Cyclin-dependent kinases are a major class ofkinases that are important in cancer
cell proliferation and deregulated oncogenic transcription. CDK7 is a cyclin-dependent
5 kinase that binds to cyclin Hand MATI to form a trimeric cyclin-activating kinase that
performs its function by phosphorylating other cyclin-activating kinases involved in cellcycle
control. These complexes control specific transitions between two subsequent
phases in the cell cycle. CDK7 is implicated in both temporal control of the cell cycle
and transcriptional activity. CDK7 is implicated in the transcriptional initiation process
10 by phosphorylation ofRbp1 subunit of RNA Polymerase II. Uncontrolled cell
proliferation and deregulated transcription is a cancer hallmark. Targeting CDK7
selectively may offer an advantage by simultaneously inhibiting active transcription and
cell-cycle progression. Therefore, CDK7 is a promising target for the treatment of
cancer, in particular aggressive and hard-to-treat cancers.
15 Some small molecule inhibitors against CDK7 have been reported in the literature
(see, e.g., WO 2015/154022, WO 2016/142855, WO 2016/160617, WO 2016/193939,
and WO 2017/044858). However, known CDK7 inhibitors may not be specific to CDK7
and have not yet been as useful as is needed to effectively treat cell proliferative
disorders, such as cancer. Thus, there remains a need to provide new selective CDK7
20 inhibitors to treat cell proliferative disorders.
Compounds of the formula:
25 (I)
pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, are
30 provided herein. In this formula, X can be -CH(OH)CH3, -CHFCH3, -CF2CH3 or -CF3;
Y can be -CH=CH2 or -C2H=C2H2; and Z can be -CH(CH3)2 or -C2H(CH3)(CH22H).
5
10
wo 2021/242602 PCT /US2021/033414
-2-
The compounds of this formula contain a chiral center providing an R-enantiomeric form
shown and S-enantiomeric form as shown here:
(R-enantiomer) (S-enantiomer)
The R-enantiomer and S-enantiomer, pharmaceutically acceptable salts thereof, or
pharmaceutical compositions thereof, in which X, Y, and Z are defined as above, are also
provided herein.
Methods ofusing the compounds of this formula, pharmaceutically acceptable
15 salts thereof, and pharmaceutical compositions thereof, to treat urothelial cancer, uterine
cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, gastric cancer,
hepatobiliary cancer, pancreatic cancer, cervical cancers, prostate cancer, hematological
cancers, sarcomas, skin cancers, or gliomas are also provided. The methods include
administering a therapeutically effective amount of a compound of this formula, or a
20 pharmaceutically acceptable salt thereof, to a patient in need. The methods can also
include testing for the presence of at least one loss of function mutation in the ARID IA,
KMT2C, KMT2D, or RBI gene in a biological sample from a patient and administering a
therapeutically effective amount of a compound of this formula, or a pharmaceutically
acceptable salt thereof, to the patient if the sample tests positive for the loss of function
25 mutation. The methods can further or alternatively include administering a
therapeutically effective amount of a compound of this formula, or a pharmaceutically
acceptable salt thereof, to the patient provided that a biological sample from the patient
contains at least one loss of function mutation in the ARIDIA, KMT2C, KMT2D, or RBI
gene. The methods can additionally or alternatively include administering a
30 therapeutically effective amount of a compound of this formula, or a pharmaceutically
acceptable salt thereof, to the patient provided that the patient is selected for treatment if a
wo 2021/242602 PCT /US2021/033414
-3-
biological sample from the patient tests positive for at least one loss of function mutation
in theARIDIA, KMT2C, KMT2D, or RBI gene.
Also provided herein, are the compounds of this formula, and pharmaceutically
acceptable salts thereof, for use in therapy. Also provided herein, are the compounds of
5 this formula, and pharmaceutically acceptable salts thereof, for use in the treatment of
urothelial cancer, uterine cancer, colorectal cancer, breast cancer, lung cancer, ovarian
cancer, gastric cancer, hepatobiliary cancer, pancreatic cancer, cervical cancers, prostate
cancer, hematological cancers, sarcomas, skin cancers, or gliomas. For further example,
the treatment can include performing an in vitro assay using a biological sample from the
10 patient, determining the presence of at least one inactivating mutation in the ARID IA,
KMT2C, KMT2D, and RBI genes, and administering a therapeutically effective amount of
a compound of this formula, or pharmaceutically acceptable salts thereof, to the patient if
at least one inactivating mutation in any of the genes is present.
The use of a compound of this formula, or pharmaceutically acceptable salts
15 thereof, in the manufacture of a medicament for treating a urothelial cancer, uterine
cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, gastric cancer,
hepatobiliary cancer, pancreatic cancer, cervical cancers, prostate cancer, hematological
cancers, sarcomas, skin cancers, or gliomas is also provided. This use can include
performing an in vitro assay using a biological sample from the patient, determining the
20 presence of at least one inactivating mutation in the ARIDIA, KMT2C, KMT2D, and RBI
genes, and administering a therapeutically effective amount of a compound of this
formula, including R- and S-enantiomeric forms, or pharmaceutically acceptable salts
thereof, to the patient if at least one inactivating mutation in any of the genes is present.
25 Description
Novel selective CDK7 inhibitor compounds are described herein. These new
compounds could address the need for potent, effective treatment of cancer, especially
cancer stemming from deregulated transcription. More specifically, these new
compounds could address the need for potent, effective treatment ofurothelial cancer,
30 uterine cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, gastric
cancer, hepatobiliary cancer, pancreatic cancer, cervical cancers, prostate cancer,
hematological cancers, sarcomas, skin cancers, and/or gliomas.
wo 2021/242602 PCT /US2021/033414
-4-
The compounds described herein are compounds of formula (I):
5 (I)
or pharmaceutically acceptable salts thereof In formula (I), X is -CH(OH)CH3, -
10 CHFCH3, -CF2CH3 or -CF3; Y is -CH=CH2 or -C2H=C2H2 and Z is -CH(CH3)2 orC2H(
CH3)(CH22H). Specific examples of formula (I) include compounds in which X isCH(
OH)CH3, -CHFCH3, or -CF2CH3; Y is -CH=CH2; and Z is-CH(CH3)2. Further
examples formula (I) include compounds in which X is -CF3; Y is -CH=CH2 orC2H=
C2H2; and Z is-CH(CH3)2 or -C2H(CH3)(CH22H). One of skill in the art will
15 appreciate that compounds as described by formula (I), or pharmaceutically acceptable
salts thereof, contain a chiral center, the position of which is indicated by an* above.
One of skill in the art will also appreciate that the Cahn-Ingold-Prelog (R) or (S)
designations for chiral centers will vary depending upon the substitution patterns around a
chiral center. The chiral center in the compound of formula (I) provides an R-
20 enantiomeric form shown by formula (II) and an S-enantiomeric from shown by formula
(III):
25 H{;~z H{;~z N N N N 0 \~ 0 \~
fa x /·a x
0 NJ 0 NJ
~ ~
30 y y
(II) (III)
wo 2021/242602 PCT /US2021/033414
-5-
Compounds of formula (II) and formula (III) or pharmaceutically acceptable salts thereof,
in which X, Y, and Z are defined as for formula (I), are also provided herein.
Specific enantiomers may be prepared beginning with chiral reagents or by stereoselective
or stereo-specific synthetic techniques. Alternatively, single enantiomers may
5 be isolated from mixtures of different chiral forms by standard chiral chromatographic or
crystallization techniques at any convenient point in the synthesis of compounds of
formula (I), formula (II), and formula (III). All individual enantiomers, as well as
mixtures of the enantiomers of the compounds of formula (II) and formula (III) including
racemates are intended to be included herein.
10
15
20
25
30
Specific examples of the compounds of formula (II) (including IUP AC
nomenclature names) are shown here:
1-[ (2R)-2-[[ 4-[[3 -isopropyl-6-( trifluoromethyl )imidazo[ 1 ,2-a ]pyridin-8-
yl ]amino ]-1-piperidyl ]methyl ]morpholin-4-yl ]prop-2-en-1-one;
1-[(2R)-2-[[ 4-[[6-(1, 1-difluoroethyl)-3-isopropyl-imidazo[1 ,2-a ]pyridin-8-
yl ]amino ]-1-piperidyl ]methyl ]morpholin-4-yl ]prop-2-en-1-one;
5
10
15
20
25
30
wo 2021/242602 PCT /US2021/033414
-6-
1-[(2R)-2-[[ 4-[[6-(1-fluoroethyl)-3-isopropyl-imidazo[ 1 ,2-a ]pyridin-8-yl ]amino]-
1-piperidyl ]methyl ]morpholin-4-yl ]prop-2-en-1-one;
1-[(2R)-2-[[ 4-[[6-(1-hydroxyethyl)-3-isopropyl-imidazo[1 ,2-a ]pyridin-8-yl ]amino ]-1-
piperidyl ]methyl ]morpholin-4-yl ]prop-2-en-1-one;
1-[(2R)-2-[[ 4-[[3-(1 ,2-dideuterio-1-methyl-ethyl)-6-(trifluoromethyl)imidazo[1 ,2-
a ]pyridin-8-yl ]amino ]-1-piperidyl ]methyl ]morpholin-4-yl ]prop-2-en-1-one; and
5
10
15
20
25
30
wo 2021/242602 PCT /US2021/033414
-7-
2,3 ,3 -trideuterio-1-[ (2R)-2-[[ 4-[[3 -isopropyl-6-( trifluoromethyl )imidazo[ 1 ,2-a ]pyridin-8-
yl]amino ]-1-piperidyl ]methyl ]morpholin-4-yl ]prop-2-en-1-one.
Specific examples of the compounds of formula (III) (including IUP AC
nomenclature names) are shown here:
1-[(2S)-2-[[ 4-[[3-isopropyl-6-(trifluoromethyl)imidazo[ 1 ,2-a ]pyridin-8-yl ]amino ]-1-
piperidyl ]methyl ]morpholin-4-yl ]prop-2-en-1-one;
1-[(2S)-2-[[ 4-[[ 6-(1, 1-difluoroethyl)-3-isopropyl-imidazo[ 1 ,2-a ]pyridin-8-yl ]amino ]-1-
piperidyl ]methyl ]morpholin-4-yl ]prop-2-en-1-one;
5
10
15
20
25
30
wo 2021/242602 PCT /US2021/033414
-8-
1-[ (2S)-2-[[ 4-[[6-(1-fluoroethyl)-3-isopropyl-imidazo[1 ,2-a ]pyridin-8-yl ]amino ]-1-
piperidyl ]methyl ]morpholin-4-yl ]prop-2-en-1-one;
1-[(2S)-2-[[ 4-[[ 6-(1-hydroxyethyl)-3-isopropyl-imidazo[ 1 ,2-a ]pyridin-8-yl ]amino ]-1-
piperidyl ]methyl ]morpholin-4-yl ]prop-2-en-1-one;
1-[(2S)-2-[[ 4-[[3-(1 ,2-dideuterio-1-methyl-ethyl)-6-(trifluoromethyl)imidazo[ 1,2-
a ]pyridin-8-yl ]amino ]-1-piperidyl ]methyl ]morpholin-4-yl ]prop-2-en-1-one; and
5
10
wo 2021/242602 PCT /US2021/033414
-9-
2,3 ,3 -trideuterio-1-[ (2S)-2-[[ 4-[[3 -isopropyl-6-( trifluoromethyl )imidazo[ 1 ,2-a ]pyridin-8-
yl]amino ]-1-piperidyl ]methyl ]morpholin-4-yl ]prop-2-en-1-one.
Several deuterated molecules are specifically described herein, e.g., compounds of
formula (I) where Y is -C2H=C2H2 and where Z is -C2H(CH3)(CH22H). Other deuterated
molecules are possible and are considered to be disclosed herein where a hydrogen can be
15 replaced by a deuterium in a disclosed molecule.
The compounds described herein may react to form pharmaceutically acceptable
salts and pharmaceutically acceptable salts of the compounds of formula (I), formula (II),
and formula (III) as well as the specific examples of the compounds of formula (I),
formula (II), and formula (III) are intended to be included. Pharmaceutically acceptable
20 salts and common methodology for preparing them are well known in the art (see, e.g., P.
Stahl, et al. Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2nd
Revised Edition (Wiley-VCH, 2011); S.M. Berge, et al., "Pharmaceutical Salts," Journal
of Pharmaceutical Sciences, Vol. 66, No.1, January 1977). Specific examples ofuseful
pharmaceutically acceptable salts include hydrochloride salts and sulfate salts, but this list
25 is not intended to be exclusive.
The compounds described herein are generally effective over a wide dosage range.
For example, dosages per day fall within the range of about 1 mg to about 2 g. It will be
understood that the amount of the compound actually administered will be determined by
a physician, in light of the relevant circumstances, including the condition to be treated,
30 the chosen route of administration, the actual compound or compounds administered, the
age, weight, and response of the individual patient, and the severity of the patient's
symptoms.
wo 2021/242602 PCT /US2021/033414
-10-
The compounds described herein can be formulated as pharmaceutical
compositions that can be administered by a variety of routes. Such pharmaceutical
compositions and processes for preparing the same are well known in the art (see, e.g.,
Remington: The Science and Practice of Pharmacy (A. Gennaro, et al., eds., 21st ed.,
5 Mack Publishing Co., 2005)). Specifically, the compounds of formula (I), formula (II),
and formula (III) as described herein, or pharmaceutically acceptable salts thereof, can be
combined with one or more pharmaceutically acceptable carriers, diluents, or excipients.
More particularly, the compounds described herein by formula (I), formula (II), and
formula (III) can be formulated as pharmaceutical compositions. Further, the compounds
10 of formula (I), formula (II), and formula (III) as described herein, or pharmaceutically
acceptable salts thereof, can be combined with one or more other therapeutic agents. For
example, the compounds of formula (I), formula (II), and formula (III) as described
herein, or pharmaceutically acceptable salts thereof, can be a component in a
pharmaceutical composition for the treatment of cancer in combination with one or more
15 pharmaceutically acceptable carriers, diluents, or excipients, and optionally with one or
more additional therapeutic agents. Pharmaceutical compositions containing the
compounds of formula (I), formula (II), and formula (III) as described herein, or
pharmaceutically acceptable salts thereof, can be used in the methods described herein.
The term "treating" (or "treat" or "treatment") as used herein refers to restraining,
20 slowing, stopping, or reversing the progression or severity of an existing symptom,
condition or disorder.

We claim:
1. A compound of the formula:
5
10
wherein,
X is −CH(OH)CH3, −CHFCH3, −CF2CH3, or −CF3;
Y is −CH=CH2 or –C2H=C2H2; and
Z is –CH(CH3)2 or –CH(CH3)(CH2
2H);
15 or a pharmaceutically acceptable salt thereof.
2. The compound according to Claim 1, wherein the compound is
20
25 or a pharmaceutically acceptable salt thereof.
3. The compound according to Claim 1, wherein the compound is
30
CLAIMS UNDER RULE 1 (PROVISIO) OF RULE 20
Clean Version
-67-
Replacement Sheet
or a pharmaceutically acceptable salt thereof.
4. The compound according to Claim 2, wherein the compound is
5
10
or a pharmaceutically acceptable salt thereof.
5. The compound according to Claim 2, wherein the compound is
15
20
.
6. The compound according to Claim 2, wherein the compound is
25
30
or a pharmaceutically acceptable salt thereof.
CLAIMS UNDER RULE 1 (PROVISIO) OF RULE 20
Clean Version
-68-
Replacement Sheet
7. The compound according to Claim 2, wherein the compound is
5
10 .
8. The compound according to any one of claims 1-4 or 6, wherein the
pharmaceutically acceptable salt is a hydrochloride salt.
15 9. The compound according to any one of claims 1-4 or 6, wherein the
pharmaceutically acceptable salt is a sulfate salt.
10. A pharmaceutical composition comprising a compound of any one of Claims 1 to
9, or a pharmaceutically acceptable salt thereof, in combination with one or more
20 pharmaceutically acceptable carriers, diluents, or excipients.