (VI)), or a salt, polymorph, solvate, enantiomer,
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stereoisomer or tautomer thereof in the manufacture of the medicament for
treatment of a disease or disorder associated with this mutant IDH enzymes, or
more specifically mutant IDH1 enzymes.
[23] In some aspects, the present invention provides processes for preparing
5 compounds and intermediates thereof disclosed in the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[24] “Alkyl” refers to and includes saturated linear and branched univalent
10 hydrocarbon structures and combination thereof, having the number of carbon
atoms designated (i.e., C1-C10 means one to ten carbons). Particular alkyl groups
are those having 1 to 20 carbon atoms (a “C1-C20 alkyl”). More particular alkyl
groups are those having 1 to 8 carbon atoms (a “C1-C8 alkyl”), 3 to 8 carbon
atoms (a “C3-C8 alkyl”), 1 to 6 carbon atoms (a “C1-C6 alkyl”), 1 to 5 carbon
15 atoms (a “C1-C5 alkyl”), or 1 to 4 carbon atoms (a “C1-C4 alkyl”). Examples of
alkyl include, but are not limited to, groups such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for
example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
[25] “Alkenyl” as used herein refers to an unsaturated linear or branched
20 univalent hydrocarbon chain or combination thereof, having at least one site of
olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and
having the number of carbon atoms designated (i.e., C2-C10 means two to ten
carbon atoms). The alkenyl group may be in “cis” or “trans” configurations, or
alternatively in “E” or “Z” configurations. Particular alkenyl groups are those
25 having 2 to 20 carbon atoms (a “C2-C20 alkenyl”), having 2 to 8 carbon atoms (a
“C2-C8 alkenyl”), having 2 to 6 carbon atoms (a “C2-C6 alkenyl”), or having 2 to 4
carbon atoms (a “C2-C4 alkenyl”). Examples of alkenyl include, but are not
limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-
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methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-
methylbuta-1,3-dienyl, homologs and isomers thereof, and the like.
[26] “Alkylene” as used herein refers to the same residues as alkyl, but
having bivalency. Particular alkylene groups are those having 1 to 6 carbon atoms
5 (a “C1-C6 alkylene”), 1 to 5 carbon atoms (a “C1-C5 alkylene”), 1 to 4 carbon
atoms (a “C1-C4 alkylene”) or 1 to 3 carbon atoms (a “C1-C3 alkylene”).
Examples of alkylene include, but are not limited to, groups such as methylene
(-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene
(-CH2CH2CH2CH2-), and the like.
10 [27] “Alkynyl” as used herein refers to an unsaturated linear or branched
univalent hydrocarbon chain or combination thereof, having at least one site of
acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C) and
having the number of carbon atoms designated (i.e., C2-C10 means two to ten
carbon atoms). Particular alkynyl groups are those having 2 to 20 carbon atoms (a
15 “C2-C20 alkynyl”), having 2 to 8 carbon atoms (a “C2-C8 alkynyl”), having 2 to 6
carbon atoms (a “C2-C6 alkynyl”), or having 2 to 4 carbon atoms (a “C2-C4
alkynyl”). Examples of alkynyl include, but are not limited to, groups such as
ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like.
20 [28] “Aryl” refers to and includes polyunsaturated aromatic hydrocarbon
groups. Aryl may contain additional fused rings (e.g., from 1 to 3 rings),
including additionally fused aryl, heteroaryl, cycloalkyl, and/or heterocyclyl rings.
In one variation, the aryl group contains from 6 to 14 annular carbon atoms.
Examples of aryl groups include, but are not limited to, phenyl, naphthyl,
25 biphenyl, and the like.
[29] “Carbonyl” refers to the group C=O.
[30] “Cycloalkyl” refers to and includes cyclic univalent hydrocarbon
structures, which may be fully saturated, mono- or polyunsaturated, but which are
non-aromatic, having the number of carbon atoms designated (e.g., C1-C10 means
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one to ten carbons). Cycloalkyl can consist of one ring, such as cyclohexyl, or
multiple rings, such as adamantly, but excludes aryl groups. A cycloalkyl
comprising more than one ring may be fused, spiro or bridged, or combinations
thereof. A preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 13
5 annular carbon atoms. A more preferred cycloalkyl is a cyclic hydrocarbon
having from 3 to 8 annular carbon atoms (a "C3-C8 cycloalkyl"). Examples of
cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornyl, and the like.
[31] “Halo” or “halogen” refers to elements of the Group 17 series having
10 atomic number 9 to 85. Preferred halo groups include fluoro, chloro, bromo and
iodo. Where a residue is substituted with more than one halogen, it may be
referred to by using a prefix corresponding to the number of halogen moieties
attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl
substituted with two (“di”) or three (“tri”) halo groups, which may be but are not
15 necessarily the same halo; thus 4-chloro-3-fluorophenyl is within the scope of
dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group
is referred to as a “perhaloalkyl.” A preferred perhaloalkyl group is trifluoroalkyl
(-CF3). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen
takes the place of each H in the hydrocarbon making up the alkyl moiety of the
20 alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).
[32] “Heteroaryl” refers to and includes unsaturated aromatic cyclic groups
having from 1 to 10 annular carbon atoms and at least one annular heteroatom,
including but not limited to heteroatoms such as nitrogen, oxygen and sulfur,
wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen
25 atom(s) are optionally quaternized. A heteroaryl group can be attached to the
remainder of the molecule at an annular carbon or at an annular heteroatom.
Heteroaryl may contain additional fused rings (e.g., from 1 to 3 rings), including
additionally fused aryl, heteroaryl, cycloalkyl, and/or heterocyclyl rings.
Examples of heteroaryl groups include, but are not limited to imidazolyl, pyrrolyl,
30 pyrazolyl, 1,2,4-triazolyl, thiophenyl, furanyl, thiazolyl, isothiazolyl, 1,3,4-
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thiadiazolyl oxazolyl, isoxazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidyl,
pyridazinyl, pyrazinyl, indolyl, indazolyl, benzoimidazolyl, pyrrolopyridinyl,
pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl,
imidazopyridinyl, purinyl, benzofuranyl, furopyridinyl, benzooxazolyl,
5 benzothiophenyl, benzothiazolyl, oxazolopyridinyl, thiazolopyridinyl,
thienopyridinyl, quinolinyl, quinolonyl, naphthyridinyl, quinazolinyl,
pyridopyrimidinyl, cinnolinyl or pyridopyridazinyl and the like.
[33] “Heterocycle” or “heterocyclyl” refers to a saturated or an unsaturated
non-aromatic group having from 1 to 10 annular carbon atoms and from 1 to 4
10 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like, wherein the
nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are
optionally quaternized. A heterocyclyl group may have a single ring or multiple
condensed rings, but excludes heteroaryl groups. A heterocycle comprising more
than one ring may be fused, spiro or bridged, or any combination thereof. In fused
15 ring systems, one or more of the fused rings can be aryl or heteroaryl. Examples
of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl,
oxetanyl, morpholinyl, thiomorpholinyl, azepanyl tetrahydropyranyl,
dihydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, thiazolidinyl,
tetrahydrofuranyl, tetrahydrothiophenyl, and the like.
20 [34] “Oxo” refers to the moiety =O.
[35] “IDH” refers to Isocitrate dehydrogenases, which includes IDH1 and
IDH2. IDH refers herein specifically to mutant IDH, more specifically mutant
IDH1.
[36] “Optionally substituted” unless otherwise specified means that a group
25 may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the
substituents listed for that group in which the substituents may be the same of
different. In one embodiment, an optionally substituted group has one substituent.
In another embodiment, an optionally substituted group has two substituents. In
another embodiment, an optionally substituted group has three substituents. In
30 another embodiment, an optionally substituted group has four substituents. In
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some embodiments, an optionally substituted group has 1 to 2, 2 to 5, 3 to 5, 2 to
3, 2 to 4, 3 to 4, 1 to 3, 1 to 4 or 1 to 5 substituents.
[37] A “medicament” or “pharmaceutical composition” refer to an
pharmaceutical formulation in administrable form comprising atleast one
5 pharmaceutically active ingredient and one or more pharmaceutically acceptable
carrier.
[38] A “pharmaceutically acceptable carrier” or “pharmaceutically
acceptable excipient” refer to an ingredient in a pharmaceutical formulation, other
than an active ingredient, which is nontoxic to a subject. A pharmaceutically
10 acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or
preservative.
[39] As used herein, “treatment” or “treating” is an approach for obtaining
beneficial or desired results including clinical results. For example, beneficial or
desired results include, but are not limited to, one or more of the following:
15 decreasing symptoms resulting from the disease, increasing the quality of life of
those suffering from the disease, decreasing the dose of other medications
required to treat the disease, delaying the progression of the disease, and/or
prolonging survival of individuals. In reference to cancers or other unwanted cell
proliferation, beneficial or desired results include shrinking a tumor (reducing
20 tumor size); decreasing the growth rate of the tumor (such as to suppress tumor
growth); reducing the number of cancer cells; inhibiting, retarding or slowing to
some extent and preferably stopping cancer cell infiltration into peripheral organs;
inhibiting (slowing to some extent and preferably stopping) tumor metastasis;
inhibiting tumor growth; preventing or delaying occurrence and/or recurrence of
25 tumor; and/or relieving to some extent one or more of the symptoms associated
with the cancer. In some embodiments, beneficial or desired results include
preventing or delaying occurrence and/or recurrence, such as of unwanted cell
proliferation.
[40] As used herein, “delaying development of a disease” means to defer,
30 hinder, slow, retard, stabilize, and/or postpone development of the disease (such
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as cancer). This delay can be of varying lengths of time, depending on the history
of the disease and/or individual being treated. As is evident to one skilled in the
art, a sufficient or significant delay can, in effect, encompass prevention, in that
the individual does not develop the disease. For example, a late stage cancer, such
5 as development of metastasis, may be delayed.
[41] As used herein, an “effective dosage” or “effective amount” of
compound or salt thereof or pharmaceutical composition is an amount sufficient to
effect beneficial or desired results. For prophylactic use, beneficial or desired
results include results such as eliminating or reducing the risk, lessening the
10 severity of, or delaying the onset of the disease, including biochemical,
histological and/or behavioral symptoms of the disease, its complications and
intermediate pathological phenotypes presenting during development of the
disease. For therapeutic use, beneficial or desired results include ameliorating,
palliating, lessening, delaying or decreasing one or more symptoms resulting from
15 the disease, increasing the quality of life of those suffering from the disease,
decreasing the dose of other medications required to treat the disease, enhancing
effect of another medication such as via targeting, delaying the progression of the
disease, and/or prolonging survival. In reference to cancers or other unwanted cell
proliferation, an effective amount comprises an amount sufficient to cause a tumor
20 to shrink and/or to decrease the growth rate of the tumor (such as to suppress
tumor growth) or to prevent or delay other unwanted cell proliferation. In some
embodiments, an effective amount is an amount sufficient to delay development.
In some embodiments, an effective amount is an amount sufficient to prevent or
delay occurrence and/or recurrence. An effective amount can be administered in
25 one or more administrations, in the case of cancer, the effective amount of the
drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor
size; (iii) inhibit, retard, slow to some extent and preferably stop cancer cell
infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and
preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay
30 occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or
more of the symptoms associated with the cancer. An effective dosage can be
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administered in one or more administrations. For purposes of this disclosure, an
effective dosage of compound or a salt thereof, or pharmaceutical composition is
an amount sufficient to accomplish prophylactic or therapeutic treatment either
directly or indirectly. It is intended and understood that an effective dosage of a
5 compound or salt thereof, or pharmaceutical composition may or may not be
achieved in conjunction with another drug, compound, or pharmaceutical
composition. Thus, an “effective dosage” may be considered in the context of
administering one or more therapeutic agents, and a single agent may be
considered to be given in an effective amount if, in conjunction with one or more
10 other agents, a desirable result may be or is achieved.
[42] As used herein, the term “individual” is a mammal, including humans.
An individual includes, but is not limited to, human, bovine, horse, feline, canine,
rodent, or primate. In some embodiments, the individual is human. The individual
(such as a human) may have advanced disease or lesser extent of disease, such as
15 low tumor burden. In some embodiments, the individual is at an early stage of a
proliferative disease (such as cancer). In some embodiments, the individual is at
an advanced stage of a proliferative disease (such as an advanced cancer).
[43] Reference to “about” a value or parameter herein includes (and
describes) embodiments that are directed to that value or parameter per se. For
20 example, description referring to “about X” includes description of “X”.
[44] It is understood that aspects and variations described herein also
include “consisting” and/or “consisting essentially of” aspects and variations.
Compounds
[45] In one aspect, provided is a compound of the formula (IA):
25
formula (IA),
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or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof,
wherein
wherein,
X is O, S, NRa
or CRbR
c
;
5 A is C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl or 3-
to 10-membered heterocyclyl, wherein each of which is optionally substituted by
R
6a;
B is hydrogen, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8
cycloalkyl or 3- to 10-membered heterocyclyl, wherein each of which is
optionally substituted by R6b 10 ;
L is a bond, -O-, -(CH2)1-3-,-NH-, -NCH3-, -SO2-, -C(O)-, -CH2-O-, -
S-, -CRbR
c
-, -C(O)NH- or -NHC(O)-;
R
a
is hydrogen or C1-C6 alkyl optionally substituted by oxo, -OH or
halogen;
R
b
and Rc 15 are independently hydrogen, halogen, -CN, C1-C6 alkyl, C3-
C6 cycloalkyl, or -(C1-C3 alkylene)(C3-C6 cycloalkyl);
R
1
is hydrogen, halogen or C1-C6 alkyl;
R
2
is hydrogen, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(O)OR2a
,
C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered
20 heteroaryl, -(C1-C3 alkylene)C6 aryl or C1-C6 alkyl optionally substituted by oxo,
halogen, -OR2a or -NR2aR
2b, wherein C3-C6 cycloalkyl, 3- to 6-membered
heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, -(C1-C3 alkylene)C6 aryl of R2
optionally substituted by C1-C6 alkyl;
or R1
and R2
are taken together with the atom to which they are
25 attached to form a C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl, each of
which is optionally substituted by oxo, -OH, halogen, -NH2, or C1-C6 alkyl
optionally substituted by oxo, -OH, halogen or -NH2;
R
2a and R2b are independently hydrogen or C1-C6 alkyl;
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R
3
and R4 are independently hydrogen, halogen, or C1-C6 alkyl
optionally substituted by oxo, -OH or halogen;
or R3
and R4
are taken together with the atom to which they are
attached to form a C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl, each of
5 which is optionally substituted by oxo, -OH, -halogen, -NH2, or C1-C6 alkyl
optionally substituted by oxo, -OH, halogen or -NH2;
R
5 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6
cycloalkyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6- heteroaryl, -CN,
halogen, C1-C6 alkoxy, C1-
C6 haloalkoxy, -OR10
, -SR10
, -S(O)2R
10
, -S(O)2NR11R
12
, -NR10S(O)2R
11 10 , -
NR11R
12
, -C(O)R10
, -NR10C(O)R11
, -NR10C(O)NR11R
12
, -C(O)OR10
,
-C(O)ONR11R
12
, -C(O)NR11R
12, wherein each of which is optionally substituted
by R8
;
each R6a and R
6b is independently oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-
15 C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C6 aryl, -CN,
halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-
C6 haloalkyl, -OR13
, -SR13
, -S(O)2R
13
, -S(O)2NR14R
15
, -NR13S(O)2R
14
, -NR14R
15
,
-C(O)R13
, -NR13C(O)R14
, -NR13C(O)NR14R
15
, -C(O)OR13
, -C(O)ONR14R
15
,
-C(O)NR14R
15
, -(C1-C3 alkylene)OR13
, -(C1-C3 alkylene)SR13
, -(C1-
C3 alkylene)S(O)2R
13
, -(C1-C3 alkylene)S(O)2NR14R
15 20 , -(C1-
C3 alkylene)NR13S(O)2R
14
, -(C1-C3 alkylene)NR14R
15
, -(C1-
C3 alkylene)C(O)R13
, -(C1-C3 alkylene)NR13C(O)R14
, -(C1-
C3 alkylene)NR13C(O)NR14R
15
, -(C1-C3 alkylene)C(O)OR13
, -(C1-
C3 alkylene)C(O)ONR14R
15
, -(C1-C3 alkylene)(C3-C8 cycloalkyl) or -(C1-
C3 alkylene)(3- to 10-membered heterocyclyl); wherein each of R6a and R
6b 25 is
independently optionally substituted by oxo, C2-C6 alkenyl, C2-C6 alkynyl, -CN,
halogen, C1-C6 alkoxy, C1-
C6 haloalkoxy, -OR16
, -SR16
, -S(O)2R
16
, -S(O)2NR17R
18
, -NR16S(O)2R
17
, -
NR17R
18
, -C(O)R16
, -NR16C(O)R17
, -C(O)OR16, C1-C6 alkyl optionally substituted
30 by oxo, OH, halogen or NH2;
15
DIP/PA/2018/1046/CA
R
7 and R
7’ are independently hydrogen, C3-C6 cycloalkyl or C1-C6 alkyl
optionally substituted by halogen or -OH;
R
7 and R
7’ are taken together with the atom to which they are attached
to form a C3-C6 cycloalkyl;
R
8 5 is halogen, oxo, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl 3-
to 6-membered heterocyclyl, -CN, C1-C6 alkoxy, C1-
C6 haloalkoxy, -OR16
, -SR16
, -S(O)2R
16
, -S(O)2NR17R
18
, -NR16S(O)2R
17
, -
NR17R
18
, -C(O)R16
, -NR16C(O)R17
, -C(O)OR16 or C1-C6 alkyl optionally
substituted by oxo, -OH, halogen or NH2;
each R10, R11 and R
12 10 is independently hydrogen, C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl,
wherein each of R10, R11 and R
12 is independently optionally substituted by oxo,
C2-C6 alkenyl, C2-C6 alkynyl, -CN, halogen, C1-C6 alkoxy, C1-
C6 haloalkoxy, -OR16
, -SR16
, -S(O)2R
16
, -S(O)2NR17R
18
, -NR16S(O)2R
17
, -
NR17R
18
, -C(O)R16
, -NR16C(O)R17
, -C(O)OR16 15 or C1-C6 alkyl optionally
substituted by oxo, OH, halogen or NH2;
or R11 and R
12 are taken together with the atom to which they attached
to form a 3- to 6-membered heterocyclyl optionally substituted by oxo, OH,
halogen, NH2, or C1-C6 alkyl optionally substituted by oxo, OH, halogen or NH2;
each R13, R14 and R
15 20 is independently hydrogen, C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, -(C1-
C3 alkylene)C3-C6 cycloalkyl or -(C1-C3 alkylene) 5- to 6-heteroaryl, wherein each
of R13, R14 and R
15 is independently optionally substituted by oxo, C2-C6 alkenyl,
C2-C6 alkynyl, -CN, halogen, C1-C6 alkoxy, C1-
C6 haloalkoxy, -OR16
, -SR16
, -S(O)2R
16
, -S(O)2NR17R
18
, -NR16S(O)2R
17 25 , -
NR17R
18
, -C(O)R16
, -NR16C(O)R17
, -C(O)OR16 or C1-C6 alkyl optionally
substituted by oxo, OH, halogen or NH2;
16
DIP/PA/2018/1046/CA
or R14 and R
15 are taken together with the atom to which they attached
to form a 3- to 6-membered heterocyclyl optionally substituted by oxo, OH or
halogen, or C1-C6 alkyl optionally substituted by oxo, OH, halogen or NH2;
each R16, R17 and R
18 is independently hydrogen, C2-C6 alkenyl, C2-C6
5 alkynyl, or C1-C6 alkyl optionally substituted by oxo, OH, halogen or NH2;
or R17 and R
18 are taken together with the atom to which they attached
to form a 3- to 6-membered heterocyclyl optionally substituted by oxo, OH,
halogen or NH2, or C1-C6 alkyl optionally substituted by oxo, OH, halogen or
NH2; and
10 m and n are independently 0, 1, 2, 3 or 4.
[46] In some embodiments of a compound of formula (IA), X is O. In some
embodiments of a compound of formula (IA), X is S. In some embodiments of a
compound of formula (IA), X is NRa
. In some embodiments of a compound of
formula (IA), X is CR
bR
c
.
[47] In some embodiments of a compound of formula (IA), X is NRa
15 . In
some embodiments of a compound of formula (IA), Ra is hydrogen. In some
embodiments of a compound of formula (IA), Ra is C1-C6 alkyl optionally
substituted by oxo, -OH or halogen. In some embodiments of a compound of
formula (IA), Ra is -CH3.
[48] In some embodiments of a compound of formula (IA), X is CR
bR
c
20 . In
some embodiments of a compound of formula (IA), R
b and R
c
are independently
selected from hydrogen, halogen, -CN, C1-C6 alkyl or C3-C6 cycloalkyl. In some
embodiments of a compound of formula (IA), R
b or R
c
is methyl or cycloproyl. In
some embodiments of a compound of formula (IA), R
b and R
c
are hydrogen. In
some embodiments of a compound of formula (IA), one of the R
b and R
c
25 is –CN;
and the other one of R
b and R
c
is cycloproyl.
[49] In some embodiments of a compound of formula (IA), A is C6-C10
aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl or 3- to 10-membered
heterocyclyl, wherein each of which is optionally substituted by R6a. In some
17
DIP/PA/2018/1046/CA
embodiments of a compound of formula (IA), A is C6-C10 aryl optionally
substituted by R6a. In some embodiments of a compound of formula (IA), A is
phenyl optionally substituted by R6a
. In some embodiments of a compound of
formula (IA), A is an unsubstituted phenyl. In some embodiments of a compound
5 of formula (IA), A is phenyl substituted by halogen, -CN, C6-aryl, C1-C6
alkyl, -OR13. In some embodiments of a compound of formula (IA), A is phenyl
substituted by -Cl, -F, methyl, -OCH3, -CN, -OCF3 and phenyl.
[50] In some embodiments of a compound of formula (IA), A is naphthyl
optionally substituted by R6a. In some embodiments of a compound of formula
(IA), A is naphthyl optionally substituted by -OR13 10 . In some embodiments of a
compound of formula (IA), A is naphthyl optionally substituted by halogen. In
some embodiments of a compound of formula (IA), A is naphthyl substituted by -
Cl or –OCH3.
[51] In some embodiments of a compound of formula (IA), A is 5- to 10-
membered heteroaryl optionally substituted by R6a 15 . In some embodiments of a
compound of formula (IA), A is 5-membered heteroaryl optionally substituted by
R
6a. In some embodiments of a compound of formula (IA), A is 6-membered
heteroaryl optionally substituted by R6a. In some embodiments of a compound of
formula (IA), A is 9-membered bicyclic heteroaryl optionally substituted by R6a
,
in which any one ring or both rings may be substituted by same or different R6a 20 . In
some embodiments of a compound of formula (IA), A is 10-membered bicyclic
heteroaryl optionally substituted by R6a, in which any one ring or both rings may
be substituted by same or different R6a
.
[52] In some embodiments of a compound of formula (IA), A is 5-
25 membered heteroaryl selected from imidazolyl, pyrrolyl, pyrazolyl, triazolyl,
thiophenyl, furanyl, thiazolyl, isothiazolyl, 1,3,4-thiadiazolyl, oxazolyl, isoxazolyl
or 1,3,4-oxadiazolyl, wherein each of which is optionally substituted by R6a
,
wherein R
6a is selected from C1-C6 alkyl, -CN, halogen, C1-C6 alkoxy, C1-
C6 haloalkoxy or C1-C6 haloalkyl.
18
DIP/PA/2018/1046/CA
[53] In some embodiments of a compound of formula (IA), A is imidazolyl,
triazolyl, oxadiazolyl or isoxazolyl optionally substituted by methyl or -F,
[54] In some embodiments of a compound of formula (IA), A is 6-
membered heteroaryl selected from pyridyl, pyrimidyl, pyridazinyl or pyrazinyl,
wherein each of which is optionally substituted by R6a wherein R
6a 5 is selected
from oxo, C1-C6 alkyl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-
C6 haloalkyl. In some embodiments, R
6a is oxo, -CH3, -OCH3 or -Cl.
[55] In some embodiments of a compound of formula (IA), A is pyridyl or
pyrimidyl optionally substituted with -CH3 or -OCH3.
10 [56] In some embodiments of a compound of formula (IA), A is 9-
membered heteroaryl selected from, but not limited to indolyl, indazolyl,
benzoimidazolyl, pyrrolopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl,
pyrazolopyridinyl, pyrazolopyrimidinyl, imidazopyridinyl, purinyl, benzofuranyl,
furopyridinyl, benzooxazolyl, benzothiophenyl, benzothiazolyl, oxazolopyridinyl,
15 thiazolopyridinyl or thienopyridinyl, wherein each of which is optionally
substituted by R6a
.
[57] In some embodiments of a compound of formula (IA), A is 10-
membered heteroaryl selected from, but not limited to quinolinyl, quinolonyl,
naphthyridinyl, quinazolinyl, pyridopyrimidinyl, cinnolinyl or pyridopyridazinyl,
wherein each of which is optionally substituted by R6a 20 . In some embodiments of a
compound of formula (IA), 10-membered heteroaryl of A is quinolinyl substituted
by oxo, methyl, -CN, -Cl, -F, -Br, -OCH3, -OCF3, -CF3, cyclopropyl or -OH. In
some embodiments of a compound of formula (IA), 10-membered heteroaryl of A
is quinolonyl substituted by methyl, -CN, -Cl, -F, -Br, -OCH3, -OCF3, -CF3 or
25 cyclopropyl.
[58] In some embodiments of a compound of formula (IA), A is 3- to 10-
membered heterocyclyl optionally substituted by R6a. In some embodiments of a
compound of formula (IA), A is 3- to 10-membered heterocyclyl selected from
aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
19
DIP/PA/2018/1046/CA
thiomorpholinyl, pyrrolidinyl or azepanyl, wherein each of which is optionally
substituted by R6a. In some embodiments, heterocyclyl ring may be fused with
aryl or heteraryl ring to form biycylic ring which is optionally substituted R6a, in
which one ring or both rings may be substituted by the same or different R6a. In
5 some embodiments, heterocyclyl ring may be saturated or partially unsaturated.
In some embodiments of a compound of formula (IA), B is hydrogen,
C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl or 3- to 10-
membered heterocyclyl, wherein each of which is optionally substituted by R6b. In
some embodiments of a compound of formula (IA), B is hydrogen. In some
15 embodiments of a compound of formula (IA), B is C6-C10 aryl optionally
23
DIP/PA/2018/1046/CA
substituted by R6b
. In some embodiments of a compound of formula (IA), B is
phenyl optionally substituted by R6b. In some embodiments of a compound of
formula (IA), B is phenyl optionally substituted by halogen. In some embodiments
of a compound of formula (IA), B is unsubstituted phenyl. In some embodiments
5 of a compound of formula (IA), B is phenyl substituted by -F, -Cl, -Br, -CN, -
OCH3, -OCF3, -CH3 or -CF3.
[62] In some embodiments of a compound of formula (IA), B is naphthyl
optionally substituted by R6b
.
[63] In some embodiments of a compound of formula (IA), B is 5- to 10-
membered heteroaryl optionally substituted by R6b 10 . In some embodiments of a
compound of formula (IA), B is 5-membered heteroaryl optionally substituted by
R
6b. In some embodiments of a compound of formula (IA), B is 6-membered
heteroaryl optionally substituted by R6b. In some embodiments of a compound of
formula (IA), B is 9-membered bicyclic heteroaryl optionally substituted by R6b
,
15 in which any one ring or both rings may be substituted by the same or different
R
6b. In some embodiments of a compound of formula (IA), B is 10-membered
bicyclic heteroaryl optionally substituted by R6b, in which any one ring or both
rings may be substituted by the same or different R6b
.
[64] In some embodiments of a compound of formula (IA), B is 5-
20 membered heteroaryl selected from imidazolyl, pyrrolyl, pyrazolyl, triazole,
thiophenyl, furanyl, thiazolyl, isothiazolyl, 1,3,4-thiadiazolyl, oxazolyl, isoxazolyl
and 1,3,4-oxadiazolyl, wherein each of which is optionally substituted by
R
6b
,wherein R
6b is selected from C1-C6 alkyl, -CN, halogen, C1-C6 alkoxy, C1-
C6 haloalkoxy or C1-C6 haloalkyl. In some embodiments of a compound of
25 formula (IA), B is triazolyl substituted by -CH3.
[65] In some embodiments of a compound of formula (IA), B is 6-
membered heteroaryl selected from pyridyl, pyrimidyl, pyridazinyl or pyrazinyl,
wherein each of which is optionally substituted by R6b. wherein R6b is selected
from oxo, C1-C6 alkyl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-
C6 haloalkyl. In some embodiments, R6b 30 is -CH3, -CF3, F or -Cl. In some
24
DIP/PA/2018/1046/CA
embodiments of a compound of formula (IA), B is pyridyl, pyrimidyl, pyridazinyl
or pyrazinyl optinally substituted by cyclopropyl, -F, -Cl, -Br, -CN, -OCH3, -
OCF3, -CH3 or -CF3.
[66] In some embodiments of a compound of formula (IA), B is 9-
5 membered heteroaryl selected from indolyl, indazolyl, benzoimidazolyl,
pyrrolopyridinyl pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrazolopyridinyl,
pyrazolopyrimidinyl, imidazopyridinyl, purinyl, benzofuranyl, furopyridinyl,
benzooxazolyl, benzothiophenyl, benzothiazolyl, oxazolopyridinyl,
thiazolopyridinyl or thienopyridinyl, wherein each of which is optionally
substituted by R6b 10 .
[67] In some embodiments of a compound of formula (IA), B is 10-
membered heteroaryl selected from quinolinyl, quinolonyl, naphthyridinyl,
quinazolinyl, pyridopyrimidinyl, cinnolinyl or pyridopyridazinyl, wherein each of
which is optionally substituted by R6b
.
15 [68] In some embodiments of a compound of formula (IA), B is 3- to 10-
membered heterocyclyl optionally substituted by R6b. In some embodiments of a
compound of formula (IA), 3- to 10-membered heterocyclyl of B is selected from
aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl or azepanyl, wherein
each of which is optionally substituted by R6b. wherein R6b 20 is selected from oxo,
C1-C6 alkyl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(O)R13 or C1-
C6 haloalkyl. In some embodiments, R6b is oxo, -C(O)CH3, -C(O)CH=CH2 or -
CH3. In some embodiments, heterocyclyl ring may be fused with aryl or heteraryl
ring to form biycylic system which is optionally substituted R6b, in which one ring
or both rings may be substituted by the same or different R6b 25 . In some
embodiments, heterocyclyl ring may be saturated or partially unsaturated.
[69] In some embodiments of a compound of formula (IA), B is C3-C8
cycloalkyl optionally substituted by R6b. In some embodiments of a compound of
formula (IA), B is cylopropyl, cyclobutyl or cyclopentyl optionally substituted by
30 –CN or -CH3.[72] In some embodiments of a compound of formula (IA), L is a bond. In
some embodiments of a compound of formula (IA), L is -O-. In some
10 embodiments of a compound of formula (IA), L is -(CH2)1-3-. In some
embodiments of a compound of formula (IA), L is -NH-. In some embodiments of
a compound of formula (IA), L is –NCH3-. In some embodiments of a compound
of formula (IA), L is -SO2-. In some embodiments of a compound of formula (IA),
L is -C(O)-. In some embodiments of a compound of formula (IA), L is -C(O)NH15 . In some embodiments of a compound of formula (IA), L is -NHC(O)-. In some
embodiments of a compound of formula (IA), L is -CH2-O-. In some
embodiments of a compound of formula (IA), L is -S-. In some embodiments of a
compound of formula (IA), L is -CR
bR
c
-, wherein Rb
and Rc is independently
hydrogen, halogen, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, or -(C1-C3 alkylene)(C3-
20 C6 cycloalkyl).
27
DIP/PA/2018/1046/CA
[73] In some embodiments of a compound of formula (IA), m is 0. In some
embodiments of a compound of formula (IA), m is 1. In some embodiments of a
compound of formula (IA), m is 2. In some embodiments, m is 3. In some
embodiments of a compound of formula (IA), m is or 4.
5 [74] In some embodiments of a compound of formula (IA), n is 0. In some
embodiments of a compound of formula (IA), n is 1. In some embodiments of a
compound of formula (IA), n is 2. In some embodiments of a compound of
formula (IA), n is 3. In some embodiments of a compound of formula (IA), n is or
4.
[75] In some embodiments of a compound of formula (IA), R1
10 is hydrogen.
In some embodiments of a compound of formula (IA), R1
is halogen. In some
embodiments of a compound of formula (IA), R1
is C1-C6 alkyl. In some
embodiments of a compound of formula (IA), R1
is -CH3.
[76] In some embodiments of a compound of formula (IA), R2
is hydrogen,
halogen, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)OR2a 15 , C3-C6
cycloalkyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered
heteroaryl -(C1-C3 alkylene)C6 aryl or C1-C6 alkyl optionally substituted by oxo,
halogen, -OR2a or -NR2aR
2b, wherein C3-C6 cycloalkyl, 3- to 6-membered
heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl and -(C1-C3 alkylene)C6 aryl
of R2 20 optionally substituted by C1-C6 alkyl; In some embodiments of a compound
of formula (IA), R2
is hydrogen. In some embodiments of a compound of formula
(IA), R2
is halogen. In some embodiments of a compound of formula (IA), R2
is
C1-C6 alkoxy. In some embodiments of a compound of formula (IA), R
2
is –
OCH3. In some embodiments of a compound of formula (IA), R2
is C6 aryl or
25 more specifically phenyl. In some embodiments of a compound of formula (IA),
R
2
is 5- to 6-membered heteroaryl. In some embodiments of a compound of
formula (IA), R2
is 5-membered heteroaryl. In some embodiments of a compound
of formula (IA), R2
is 5-membered heteroaryl substituted with C1-C6 alkyl. In
28
DIP/PA/2018/1046/CA
some embodiments of a compound of formula (IA), R2
is . In some
embodiments of a compound of formula (IA), R
2
is 6-membered heteroaryl or
more specifically pyridyl. In some embodiments of a compound of formula (IA),
R
2
is wherein dotted line indicates point of attachment. In some
embodiments of a compound of formula (IA), R2
5 is wherein dotted line
indicates point of attachment. In some embodiments of a compound of formula
(IA), R2
is wherein dotted line indicates point of attachment. In some
embodiments of a compound of formula (IA), R2
is C1-C6 alkyl optionally
substituted by oxo, halogen, -OR2a or -NR2aR
2b. In some embodiments of a
compound of formula (IA), R2
10 is unsubstituted C1-C6 alkyl. In some embodiments
of a compound of formula (IA), R2
is methyl. In some embodiments of a
compound of formula (IA), R2
is ethyl. In some embodiments of a compound of
formula (IA), R2
is isopropyl. In some embodiments of a compound of formula
(IA), R2
is isobutyl. In some embodiments of a compound of formula (IA), R2
is
C1-C6 alkyl substituted by -OR2a, wherein R2a 15 is hydrogen or C1-C6 alkyl. In some
embodiments of a compound of formula (IA), R2
is C1-C6 alkyl substituted by –
OH. In some embodiments of a compound of formula (IA), R2
is C1-C6 alkyl
substituted by –OCH3. In some embodiments of a compound formula (IA), R2
is
C1-C6 alkyl substituted by –OCH2CH3. In some embodiments of a compound
formula (IA), R2
20 is C1-C6 alkyl substituted by –OCH(CH3)2. In some
embodiments of a compound of formula (IA), R2
is C1-C6 alkyl substituted by –
OC(CH3)3. In some embodiments of a compound of formula (IA), R2
is -
CH(OH)CH3. In some embodiments of a compound of formula (IA), R2
is C1-C6
alkyl substituted by -NR2aR
2b. In some embodiments of a compound of formula
29
DIP/PA/2018/1046/CA
(IA), R2
is C1-C6 alkyl substituted by-NH2. In some embodiments of a compound
of formula (IA), R2
is -CH(CH3)NH2. In some embodiments of a compound of
formula (IA), R2
is C1-C6 alkyl substituted by NHCH3. In some embodiments of a
compound of formula (IA), R2
is -CH(CH3)NHCH3. In some embodiments of a
compound of formula (IA), R2
5 is C1-C6 alkyl substituted by -N(CH3)2. In some
embodiments of a compound of formula (IA), R2
is -CH(CH3)-N(CH3)2. In some
embodiments of a compound of formula (IA), R2
is C1-C6 alkyl substituted by
halogen. In some embodiments of a compound of formula (IA), R2
is C1-C6 alkyl
substituted by one or more -F. In some embodiments of a compound of formula
(IA), R2
10 is C1-C6 alkyl substituted by monofluoro. In some embodiments of a
compound of formula (IA), R2
is -CH(CH3)CH2F. In some embodiments of a
compound of formula (IA), R
2
is -CH2F. In some embodiments of a compound of
formula (IA), R2
is -C2H5F. In some embodiments of a compound of formula (IA),
R
2
is C1-C6 alkyl substituted by difluoro. In some embodiments of a compound of
formula (IA), R2
15 is -CHF2. In some embodiments of a compound of formula (IA),
R
2
is -CH(CH3)CHF2. In some embodiments of a compound of formula (IA), R2
is
-CH(CH2F)2. In some embodiments of a compound of formula (IA), R2
is C1-C6
alkyl substituted by trifluoro. In some embodiments of a compound of formula
(IA), R2
is -CF3.In some embodiments of a compound of formula (IA), R2
is -
CH(CH3)CF3. In some embodiments of a compound of formula (IA), R2
20 is C3-C6
cycloalkyl. In some embodiments of a compound of formula (IA), R2
is
cyclopropyl. In some embodiments of a compound of formula (IA), R2
is -(C1-
C3 alkylene)C6 aryl. In some embodiments of a compound of formula (IA), R2
is -(CH2)phenyl. In some embodiments of a compound of formula (IA), R1
and R2
25 are taken together with the atom to which they are attached to form a C3-C6
cycloalkyl or 3- to 6-membered heterocyclyl, each of which is optionally
substituted by oxo, -OH, halogen, -NH2, or C1-C6 alkyl optionally substituted by
oxo, -OH, halogen or -NH2. In some embodiments of a compound of formula
(IA), R1
and R2
are taken together with the atom to which they are attached to
30 form cyclopropyl.
30
DIP/PA/2018/1046/CA
[77] In some embodiments of a compound of formula (IA), R1
and R2
both
are hydrogen. In some embodiments of a compound of formula (IA), R1
and R2
both are C1-C6 alkyl. In some embodiments of a compound of formula (IA), R1
and R2
both are methyl. In some embodiments of a compound of formula (IA), R1
is hydrogen and R2
5 is C1-C6 alkyl. In some embodiments of a compound of
formula (IA), R1
is hydrogen and R2
is –CH3. In some embodiments of a
compound of formula (IA), R1
is hydrogen and R2
is ethyl. In some embodiments
of a compound of formula (IA), R1
is hydrogen and R2
is propyl. In some
embodiments of a compound of formula (IA), R1
is hydrogen and R2
is isopropyl.
In some embodiments of a compound of formula (IA), R1
is hydrogen and R2
10 is
isobutyl. In some embodiments of a compound of formula (IA), R1
is hydrogen
and R2
is -CH2F. In some embodiments of a compound of formula (IA), R1
is
hydrogen and R2
is –CHF2. In some embodiments of a compound of formula (IA),
R
1
is hydrogen and R2
is -CH(CH3)CHF2. In some embodiments of a compound of
formula (IA), R1
is hydrogen and R2
15 is phenyl. In some embodiments of a
compound of formula (IA), R1
is hydrogen and R2
is cyclopropyl. In some
embodiments of a compound of formula (IA), R1
is hydrogen and R2
is -(C1-
C3 alkylene)C6 aryl. In some embodiments of a compound of formula (IA), R1
is
hydrogen and R2
is -(CH2)phenyl. In some embodiments of a compound of
formula (IA), R
1
is hydrogen and R
2
20 is 5-membered heteroaryl. In some
embodiments of a compound of formula (IA), R1
is hydrogen and R2
is 5-
membered heteroaryl substituted with C1-C6 alkyl. In some embodiments of a
compound of formula (IA), R1
is hydrogen and R2
is . In some
embodiments of a compound of formula (IA), R1
is hydrogen and R2
is 6-
25 membered heteroaryl or more specifically pyridyl. In some embodiments of a
compound of formula (IA), R1
is hydrogen and R2
is wherein dotted line
indicates point of attachment. In some embodiments of a compound of formula
31
DIP/PA/2018/1046/CA
(IA), R1
is hydrogen and R2
is wherein dotted line indicates point of
attachment. In some embodiments of a compound of formula (IA), R1
is hydrogen
and R2
is wherein dotted line indicates point of attachment.
[78] In some embodiments of a compound of formula (IA), R3
5 is hydrogen,
halogen, or C1-C6 alkyl optionally substituted by oxo, -OH or halogen. In some
embodiments of a compound of formula (IA), R3
is hydrogen. In some
embodiments of a compound of formula (IA), R3
is halogen. In some
embodiments of a compound of formula (IA), R3
is C1-C6 alkyl optionally
10 substituted by oxo, -OH or halogen.
[79] In some embodiments of a compound of formula (IA), R4
is hydrogen,
halogen, or C1-C6 alkyl optionally substituted by oxo, -OH or halogen. In some
embodiments of a compound of formula (IA), R4
is hydrogen. In some
embodiments of a compound of formula (IA), R4
is halogen. In some
embodiments of a compound of formula (IA), R4
15 is C1-C6 alkyl optionally
substituted by oxo, -OH or halogen.
[80] In some embodiments of a compound of formula (IA), R3
is hydrogen
and R4
is halogen, or C1-C6 alkyl optionally substituted by oxo, -OH or halogen.
In some embodiments of a compound of formula (IA), R3
is hydrogen and R4
is
halogen. In some embodiments of a compound of formula (IA), R3
20 is hydrogen
and R4
is C1-C6 alkyl optionally substituted by oxo, -OH or halogen. In some
embodiments of a compound of formula (IA), R3 is hydrogen and R4
is –CH3. In
some embodiments of a compound of formula (IA), R4
is hydrogen and R3
is
halogen, or C1-C6 alkyl optionally substituted by oxo, -OH or halogen. In some
embodiments of a compound of formula (IA), R4
is hydrogen and R3
25 is halogen.
In some embodiments of a compound of formula (IA), R4
is hydrogen and R3
is
C1-C6 alkyl optionally substituted by oxo, -OH or halogen. In some embodiments
32
DIP/PA/2018/1046/CA
of a compound of formula (IA), R4 is hydrogen and R3
is –CH3. In some
embodiments of a compound of formula (IA), R3
and R4
both are hydrogen. In
some embodiments of a compound of formula (IA), R3
and R4
both are –CH3.
[81] In some embodiments of a compound of formula (IA), R3
and R4
are
5 taken together with the atom to which they are attached to form a C3-C6 cycloalkyl
or 3-6 membered heterocyclyl, each of which is optionally substituted by oxo, -
OH, halogen, -NH2, or C1-C6 alkyl optionally substituted by oxo, -OH, halogen or
-NH2. In some embodiments of a compound of formula (IA), R3
and R4
are taken
together with the atom to which they are attached to form cyclopropyl. In some
embodiments of a compound of formula (IA), R3
and R4
10 are taken together with
the atom to which they are attached to form oxytanyl ring.
[82] In some embodiments of a compound of formula (IA), R5 is hydrogen,
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered
heterocyclyl, C6-aryl, 5- to 6-membered heteroaryl, -CN, halogen, C1-C6 alkoxy,
C1-C6 haloalkoxy, -OR10
, -SR10
, -S(O)2R
10
, -S(O)2NR11R
12
, -NR10S(O)2R
11 15 , -
NR11R
12
, -C(O)R10
, -NR10C(O)R11
, -NR10C(O)NR11R
12
, -C(O)OR10
,
-C(O)ONR11R
12
, -C(O)NR11R
12, wherein each of which is optionally substituted
by R8
. In some embodiments of a compound of formula (IA), R5 is hydrogen. In
some embodiments of a compound of formula (IA), R5 is C1-C6 alkyl optionally
substituted by R8
. In some embodiments of a compound of formula (IA), R5 20 is C3-
C6 cycloalkyl optionally substituted by R8
. In some embodiments of a compound
of formula (IA), R5 is 3- to 6-membered heterocyclyl optionally substituted by R8
.
In some embodiments of a compound of formula (IA), R5 is -CN. In some
embodiments of a compound of formula (IA), R5 is halogen. In some
embodiments of a compound of formula (IA), R5 25 is C1-C6 alkoxy. In some
embodiments of a compound of formula (IA), R5 is C1-C6 haloalkoxy. In some
embodiments of a compound of formula (IA), R5 is -OR10. In some embodiments
of a compound of formula (IA), R5 is -S(O)2R
10. In some embodiments of a
compound of formula (IA), R5 is -OR10. In some embodiments of a compound of
formula (IA), R5 is -S(O)2NR11R
12 30 . In some embodiments of a compound of
33
DIP/PA/2018/1046/CA
formula (IA), R5 is -NR10S(O)2R
11. In some embodiments of a compound of
formula (IA), R5 is -C(O)R10. In some embodiments of a compound of formula
(IA), R5 is -NR10C(O)R11. In some embodiments of a compound of formula (IA),
R
5 is -C(O)OR10. In some embodiments of a compound of formula (IA), R5
is -C(O)NR11R
12 5 .
[83] In some embodiments of a compound of formula (IA), R5 is hydrogen.
In some embodiments of a compound of formula (IA), R5 is methyl. In some
embodiments of a compound of formula (IA), R5 is ethyl. In some embodiments of
a compound of formula (IA), R5 is ter-butyl. In some embodiments of a compound
of formula (IA), R5 10 is iso-butyl. In some embodiments of a compound of formula
(IA), R5 is cyclopropyl. In some embodiments of a compound of formula (IA), R5
is phenyl. In some embodiments of a compound of formula (IA), R5 is –CN. In
some embodiments of a compound of formula (IA), R5 is –N(CH3)2. In some
embodiments of a compound of formula (IA), R5 is -Cl. In some embodiments of a
compound of formula (IA), R5 15 is -Br. In some embodiments of a compound of
formula (IA), R5 is -OCH3. In some embodiments of a compound of formula (IA),
R
5 is -OC3H7. In some embodiments of a compound of formula (IA), R5 is -
OCH(CH3)2. In some embodiments of a compound of formula (IA), R5 is -OCF3.
In some embodiments of a compound of formula (IA), R5 is -CF3. In some
embodiments of a compound of formula (IA), R5 20 is -SCH3. In some embodiments
of a compound of formula (IA), R5 is aziridinyl. In some embodiments of a
compound of formula (IA), R5 is piperidinyl. In some embodiments of a
compound of formula (IA), R5 is propyne. In some embodiments of a compound
of formula (IA), R5 is -SO2NHCH3. In some embodiments of a compound of
formula (IA), R
5 25 is C(O)OCH3. In some embodiments of a compound of formula
(IA), R5 is isopropene. In some embodiments of a compound of formula (IA), R5 is
thiazolyl.
[84] In some embodiments of a compound of formula (IA), R7 and R
7’ are
independently hydrogen, C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by
halogen or -OH. In some embodiments of a compound of formula (IA), R7 and R
7’ 30
34
DIP/PA/2018/1046/CA
both are hydrogen. In some embodiments of a compound of formula (IA), R7 and
R
7’ both are CH3. In some embodiments of a compound of formula (IA), R7 is
hydrogen and R7’ is -CH3. In some embodiments of a compound of formula (IA),
R
7 is hydrogen and R7’ is ethyl. In some embodiments of a compound of formula
(IA), R7 is hydrogen and R7’ 5 is isopropyl. In some embodiments of a compound of
formula (IA), R7 is hydrogen and R7’ is n-propyl. In some embodiments of a
compound of formula (IA), R7 is hydrogen and R7’ is ter-butyl. In some
embodiments of a compound of formula (IA), R7 is hydrogen and R7’ is
cyclopropyl. In some embodiments of a compound of formula (IA), R7 is
hydrogen and R7’ 10 is cyclobutyl. In some embodiments of a compound of formula
(IA), R7 is hydrogen and R7’ is -CF3. In some embodiments of a compound of
formula (IA), R7 is hydrogen and R7’ is -CH2F. In some embodiments of a
compound of formula (IA), R7 is methyl and R7’ is isopropyl.
[85] In some embodiments of a compound of formula (IA), R7 and R
7’ are
15 taken together with the atom to which they are attached to form a C3-C6
cycloalkyl. In some embodiments of a compound of formula (IA), R
7 and R
7’ are
taken together with the atom to which they are attached to form a cyclopropyl.
[86] In some embodiments of a compound of formula (IA), A, B, L, R6a,
R
6b, m and n are together is . In some embodiments of a
compound of formula (IA), A, B, L, R
6a
, R
6b 20 , m and n are together is
. In some embodiments of a compound of formula (IA), A, B, L,
R
6a
, and m are together is .
35
DIP/PA/2018/1046/CA
[87] In some embodiments of a compound of formula (IA), A, B, L, R6a
,
R
6b, m and n are together selected from the group of [89] In some embodiments, the compound of formula (IA) is a compound
of the formula (I):
formula (I),
5 or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof,
wherein
wherein,
X is O, S or NRa
;
R
a
is hydrogen or C1-C6 alkyl optionally substituted by oxo, -OH or
10 halogen;
A is C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl or 3-
to 10-membered heterocyclyl, wherein each of which is optionally substituted by
R
6a;
B is hydrogen, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8
15 cycloalkyl or 3- to 10-membered heterocyclyl, wherein each of which is
optionally substituted by R6b;
L is a bond, -O-, -(CH2)1-3-,-NH-, -NCH3-, -SO2-, -C(O)-, -C(O)NHor -NHC(O)-;
R
1
is hydrogen, halogen or C1-C6 alkyl;
R
2
20 is hydrogen, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C6 aryl, 5- to
6-membered heteroaryl or C1-C6 alkyl optionally substituted by oxo, halogen, -
OR2a or -NR2aR
2b;
R
2a and R2b are independently hydrogen or C1-C6 alkyl;
42
DIP/PA/2018/1046/CA
or R1
and R2
are taken together with the atom to which they are
attached to form a C3-C6 cycloalkyl or 3- to 6- membered heterocyclyl, each of
which is optionally substituted by oxo, -OH, halogen, -NH2, or C1-C6 alkyl
optionally substituted by oxo, -OH, halogen or -NH2;
R
3
and R4 5 are independently hydrogen, halogen, or C1-C6 alkyl
optionally substituted by oxo, -OH or halogen;
or R3
and R4
are taken together with the atom to which they are
attached to form a C3-C6 cycloalkyl or 3-to 6membered heterocyclyl, each of
which is optionally substituted by oxo, -OH, -halogen, -NH2, or C1-C6 alkyl
10 optionally substituted by oxo, -OH, halogen or -NH2;
R
5 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6
cycloalkyl, 3- to 6-membered heterocyclyl, -CN, halogen, C1-C6 alkoxy, C1-
C6 haloalkoxy, -OR10
, -SR10
, -S(O)2R
10
, -S(O)2NR11R
12
, -NR10S(O)2R
11
, -
NR11R
12
, -C(O)R10
, -NR10C(O)R11
, -NR10C(O)NR11R
12
, -C(O)OR10
,
-C(O)ONR11R
12
, -C(O)NR11R
12 15 , wherein each of which is optionally substituted
by R8
;
each R6a and R6b is independently oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-
C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, -CN, halogen, C1-
C6 alkoxy, C1-C6 haloalkoxy, C1-
C6 haloalkyl, -OR13
, -SR13
, -S(O)2R
13
, -S(O)2NR14R
15
, -NR13S(O)2R
14
, -NR14R
15 20 ,
-C(O)R13
, -NR13C(O)R14
, -NR13C(O)NR14R
15
, -C(O)OR13
, -C(O)ONR14R
15
,
-C(O)NR14R
15
, -(C1-C3 alkylene)OR13
, -(C1-C3 alkylene)SR13
, -(C1-
C3 alkylene)S(O)2R
13
, -(C1-C3 alkylene)S(O)2NR14R
15
, -(C1-
C3 alkylene)NR13S(O)2R
14
, -(C1-C3 alkylene)NR14R
15
, -(C1-
C3 alkylene)C(O)R13
, -(C1-C3 alkylene)NR13C(O)R14 25 , -(C1-
C3 alkylene)NR13C(O)NR14R
15
, -(C1-C3 alkylene)C(O)OR13
, -(C1-
C3 alkylene)C(O)ONR14R
15
, -(C1-C3 alkylene)(C3-C8 cycloalkyl) or -(C1-
C3 alkylene)(3-10-membered heterocyclyl); wherein each of R6a and R6b is
independently optionally substituted by oxo, C2-C6 alkenyl, C2-C6 alkynyl, -CN,
30 halogen, C1-C6 alkoxy, C1-
43
DIP/PA/2018/1046/CA
C6 haloalkoxy, -OR16
, -SR16
, -S(O)2R
16
, -S(O)2NR17R
18
, -NR16S(O)2R
17
, -
NR17R
18
, -C(O)R16
, -NR16C(O)R17
, -C(O)OR16, C1-C6 alkyl optionally substituted
by oxo, OH, halogen or NH2;
m and n is independently 0, 1, 2, 3 or 4;
R
7 5 is hydrogen or CH3;
R
8 is halogen, oxo, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or
3- to 6-membered heterocyclyl, -CN, C1-C6 alkoxy, C1-
C6 haloalkoxy, -OR16
, -SR16
, -S(O)2R
16
, -S(O)2NR17R
18
, -NR16S(O)2R
17
, -
NR17R
18
, -C(O)R16
, -NR16C(O)R17
, -C(O)OR16 or C1-C6 alkyl optionally
10 substituted by oxo, -OH, halogen or NH2;
each R10, R11 and R
12 is independently hydrogen, C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl,
wherein each of R10, R11 and R
12 is independently optionally substituted by oxo,
C2-C6 alkenyl, C2-C6 alkynyl, -CN, halogen, C1-C6 alkoxy, C1-
C6 haloalkoxy, -OR16
, -SR16
, -S(O)2R
16
, -S(O)2NR17R
18
, -NR16S(O)2R
17
15 , -
NR17R
18
, -C(O)R16
, -NR16C(O)R17
, -C(O)OR16 or C1-C6 alkyl optionally
substituted by oxo, OH, halogen or NH2;
or R11 and R
12 are taken together with the atom to which they attached
to form a 3-6 membered heterocyclyl optionally substituted by oxo, OH, halogen,
20 NH2, or C1-C6 alkyl optionally substituted by oxo, OH, halogen or NH2;
each R13, R14 and R
15 is independently hydrogen, C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl,
wherein each of R13, R14 and R
15 is independently optionally substituted by oxo,
C2-C6 alkenyl, C2-C6 alkynyl, -CN, halogen, C1-C6 alkoxy, C1-
C6 haloalkoxy, -OR16
, -SR16
, -S(O)2R
16
, -S(O)2NR17R
18
, -NR16S(O)2R
17 25 , -
NR17R
18
, -C(O)R16
, -NR16C(O)R17
, -C(O)OR16 or C1-C6 alkyl optionally
substituted by oxo, OH, halogen or NH2;
44
DIP/PA/2018/1046/CA
or R14 and R
15 are taken together with the atom to which they attached
to form a 3-to 6- membered heterocyclyl optionally substituted by oxo, OH or
halogen, or C1-C6 alkyl optionally substituted by oxo, OH, halogen or NH2;
each R16, R17 and R
18 is independently hydrogen, C2-C6 alkenyl, C2-C6
5 alkynyl, or C1-C6 alkyl optionally substituted by oxo, OH, halogen or NH2;
or R17 and R
18 are taken together with the atom to which they attached
to form a 3-6 membered heterocyclyl optionally substituted by oxo, OH, halogen
or NH2, or C1-C6 alkyl optionally substituted by oxo, OH, halogen or NH2.
[90] In some embodiments, a compound of formula (IA) is a compound of
10 any of the compounds of formula (Ia-1) to (Ia-14),[100] Also provided are salts of compounds referred to herein, such as
pharmaceutically acceptable salts. The invention also includes any or all of the
52
DIP/PA/2018/1046/CA
stereochemical forms, including any enantiomeric or diastereomeric forms, and
any tautomers or other forms of the compounds described.
[101] A compound as detailed herein may in one aspect be in a purified form
and compositions comprising a compound in purified forms are detailed herein.
5 Compositions comprising a compound as detailed herein or a salt thereof are
provided, such as compositions of substantially pure compounds. In some
embodiments, a composition containing a compound as detailed herein or a salt
thereof is in substantially pure form. Unless otherwise stated, “substantially pure”
intends a composition that contains no more than 35 % impurity, wherein the
10 impurity denotes a compound other than the compound comprising the majority of
the composition or a salt thereof. In some embodiments, a composition of
substantially pure compound or a salt thereof is provided wherein the composition
contains no more than 25 %, 20%, 15%, 10%, or 5% impurity. In some
embodiments, a composition of substantially pure compound or a salt thereof is
15 provided wherein the composition contains or no more than 3 %, 2%, 1% or 0.5%
impurity.
[102] Representative compounds of the present invention (collectively, a
compound of formula (IA), (I), (Ia-1) to (Ia-14), (Ib-1) to (Ib-11), (II) , (IIa-1) to
(IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (IVa-1) to (IVa-7), (V) or (VI)),) are listed
20 in table-1 and table-2. It is understood that individual enantiomers and
diastereomers are included in the generic compound structures shown in table-1
and table-2. Specific synthetic methods for preparing compounds of table-1 are
provided example herein.
T[104] In some embodiments, provided herein are compounds described in
table-1 and table-2, or a salt, polymorph, solvate, enantiomer, stereoisomer or
tautomer thereof, and uses thereof.
5 [105] The embodiments and variations described herein are suitable for
compounds of any formulae detailed herein, where applicable.
[106] Representative examples of compounds detailed herein, including
intermediates and final compounds according to the present disclosure are
depicted herein. It is understood that in one aspect, any of the compounds
10 described herein may be used in the methods detailed herein, including, where
applicable, intermediate compounds that may be isolated and administered to an
individual.
[107] The compounds depicted herein may be present as salts even if salts
are not depicted and it is understood that the present disclosure embraces all salts
15 and solvates of the compounds depicted here, as well as the non-salt and nonsolvate form of the compound, as is well understood by the skilled artisan. In
some embodiments, the salts of the compounds provided herein are
pharmaceutically acceptable salts. Where one or more tertiary amine moiety is
present in the compound, the N-oxides are also provided and described.
108
DIP/PA/2018/1046/CA
[108] Where tautomeric forms may be present for any of the compounds
described herein, each and every tautomeric form is intended even though only
one or some of the tautomeric forms may be explicitly depicted. The tautomeric
forms specifically depicted may or may not be the predominant forms in solution
5 or when used according to the methods described herein.
[109] The present disclosure also includes any or all of the stereochemical
forms, including any enantiomeric or diastereomeric forms of the compounds
described. The structure or name is intended to embrace all possible stereoisomers
of a compound depicted, and each unique stereoisomer has a compound number
10 bearing a suffix “a”, “b”, etc. All forms of the compounds are also embraced by
the invention, such as crystalline or non-crystalline forms of the compounds.
Compositions comprising a compound of the invention are also intended, such as
a composition of substantially pure compound, including a specific stereochemical
form thereof, or a composition comprising mixtures of compounds of the
15 invention in any ratio, including two or more stereochemical forms, such as in a
racemic or non-racemic mixture.
[110] The invention also intends isotopically-labeled and/or isotopicallyenriched forms of compounds described herein. The compounds herein may
contain unnatural proportions of atomic isotopes at one or more of the atoms that
20 constitute such compounds. In some embodiments, the compound is isotopicallylabeled, such as an isotopically-labeled compound of the formula (IA) or
variations thereof described herein, where a fraction of one or more atoms are
replaced by an isotope of the same element. Exemplary isotopes that can be
incorporated into compounds of the invention include isotopes of hydrogen,
carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2H, 3H, 11C, 13 25 C,
14C 13N, 15O, 17O, 32P, 35S, 18F, 36Cl. Certain isotope labeled compounds (e.g. 3H
and 14C) are useful in compound or substrate tissue distribution studies.
Incorporation of heavier isotopes such as deuterium (2H) can afford certain
therapeutic advantages resulting from greater metabolic stability, for example,
109
DIP/PA/2018/1046/CA
increased in vivo half-life, or reduced dosage requirements and, hence may be
preferred in some instances.
[111] Isotopically-labeled compounds of the present invention can generally
be prepared by standard methods and techniques known to those skilled in the art
5 or by procedures similar to those described in the accompanying Examples
substituting appropriate isotopically-labeled reagents in place of the corresponding
non-labeled reagent.
[112] The invention also includes any or all metabolites of any of the
compounds described. The metabolites may include any chemical species
10 generated by a biotransformation of any of the compounds described, such as
intermediates and products of metabolism of the compound, such as would be
generated in vivo following administration to a human.
[113] Articles of manufacture comprising a compound described herein, or a
salt or solvate thereof, in a suitable container are provided. The container may be
15 a vial, jar, ampoule, preloaded syringe, i.v. bag, and the like.
[114] Preferably, the compounds detailed herein are orally bioavailable.
However, the compounds may also be formulated for parenteral (e.g., intravenous)
administration.
[115] One or several compounds described herein can be used in the
20 preparation of a medicament by combining the compound or compounds as an
active ingredient with a pharmacologically acceptable carrier, which are known in
the art. Depending on the therapeutic form of the medication, the carrier may be
in various forms. In one variation, the manufacture of a medicament is for use in
any of the methods disclosed herein, e.g., for the treatment of cancer.
25 General synthetic methods
[116] The compounds of the invention may be prepared by a number of
processes as generally described below and more specifically in the Examples
hereinafter (such as the schemes provided in the Examples below). In the
following process descriptions, the symbols when used in the formulae depicted
110
DIP/PA/2018/1046/CA
are to be understood to represent those groups described above in relation to the
formulae herein.
[117] Where it is desired to obtain a particular enantiomer of a compound,
this may be accomplished from a corresponding mixture of enantiomers using any
5 suitable conventional procedure for separating or resolving enantiomers. Thus,
for example, diastereomeric derivatives may be produced by reaction of a mixture
of enantiomers, e.g., a racemate, and an appropriate chiral compound. The
diastereomers may then be separated by any convenient means, for example by
crystallization and the desired enantiomer recovered. In another resolution
10 process, a racemate may be separated using chiral High Performance Liquid
Chromatography. Alternatively, if desired a particular enantiomer may be
obtained by using an appropriate chiral intermediate in one of the processes
described.
[118] Chromatography, recrystallization and other conventional separation
15 procedures may also be used with intermediates or final products where it is
desired to obtain a particular isomer of a compound or to otherwise purify a
product of a reaction.
[119] Solvates and/or polymorphs of a compound provided herein or a
pharmaceutically acceptable salt thereof are also contemplated. Solvates contain
20 either stoichiometric or non-stoichiometric amounts of a solvent, and are often
formed during the process of crystallization. Hydrates are formed when the
solvent is water, or alcoholates are formed when the solvent is alcohol.
Polymorphs include the different crystal packing arrangements of the same
elemental composition of a compound. Polymorphs usually have different X-ray
25 diffraction patterns, infrared spectra, melting points, density, hardness, crystal
shape, optical and electrical properties, stability, and/or solubility. Various factors
such as the recrystallization solvent, rate of crystallization, and storage
temperature may cause a single crystal form to dominate
[120] In some embodiments, compounds of the present invention
30 (collectively, a compound of formula (IA), (I), (Ia-1) to (Ia-14), (Ib-1) to (Ib-11),
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(II) , (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (IVa-1) to (IVa-7), (V) or
(VI)) may be synthesized according to general Scheme 1.
Scheme 1:
wherein X, A, B, L, R
1
, R2
, R3
, R4
, R5
, R6a, R6b
, R
7
, R7’ 5 , m and n are as defined for
formula (IA), or any variation thereof detailed herein;
[121] In some embodiments, compounds of the present invention
(collectively, a compound of formula (IA), (I), (Ia-1) to (Ia-14), (Ib-1) to (Ib-11),
(II) , (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (IVa-1) to (IVa-7), (V) or
10 (VI)) may be synthesized according to general Scheme 2.
Scheme 2:
wherein A, B, L, R
1
, R2
, R3
, R4
, R5
, R6a
, R6b
, R
7
, m and n are as defined for
formula (IA), or any variation thereof detailed herein; X is a heteroatom selected
from O, S, NR
a
15 or NH.
[122] In some cases, stereoisomers are separated to give single enantiomers
or diastereomers as single, unknown stereoisomers, and are arbitrarily drawn as
single isomers. Where appropriate, information is given on separation method and
elution time and order.
20 UPLC-MS Standard Procedures
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[123] Analytical UPLC-MS was performed as described below. The masses
(m/z) are reported from the positive mode electrospray ionization unless the
negative mode is indicated.
UPLC-MS Method-1
5 [124] Instrument: Waters Acquity UPLC-MS SQD 3100; Column: Acquity
UPLC BEH Shield RP 18, 1.7 µm, 2.1 x 50 mm; Eluent A: 0.05% TFA in Water,
Eluent B: Acetonitrile; Gradient: 10%B to 50% B in 7 min, hold for 5 min, 50 %B
to 10 % B in 1 min (Run time: 16 min); Flow rate 0.35 ml /min; Temperature: 25
0C; PDA Scan:210-400 nm.
10 UPLC-MS Method-2
[125] Instrument: Waters Acquity UPLC-MS SQD 3100; Column: Acquity
UPLC BEH Shield RP 18, 1.7 µm, 2.1 x 50 mm; Eluent A: 0.05% TFA in Water,
Eluent B: Acetonitrile; Gradient: 10%B to 50%B in 2 min, hold for 1 min, 90%B
in 0.5 min hold for 1 min, 10%B in 0.1 min (Run time: 6.0 min); Flow rate 0.35
ml /min; Temperature: 25 0
15 C; PDA Scan:210-400 nm.
UPLC-MS Method-3
[126] Instrument: Waters Acquity UPLC-MS SQD 3100; Column: Acquity
UPLC BEH Shield RP 18, 1.7 µm, 2.1 x 50 mm; Eluent A: 0.05% TFA in Water,
Eluent B: Acetonitrile; Gradient: 10%B to 50%B in 4.5 min, hold for 3 min,
20 50%B to 10% B in 0.5 min (Run time: 10.0 min); Flow rate 0.35 ml /min;
Temperature: 25 0C; PDA Scan: 210-400 nm.
UPLC-MS Method-4
[127] Instrument: Waters Acquity UPLC-MS SQD 3100; Column: Acquity
UPLC BEH Shield RP 18, 1.7 µm, 2.1 x 50 mm; Eluent A: 0.05% TFA in Water,
25 Eluent B: Acetonitrile; Gradient: 10%B hold for 0.2 min,10%B to 90%B in 1.8
min, hold for 1.5 min, 90%B to 10%B in 0.1 min (Run time: 6.0 min); Flow rate
0.35 ml /min ;Temperature: 25 0C; PDA Scan:210-400 nm.
UPLC-MS Method-5
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[128] Instrument: Waters Acquity UPLC-MS SQD 3100; Column: Acquity
UPLC BEH Shield RP 18, 1.7 µm, 2.1 x 50 mm; Eluent A: 0.05% TFA in Water,
Eluent B: Acetonitrile; Gradient: 2%B hold for 0.5 min, 2%B to 20%B in 3 min,
hold for 1.5 min, 20%B to 2%B in 0.1 min (Run time: 6.0 min); Flow rate 0.35 ml
/min; Temperature: 25 0
5 C; PDA Scan:210-400 nm.
UPLC-MS Method-6
[129] Instrument: Waters Acquity UPLC-MS SQD 3100; Column: Acquity
UPLC BEH Shield RP 18, 1.7 µm, 2.1 x 50 mm; Eluent A: 0.05% TFA in Water,
Eluent B: Acetonitrile; Gradient: 10%B to 50%B in 4.5 min, hold for 3 min, 50
10 %B to 10 % B in 0.5 min (Run time: 10.0 min); Flow rate 0.35 ml /min;
Temperature: 25 0C; PDA Scan:210-400 nm.
UPLC-MS Method-7
[130] Instrument: Waters Acquity UPLC-MS SQD 3100; Column: Acquity
UPLC BEH Shield RP 18, 1.7 µm, 2.1 x 50 mm; Eluent A: 0.05% TFA in Water,
15 Eluent B: Acetonitrile; Gradient: 10% B to 90%B in 4.5 min, hold for 3 min,
90%B to 10% B in 0.5 min (Run time: 10.0 min); Flow rate 0.35 ml /min;
Temperature: 25 0C; PDA Scan:210-400 nm.
Pharmaceutical Compositions and Formulations
[131] Pharmaceutical compositions of any of the compounds detailed herein
20 are embraced by this disclosure. Thus, the present disclosure includes
pharmaceutical compositions comprising a compound as detailed herein or a salt
thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the
pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with
an inorganic or organic acid. Pharmaceutical compositions may take a form
25 suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a
form suitable for administration by inhalation.
[132] A compound as detailed herein may in one aspect be in a purified form
and compositions comprising a compound in purified forms are detailed herein.
Compositions comprising a compound as detailed herein or a salt thereof are
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provided, such as compositions of substantially pure compounds. In some
embodiments, a composition containing a compound as detailed herein or a salt
thereof is in substantially pure form.
[133] In one variation, the compounds herein are synthetic compounds
5 prepared for administration to an individual. In another variation, compositions
are provided containing a compound in substantially pure form. In another
variation, the present disclosure embraces pharmaceutical compositions
comprising a compound detailed herein and a pharmaceutically acceptable carrier.
In another variation, methods of administering a compound are provided. The
10 purified forms, pharmaceutical compositions and methods of administering the
compounds are suitable for any compound or form thereof detailed herein.
[134] A compound detailed herein or salt thereof may be formulated for any
available delivery route, including an oral, mucosal (e.g., nasal, sublingual,
vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or
15 intravenous), topical or transdermal delivery form. A compound or salt thereof
may be formulated with suitable carriers to provide delivery forms that include,
but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or
soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions,
suppositories, ointments, cataplasms (poultices), pastes, powders, dressings,
20 creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels,
suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water
emulsions or water-in-oil liquid emulsions), solutions and elixirs.
[135] One or several compounds described herein or a salt thereof can be
used in the preparation of a formulation, such as a pharmaceutical formulation, by
25 combining the compound or compounds, or a salt thereof, as an active ingredient
with a pharmaceutically acceptable carrier, such as those mentioned above.
Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral
tablet), the carrier may be in various forms. In addition, pharmaceutical
formulations may contain preservatives, solubilizers, stabilizers, re-wetting
30 agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of
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osmotic pressure, buffers, coating agents or antioxidants. Formulations
comprising the compound may also contain other substances which have valuable
therapeutic properties. Pharmaceutical formulations may be prepared by known
pharmaceutical methods. Suitable formulations can be found, e.g., in Remington’s
Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20th 5 ed.
(2000), which is incorporated herein by reference.
[136] Compounds as described herein may be administered to individuals in
a form of generally accepted oral compositions, such as tablets, coated tablets, and
gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of
10 carriers, which may be used for the preparation of such compositions, are lactose,
corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for
gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and
liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain
preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners,
15 dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating
agents or antioxidants.
[137] Any of the compounds described herein can be formulated in a tablet
in any dosage form described, for example, a compound as described herein or a
salt thereof can be incorporated in tablet in an amount ranging from about 1 mg to
20 about 1000 mg.
[138] Compositions comprising a compound provided herein are also
described. In one variation, the composition comprises a compound or salt thereof
and a pharmaceutically acceptable carrier or excipient. In another variation, a
composition of substantially pure compound is provided.
25 Methods of Use
[139] Compounds and compositions detailed herein, such as a
pharmaceutical composition containing a compound of any formula provided
herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, may
be used in methods of administration and treatment as provided herein. The
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compounds and compositions may also be used in in vitro methods, such as in
vitro methods of administering a compound or composition to cells for screening
purposes and/or for conducting quality control assays.
[140] Provided herein is a method of treating a disease in an individual
5 comprising administering an effective amount of a compounds of the present
invention (collectively, a compound of formula (IA), (I), (Ia-1) to (Ia-14), (Ib-1) to
(Ib-11), (II) , (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (IVa-1) to (IVa-7),
(V) or (VI)) or any embodiment, variation or aspect thereof or the present
compounds or the compounds detailed or described herein) or a pharmaceutically
10 acceptable salt thereof, to the individual. Further provided herein is a method of
treating a proliferative disease in an individual, comprising administering an
effective amount of the compounds of the present invention (collectively, a
compound of formula (IA), (I), (Ia-1) to (Ia-14), (Ib-1) to (Ib-11), (II) , (IIa-1) to
(IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (IVa-1) to (IVa-7), (V) or (VI)) or a
15 pharmaceutically acceptable salt thereof, to the individual. Also provided herein
is a method of treating cancer in an individual comprising administering an
effective amount of the compounds of the present invention (collectively, a
compound of formula (IA), (I), (Ia-1) to (Ia-14), (Ib-1) to (Ib-11), (II) , (IIa-1) to
(IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (IVa-1) to (IVa-7), (V) or (VI)) or a
20 pharmaceutically acceptable salt thereof, to the individual. In some embodiments,
the compound is administered to the individual according to a dosage and/or
method of administration described herein.
[141] Another aspect of the invention relates to a method of treating a
disease or disorder associated with mutant isocitrate dehydrogenase. The method
25 involves administering to a patient in need of a treatment for diseases or disorders
associated with mutant isocitrate dehydrogenase an effective amount of the
compositions and compounds of the present invention (collectively, a compound
of formula (IA), (I), (Ia-1) to (Ia-14), (Ib-1) to (Ib-11), (II) , (IIa-1) to (IIa-8), (III),
(IIIa-1) to (IIIa-8), (IV), (IVa-1) to (IVa-7), (V) or (VI)) or a pharmaceutically
30 acceptable salt thereof.
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[142] Another aspect of the invention is directed to a method inhibiting
mutant isocitrate dehydrogenase. The method involves administering to a patient
in need thereof an effective amount of the compositions or compounds of formula
(IA), (I), (Ia-1) to (Ia-14), (Ib-1) to (Ib-11), (II) , (IIa-1) to (IIa-8), (III), (IIIa-1) to
5 (IIIa-8), (IV), (IVa-1) to (IVa-7), (V) or (VI)) or a pharmaceutically acceptable
salt thereof.
[143] Examples of a mutant IDH protein having a neomorphic activity are
mutant IDH1 and mutant IDH2. A neomorphic activity associated with mutant
IDH1 and mutant IDH2 is the ability to produce 2-hydroxyglutarate (2-HG
10 neomorphic activity), specifically R-2-HG (R-2-HG neomorphic activity).
Mutations in IDH 1 associated with 2-HG neomorphic activity, specifically R-2-
HG neomorphic activity, include mutations at residues 97, 100, and 132, e.g.
G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V. Mutations
in IDH2 associated with 2-HG neoactivity, specifically R-2-HG neomorphic
15 activity, include mutations at residues 140 and 172, e.g. R140Q, R140G, R172K,
R172M, R172S, R172G, and R172W.
[144] Another aspect of the invention relates to method of reducing alphaketoglutarate. The method comprises administering to a patient in need thereof an
effective amount of the compositions or compounds of the present invention of
20 formula (IA), (I), (Ia-1) to (Ia-14), (Ib-1) to (Ib-11), (II) , (IIa-1) to (IIa-8), (III),
(IIIa-1) to (IIIa-8), (IV), (IVa-1) to (IVa-7), (V) or (VI)) or a pharmaceutically
acceptable salt thereof.
[145] One therapeutic use of the compounds or compositions of the present
invention which inhibit mt-IDH is to provide treatment to patients or subjects
25 suffering from cell proliferative diseases and cancers including, without
limitation, glioma, glioblastoma multiforme, paraganglioma, supratentorial
primordial neuroectodermal tumors, acute myeloid leukemia (AML), prostate
cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma,
peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC),
30 myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), and other
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solid tumors. Targeted treatments for these cancers and cell proliferative diseases
are not currently available to patients suffering from these conditions. Therefore,
there is a need for new therapeutic agents selective to these conditions.
[146] Another therapeutic use of the compounds or compositions of the present
5 invention which inhibit mt-IDH is to provide treatment to patients or subjects
suffering from cell proliferative diseases and cancers including sarcomas and
carcinomas, In some embodiments, examples such as sarcomas and carcinomas
are cancer that may be treated as solid tumors. In some embodiments, examples
such as leukemia are the cancer that may be treated as liquid tumors. Present
10 invention may treat different types of cancers that include, but are not limited to,
adrenocortical cancer, bladder cancer, brain tumors, breast cancer, prostate cancer,
colorectal cancer, colon cancer, endometrial cancer, gallbladder cancer, gastric
cancer, head and neck cancer, hematopoietic cancer, kidney cancer, leukemia, oral
cancer, uterine carcinoma, Hodgkin lympoma, liver cancer, lung cancer,
15 pancreatic cancer, prostate cancer, ovarian cancer, sarcoma, skin cancer and
thyroid cancer. In some embodiments, the breast cancer is classified as carcinoma
of breast (ER negative or ER positive), mammary adenocarcinoma, primary breast
ductal carcinoma, mammary ductal carcinoma (ER positive, ER negative or HER2
positive), triple negative breast cancer (TNBC), HER2 positive breast cancer or
20 luminal breast cancer. In some embodiments, the breast cancer is unclassified. In
some embodiments, a basal-like TNBC, an immunomodulatory TNBC,
mesenchymal TNBC (mesenchymal or mesenchymal stem-like) or a luminal
androgen receptor TNBC are triple negative breast. In some embodiments,
prostate adenocarcinoma is prostate cancer. In some embodiments, the ovary
25 adenocarcinoma is ovarian cancer. In some embodiments, lung carcinoma,
adenocarcinoma, non-small lung carcinoma, mucoepidermoid, anaplastic large
cell are lung cancer. In some embodiments, the lung cancer is unclassified. In
some embodiments, the colon adenocarcinomas, colon carcinoma, metastatic
colorectal cancer, colon adenocarcinoma from a metastatic site lymph node are
30 colon cancer. In some embodiments astrocytoma, glioblastoma, meduloblastoma,
neuroblastoma or meningioma is brain tumor. In some embodiments, stomach
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cancer is gastric cancer. In some embodiments, cholangiocarcinoma or
hepatoblastoma, hepatocellular carcinoma are liver cancers. In some
embodiments, liver cancer is derived from hepatitis B virus. In some
embodiments, liver cancer is virus negative. In some embodiments, medullary
5 thyroid cancer or follicular thyroid cancer, papillary thyroid carcinomas are
classified as thyroid cancer. In some embodiments, uterine papillary serous
carcinoma or uterine clear cell carcinoma, high grade endometroid cancer are
endometrial cancer.

I/We Claim:
1. A compound of Formula (IA):
formula (IA),
5 or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof,
wherein
wherein,
X is O, S, NRa
or CRbR
c
;
A is C6-C10 aryl, 5- to 10 membered heteroaryl, C3-C8 cycloalkyl or 3-
10 to 10-membered heterocyclyl, wherein each of which is optionally substituted by
R
6a;
B is hydrogen, C6-C10 aryl, 5- to 10- membered heteroaryl, C3-C8
cycloalkyl or 3- to 10-membered heterocyclyl, wherein each of which is
optionally substituted by R6b;
15 L is a bond, -O-, -(CH2)1-3-,-NH-, -NCH3-, -SO2-, -C(O)-, -CH2-O-, -
S-, -CR
bR
c
-, -C(O)NH- or -NHC(O)-;
R
a
is hydrogen or C1-C6 alkyl optionally substituted by oxo, -OH or
halogen;
R
b
and Rc are independently hydrogen, halogen, -CN, C1-C6 alkyl, C3-
20 C6 cycloalkyl, or -(C1-C3 alkylene)(C3-C6 cycloalkyl);
R
1
is hydrogen, halogen or C1-C6 alkyl;
R
2
is hydrogen, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(O)OR2a
,
C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered
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heteroaryl, -(C1-C3 alkylene)C6 aryl or C1-C6 alkyl optionally substituted by oxo,
halogen, -OR2a or -NR2aR
2b, wherein C3-C6 cycloalkyl, 3- to 6-membered
heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, -(C1-C3 alkylene)C6 aryl of R
2
optionally substituted by C1-C6 alkyl;
or R1
and R2
5 are taken together with the atom to which they are
attached to form a C3-C6 cycloalkyl or 3- to 6- membered heterocyclyl, each of
which is optionally substituted by oxo, -OH, halogen, -NH2, or C1-C6 alkyl
optionally substituted by oxo, -OH, halogen or -NH2;
R
2a and R2b are independently hydrogen or C1-C6 alkyl;
R
3
and R4 10 are independently hydrogen, halogen, or C1-C6 alkyl
optionally substituted by oxo, -OH or halogen;
or R
3
and R4
are taken together with the atom to which they are
attached to form a C3-C6 cycloalkyl or 3- to 6- membered heterocyclyl, each of
which is optionally substituted by oxo, -OH, -halogen, -NH2, or C1-C6 alkyl
15 optionally substituted by oxo, -OH, halogen or -NH2;
R
5 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6
cycloalkyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6- membered heteroaryl,
-CN, halogen, C1-C6 alkoxy, C1-
C6 haloalkoxy, -OR10
, -SR10
, -S(O)2R
10
, -S(O)2NR11R
12
, -NR10S(O)2R
11
, -
NR11R
12
, -C(O)R10
, -NR10C(O)R11
, -NR10C(O)NR11R
12
, -C(O)OR10 20 ,
-C(O)ONR11R
12
, -C(O)NR11R
12, wherein each of which is optionally substituted
by R8
;
each R6a and R
6b is independently oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-
C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C6 aryl, -CN,
25 halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-
C6 haloalkyl, -OR13
, -SR13
, -S(O)2R
13
, -S(O)2NR14R
15
, -NR13S(O)2R
14
, -NR14R
15
,
-C(O)R13
, -NR13C(O)R14
, -NR13C(O)NR14R
15
, -C(O)OR13
, -C(O)ONR14R
15
,
-C(O)NR14R
15
, -(C1-C3 alkylene)OR13
, -(C1-C3 alkylene)SR13
, -(C1-
C3 alkylene)S(O)2R
13
, -(C1-C3 alkylene)S(O)2NR14R
15
, -(C1-
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C3 alkylene)NR13S(O)2R
14
, -(C1-C3 alkylene)NR14R
15
, -(C1-
C3 alkylene)C(O)R13
, -(C1-C3 alkylene)NR13C(O)R14
, -(C1-
C3 alkylene)NR13C(O)NR14R
15
, -(C1-C3 alkylene)C(O)OR13
, -(C1-
C3 alkylene)C(O)ONR14R
15
, -(C1-C3 alkylene)(C3-C8 cycloalkyl) or -(C1-
C3 alkylene)(3- to 10- membered heterocyclyl); wherein each of R6a and R
6b 5 is
independently optionally substituted by oxo, C2-C6 alkenyl, C2-C6 alkynyl, -CN,
halogen, C1-C6 alkoxy, C1-
C6 haloalkoxy, -OR16
, -SR16
, -S(O)2R
16
, -S(O)2NR17R
18
, -NR16S(O)2R
17
, -
NR17R
18
, -C(O)R16
, -NR16C(O)R17
, -C(O)OR16, C1-C6 alkyl optionally substituted
10 by oxo, OH, halogen or NH2;
R
7 and R
7’ are independently hydrogen, C3-C6 cycloalkyl or C1-C6 alkyl
optionally substituted by halogen or -OH;
or R
7 and R
7’ are taken together with the atom to which they are
attached to form a C3-C6 cycloalkyl;
R
8 15 is halogen, oxo, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl 3-
to 6-membered heterocyclyl, -CN, C1-C6 alkoxy, C1-
C6 haloalkoxy, -OR16
, -SR16
, -S(O)2R
16
, -S(O)2NR17R
18
, -NR16S(O)2R
17
, -
NR17R
18
, -C(O)R16
, -NR16C(O)R17
, -C(O)OR16 or C1-C6 alkyl optionally
substituted by oxo, -OH, halogen or NH2;
each R10, R11 and R
12 20 is independently hydrogen, C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl,
wherein each of R10, R11 and R
12 is independently optionally substituted by oxo,
C2-C6 alkenyl, C2-C6 alkynyl, -CN, halogen, C1-C6 alkoxy, C1-
C6 haloalkoxy, -OR16
, -SR16
, -S(O)2R
16
, -S(O)2NR17R
18
, -NR16S(O)2R
17
, -
NR17R
18
, -C(O)R16
, -NR16C(O)R17
, -C(O)OR16 25 or C1-C6 alkyl optionally
substituted by oxo, OH, halogen or NH2;
or R11 and R
12 are taken together with the atom to which they attached
to form a 3-6 membered heterocyclyl optionally substituted by oxo, OH, halogen,
NH2, or C1-C6 alkyl optionally substituted by oxo, OH, halogen or NH2;
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each R13, R14 and R
15 is independently hydrogen, C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, -(C1-
C3 alkylene)C3-C6 cycloalkyl or -(C1-C3 alkylene) 5- to 6- heteroaryl, wherein
each of R13, R14 and R
15 is independently optionally substituted by oxo, C2-C6
5 alkenyl, C2-C6 alkynyl, -CN, halogen, C1-C6 alkoxy, C1-
C6 haloalkoxy, -OR16
, -SR16
, -S(O)2R
16
, -S(O)2NR17R
18
, -NR16S(O)2R
17
, -
NR17R
18
, -C(O)R16
, -NR16C(O)R17
, -C(O)OR16 or C1-C6 alkyl optionally
substituted by oxo, OH, halogen or NH2;
or R14 and R
15 are taken together with the atom to which they attached
10 to form a 3- to 6- membered heterocyclyl optionally substituted by oxo, OH or
halogen, or C1-C6 alkyl optionally substituted by oxo, OH, halogen or NH2;
each R16, R17 and R
18 is independently hydrogen, C2-C6 alkenyl, C2-C6
alkynyl, or C1-C6 alkyl optionally substituted by oxo, OH, halogen or NH2;
or R17 and R
18 are taken together with the atom to which they attached
15 to form a 3- to 6- membered heterocyclyl optionally substituted by oxo, OH,
halogen or NH2, or C1-C6 alkyl optionally substituted by oxo, OH, halogen or
NH2;
m and n is independently 0, 1, 2, 3 or 4.
2. The compound of claim 1, wherein X is O.
20 3. The compound of claim 1, wherein X is S.
4. The compound of claim 1, wherein X is NRa
.
5. The compound of claim 4, wherein R
a
is selected from hydrogen or
methyl.
6. The compound of claim 1, wherein X is CRbR
c
.
7. The compound of claim 6, wherein R
b
and R
c
25 are independently selected
from hydrogen, halogen, -CN, methyl or cylcopropyl.
8. The compound of claim 1, wherein A is selected from C6-C10 aryl or 5- to
10 membered heteroaryl each of which is optionally substituted by R6a
.
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9. The compound of claim 1, wherein A is selected from ,
, , , , ,
, , , ,
, , , ,
5 , , , , ,
, , , , ,
, , , , ,
, , , , ,
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, or , wherein wavy line indicates
attachment points to the alkylamine and dotted line indicates attachment points to
the L.
10. The compound of claim 9, wherein m is 0, 1, 2, 3 or 4.
11. The compound of claim 1, wherein R
6a 5 are independently selected from
oxo, halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkyl,
–OR13 or C6-aryl optionally substituted by halogen.
12. The compound of claim 11, wherein R
6a are independently selected from
oxo, -CN, -Cl, -F, -Br, methyl, -OCH3, -CF3, -CH2CHF2, -OCF3, chlorophenyl or
10 phenyl.
13. The compound of claim 1, wherein A optionally substituted with R
6a is
selected from , , , ,
, , , , ,
, , , , ,
15 , , , ,
, , , , ,
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, , , , ,
, , , , ,
, , , ,
, , , ,
5 , , , , ,
, , , , ,
, , , , ,
, , , ,
, , , ,
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, , , ,
, , , ,
, , , ,
, , , ,
5 , , , ,
, , , , ,
, , , , ,
or , wherein wavy line indicates attachment
points to the alkylamine and dotted line indicates attachment points to the L.
10 14. The compound of claim 1, wherein B is selected from hydrogen, C6-C10
aryl, 5- to 10- membered heteroaryl, C3-C8 cycloalkyl or 3- to 10-membered
heterocyclyl each of which is optionally substituted by R6b
.
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15. The compound of claim 1, wherein B is selected from hydrogen,
, , , , ,
, , , , ,
, , , , ,
5 , or , wherein dotted line indicates
attachment points to the L.
16. The compound of claim 15, wherein n is 0, 1, 2, 3 or 4.
17. The compound of claim 1, wherein R6b are independently selected from
halogen, -CN, C3-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-
C6 haloalkyl, -C(O)R13 or -OR13 10 .
18. The compound of claim 17, wherein R6b
are independently selected from
oxo, -CN, -Cl, -F, methyl, -OCH3, -CF3, -OCF3, -C(O)CH3, -C(O)CH=CH2 or
cyclopropyl.
19. The compound of claim 1, wherein B optionally substituted with R
6b
is
15 selected from , , , , ,
, , , , , , ,
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, , , , ,
, , , , , , ,
, , , , , ,
, , , , ,
5 , , , , , , ,
, , , , , ,
, , , , ,
, , , , , ,
, , , , , or wherein
10 the dotted line denotes attachment point.
20. The compound of claim 1, wherein L is a selected from a bond, -O-, -
(CH2)1-3-,-NH-, -C(O)-, -CH2-O-, -S-, -CR
bR
c
-, -C(O)NH- or -NHC(O)-.
21. The compound of claim 20, wherein L is selected from a bond, -O-, -CH2-,
-CH2-O-, -S-, -NH-, -CH(C2H5)-, CH(CH2(cyclopropyl))-, -CF2- or -C(O)-.
15 22. The compound of claim 20, wherein L is a bond.
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23. The compound of claim 20, wherein L is -O-.
24. The compound of claim 1, wherein A, B, L, R6a, R
6b, m and n together are
selected from , or .
25. The compound of claim 1, wherein A, B, L, R6a, R
6b, m and n together are
5 selected from , , ,
, , , ,
, , ,
, , ,
, , , ,
10 , , , ,
, , , ,
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, , , ,
, , , ,
, , , , ,
, , , ,
5 , , , ,
, , , ,
, , , ,
, , , ,
, , ,
10 , , ,
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, , ,
, , , ,
, , ,
, , ,
5 , , ,
, , ,
, , , ,
, , , , ,
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, , , , ,
, , , , ,
, , , ,
, , , ,
5 , , , ,
, , , ,
, , , ,
, , , ,
, , , ,
10 , , , ,
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, , , ,
, , , , ,
, , , ,
, , ,
5 , , , ,
, , , ,
, , , ,
, , , ,
, , , ,
10 , , , ,
, , , ,
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, , , ,
, , , ,
, , , ,
, , , ,
5 , , , ,
, , ,
, , ,
, , ,
, or , wherein
10 the wavy line denotes attachment point.
26. The compound of claim 1, wherein R1
is selected from the group
consisting of hydrogen, halogen or C1-C6 alkyl.
27. The compound of claim 26, wherein R1
is selected from hydrogen or
methyl.
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28. The compound of claim 1, wherein R2
is selected from hydrogen, halogen,
C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl,
C6 aryl, 5- to 6-membered heteroaryl or C1-C6 alkyl optionally substituted by oxo,
halogen, -OR2a or -NR2aR
2b
.
29. The compound of claim 28, wherein R2
5 is selected from hydrogen, methyl,
-CF3, -CHF2-, ethyl, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH2F)2, -C2H4F,
isopropyl, isobutyl, –OCH3, –OCH2CH3, –OCH(CH3)2, –OC(CH3)3, -
CH(OH)CH3, -NH2, CH(CH3)NH2, -CH(CH3)NHCH3, -CH(CH3)-N(CH3)2, -
CH(CH3)CH2F, cyclopropyl, phenyl, -(CH2)phenyl, , ,
10 or , wherein the dotted line denotes the attachment point.
30. The compound of claim 28, wherein R2
is selected from ethyl or isopropyl.
31. The compound of claim 1, wherein R
1
and R2
are taken together with the
atom to which they are attached to form a C3-C6 cycloalkyl or 3-6 membered
heterocyclyl, each of which is optionally substituted by oxo, -OH, halogen, -NH2,
15 or C1-C6 alkyl optionally substituted by oxo, -OH, halogen or -NH2.
32. The compound of claim 31, wherein R
1
and R2
are taken together with the
atom to which they are attached to form cyclopropyl or cyclobutyl.
33. The compound of claim 1, wherein R
3
and R4 are independently hydrogen,
halogen, or C1-C6 alkyl optionally substituted by oxo, -OH or halogen.
34. The compound of claim 33, wherein R
3
and R4 20 are hydrogen.
35. The compound of claim 1, wherein R
3
and R4
are taken together with the
atom to which they are attached to form a C3-C6 cycloalkyl or 3-6 membered
heterocyclyl, each of which is optionally substituted by oxo, -OH, halogen, -NH2,
or C1-C6 alkyl optionally substituted by oxo, -OH, halogen or -NH2.
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36. The compound of claim 35, wherein R
3
and R4
are taken together with the
atom to which they are attached to form cyclopropyl or oxytanyl ring.
37. The compound of claim 1, wherein R5
is selected from hydrogen, C1-C6
alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered
5 heterocyclyl, C6-aryl, C5-C6 heteroaryl, -CN, halogen, C1-C6 alkoxy, C1-
C6 haloalkoxy, -OR10
, -SR10
, -S(O)2R
10
, -S(O)2NR11R
12
, -NR10S(O)2R
11
, -
NR11R
12
, -C(O)R10
, -NR10C(O)R11
, -NR10C(O)NR11R
12
, -C(O)OR10
,
-C(O)ONR11R
12
, -C(O)NR11R
12, wherein each of which is optionally substituted
by R8
.
38. The compound of claim 37, wherein R5
10 is selected from hydrogen, methyl,
ethyl, ter-butyl, iso-butyl, cyclopropyl, phenyl,–CN,–N(CH3)2, -Cl, -Br, -OCH3, -
OC3H7, -OCH(CH3)2, -OCF3, -CF3, -SCH3, aziridinyl, piperidinyl, propyne, -
SO2NHCH3, -C(O)OCH3, isopropene or thiazolyl.
39. The compound of claim 37, wherein R5
is hydrogen or methyl.
40. The compound of claim 1, wherein R7 and R7’ 15 are independently selected
from hydrogen, C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by halogen
or -OH.
41. The compound of claim 40, wherein R7 and R7’ are independently selected
from hydrogen, -CH3, ethyl, isopropyl, n-propyl, ter-butyl, cyclopropyl,
20 cyclobutyl or -CH2F.
42. The compound of claim 40, wherein R7 is hydrogen and R
7’ is -CH3.
43. The compound of claim 1, wherein R7 and R7’ are taken together with the
atom to which they are attached to form a C3-C6 cycloalkyl;
44. The compound of claim 43, wherein R7 and R7’ are taken together with the
25 atom to which they are attached to form a cyclopropyl.
45. The compound of claim 1, wherein the compound is a compound of
formula (I),
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formula (I),
or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof,
wherein X, A,B, L, R1
, R2
, R3
, R4
, R5
, R6a, R6b
, R
7
, mand n are as defined in claim
5 1.
46. The compound of claim 1, wherein the compound is any of the compounds
of formula (Ia-1) to (Ia-14),
(Ia-1) (Ia-2)
(Ia-3) (Ia-4)
(Ia-5) (Ia-6)
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(Ia-7) (Ia-8)
(Ia-9) (Ia-10)
(Ia-11) (Ia-12)
(Ia-13) (Ia-14)
or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof,
wherein B, X, L, R
1
, R2
, R
3
, R4
, R5
, R7
, R6a
, R
6b, mand n are as defined in claim 1.
47. The compound of claim 1, wherein the compound is any of the compounds
of formula (Ib-1) to (Ib-11),
(Ib-1) (Ib-2)
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(Ib-3) (Ib-4)
(Ib-5) (Ib-6)
(Ib-7) (Ib-8)
(Ib-9) (Ib-10)
(Ib-11)
or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof,
wherein A, X, L, R
1
, R2
, R3
, R4
, R5
, R7
, R6a
, R
6b, mand n are as defined in claim 1.
48. The compound of claim 1, wherein the compound is a compound of
formula (II):
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formula (II),
or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof,
wherein A, B, X, R1
, R2
, R3
, R4
, R5
, R7
, R6a, R6b, m and n are as defined in claim
5 1.
49. The compound of claim 1, wherein the compound is any of the compounds
of formula (IIa-1) to (IIa-8),
(IIa-1) (IIa-2)
(IIa-3) (IIa-4)
(IIa-5) (IIa-6)
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(IIa-7) (IIa-8)
or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof,
wherein A, X, L, R1
, R2
, R3
, R4
, R5
, R7
, R6a, R6b, mand n are as defined in claim 1.
50. The compound of claim 1, wherein the compound is a compound of
formula (III):
5
formula (III),
or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof,
wherein A, X, R
1
, R2
, R3
, R4
, R5
, R7
, R6a and m are as defined in claim 1.
51. The compound of claim 1, wherein the compound is any of the compounds
10 of formula (IIIa-1) to (IIIa-8),
(IIIa-1) (IIIa-2)
(IIIa-3) (IIIa-4)
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(IIIa-5) (IIIa-6)
(IIIa-7) (IIIa-8)
or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof,
wherein X, R
1
, R2
, R3
, R4
, R5
, R7
, R6a and m are as defined in claim 1.
52. The compound of claim 1, wherein the compound is a compound of
formula (IV),
5
formula (IV)
or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof,
wherein X, R1
, R2
, R3
, R4
, R5
, R7
, R6a and m are as defined in claim 1.
53. The compound of claim 1, wherein the compound is any of the compounds
10 of formula (IVa-1) to (IVa-7),
(IVa-1) (IVa-2)
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(IVa-3) (IVa-4)
(IVa-5) (IVa-6)
(IVa-7)
or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof,
wherein X, R1
, R2
, R3
, R4
, R5
, R7
, R6a and m are as defined in claim 1.
54. The compound of claim 1, wherein the compound is a compound of
formula (V),
5
formula (V)
or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof,
wherein X, R1
, R2
, R3
, R4
, R5
, R7
, R6a and m are as defined in claim 1.
55. The compound of claim 1, wherein the compound is a compound of
10 formula (VI),
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formula (VI)
or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof,
wherein X, R1
, R2
, R3
, R4
, R5
, R7
, R6a and m are as defined in claim 1.
5 56. The compound of claim 1, wherein the compound is selected from
Compound Nos. 1.1 to 1.113 in Table 1 or a salt, polymorph, solvate, enantiomer,
stereoisomer or tautomer thereof.
57. The compound of claim 1, wherein the compound is selected from
Compound Nos. 2.1 to 2.462 in Table 2 or a salt, polymorph, solvate, enantiomer,
10 stereoisomer or tautomer thereof.
58. The compound of claim 1, wherein the said compound is being used in the
manufacture of a medicament for treatment of a disease mediated by a mutant
isocitrate dehydrogenase (IDH), preferably mutant IDH1.
59. A pharmaceutical composition comprising the compound of claim 1, or a
15 salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof, and a
pharmaceutically acceptable carrier