CROSS REFERENCE TO RELATED APPLICATION
[1] This application claims the priority benefit of INDIAN Provisional
Patent Application No. 201911004152, filed on August 01, 2019, disclosures of
which is incorporated herein by reference in its entireties.
5
FIELD OF THE INVENTION
[2] The present invention generally relates to compounds having
Checkpoint kinase-1 (CHK-1) inhibitory activity. The invention also discloses
method of treating conditions associated with excessive activity of CHK-1
10 enzymes using such compounds, pharmaceutical compositions, methods of
treating using said pharmaceutical compositions and kits. Method of synthesis of
said compounds is also disclosed.
BACKGROUND OF THE INVENTION
15 [3] A wide range of cancer chemotherapeutic agents act through DNA
damaging pathway to induce DNA damage causing tumor growth inhibition.
However, these chemotherapeutic agents lead to cell cycle arrest by induction of
checkpoints at either S-phase or G2/M boundary. The G2 arrest allows the cell
time to repair the damaged DNA before entering mitosis. Checkpoint kinase-1
20 (CHK-1) and an unrelated serine/threonine kinase, Checkpoint kinase-2 (CHK-2),
play a central role in arresting the cell cycle at the G2-M boundary (O'Connell et
al EMBO J (1997) vol. 16 p. 545-554). CHK-1 and/or CHK-2 induce this
checkpoint by phosphorylating serine 216 of the CDC25 phosphatase, inhibiting
the removal of two inactivating phosphates on cyclin dependent kinases (CDKs)
25 (Zheng et al Nature (1998) vol. 395 p. 507-510). Another overlapping pathway
mediated by p53 also elicits cycle arrest in response to DNA-damage. However,
p53 is mutationally inactivated in many cancers, resulting in a partial deficiency in
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their ability to initiate a DNA-repair response. If CHK-1 activity is also inhibited
in p53-negative cancers, all ability to arrest and repair DNA in response to DNAdamage is removed resulting in mitotic catastrophe and enhancing the effect of the
DNA damaging agents (Konarias et al. Oncogene (2001) vol. 20 p 7453-7463,
5 Bunch and Eastman Clin. Can. Res. (1996) vol. 2 p 791-797, Tenzer and Pruschy
Curr. Med Chem (2003) vol 3 p 35-46).
[4] CHK-1 inhibition, therefore, represents a novel therapeutic strategy to
increase the lethality of DNA-damaging chemotherapeutic drugs in p53 pathway
defective cancers. Abrogation of the remaining intact checkpoint should result in
10 increased tumor cell death. CHK-1 inhibitors have demonstrated potentiation of a
range of cytotoxic chemotherapy drugs both in vitro and in a range of pre-clinical
models of human cancer including gemcitabine, irinotecan, cytarabine, and
cisplatin. This “synthetic lethality” approach should increase the therapeutic
activity of the chemotherapeutic drug without increasing the systemic toxicity as
15 normal cells should remain protected by their functional p53 pathway. CHK-1
inhibitors have, therefore, the potential to be combined with a wide range of
cytotoxic chemotherapeutic agents for the treatment of a diverse selection of
human cancers.
[5] Various attempts have been made to develop CHK-1 kinase inhibitors.
20 For example, US10000481B2 (Vernalis) disclose 1H-pyrrolo[2,3-B] pyridine
derivatives compounds as CHK-1 kinase inhibitors. US10010547B2 (Cascadian
Therapeutics) discloses pyrazol amino pyrazine derivatives as kinase inhibitors.
WO/2018/086546A1 (Zhejiang university) disclose 2-polysubstituted aromatic
ring-pyrimidine derivatives as CHK-1 inhibitors. Few small molecule inhibitors of
25 CHK-1 (Prexasertib/LY2606368, LY2603618 and SRA737) are currently in
Phase I/II clinical evaluation in combination with gemcitabine, pemetrexed,
fludarabine, cytarabine, and cisplatin.
[6] Thus, there remains a continuing need for developing new CHK-1
inhibitors with pharmacokinetic and pharmacodynamic properties making them
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suitable for use as pharmaceutical agents. The object of the present invention is to
provide such pharmaceutical agents and treatments.
SUMMARY OF THE INVENTION
5 [7] In one aspect, the present invention provides a compound of formula
(IA):
formula (IA),
or a salt thereof, wherein A, D, L, Y and R
1
are as detailed herein.
10 [8] In one aspect, the compound of formula (IA) or a salt thereof, is a
compound of formula (I) or a salt thereof, as detailed herein.
[9] In one aspect, the compound of formula (IA) or a salt thereof, is a
compound of formula (II) or a salt thereof, as detailed herein.
[10] In one aspect, the compound of formula (IA) or a salt thereof, is a
15 compound of formula (III) or a salt thereof, as detailed herein.
[11] In one aspect, the compound of formula (IA) or a salt thereof, is a
compound of formula (IV) or a salt thereof, as detailed herein.
[12] In some aspects, the compound of formula (II) or a salt thereof, is any
of the compounds of formula (IIa-1) to (IIa-10) or a salt thereof, as detailed
20 herein.
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[13] In some aspects, the compound of formula (II) or a salt thereof, is any
of the compounds of formula (IIb-1) to (IIb-20) or a salt thereof, as detailed
herein.
[14] In some aspects, the compound of formula (III) or a salt thereof, is any
5 of the compounds of formula (IIIa-1) to (IIIa-10) or a salt thereof, as detailed
herein.
[15] In some aspects, the compound of formula (III) or a salt thereof, is any
of the compounds of formula (IIIb-1) to (IIIb-20) or a salt thereof, as detailed
herein.
10 [16] In some aspects, the compound of formula (IV) or a salt thereof, is any
of the compounds of formula (IVa-1) to (IVa-15) or a salt thereof, as detailed
herein.
[17] In some another aspects, the present invention provides method of
treating a disease or disorder associated with this CHK kinase enzymes, more
15 specifically CHK-1 kinase 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),
(II), (IIa-1) to (IIa-10), (IIb-1) to (IIb-20), (III), (IIIa-1) to (IIIa-10), (IIIb-1) to
(IIIb-20), (IV) or (IVa-1) to (IVa-15)), or a salt thereof.
20 [18] In some another aspects, the present invention provides method of
inhibiting CHK-1 kinase enzyme 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),
(II), (IIa-1) to (IIa-10), (IIb-1) to (IIb-20), (III), (IIIa-1) to (IIIa-10), (IIIb-1) to
25 (IIIb-20), (IV) or (IVa-1) to (IVa-15)), or a salt thereof.
[19] In some another aspects, the present invention provides method of
treating cancer 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), (II), (IIa-1) to (IIa-10),
(IIb-1) to (IIb-20), (III), (IIIa-1) to (IIIa-10), (IIIb-1) to (IIIb-20), (IV) or (IVa-1)
to (IVa-15)), or a salt thereof.
5 [20] In some another aspects, the present invention provides method of
treating a disease or disorder associated with this CHK kinase enzymes, or more
specifically CHK-1 kinase 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),
10 (II), (IIa-1) to (IIa-10), (IIb-1) to (IIb-20), (III), (IIIa-1) to (IIIa-10), (IIIb-1) to
(IIIb-20), (IV) or (IVa-1) to (IVa-15)), or a salt thereof in combination with
another therapeutic agent.
[21] In some another aspects, the present invention provides pharmaceutical
compositions, comprising a compound of the present invention (collectively, a
15 compound of formula (IA), (I), (II), (IIa-1) to (IIa-10), (IIb-1) to (IIb-20), (III),
(IIIa-1) to (IIIa-10), (IIIb-1) to (IIIb-20), (IV) or (IVa-1) to (IVa-15)), or a salt
thereof, and at least one pharmaceutically acceptable carrier.
[22] In some another aspects, the present invention provides method of
treating a disease or disorder associated with this CHK kinase enzymes, or more
20 specifically CHK-1 kinase enzymes in an individual in need thereof, wherein the
method comprises administering to the individual an effective amount of a
pharmaceutical composition comprising a compound of the present invention
(collectively, a compound of formula (IA), (I), (II), (IIa-1) to (IIa-10), (IIb-1) to
(IIb-20), (III), (IIIa-1) to (IIIa-10), (IIIb-1) to (IIIb-20), (IV) or (IVa-1) to (IVa25 15)), or a salt thereof.
[23] In some another aspects, the present invention provides method of
treating a disease or disorder associated with this CHK kinase enzymes, or more
specifically CHK-1 kinase enzymes in an individual in need thereof, wherein the
method comprises administering to the individual an effective amount of a
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pharmaceutical composition comprising a compound of the present invention
(collectively, a compound of formula (IA), (I), (II), (IIa-1) to (IIa-10), (IIb-1) to
(IIb-20), (III), (IIIa-1) to (IIIa-10), (IIIb-1) to (IIIb-20), (IV) or (IVa-1) to (IVa15)), or a salt thereof in combination with another therapeutic agent.
5 [24] In some another aspects, the present invention provides processes for
preparing compounds and intermediates thereof disclosed in the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
10 [25] “Alkyl” refers to and includes saturated linear and branched univalent
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
15 atoms (a “C3-C8 alkyl”), 1 to 6 carbon atoms (a “C1-C6 alkyl”), 1 to 5 carbon
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.
20 [26] “Alkenyl” as used herein refers to an unsaturated linear or branched
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
25 alternatively in “E” or “Z” configurations. Particular alkenyl groups are those
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
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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-
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.
5 [27] “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
(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
10 (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene
(-CH2CH2CH2CH2-), and the like.
[28] “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
15 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
“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
20 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.
[29] “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.
25 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,
biphenyl, and the like.
[30] “Carbonyl” refers to the group C=O.
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[31] “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
one to ten carbons). Cycloalkyl can consist of one ring, such as cyclohexyl, or
5 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
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
10 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornyl, and the like.
[32] “Halo” or “halogen” refers to elements of the Group 17 series having
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
15 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
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
20 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
alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).
[33] “Heteroaryl” refers to and includes unsaturated aromatic cyclic groups
25 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
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.
30 Heteroaryl may contain additional fused rings (e.g., from 1 to 3 rings), including
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additionally fused aryl, heteroaryl, cycloalkyl, and/or heterocyclyl rings.
Examples of heteroaryl groups include, but are not limited to imidazolyl, pyrrolyl,
pyrazolyl, 1,2,4-triazolyl, thiophenyl, furanyl, thiazolyl, isothiazolyl, thiadiazolyl,
oxazolyl, isoxazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyridazinyl or pyrazinyl,
5 and the like.
[34] “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
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
10 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
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,
15 oxetanyl, morpholinyl, thiomorpholinyl, azepanyl tetrahydropyranyl,
dihydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, thiazolidinyl,
tetrahydrofuranyl, tetrahydrothiophenyl, and the like.
[35] “Oxo” refers to the moiety =O.
[36] “CHK” refers to Checkpoint kinase, which includes Checkpoint
20 kinase-1 (CHK-1) and Checkpoint kinase-2 (CHK-2). Preferably, CHK refers to
CHK-1.
[37] “Optionally substituted” unless otherwise specified means that a group
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
25 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
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.
[38] A “pharmaceutically acceptable carrier” refers to an ingredient in a
pharmaceutical formulation, other than an active ingredient, which is nontoxic to a
5 subject. A pharmaceutically 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:
10 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
15 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
20 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.

I/We Claim:
1. A compound of formula (IA):
formula (IA),
5 wherein,
Y is N or CRy
;
A is 5- to 6- membered heteroaryl optionally substituted with 0-4
R
x
;
R
x
and R
y are independently hydrogen, C1-C6 alkyl, C3-C6
10 cycloalkyl, 3- to 6-membered heterocyclyl, -CN, halogen, C1-C6 alkoxy,
C1-C6 haloalkoxy, C1-C6 haloalkyl, -OR7
, -
NR8R
9
, -C(O)R7
, -NR7C(O)R8
, -C(O)OR7
, -C(O)NR8R
9
, each of which is
optionally substituted by oxo, halogen, CN, -OR10 or -NR11R
12;
D is -(C1-C6 alkylene)OR10
, -(C1-C6 alkylene)NR11R
12, 3- to 6-
15 membered heterocyclyl, -(C1-C6 alkylene)C3-C6 cycloalkyl or -(C1-
C6 alkylene)3- to 10-membered heterocyclyl, each of which is optionally
substituted by R2
;
L is -CH2-, -O-, -NH-, -N(CH3)-, -SO2-, -C(O)-, -C(O)NH- or -
NHC(O)-;
R
1 20 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6
cycloalkyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 10-membered
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heteroaryl, -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 5 , -(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
, -(C1-C3 alkylene)NR13C(O)NR14R
15
, -(C1-
C3 alkylene)C(O)OR13
, -(C1-C3 alkylene)C(O)ONR14R
15
, -(C1-
10 C3 alkylene)(C3-C8 cycloalkyl) or -(C1-C3 alkylene)(3-10-membered
heterocyclyl); wherein each of R1
is optionally substituted by R3
;
R
2 is 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;
R
3
is 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 20 , C3-C6 cycloalkyl, C6 aryl, 5- to 6-
membered heteroaryl, 3- to 6-membered heterocyclyl, or C1-C6 alkyl
optionally substituted by oxo, -OH, halogen or -NH2;
each R7
, R8 and R
9 is independently hydrogen or C1-C6 alkyl
optionally substituted by oxo, -OH, halogen or -NH2;
R
10 25 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or 3- to 10-
membered heterocyclyl, wherein each of which is optionally substituted by
R
2
;
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each R11 and R
12 is independently hydrogen, C1-C6 alkyl, C3-C8
cycloalkyl or 3- to 10-membered heterocyclyl, wherein each of which is
optionally substituted by R2
;
or R11 and R
12 are taken together with the atom to which they
5 attached to form a 3- to 6- membered heterocyclyl optionally substituted
by R2
;
each R13, R14 and R
15 is independently hydrogen, C1-C6 alkyl, C1-C6
haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-
membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, -(C1-
10 C3 alkylene)C3-C6 cycloalkyl, -(C1-C3 alkylene)3- to 6-membered
heterocyclyl, or -(C1-C3 alkylene)5- to 6-membered 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
, -
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 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,
20 halogen or -NH2;
each R16, R17 and R
18 is independently hydrogen, C2-C6 alkenyl, C2-
C6 alkynyl, C6 aryl, 5- to 6-membered heteroaryl, 3- to 6-membered
heterocyclyl, C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by
oxo, -OH, halogen or -NH2; and
or R17 and R
18 25 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;
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or a salt thereof.
2. The compound of claim 1, wherein Y is selected from N or CRy
, wherein
R
y is as defined in claim 1.
3. The compound of claim 1, wherein R
y is selected from hydrogen F, Cl or
5 CH3.
4. The compound of claim 1, wherein A is 5- to 6- membered heteroaryl
optionally substituted with 0-4 Rx
, wherein Rx is as defined in claim 1.
5. The compound of claim 1, wherein A is selected from imidazolyl, pyrrolyl,
pyrazolyl, triazolyl, thiophenyl, furanyl, thiazolyl, isothiazolyl,
10 thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridyl, pyrimidyl,
pyridazinyl or pyrazinyl, wherein each of which is optionally substituted
by group selected from -CN, -CONH2, -CH3, -CF3, -CH2CF3 or -CH2OH.
6. The compound of claim 1, wherein A is selected from ,
, , , ,
15 , , , , ,
, , , , ,
, , , ,
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or wherein, the wavy lines denote attachment points to rest
of the molecule
7. The compound of claim 1, wherein D is selected from -(C1-
C6 alkylene)OR10
, -(C1-C6 alkylene)NR11R
12
, 3- to 6-membered
5 heterocyclyl, -(C1-C6 alkylene)C3-C6 cycloalkyl or -(C1-C6 alkylene)3- to
10-membered heterocyclyl, wherein each of which is optionally
substituted by R2
, wherein R2
, R10, R11 and R12 are as defined in claim 1.
8. The compound of claim 1, wherein D is selected from , ,
, , , , , , ,
10 , , , , , , ,
, , , , ,
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, , , , , ,
, , , , , ,
, , , , , ,
, , , , ,
5 , , , , , ,
, , , , , or
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, wherein the wavy lines denote attachment points to rest of the
molecule.
9. The compound of claim 1, wherein L is selected from -CH2-, -O-, -NH-, -
NCH3-, -SO2-, -C(O)-, -C(O)NH- or -NHC(O)-.
5 10. The compound of claim 1, wherein L is selected from -NH- or -O-.
11. The compound of claim 1, wherein R1
is selected from hydrogen, C1-C6
alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered
heterocyclyl, C6 aryl, 5- to 10-membered heteroaryl, -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 10 ,
-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 15 , -(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)(3-10-membered
heterocyclyl); wherein each of R
1
is optionally substituted by R3
, wherein
R
3
,R
13, R14 and R15 20 are as defined in claim 1.
12. The compound of claim 1, wherein R1
is -C(O)NR14R
15
, wherein R14 and
R
15 are independently selected from hydrogen, C1-C6 alkyl or C3-C6
cycloalkyl.
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13. The compound of claim 1, wherein R1
is selected from hydrogen, -CH3,
, , , , , , ,
, , , , ,
, , , , ,
5 , , , , , ,
, , , , , ,
, , , , , ,
, , , , , ,
, , , , , , ,
10 , , , , , , , ,
, , , , , ,
, , , , , ,
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, , , , , ,
, , , , ,
, , , , , , ,
, , , ,
5 , , , , ,
, , or , wherein the wavy lines denote
attachement point to rest of the molecule.
14. The compound of claim 1, wherein R1
is selected from ,
or .
10 15. The compound of claim 1, wherein the compound is a compound of
formula (II):
formula (II),
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or a salt thereof, wherein A, D, L, R1
and Ry
are as defined in claim 1.
16. The compound of claim 1, wherein the compound is any of the compounds
of formula (IIa-1) to (IIa-10),
(IIa-1) (IIa-2)
(IIa-3) (IIa-4)
(IIa-5) (IIa-6)
(IIa-7) (IIa-8)
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(IIa-9) (IIa-10)
or a salt thereof, wherein D, L, R1
, Rx
and Ry are as defined in claim 1.
17. The compound of claim 1, wherein the compound is any of the compounds
of formula (IIb-1) to (IIb-20),
(IIb-1) (IIb-2)
(IIb-3) (IIb-4)
(IIb-5) (IIb-6)
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(IIb-7) (IIb-8)
(IIb-9) (IIb-10)
(IIb-11) (IIb-12)
(IIb-13) (IIb-14)
(IIb-15) (IIb-16)
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(IIb-17) (IIb-18)
(IIb-19) (IIb-20)
or a salt thereof, wherein D, L, R1
, Rx
and Ry are as defined in claim1.
18. The compound of claim 1, wherein the compound is a compound of
formula (III):
5 formula (III),
or a salt thereof, wherein A, D, L, and R1
are as defined in claim 1.
19. The compound of claim 1, wherein the compound is any of the compounds
of formula (IIIa-1) to (IIIa-10),
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(IIIa-1) (IIIa-2)
(IIIa-3) (IIIa-4)
(IIIa-5) (IIIa-6)
(IIIa-7) (IIIa-8)
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(IIIa-9) (IIIa-10)
or a salt thereof, wherein D, L, R1
and Rx are as defined in claim 1.
20. The compound of claim 1, wherein the compound is any of the compounds
of formula (IIIb-1) to (IIIb-20),
(IIIb-1) (IIIb-2)
(IIIb-3) (IIIb-4)
(IIIb-5) (IIIb-6)
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(IIIb-7) (IIIb-8)
(IIIb-9) (IIIb-10)
(IIIb-11) (IIIb-12)
(IIIb-13) (IIIb-14)
(IIIb-15) (IIIb-16)
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(IIIb-17) (IIIb-18)
(IIIb-19) (IIIb-20)
or a salt thereof, wherein D, L, R1
and Rx are as defined in claim 1.
21. The compound of claim 1, wherein the compound is a compound of
formula (IV):
5 formula (IV),
or a salt thereof, wherein A, D, L, R
y
and R15
are as defined in claim 1.
22. The compound of claim 1, wherein the compound is any of the compounds
of formula (IVa-1) to (IVa-15),
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(IVa-1) (IVa-2)
(IVa-3) (IVa-4)
(IVa-5) (IVa-6)
(IVa-7) (IVa-8)
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(IVa-9) (IVa-10)
(IVa-11) (IVa-12)
(IVa-13) (IVa-14)
(IVa-15)
or a salt thereof, wherein D, L, R
15
, R
x
and R
y
are as defined in claim 1.
23. The compound of claim 1, wherein the compound is selected from
Compound Nos. 1.1 to 1.36 in table-1 or a salt thereof.
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24. The compound of claim 1, wherein the compound is selected from
Compound Nos. 2.1 to 2.334 in table-2 or a salt thereof.
25. The compound of claim 1, wherein the said compound is being used in the
manufacture of a medicament for treatment of a disease or disorder
5 mediated by Chekpoint Kinase (CHK).
26. The compound of claim 25, wherein the CHK is CHK-1.
27. A pharmaceutical composition comprising a compound of claim 1, or a
salt thereof, and a pharmaceutically acceptable carrier.