Note: Descriptions are shown in the official language in which they were submitted.
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ErbB RECEPTOR INHIBITORS AS ANTI-TUMOR AGENTS
FIELD OF THE DISCLOSURE
The present application relates to novel compounds as inhibitors of type I
receptor
tyrosine kinases (e.g., HER2), the pharmaceutical compositions comprising one
or more of
the compounds and salts thereof as an active ingredient, and the use of the
compounds and
salts thereof in the treatment of hyperproliferative diseases associated with
ErbBs (e.g.,
HER2), such as cancer and inflammation, in mammals and especially in humans.
BACKGROUND OF THE DISCLOSURE
The type I tyrosine kinase receptor family consists of four structurally
related receptors:
EGFR (ErbB1 or HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4) (Reviewed
in
Riese and Stern, Bioessays (1998) 20:41-48; Olayioye et ah, EMBO Journal
(2000)
19:3159-3167; and Schlessinger, Cell (2002) 110:669-672). The structures of
all the four
family members are nearly the same, made up of an extracellular region or
ectodomain or
ligand binding region, a single transmembrane-spanning region, and an
intracellular
cytoplasmic tyrosine kinase domain.
It has been demonstrated that HER2 plays a role in development of cancer. HER2
overexpression occurs in 20-25% of breast cancer(BC) patients (Leyland-Jones
B, J Clin
Oncol. 2009, 5278-86). About 1.7 million new BC incidences are diagnosed every
year
(Cardoso F, et al. Breast 2018, 131-138) and 80% of BC are invasive, which
require
chemotherapy, radiation or target therapy besides surgery (Dai X., et al. Am J
Cancer Res,
2015, 2929-2943). Brain metastases are a frequent occurrence in metastatic
breast cancer
patients. Overall survival for breast cancer brain metastases (BCBM) patients
ranges from
2-25.3 months (Leone J.P.Exp. Hematol. Oncol. 2015, 4,33). Surgery, whole
brain radiation
therapy (WBRT) and stereotactic radiosurgery (SRS) are the three main
treatment options for
BCBM. Surgery is used for solitary or up to three brain metastases. SRS can be
used in
patients with four or fewer intracranial lesions. WBRT is used to manage
multiple brain
metastases, but can lead to significant neuro-cognitive decline (Venur V.A. et
al. Int. J.Mol.
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Sci. 2016, 1543).
Compared to other types of breast cancer, HER2 positive tumors have a higher
incidence
of brain metastases, up to 50% of HER2positive breast cancer patients develop
intracranial
metastases (Leyland-Jones B, J Clin Oncol. 2009, 5278-86). The high prevalence
of BCBM
in HER2 positive patients is ascribed to inherent tropism of HER2 positive
breast cancer
cells to the brain, prolonged survival of patients treated with anti-HER2
therapy and limited
intracranial activity of anti-HER2 therapy (Venur V.A. et al. Int. J.Mol.
Sci.2016, 17, 1543).
Several anti-HER2 agents have been developed for clinical use, but none of
them is
central nervous system (CNS) penetrable. The blood-brain barrier (BBB) is
essential to
protect the CNS from potentially harmful agents in the peripheral circulation;
however, it
also prevents potential therapeutics from reaching the site of action. It is
estimated that 98%
of all small molecules and 100% large molecules, such as antibodies and
antibody drug
conjugate do not cross the BBB (Pardridge W.M. NeuroRx, 2005, 2, 3-14), which
presents
great challenges to CNS drug discovery. Efflux transport is a major
determinant of drug
disposition to the CNS. Several ATP-dependent efflux pumps from the ABC
superfamily
(P-gp and BCRP) have been localized at the luminal side of human brain
capillary
endothelial cells (Giacomini K.M. et. al. Nature Reviews Drug Discovery, 2010,
9, 215-236)
and Pgp and BCRP have been shown to play an important role in limiting entry
of various
drugs into the CNS (Enokizono, J. et al. Drug Metabolism and Disposition,
2008, 36,
995-1002. Zhou, L. et al. Drug Metabolism and Disposition, 2009, 37, 946-955).
Trastuzumab, like other monoclonal antibodies, does not cross blood-brain
barrier (BBB)
with brain to blood ratio (Kr) <0.01 (Kabraji S. et al. Clinical Cancer
Research. 2018, 3351).
T-DM1, an antibody drug conjugate (ADC), does not cross BBB either with
Kr<0.01
(Askoxylakis V, et al. JNCI J Nall Cancer Inst, 2015, 763-763). Approved
tyrosine kinase
inhibitors (TKIs) lapatinib, neratinib and afatinib are strong Pgp substrates,
and have poor
brain penetration with Kr of 0.04, 0.079 and <0.08, respectively (Tanaka, Y.et
al, Scientific
Reports, 2018, 343; Zhang, Shirong, et al, Acta Pharmacologica Sin/ca, 2017,
233-240).
Tucatinib, a HER2 reversible inhibitor in phase 2 clinical trial, is also a
strong Pgp substrate
and does not cross BBB with Kr at 0.02-0.05 (Dinkel V, et al. Cancer Research,
2012, 72).
In addition, the evaluation of resected brain metastases has revealed that the
BBB was
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preserved in patients with HER2-postive breast cancer, despite having brain
metastases
(Yonemori K, et al. Cancer, 2010, 302-308). Limited clinical efficacy observed
when treating
BCBM patients with non-brain penetrable aforementioned antibody, ADC and TKIs.
Accordingly, there remains a need to develop new compounds that act as BBB
penetrable
HER2 inhibitor to treat HER2 positive BCBM patients.
SUMMARY OF THE DISCLOSURE
Disclosed herein are novel compounds that inhibit type I receptor tyrosine
kinases,
demonstrate good brain penetration in animals, and possess favourable toxicity
profiles. As a
result, the compounds of the present application are particularly useful in
the treatment of
type I receptor tyrosine kinases mediated diseases or conditions, in
particular
HER2-associated disease or conditions, including cancer (e.g., metastatic
cancer, such as
brain metastases).
In one aspect, the present disclosure provides compounds of Formula (I):
( R4 ) n1
X
Ii A
R3
R2
HN X4 X7
G
R )
n N
(I)
or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester
thereof, wherein:
G is C(R5) or N;
A is CH or N;
B is CH or N;
D is CH of N;
Xi, X2, X3, X4, X5, X6, and X7 are each independently CH or N;
E is 0, NH, or S;
L is selected from the group consisting of 0, C(=0), S, SO, SO2 and N(R);
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Ri is selected from the group consisting of hydrogen, halogen, cyano, nitro,
amino,
hydroxyl, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl,
heteroalkenyl,
heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or
partially unsaturated
heterocyclyl, aryl, N(R7)(R8), and 0(R9), wherein said cycloalkyl and
heterocyclyl are
optionally substituted with one or more groups independently selected from the
group
consisting of halogen, cyano, nitro, hydroxyl, carboxy, carbamoyl, acyl,
alkyl, alkenyl,
alkynyl, alkyl-OH and haloalkyl;
R2 is selected from the group consisting of alkyl, saturated or partially
unsaturated
cycloalkyl, saturated or partially unsaturated heterocyclyl, wherein said
alkyl, cycloalkyl, and
heterocyclyl are optionally substituted with one or more groups independently
selected from
the group consisting of halogen, cyano, nitro, hydroxyl, alkyl-OH, carboxy,
carbamoyl, alkyl,
alkenyl, alkynyl, haloalkyl, saturated or partially unsaturated cycloalkyl,
and N(Rio)(Rii);
R6 is hydrogen or alkyl; or when L is N(R6), R2 and R6 together with the
nitrogen atom
to which they are attached form a 3 to 10 membered saturated or partially
unsaturated
heterocyclyl ring optionally containing one or more additional heteroatoms
selected from N,
0 and S, wherein said 3 to 10 membered heterocyclyl ring is optionally
substituted with one
or more groups independently selected from the group consisting of halogen,
cyano, nitro,
carboxy, carbamoyl, alkyl, alkenyl, alkynyl, alkyl-OH, haloalkyl, saturated
and partially
unsaturated cycloalkyl, and MR10)(R11);
R3 and R4 are each independently selected from the group consisting of
hydrogen,
halogen, cyano, amino, hydroxyl, nitro, alkyl, alkenyl, alkynyl, alkyl-OH,
haloalkyl and
alkoxyl;
R5 is selected from the group consisting of hydrogen, halogen and cyano;
R7 and Rs are each independently selected from the group consisting of
hydrogen, alkyl,
alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, acyl,
saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated heterocyclyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or
heterocyclylalkyl, wherein said
alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocyclyl,
cycloalkylalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl are
optionally substituted
with one or more groups independently selected from the group consisting of
alkyl, alkenyl,
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alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkylamino, saturated and
partially
unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl
optionally substituted
by alkyl, aryl, and heteroaryl; or
R7 and Rs together with the atom to which they are attached form a 3 to 10
membered
saturated or partially unsaturated heterocyclyl ring optionally containing one
or more
additional heteroatoms selected from N, 0, S, SO, SO2 and NR12, wherein said
heterocyclyl
ring is optionally substituted with one or more groups independently selected
from the group
consisting of oxo, halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl,
saturated and
partially unsaturated cycloalkyl, saturated and partially unsaturated
heterocyclyl,
cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl,
arylalkyl,
heteroarylalkyl, and heterocyclylalkyl;
R9 is selected from the group consisting of alkyl, alkyl-OH, haloalkyl,
alkenyl, alkynyl,
acyl, saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated
heterocyclyl, wherein said alkyl, alkenyl, alkynyl, acyl, cycloalkyl,
heterocyclyl are
optionally substituted by one or more groups independently selected from the
group
consisting of halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, alkoxyl,
acyl, saturated
and partially unsaturated cycloalkyl, saturated and partially unsaturated
heterocyclyl,
cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl,
arylalkyl,
heteroarylalkyl, and heterocyclylalkyl;
Rio and Rii are each independently selected from the group consisting of
hydrogen,
alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl,
saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated heterocyclyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or
heterocyclylalkyl, wherein said
alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,
cycloalkylalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl are optionally
substituted with
one or more groups independently selected from alkyl, alkyl-OH, haloalkyl,
alkenyl, alkynyl,
heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partially unsaturated
cycloalkyl,
saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl; or
Rio and Rii together with the atom to which they are attached form a 3 to 10
membered
saturated or partially unsaturated heterocyclyl ring optionally containing one
or more
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additional heteroatoms selected from N, 0, S, SO, SO2 and NR12, wherein said
heterocyclyl
ring is optionally substituted with one or more groups independently selected
from the group
consisting of oxo, halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl,
saturated and
partially unsaturated cycloalkyl, saturated and partially unsaturated
heterocyclyl,
cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl,
arylalkyl,
heteroarylalkyl, and heterocyclylalkyl;
R12 is selected from the group consisting of hydrogen, alkyl, alkyl-OH,
haloalkyl,
saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated heterocyclyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl, wherein
said alkyl, alkyl-OH,
haloalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, and
heterocyclylalkyl are optionally substituted with one or more groups
independently selected
from halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, saturated and
partially
unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl,
cycloalkylalkyl,
cyano, nitro, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and
heterocyclylalkyl;
n is 0, 1 or 2;
n1 is 0, 1 or 2.
In some embodiments according to Formula (I), at least one of Xi, X6 and X7 is
N.
In another aspect, the present disclosure provides compounds of Formula (II):
(R4)n1
VX2 E Xi
X
R3
ir A
R2 X5 X6
L HN X4 X7
\
R1) II
,,
m
or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester
thereof, wherein:
G is C(R5) or N;
M is CH or N;
A is CH or N;
B is CH or N;
D is CH of N;
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Xi, X2, X3, X4, X5, X6, and X7 are each independently CH or N, with the
proviso that
when M is CH, at least one of Xi, X6 and X7 is N;
E is 0, NH, or S;
L is selected from the group consisting of 0, C(=0), S, SO, SO2 and N(R6);
Ri is selected from the group consisting of hydrogen, halogen, cyano, nitro,
amino,
hydroxyl, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl,
heteroalkenyl,
heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or
partially unsaturated
heterocyclyl, aryl, N(R7)(R8), and 0(R9), wherein said cycloalkyl and
heterocyclyl are
optionally substituted with one or more groups independently selected from the
group
consisting of halogen, cyano, nitro, hydroxyl, carboxy, carbamoyl, acyl,
alkyl, alkenyl,
alkynyl, alkyl-OH and haloalkyl;
R2 is selected from the group consisting of alkyl, saturated or partially
unsaturated
cycloalkyl, saturated or partially unsaturated heterocyclyl, wherein said
alkyl, cycloalkyl, and
heterocyclyl are optionally substituted with one or more groups independently
selected from
the group consisting of halogen, cyano, nitro, hydroxyl, alkyl-OH, carboxy,
carbamoyl, alkyl,
alkenyl, alkynyl, haloalkyl, saturated or partially unsaturated cycloalkyl,
and N(Rio)(Ri 1);
R6 is hydrogen or alkyl; or
when L is N(R6), R2 and R6 together with the nitrogen atom to which they are
attached
form a 3 to 10 membered saturated or partially unsaturated heterocyclyl ring
optionally
containing one or more additional heteroatoms selected from N, 0 and S,
wherein said 3 to
membered heterocyclyl ring is optionally substituted with one or more groups
independently selected from the group consisting of halogen, cyano, nitro,
carboxy,
carbamoyl, alkyl, alkenyl, alkynyl, haloalkyl, saturated and partially
unsaturated cycloalkyl,
and N(Rio)(Ri 1);
R3 and R4 are each independently selected from the group consisting of
hydrogen,
halogen, cyano, amino, hydroxyl, nitro, alkyl, alkenyl, alkynyl, alkyl-OH,
haloalkyl and
alkoxyl;
R5 is selected from the group consisting of hydrogen, halogen and cyano;
R7 and Rs are each independently selected from the group consisting of
hydrogen, alkyl,
alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, acyl,
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saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated heterocyclyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or
heterocyclylalkyl, wherein said
alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocyclyl,
cycloalkylalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl are
optionally substituted
with one or more groups independently selected from the group consisting of
alkyl, alkenyl,
alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkylamino, saturated and
partially
unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl
optionally substituted
by alkyl, aryl, and heteroaryl; or
R7 and Rs together with the atom to which they are attached form a 3 to 10
membered
saturated or partially unsaturated heterocyclyl ring optionally containing one
or more
additional heteroatoms selected from N, 0, S, SO, SO2 and NR12, wherein said
heterocyclyl
ring is optionally substituted with one or more groups independently selected
from the group
consisting of oxo, halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl,
saturated and
partially unsaturated cycloalkyl, saturated and partially unsaturated
heterocyclyl,
cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl,
arylalkyl,
heteroarylalkyl, and heterocyclylalkyl;
R9 is selected from the group consisting of alkyl, alkyl-OH, haloalkyl,
alkenyl, alkynyl,
acyl, saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated
heterocyclyl, wherein said alkyl, alkenyl, alkynyl, acyl, cycloalkyl,
heterocyclyl are
optionally substituted by one or more groups independently selected from the
group
consisting of halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, alkoxyl,
acyl, saturated
and partially unsaturated cycloalkyl, saturated and partially unsaturated
heterocyclyl,
cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl,
arylalkyl,
heteroarylalkyl, and heterocyclylalkyl;
Rio and Rii are each independently selected from the group consisting of
hydrogen,
alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl,
saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated heterocyclyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or
heterocyclylalkyl, wherein said
alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,
cycloalkylalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl are optionally
substituted with
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one or more groups independently selected from alkyl, alkyl-OH, haloalkyl,
alkenyl, alkynyl,
heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partially unsaturated
cycloalkyl,
saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl; or
Rio and Rii together with the atom to which they are attached form a 3 to 10
membered
saturated or partially unsaturated heterocyclyl ring optionally containing one
or more
additional heteroatoms selected from N, 0, S, SO, SO2 and NR12, wherein said
heterocyclyl
ring is optionally substituted with one or more groups independently selected
from the group
consisting of oxo, halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl,
saturated and
partially unsaturated cycloalkyl, saturated and partially unsaturated
heterocyclyl,
cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl,
arylalkyl,
heteroarylalkyl, and heterocyclylalkyl;
R12 is selected from the group consisting of hydrogen, alkyl, alkyl-OH,
haloalkyl,
saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated heterocyclyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl, wherein
said alkyl, alkyl-OH,
haloalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, and
heterocyclylalkyl are optionally substituted with one or more groups
independently selected
from halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, saturated and
partially
unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl,
cycloalkylalkyl,
cyano, nitro, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and
heterocyclylalkyl;
n is 0, 1 or 2;
n1 is 0, 1 or 2.
In some embodiments of the compounds according to Formula (II), at least one
of Xi,
X6 and X7 is N. In some embodiments, X7 is N, and at least one of Xi and X6 is
N. In some
embodiments, M is N, X7 is N, and at least one of Xi and X6 is N.
In another aspect, the present disclosure provides compounds of Formula (III):
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E
Xv X2
I 13
R3
R2
L HN X4
( R11 (III)
or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester
thereof, wherein:
Ri is selected from the group consisting of hydrogen, halogen, cyano, nitro,
amino,
hydroxyl, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl,
heteroalkenyl,
heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or
partially unsaturated
heterocyclyl, aryl, N(R7)(R8), and 0(R9), wherein said cycloalkyl and
heterocyclyl are
optionally substituted with one or more groups independently selected from the
group
consisting of halogen, cyano, nitro, hydroxyl, carboxy, carbamoyl, acyl,
alkyl, alkenyl,
alkynyl, alkyl-OH and haloalkyl;
G is C(R5) or N;
M is CH or N;
A is CH or N;
B is CH or N;
D is CH of N;
X2, X3, X4, X5, are each independently CH or N;
E is 0, NH, or S;
Y is a bicyclic aryl formed by:
(a) Y1 fused with Y2, wherein Y1 is a 6-membered heteroaryl, and Y2 is a
6-membered aryl or heteroaryl, or
(b) Y3 fused with Y4, wherein Y3 is a 5-membered aryl or heteroaryl, and Y4 is
a
5-membered aryl or heteroaryl, or
(c) Y5 fused with Y6, wherein Y5 is a 5-membered aryl or heteroaryl, and Y6 is
a
6-membered aryl or heteroaryl, wherein one of the ring-forming carbon of Y5 is
directly bonded to E
wherein each of Yi, Y2, Y3, Y4, Y5, and Y6 is optionally substituted by one or
more of
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groups each independently having the same definition as Ri;
L is selected from the group consisting of 0, C(=0), S, SO, SO2 and N(R6);
R2 is selected from the group consisting of alkyl, saturated or partially
unsaturated
cycloalkyl, saturated or partially unsaturated heterocyclyl, wherein said
alkyl, cycloalkyl, and
heterocyclyl are optionally substituted with one or more groups independently
selected from
the group consisting of halogen, cyano, nitro, hydroxyl, alkyl-OH, carboxy,
carbamoyl, alkyl,
alkenyl, alkynyl, haloalkyl, saturated or partially unsaturated cycloalkyl,
and N(Rio)(Rii);
R6 is hydrogen or alkyl; or
when L is N(R6), R2 and R6 together with the nitrogen atom to which they are
attached
form a 3 to 10 membered saturated or partially unsaturated heterocyclyl ring
optionally
containing one or more additional heteroatoms selected from N, 0 and S,
wherein said 3 to
membered heterocyclyl ring is optionally substituted with one or more groups
independently selected from the group consisting of halogen, cyano, nitro,
carboxy,
carbamoyl, alkyl, alkenyl, alkynyl, haloalkyl, saturated and partially
unsaturated cycloalkyl,
and N(Rio)(Ri 1);
R3 and R4 are each independently selected from the group consisting of
hydrogen,
halogen, cyano, amino, hydroxyl, nitro, alkyl, alkenyl, alkynyl, alkyl-OH,
haloalkyl and
alkoxyl;
R5 is selected from the group consisting of hydrogen, halogen and cyano;
R7 and Rs are each independently selected from the group consisting of
hydrogen, alkyl,
alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, acyl,
saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated heterocyclyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or
heterocyclylalkyl, wherein said
alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocyclyl,
cycloalkylalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl are
optionally substituted
with one or more groups independently selected from the group consisting of
alkyl, alkenyl,
alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkylamino, saturated and
partially
unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl
optionally substituted
by alkyl, aryl, and heteroaryl; or
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R7 and R8 together with the atom to which they are attached form a 3 to 10
membered
saturated or partially unsaturated heterocyclyl ring optionally containing one
or more
additional heteroatoms selected from N, 0, S, SO, SO2 and NR12, wherein said
heterocyclyl
ring is optionally substituted with one or more groups independently selected
from the group
consisting of oxo, halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl,
saturated and
partially unsaturated cycloalkyl, saturated and partially unsaturated
heterocyclyl,
cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl,
arylalkyl,
heteroarylalkyl, and heterocyclylalkyl;
R9 is selected from the group consisting of alkyl, alkyl-OH, haloalkyl,
alkenyl, alkynyl,
acyl, saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated
heterocyclyl, wherein said alkyl, alkenyl, alkynyl, acyl, cycloalkyl,
heterocyclyl are
optionally substituted by one or more groups independently selected from the
group
consisting of halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, alkoxyl,
acyl, saturated
and partially unsaturated cycloalkyl, saturated and partially unsaturated
heterocyclyl,
cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl,
arylalkyl,
heteroarylalkyl, and heterocyclylalkyl;
Rio and Rii are each independently selected from the group consisting of
hydrogen,
alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl,
saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated heterocyclyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or
heterocyclylalkyl, wherein said
alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,
cycloalkylalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl are optionally
substituted with
one or more groups independently selected from alkyl, alkyl-OH, haloalkyl,
alkenyl, alkynyl,
heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partially unsaturated
cycloalkyl,
saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl; or
Rio and Rii together with the atom to which they are attached form a 3 to 10
membered
saturated or partially unsaturated heterocyclyl ring optionally containing one
or more
additional heteroatoms selected from N, 0, S, SO, SO2 and NR12, wherein said
heterocyclyl
ring is optionally substituted with one or more groups independently selected
from the group
consisting of oxo, halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl,
saturated and
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partially unsaturated cycloalkyl, saturated and partially unsaturated
heterocyclyl,
cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl,
arylalkyl,
heteroarylalkyl, and heterocyclylalkyl;
R12 is selected from the group consisting of hydrogen, alkyl, alkyl-OH,
haloalkyl,
saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated heterocyclyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl, wherein
said alkyl, alkyl-OH,
haloalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, and
heterocyclylalkyl are optionally substituted with one or more groups
independently selected
from halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, saturated and
partially
unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl,
cycloalkylalkyl,
cyano, nitro, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and
heterocyclylalkyl;
n is 0, 1 or 2;
and n1 is 0, 1 or 2.
In another aspect, there is provided a pharmaceutical composition comprising:
(i) a
compound of any of Formula (I), Formula (II), and Formula (III), or a solvate,
hydrate,
stereoisomer, or a pharmaceutically salt or ester thereof, and (ii) at least
one pharmaceutically
acceptable diluent, excipient or carrier.
In a further aspect, there is provided a method of treating type I receptor
kinases-associated diseases or conditions in a subject in need thereof,
comprising
administering to the subject a therapeutically effective amount of a compound
of any of
Formula (I), Formula (II), and Formula (III), or a solvate, hydrate,
stereoisomer, or a
pharmaceutically salt or ester thereof.
In a further aspect, there is provided a method of treating HER2-associated
diseases or
conditions in a subject in need thereof, comprising administering to the
subject a
therapeutically effective amount of a compound of any of Formula (I), Formula
(II), or
Formula (III), or a solvate, hydrate, stereoisomer, or a pharmaceutically salt
or ester thereof.
In a further aspect, there is provided a compound of any of Formula (I),
Formula (II), or
Formula (III), or a solvate, hydrate, stereoisomer, or a pharmaceutically salt
or ester thereof,
for use in the treatment of type I receptor kinases-associated diseases or
conditions, in
particular HER2-associated diseases or conditions.
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In a further aspect, there is provided use of a compound of any of Formula
(I), Formula
(II), or Formula (III), or a solvate, hydrate, stereoisomer, or a
pharmaceutically salt or ester
thereof, in the manufacture of a medicament for the treatment of type I
receptor
kinases-associated diseases or conditions, in particular HER2-associated
diseases or
conditions.
In a further aspect, there is provided a compound of any of Formula (I),
Formula (II), or
Formula (III), or a solvate, hydrate, stereoisomer, or a pharmaceutically salt
or ester thereof
for use in the treatment of type I receptor kinases-associated diseases or
conditions, in
particular HER2-associated diseases or conditions, wherein the compound is
administered
simultaneously, separately or sequentially with radiotherapy.
In a further aspect, there is provided a compound of any of Formula (I),
Formula (II), or
Formula (III), a solvate, hydrate, stereoisomer, or a pharmaceutically salt or
ester thereof or a
pharmaceutically acceptable salt thereof, administered simultaneously,
separately or
sequentially with one or more additional chemotherapeutic agents.
In a further aspect, there is provided a compound of any of Formula (I),
Formula (II), or
Formula (III), or a solvate, hydrate, stereoisomer, or a pharmaceutically salt
or ester thereof,
administered simultaneously, separately or sequentially with one or more
additional HER2
targeted antibodies.
In a further aspect, there is provided a kit for the treatment or prevention
of type I
receptor kinases-associated diseases or conditions, in particular HER2-
associated diseases or
conditions, said kit comprising a compound of any of Formula (I), Formula
(II), or Formula
(III), or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or
ester thereof, a
container, and optionally a package insert or label indicating a treatment.
The kit may further
comprise a second compound or formulation comprising a second pharmaceutical
agent
useful for treating said disease or disorder.
DETAILED DESCRIPTION OF THE DISCLOSURE
Reference will now be made in detail to certain embodiments of the invention,
examples
of which are illustrated in the accompanying structures and formulas. While
the invention
will be described in conjunction with the enumerated embodiments, it will be
understood that
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they are not intended to limit the invention to those embodiments. On the
contrary, the
invention is intended to cover all alternatives, modifications, and
equivalents, which may be
included within the scope of the present invention as defined by the claims.
One skilled in the
art will recognize many methods and materials similar or equivalent to those
described herein,
which could be used in the practice of the present invention. The present
invention is in no
way limited to the methods and materials described. In the event that one or
more of the
incorporated literature and similar materials differs from or contradicts this
application,
including but not limited to defined terms, term usage, described techniques,
or the like, this
application controls.
It is appreciated that certain features of the present disclosure, which are,
for clarity,
described in the context of separate embodiments, can also be provided in
combination in a
single embodiment. Conversely, various features of the present disclosure,
which are, for
brevity, described in the context of a single embodiment, can also be provided
separately or
in any suitable sub-combination.
DEFINITIONS
Definitions of specific functional groups and chemical terms are described in
more
detail below. For purposes of this disclosure, the chemical elements are
identified in
accordance with the Periodic Table of the Elements, CAS version, Handbook of
Chemistry
and Physics, 75th
ta inside cover, and specific functional groups are generally defined as
described therein. Additionally, general principles of organic chemistry, as
well as specific
functional moieties and reactivity, are described in Organic Chemistry, Thomas
Sorrell,
University Science Books, Sausalito, 1999; Smith and March March's Advanced
Organic
Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock,
Comprehensive
Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers,
Some Modern
Methods of Organic Synthesis, 3rd Edition, Cambridge University Press,
Cambridge, 1987;
the entire contents of each of which are incorporated herein by reference.
At various places in the present disclosure, linking substituents are
described. Where the
structure clearly requires a linking group, the Markush variables listed for
that group are
understood to be linking groups. For example, if the structure requires a
linking group and
the Markush group definition for that variable lists "alkyl", then it is
understood that the
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"alkyl" represents a linking alkylene group.
As used herein, the term "substituted", when refers to a chemical group, means
the
chemical group has one or more hydrogen atoms that is/are removed and replaced
by
substituents. The term "substituent", as used herein, has the ordinary meaning
known in the
art and refers to a chemical moiety that is covalently attached to, or if
appropriate, fused to, a
parent group. As used herein, the term "optionally substituted" or
"optionally... substituted"
means that the chemical group may have no substituents (i.e. unsubstituted) or
may have one
or more substituents (i.e. substituted). It is to be understood that
substitution at a given
atom is limited by valency.
As used herein, the term "Ci_j" indicates a range of the carbon atoms numbers,
wherein i
and j are integers and the range of the carbon atoms numbers includes the
endpoints (i.e. i
and j) and each integer point in between, and wherein j is greater than i. For
examples, C1-6
indicates a range of one to six carbon atoms, including one carbon atom, two
carbon atoms,
three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms.
In some
embodiments, the term "C1_12" indicates 1 to 12, particularly 1 to 10,
particularly 1 to 8,
particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1
to 3 or particularly 1
to 2 carbon atoms.
As used herein, the term "alkyl", whether as part of another term or used
independently,
refers to a saturated linear or branched-chain hydrocarbon radical, which may
be optionally
substituted independently with one or more substituents described below. The
term "Ci_j alkyl"
refers to an alkyl having i to j carbon atoms. In some embodiments, alkyl
groups contain 1 to
12 carbon atoms. In some embodiments, alkyl groups contain 1 to 11 carbon
atoms. In some
embodiments, alkyl groups contain 1 to 11 carbon atoms, 1 to 10 carbon atoms,
1 to 9 carbon
atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5
carbon atoms, 1
to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of
alkyl group
include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl), 2-propyl
(isopropyl),
I-butyl (n-butyl), 2-methyl-l-propyl (i-butyl), 2-butyl (s-butyl), 2-methyl-2-
propyl (t-butyl),
1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl -2-butyl, 3-methy1-2-butyl,
3-methyl-1-butyl,
2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methy1-2-
pentyl,
4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethy1-2-butyl,
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3,3-dimethy1-2-butyl, 1-heptyl, 1-octyl, and the like. Examples of "C112
alkyl" include, but
are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, nonyl, decyl,
undecyl, dodecyl. Examples of "C16 alkyl" are methyl, ethyl, propyl,
isopropyl, n-butyl,
i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-
methy1-2-butyl,
3-methyl-1-butyl, 2-methyl- 1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-
pentyl,
3-methy1-2-pentyl, 4-methyl-2-pentyl, 3-methy1-3-pentyl, 2-methyl-3-pentyl,
2,3-dimethy1-2-butyl, 3,3-dimethy1-2-butyl, and the like.
The alkyl groups can be further substituted by substituents which
independently replace
one or more hydrogen atoms on one or more carbons of the alkyl groups.
Examples of such
substituents can include, but are not limited to, acyl, alkyl, alkenyl,
alkynyl, halogen,
hydroxyl, alkoxyl, haloalkyl, haloalkoxyl, alkylcarbonyloxy, arylcarbonyloxy,
alkoxycarbonyloxy, aryl oxycarbonyloxy, carboxylate, alkylcarbonyl, aryl
carbonyl,
alkoxycarbonyl, aminocarbonyl, alkyl aminocarbonyl, dialkylaminocarbonyl,
alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including
alkylamino,
dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino,
sulfhydryl,
alkylthio, arylthio, thiocarboxylate, sulfates, alkyl sulfmyl, sulfonate,
sulfamoyl, sulfonamido,
nitro, trifluoromethyl, cyano, nitro, azido, heterocyclyl, alkylaryl, or an
aromatic or
heteroaromatic moiety. Alkenyl, alkynyl, saturated or partially unsaturated
cycloalkyl,
heteroalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl,
cycloalkyl alkyl, aryl
and heteroaryl groups as described below may also be similarly substituted.
As used herein, the term "alkenyl", whether as part of another term or used
independently, refers to linear or branched-chain hydrocarbon radical having
at least one
carbon-carbon double bond, which may be optionally substituted independently
with one or
more substituents described herein, and includes radicals having "cis" and
"trans"
orientations, or alternatively, "E" and "Z" orientations. In some embodiments,
alkenyl groups
contain 2 to 12 carbon atoms. In some embodiments, alkenyl groups contain 2 to
11 carbon
atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms, 2 to
10 carbon
atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6
carbon atoms, 2
to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some
embodiments,
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alkenyl groups contain 2 carbon atoms. Examples of alkenyl group include, but
are not
limited to, ethylenyl (or vinyl), propenyl, butenyl, pentenyl, 1-methyl-2
buten-l-yl,
5-hexenyl, and the like.
As used herein, the term "alkynyl", whether as part of another term or used
independently, refers to a linear or branched hydrocarbon radical having at
least one
carbon-carbon triple bond, which may be optionally substituted independently
with one or
more substituents described herein. In some embodiments, alkenyl groups
contain 2 to 12
carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon
atoms. In
some embodiments, alkynyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon
atoms, 2 to
9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms,
2 to 5 carbon
atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments,
alkynyl groups
contain 2 carbon atoms. Examples of alkynyl group include, but are not limited
to,
ethyny1,1-propynyl, 2-propynyl, and the like.
As used herein, the term "alkoxy" or "alkoxyl", whether as part of another
term or used
independently, refers to an alkyl group, as previously defined, attached to
the parent molecule
through an oxygen atom. The term "Ci_j alkoxy" means that the alkyl moiety of
the alkoxy
group has i to j carbon atoms. In some embodiments, alkoxy groups contain 1 to
12 carbon
atoms. In some embodiments, alkoxy groups contain 1 to 11 carbon atoms. In
some
embodiments, alkoxy groups contain 1 to 11 carbon atoms, 1 to 10 carbon atoms,
1 to 9
carbon atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1
to 5 carbon
atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
Examples of
"Ci_12 alkoxyl" include, but are not limited to, methoxy, ethoxy, propoxy
(e.g. n-propoxy and
isopropoxy), t-butoxy, neopentoxy, n-hexoxy, and the like.
As used herein, the term "acyl" refers to a carbonyl-containing functionality,
e.g.,
-C(0)R, wherein R is hydrogen or an optionally substituted aliphatic,
heteroaliphatic,
heterocyclic, aryl, heteroaryl group, or is a substituted (e.g. , with
hydrogen or aliphatic,
heteroaliphatic, aryl, or heteroaryl moieties) oxygen or nitrogen containing
functionality
(e.g. , forming a carboxylic acid, ester, or amide functionality). Examples of
the "acyl"
group include but not limited to a formyl group, a carboxy group, a C1-6 alkyl-
carbonyl group,
a C2-6 alkenyl-carbonyl group (e.g., acryloyl), a C3-10 cycloalkyl-carbonyl
group (e.g.,
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cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,
cycloheptanecarbonyl), a
C310cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), a C6_14 aryl-
carbonyl group,
a C7-16 aralkyl-carbonyl group, a 5- to 14-membered heteroaryl-carbonyl group,
a 3- to
14-membered heterocyclyl-carbonyl group (e.g., piperzyl-carbonyl), a C1-6
alkoxy-carbonyl
group, a C6-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl,
naphthyloxycarbonyl), a
C7_16aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,
phenethyloxycarbonyl), a
carbamoyl group, a mono- or di-C1-6 alkyl-carbamoyl group, a mono- or di-C2-6
alkenyl-carbamoyl group (e.g., diallylcarbamoyl), a mono- or di-C3-10
cycloalkyl-carbamoyl
group (e.g., cyclopropylcarbamoyl), a mono- or di-C6_14 aryl-carbamoyl group
(e.g.,
phenylcarbamoyl), a mono- or di-C7_16 aralkyl-carbamoyl group, a 5- to 14-
membered
aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl), a thiocarbamoyl
group, and
the like. As used herein, the term "acyloxy" refers to an acyl group attached
to the parent
molecule through an oxygen atom.
As used herein, the term "amino" or "amine" refers to moieties where a
nitrogen atom is
covalently bonded to at least one carbon or heteroatom. "Alkylamino" includes
groups of
compounds wherein nitrogen is bound to at least one alkyl group. Examples of
alkylamino
groups include benzylamino, methylamino, ethylamino, phenethylamino, etc.
"Dialkylamino" includes groups wherein the nitrogen atom is bound to at least
two additional
alkyl groups. Examples of dialkylamino groups include, but are not limited to,
dimethylamino and diethylamino. "Arylamino" and "diarylamino" include groups
wherein
the nitrogen is bound to at least one or two aryl groups, respectively.
"Alkylarylamino",
"alkylaminoaryl" or "arylaminoalkyl" refers to an amino group which is bound
to at least one
alkyl group and at least one aryl group. "Alkaminoalkyl" refers to an alkyl,
alkenyl, or
alkynyl group bound to a nitrogen atom which is also bound to an alkyl group.
"Acylamino"
includes groups wherein nitrogen is bound to an acyl group. Examples of
acylamino
include, but are not limited to, alkylcarbonylamino, arylcarbonylamino,
carbamoyl and
ureido groups.
As used herein, the term "amide" or "aminocarboxy" refers to compounds or
moieties
that contain a nitrogen atom that is bound to the carbon of a carbonyl or a
thiocarbonyl group.
The term includes "alkaminocarboxy" groups that include alkyl, alkenyl or
alkynyl groups
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bound to an amino group which is bound to the carbon of a carbonyl or
thiocarbonyl group.
It also includes "arylaminocarboxy" groups that include aryl or heteroaryl
moieties bound to
an amino group that is bound to the carbon of a carbonyl or thiocarbonyl
group. The terms
"alkylaminocarboxy", "alkenylaminocarboxy", "alkynylaminocarboxy" and
"arylaminocarboxy" include moieties wherein alkyl, alkenyl, alkynyl and aryl
moieties,
respectively, are bound to a nitrogen atom which is in turn bound to the
carbon of a carbonyl
group. Amides can be substituted with substituents such as straight chain
alkyl, branched
alkyl, cycloalkyl, aryl, heteroaryl or heterocycle. Substituents on amide
groups may be
further substituted.
As used herein, the term "aryl", whether as part of another term or used
independently,
refers to monocyclic and polycyclic ring systems having a total of 5 to 20
ring members,
wherein at least one ring in the system is aromatic and wherein each ring in
the system
contains 3 to 12 ring members. Examples of "aryl" include, but are not limited
to, phenyl,
biphenyl, naphthyl, anthracyl and the like, which may bear one or more
substituents. Also
included within the scope of the term "aryl", as it is used herein, is a group
in which an
aromatic ring is fused to one or more additional rings. In the case of
polycyclic ring system,
only one of the rings needs to be aromatic (e.g., 2,3-dihydroindole), although
all of the rings
may be aromatic (e.g., quinoline). The second ring can also be fused or
bridged. Examples
of polycyclic aryl include, but are not limited to, benzofuranyl, indanyl,
phthalimidyl,
naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. Aryl
groups can be
substituted at one or more ring positions with substituents as described
above.
As used herein, the term "arylalkyl", whether as part of another term or used
independently, means an alkyl moiety substituted with one or more aryl moiety.
Examples of
arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, and
the like.
As used herein, the term "azido", whether as part of another term or used
independently,
refers to ¨N3 group.
As used herein, the term "carboxy", whether as part of another term or used
independently, refers to a group represented by formula ¨COOH.
As used herein, the term "carbamoyl", whether as part of another term or used
independently, refers to aminocarbonyl group as defined above. Examples of "N-
(C112
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alkyl)carbamoyl" include, but are not limited to, methylaminocarbonyl and
ethylaminocarbonyl. Examples of "N,N-(C 1-12 alky1)2carbamoyl" include, but
are not
limited to, dimethylaminocarbonyl and methylethylaminocarbonyl.
As used herein, the terms "cycloalkyl", "carbocycly1" and "carbocycle" are
interchangeable and whether as part of another term or used independently,
refer to a
monovalent non-aromatic, saturated or partially unsaturated monocyclic and
polycyclic ring
system, in which all the ring atoms are carbon and which contains at least
three ring forming
carbon atoms. In some embodiments, the cycloalkyl may contain 3 to 12 ring
forming
carbon atoms, 3 to 10 ring forming carbon atoms, 3 to 9 ring forming carbon
atoms, 3 to 8
ring forming carbon atoms, 3 to 7 ring forming carbon atoms, 3 to 6 ring
forming carbon
atoms, 3 to 5 ring forming carbon atoms, 4 to 12 ring forming carbon atoms, 4
to 10 ring
forming carbon atoms, 4 to 9 ring forming carbon atoms, 4 to 8 ring forming
carbon atoms, 4
to 7 ring forming carbon atoms, 4 to 6 ring forming carbon atoms, 4 to 5 ring
forming carbon
atoms. Cycloalkyl groups may be saturated or partially unsaturated. Cycloalkyl
groups may
be substituted. In some embodiments, the cycloalkyl group may be a saturated
cyclic alkyl
group. In some embodiments, the cycloalkyl group may be a partially
unsaturated cyclic
alkyl group that contains at least one double bond or triple bond in its ring
system.
In some embodiments, the cycloalkyl group may be saturated or partially
unsaturated
monocyclic carbocyclic ring system, examples of which include, but are not
limited to,
cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,
1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-
cyclohex-3-enyl,
cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl
and
cyclododecyl.
In some embodiments, the cycloalkyl group may be saturated or partially
unsaturated
polycyclic (e.g., bicyclic and tricyclic) carbocyclic ring system, which can
be arranged as a
fused, spiro or bridged ring system. As used herein, the term "fused ring"
refers to a ring
system having two rings sharing two adjacent atoms, the term "spiro ring"
refers to a ring
systems having two rings connected through one single common atom, and the
term "bridged
ring" refers to a ring system with two rings sharing three or more atoms.
Examples of fused
carbocyclyl include, but are not limited to, naphthyl, benzopyrenyl,
anthracenyl,
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acenaphthenyl, fluorenyl and the like. Examples of spirocarbocyclyl include,
but are not
limited to, spiro[5.5]undecanyl, spiro-pentadienyl, spiro[3.6]-decanyl, and
the like. Examples
of bridged carbocyclyl include, but are not limited to bicyclo[1,1,1]pentenyl,
bicyclo[2,2,1]heptenyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl,
bicyclo[3.3.1]nonanyl,
bicyclo[3.3.3]undecanyl, and the like.
As used herein, the term "cycloalkylalkyl" means an alkyl moiety substituted
with a
cycloalkyl moiety. Examples of cycloalkylalkyl include, for example, 5- or 6-
membered
cycloalkyl-C1_3 alkyl, such as, but not limited to, cyclopropylmethyl.
As used herein, the term "cyano" refers to ¨CN.
As used herein, the term "halo" or "halogen" refers to an atom selected from
fluorine (or
fluoro), chlorine (or chloro), bromine (or bromo) and iodine (or iodo).
As used herein, the term "haloalkyl" refers to an alkyl group substituted with
one or
more halogen atoms.
As used herein, the term "haloalkoxy" or "haloalkoxyl" refers to an alkoxyl
group
substituted with one or more halogen atoms.
As used herein, the term "heteroalkyl" refers to an alkyl, at least one of the
carbon
atoms of which is replaced with a heteroatom selected from N, 0, or S. The
heteroalkyl
may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear
in the middle
or at the end of the radical), and may be optionally substituted independently
with one or
more substituents described herein. The term "heteroalkyl" encompasses alkoxy
and
heteroalkoxy radicals.
As used herein, the term "heteroalkenyl" refers to an alkenyl, at least one of
the carbon
atoms of which is replaced with a heteroatom selected from N, 0, or S. The
heteroalkenyl
may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear
in the middle
or at the end of the radical), and may be optionally substituted independently
with one or
more substituents described herein.
As used herein, the term "heteroalkynyl" refers to an alkynyl, at least one of
the carbon
atoms of which is replaced with a heteroatom selected from N, 0, or S. The
heteroalkynyl
may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear
in the middle
or at the end of the radical), and may be optionally substituted independently
with one or
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more substituents described herein.
As used herein, the term "heteroatom" refers to nitrogen, oxygen, or sulfur,
and includes
any oxidized form of nitrogen or sulfur, and any quaternized form of a basic
nitrogen.
As used herein, the term "heteroaryl", whether as part of another term or used
independently, refers to an aryl group having, in addition to carbon atoms,
one or more
heteroatoms. Examples of heteroaryl include, but are not limited to, thienyl,
furanyl,
pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
oxadiazolyl,
thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, indolizinyl,
purinyl, naphthyridinyl, benzofuranyl and pteridinyl. The heteroaryl also
includes groups in
which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or
heterocyclyl rings,
where the radical or point of attachment is on the heteroaromatic ring. Non-
limiting
examples include indolyl, isoindolyl, benzothienyl, benzofuranyl,
dibenzofuranyl, indazolyl,
benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl,
phthalazinyl, quinazolinyl,
quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl,
phenothiazinyl,
phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and
pyrido[2,3-b]-1 ,4-oxazin-3(4H)-one. In some embodiments, the term "5- to 10-
membered
heteroaryl" refers to a 5-to 6-membered heteroaryl ring having 1 to 3
heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-
membered bicyclic
heteroaryl ring having 1 to 4 heteroatoms independently selected from
nitrogen, oxygen, or
sulfur. In certain embodiments, the term "5- to 12-membered heteroaryl" refers
to a 5- to
6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected
from nitrogen,
oxygen, or sulfur, or an 8- to 12-membered bicyclic heteroaryl ring having 1
to 4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur.
As used herein, the term "heterocycle" or "heterocyclyl" refers to a saturated
or
unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms
independently selected from oxygen, sulfur, nitrogen, phosphorus, and the
like, the remaining
ring atoms being carbon, wherein one or more ring atoms may be optionally
substituted
independently with one or more substituents. In some embodiments, the
heterocyclyl is a
saturated heterocyclyl. In some embodiments, the heterocyclyl is a partially
unsaturated
heterocyclyl having one or more double bonds in its ring system. In some
embodiments, the
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heterocyclyl may contains any oxidized form of carbon, nitrogen or sulfur, and
any
quaternized form of a basic nitrogen. "Heterocycly1" also includes radicals
wherein the
heterocyclyl radicals are fused with a saturated, partially unsaturated, or
fully unsaturated
(i.e., aromatic) carbocyclic or heterocyclic ring. The heterocyclyl radical
may be carbon
linked or nitrogen linked where such is possible. In some embodiments, the
heterocycle is
carbon linked. In some embodiments, the heterocycle is nitrogen linked. For
example, a
group derived from pyrrole may be pyrrol-1-y1 (nitrogen linked) or pyrrol-3-y1
(carbon
linked). Further, a group derived from imidazole may be imidazol-1-y1
(nitrogen linked) or
imidazol-3-y1 (carbon linked).
In some embodiments, the term "3- to 12-membered heterocyclyl" refers to a 3-
to
12-membered saturated or partially unsaturated monocyclic or polycyclic
heterocyclic ring
system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen,
or sulfur.
The fused, spiro and bridged ring systems are also included within the scope
of this
definition. Examples of monocyclic heterocyclyl include, but are not limited
to oxetanyl,
1,1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolyl,
furanyl, thienyl,
pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl,
morpholinyl,
pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl,
pyrimidonyl, pyrazinonyl,
pyrimidonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like. Examples of
fused
heterocyclyl include, but are not limited to, phenyl fused ring or pyridinyl
fused ring, such as
quinolinyl, isoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl,
azaindolizinyl, pteridinyl,
chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl,
benzofuranyl,
isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl,
phenazinyl,
phenothiazinyl, phenanthridinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-
a]pyridinyl,
[1,2,3]triazolo[4,3-a]pyridinyl groups, and the like. Examples of
spiroheterocyclyl include,
but are not limited to, spiropyranyl, spirooxazinyl, and the like. Examples of
bridged
heterocyclyl include, but are not limited to, morphanyl,
hexamethylenetetraminyl,
3-aza-bicyclo[3.1.0]hexane, 8-aza-bicyclo[3.2.1]octane, 1-aza-
bicyclo[2.2.2]octane,
1,4-diazabicyclo[2.2.2]octane (DABCO), and the like.
As used herein, the term "heteroarylalkyl" means an alkyl moiety substituted
with a
heteroaryl moiety. Examples of heteroarylalkyl include 5- or 6-membered
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heteroaryl-C1_3alkyl such as, but not limited to, oxazolylmethyl, pyridylethyl
and the like.
As used herein, the term "heterocyclylalkyl" means an alkyl moiety substituted
with a
heterocyclyl moiety. Examples of heterocyclylalkyl radicals include 5- or 6-
membered
heterocyclyl-C1_3alkyls such as, but not limited to, tetrahydropyranylmethyl.
As used herein, the term "hydroxy" refers to ¨OH group.
As used herein, the term "nitro" refers to ¨NO2 group.
As used herein, the term "partially unsaturated" refers to a radical that
includes at least
one double or triple bond. The term "partially unsaturated" is intended to
encompass rings
having multiple sites of unsaturation, but is not intended to include aromatic
(i.e., fully
unsaturated) moieties.
As used herein, the term "substituted", whether preceded by the term
"optionally" or not,
means that one or more hydrogens of the designated moiety are replaced with a
suitable
substituent. It will be understood that "substitution" or "substituted with"
includes the
implicit proviso that such substitution is in accordance with permitted
valence of the
substituted atom and that the substitution results in a stable or chemically
feasible compound,
e.g., which does not spontaneously undergo transformation such as by
rearrangement,
cyclization, elimination, etc. Unless otherwise indicated, an "optionally
substituted" group
may have a suitable substituent at each substitutable position of the group,
and when more
than one position in any given structure may be substituted with more than one
substituent
selected from a specified group, the substituent may be either the same or
different at every
position. It will be understood by those skilled in the art that substituents
can themselves be
substituted, if appropriate. Unless specifically stated as "unsubstituted",
references to
chemical moieties herein are understood to include substituted variants. For
example,
reference to an "aryl" group or moiety implicitly includes both substituted
and unsubstituted
variants.
When a bond to a substituent is shown to cross a bond connecting two atoms in
a ring,
then such substituent may be bonded to any atom in the ring. When a
substituent is listed
without indicating the atom via which such substituent is bonded to the rest
of the compound
of a given formula, then such substituent may be bonded via any atom in such
formula.
Combinations of substituents and/or variables are permissible, but only if
such combinations
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result in stable compounds.
When any variable (e.g., Ri) occurs more than one time in any constituent or
formula for
a compound, its definition at each occurrence is independent of its definition
at every other
occurrence. Thus, for example, if a group is shown to be substituted with 0-2
Ri moieties,
then the group may optionally be substituted with up to two Ri moieties and Ri
at each
occurrence is selected independently from the definition of Ri. Also,
combinations of
substituents and/or variables are permissible, but only if such combinations
result in stable
compounds.
COMPOUNDS
The present disclosure provides compounds of Formula (I), Formula (II),
Formula (III)
and solvates, hydrates, stereoisomers, and pharmaceutically salts or esters
thereof, synthetic
methods for making the compounds, pharmaceutical compositions containing them
and
various uses of the disclosed compounds.
In one aspect, the present disclosure provides a compound of Formula (I):
(R4) n1
õ..X2 E
X
ir A
R3 >
R2 X5 X6 N
L HN X4 X7
(R1) ii I
n N
(I)
or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester
thereof, wherein:
G is C(R5) or N;
A is CH or N;
B is CH or N;
D is CH of N;
Xi, X2, X3, X4, X5, X6, and X7 are each independently CH or N;
E is 0, NH, or S;
L is selected from the group consisting of 0, C(=0), S, SO, SO2 and N(R6);
Ri is selected from the group consisting of hydrogen, halogen, cyano, nitro,
amino,
hydroxyl, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl,
heteroalkenyl,
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heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or
partially unsaturated
heterocyclyl, aryl, N(R7)(R8), and 0(R9), wherein said cycloalkyl and
heterocyclyl are
optionally substituted with one or more groups independently selected from the
group
consisting of halogen, cyano, nitro, hydroxyl, carboxy, carbamoyl, acyl,
alkyl, alkenyl,
alkynyl, alkyl-OH and haloalkyl;
R2 is selected from the group consisting of alkyl, saturated or partially
unsaturated
cycloalkyl, saturated or partially unsaturated heterocyclyl, wherein said
alkyl, cycloalkyl, and
heterocyclyl are optionally substituted with one or more groups independently
selected from
the group consisting of halogen, cyano, nitro, hydroxyl, alkyl-OH, carboxy,
carbamoyl, alkyl,
alkenyl, alkynyl, haloalkyl, saturated or partially unsaturated cycloalkyl,
and N(Rio)(Rii);
R6 is hydrogen or alkyl; or
when L is N(R), R2 and R6 together with the nitrogen atom to which they are
attached
form a 3 to 10 membered saturated or partially unsaturated heterocyclyl ring
optionally
containing one or more additional heteroatoms selected from N, 0 and S,
wherein said 3 to
membered heterocyclyl ring is optionally substituted with one or more groups
independently selected from the group consisting of halogen, cyano, nitro,
carboxy,
carbamoyl, alkyl, alkenyl, alkynyl, haloalkyl, saturated and partially
unsaturated cycloalkyl,
and N(Rio)(Ril);
R3 and R4 are each independently selected from the group consisting of
hydrogen,
halogen, cyano, amino, hydroxyl, nitro, alkyl, alkenyl, alkynyl, alkyl-OH,
haloalkyl and
alkoxyl;
R5 is selected from the group consisting of hydrogen, halogen and cyano;
R7 and R8 are each independently selected from the group consisting of
hydrogen, alkyl,
alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, acyl,
saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated heterocyclyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or
heterocyclylalkyl, wherein said
alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocyclyl,
cycloalkylalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl are
optionally substituted
with one or more groups independently selected from the group consisting of
alkyl, alkenyl,
alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkylamino, saturated and
partially
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unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl
optionally substituted
by alkyl, aryl, and heteroaryl; or
R7 and R8 together with the atom to which they are attached form a 3 to 10
membered
saturated or partially unsaturated heterocyclyl ring optionally containing one
or more
additional heteroatoms selected from N, 0, S, SO, SO2 and NR12, wherein said
heterocyclyl
ring is optionally substituted with one or more groups independently selected
from the group
consisting of oxo, halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl,
saturated and
partially unsaturated cycloalkyl, saturated and partially unsaturated
heterocyclyl,
cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl,
arylalkyl,
heteroarylalkyl, and heterocyclylalkyl;
R9 is selected from the group consisting of alkyl, alkyl-OH, haloalkyl,
alkenyl, alkynyl,
acyl, saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated
heterocyclyl, wherein said alkyl, alkenyl, alkynyl, acyl, cycloalkyl,
heterocyclyl are
optionally substituted by one or more groups independently selected from the
group
consisting of halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, alkoxyl,
acyl, saturated
and partially unsaturated cycloalkyl, saturated and partially unsaturated
heterocyclyl,
cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl,
arylalkyl,
heteroarylalkyl, and heterocyclylalkyl;
Rio and Rii are each independently selected from the group consisting of
hydrogen,
alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl,
saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated heterocyclyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or
heterocyclylalkyl, wherein said
alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,
cycloalkylalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl are optionally
substituted with
one or more groups independently selected from alkyl, alkyl-OH, haloalkyl,
alkenyl, alkynyl,
heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partially unsaturated
cycloalkyl,
saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl; or
Rio and Rii together with the atom to which they are attached form a 3 to 10
membered
saturated or partially unsaturated heterocyclyl ring optionally containing one
or more
additional heteroatoms selected from N, 0, S, SO, SO2 and NR12, wherein said
heterocyclyl
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ring is optionally substituted with one or more groups independently selected
from the group
consisting of oxo, halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl,
saturated and
partially unsaturated cycloalkyl, saturated and partially unsaturated
heterocyclyl,
cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl,
arylalkyl,
heteroarylalkyl, and heterocyclylalkyl;
R12 is selected from the group consisting of hydrogen, alkyl, alkyl-OH,
haloalkyl,
saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated heterocyclyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl, wherein
said alkyl, alkyl-OH,
haloalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, and
heterocyclylalkyl are optionally substituted with one or more groups
independently selected
from halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, saturated and
partially
unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl,
cycloalkylalkyl,
cyano, nitro, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and
heterocyclylalkyl;
n is 0, 1 or 2;
n1 is 0, 1 or 2.
In some embodiments according to Formula (I), at least one of Xi, X6 and X7 is
N.
In another aspect, the present disclosure provides compounds of Formula (II):
(R4)ni
,x2 E N\
Ii N
A
R2 X5 X6
L HN X4 X7
\
( R1) II
n NA
(II)
or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester
thereof, wherein:
G is C(R5) or N;
M is CH or N;
A is CH or N;
B is CH or N;
D is CH of N;
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Xi, X2, X3, X4, X5, X6, and X7 are each independently CH or N, with the
proviso that
when M is CH, at least one of Xi, X6 and X7 is N;
E is 0, NH, or S;
L is selected from the group consisting of 0, C(=0), S, SO, SO2 and N(R6);
Ri is selected from the group consisting of hydrogen, halogen, cyano, nitro,
amino,
hydroxyl, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl,
heteroalkenyl,
heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or
partially unsaturated
heterocyclyl, aryl, N(R7)(R8), and 0(R9), wherein said cycloalkyl and
heterocyclyl are
optionally substituted with one or more groups independently selected from the
group
consisting of halogen, cyano, nitro, hydroxyl, carboxy, carbamoyl, acyl,
alkyl, alkenyl,
alkynyl, alkyl-OH and haloalkyl;
R2 is selected from the group consisting of alkyl, saturated or partially
unsaturated
cycloalkyl, saturated or partially unsaturated heterocyclyl, wherein said
alkyl, cycloalkyl, and
heterocyclyl are optionally substituted with one or more groups independently
selected from
the group consisting of halogen, cyano, nitro, hydroxyl, alkyl-OH, carboxy,
carbamoyl, alkyl,
alkenyl, alkynyl, haloalkyl, saturated or partially unsaturated cycloalkyl,
and N(Rio)(Ri 1);
R6 is hydrogen or alkyl; or
when L is N(R6), R2 and R6 together with the nitrogen atom to which they are
attached
form a 3 to 10 membered saturated or partially unsaturated heterocyclyl ring
optionally
containing one or more additional heteroatoms selected from N, 0 and S,
wherein said 3 to
membered heterocyclyl ring is optionally substituted with one or more groups
independently selected from the group consisting of halogen, cyano, nitro,
carboxy,
carbamoyl, alkyl, alkenyl, alkynyl, haloalkyl, saturated and partially
unsaturated cycloalkyl,
and N(Rio)(Ri 1);
R3 and R4 are each independently selected from the group consisting of
hydrogen,
halogen, cyano, amino, hydroxyl, nitro, alkyl, alkenyl, alkynyl, alkyl-OH,
haloalkyl and
alkoxyl;
R5 is selected from the group consisting of hydrogen, halogen and cyano;
R7 and Rs are each independently selected from the group consisting of
hydrogen, alkyl,
alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, acyl,
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saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated heterocyclyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or
heterocyclylalkyl, wherein said
alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocyclyl,
cycloalkylalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl are
optionally substituted
with one or more groups independently selected from the group consisting of
alkyl, alkenyl,
alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkylamino, saturated and
partially
unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl
optionally substituted
by alkyl, aryl, and heteroaryl; or
R7 and Rs together with the atom to which they are attached form a 3 to 10
membered
saturated or partially unsaturated heterocyclyl ring optionally containing one
or more
additional heteroatoms selected from N, 0, S, SO, SO2 and NR12, wherein said
heterocyclyl
ring is optionally substituted with one or more groups independently selected
from the group
consisting of oxo, halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl,
saturated and
partially unsaturated cycloalkyl, saturated and partially unsaturated
heterocyclyl,
cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl,
arylalkyl,
heteroarylalkyl, and heterocyclylalkyl;
R9 is selected from the group consisting of alkyl, alkyl-OH, haloalkyl,
alkenyl, alkynyl,
acyl, saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated
heterocyclyl, wherein said alkyl, alkenyl, alkynyl, acyl, cycloalkyl,
heterocyclyl are
optionally substituted by one or more groups independently selected from the
group
consisting of halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, alkoxyl,
acyl, saturated
and partially unsaturated cycloalkyl, saturated and partially unsaturated
heterocyclyl,
cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl,
arylalkyl,
heteroarylalkyl, and heterocyclylalkyl;
Rio and Rii are each independently selected from the group consisting of
hydrogen,
alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl,
saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated heterocyclyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or
heterocyclylalkyl, wherein said
alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,
cycloalkylalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl are optionally
substituted with
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one or more groups independently selected from alkyl, alkyl-OH, haloalkyl,
alkenyl, alkynyl,
heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partially unsaturated
cycloalkyl,
saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl; or
Rio and Rii together with the atom to which they are attached form a 3 to 10
membered
saturated or partially unsaturated heterocyclyl ring optionally containing one
or more
additional heteroatoms selected from N, 0, S, SO, SO2 and NR12, wherein said
heterocyclyl
ring is optionally substituted with one or more groups independently selected
from the group
consisting of oxo, halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl,
saturated and
partially unsaturated cycloalkyl, saturated and partially unsaturated
heterocyclyl,
cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl,
arylalkyl,
heteroarylalkyl, and heterocyclylalkyl;
R12 is selected from the group consisting of hydrogen, alkyl, alkyl-OH,
haloalkyl,
saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated heterocyclyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl, wherein
said alkyl, alkyl-OH,
haloalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, and
heterocyclylalkyl are optionally substituted with one or more groups
independently selected
from halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, saturated and
partially
unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl,
cycloalkylalkyl,
cyano, nitro, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and
heterocyclylalkyl;
n is 0, 1 or 2;
n1 is 0, 1 or 2.
In some embodiments of the compounds according to Formula (II), at least one
of Xi,
X6 and X7 is N. In some embodiments, X7 is N, and at least one of Xi and X6 is
N. In some
embodiments, M is N, X7 is N, and at least one of Xi and X6 is N.
In another aspect, the present disclosure provides compounds of Formula (III):
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z X2 E
X
R2.N.
L HN X4
Ri)
n NA
(III)
or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester
thereof, wherein:
Ri is selected from the group consisting of hydrogen, halogen, cyano, nitro,
amino,
hydroxyl, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl,
heteroalkenyl,
heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or
partially unsaturated
heterocyclyl, aryl, N(R7)(R8), and 0(R9), wherein said cycloalkyl and
heterocyclyl are
optionally substituted with one or more groups independently selected from the
group
consisting of halogen, cyano, nitro, hydroxyl, carboxy, carbamoyl, acyl,
alkyl, alkenyl,
alkynyl, alkyl-OH and haloalkyl;
G is C(R5) or N;
M is CH or N;
A is CH or N;
B is CH or N;
D is CH of N;
X2, X3, X4, X5, are each independently CH or N;
E is 0, NH, or S;
Y is a bicyclic aryl formed by:
(a) Y1 fused with Y2, wherein Y1 is a 6-membered heteroaryl, and Y2 is a
6-membered aryl or heteroaryl, or
(b) Y3 fused with Y4, wherein Y3 is a 5-membered aryl or heteroaryl, and Y4 is
a
5-membered aryl or heteroaryl, or
(c) Y5 fused with Y6, wherein Y5 is a 5-membered aryl or heteroaryl, and Y6 is
a
6-membered aryl or heteroaryl, wherein one of the ring-forming carbon of Y5 is
directly bonded to E;
wherein each of Yi, Y2, Y3, Y4, Y5, and Y6 is optionally substituted by one or
more of
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groups each independently having the same definition as Ri;
L is selected from the group consisting of 0, C(=0), S, SO, SO2 and N(R6);
R2 is selected from the group consisting of alkyl, saturated or partially
unsaturated
cycloalkyl, saturated or partially unsaturated heterocyclyl, wherein said
alkyl, cycloalkyl, and
heterocyclyl are optionally substituted with one or more groups independently
selected from
the group consisting of halogen, cyano, nitro, hydroxyl, alkyl-OH, carboxy,
carbamoyl, alkyl,
alkenyl, alkynyl, haloalkyl, saturated or partially unsaturated cycloalkyl,
and N(Rio)(Rii);
R6 is hydrogen or alkyl; or
when L is N(R6), R2 and R6 together with the nitrogen atom to which they are
attached
form a 3 to 10 membered saturated or partially unsaturated heterocyclyl ring
optionally
containing one or more additional heteroatoms selected from N, 0 and S,
wherein said 3 to
membered heterocyclyl ring is optionally substituted with one or more groups
independently selected from the group consisting of halogen, cyano, nitro,
carboxy,
carbamoyl, alkyl, alkenyl, alkynyl, haloalkyl, saturated and partially
unsaturated cycloalkyl,
and N(Rio)(Ri 1);
R3 and R4 are each independently selected from the group consisting of
hydrogen,
halogen, cyano, amino, hydroxyl, nitro, alkyl, alkenyl, alkynyl, alkyl-OH,
haloalkyl and
alkoxyl;
R5 is selected from the group consisting of hydrogen, halogen and cyano;
R7 and Rs are each independently selected from the group consisting of
hydrogen, alkyl,
alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, acyl,
saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated heterocyclyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or
heterocyclylalkyl, wherein said
alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocyclyl,
cycloalkylalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl are
optionally substituted
with one or more groups independently selected from the group consisting of
alkyl, alkenyl,
alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkylamino, saturated and
partially
unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl
optionally substituted
by alkyl, aryl, and heteroaryl; or
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R7 and R8 together with the atom to which they are attached form a 3 to 10
membered
saturated or partially unsaturated heterocyclyl ring optionally containing one
or more
additional heteroatoms selected from N, 0, S, SO, SO2 and NR12, wherein said
heterocyclyl
ring is optionally substituted with one or more groups independently selected
from the group
consisting of oxo, halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl,
saturated and
partially unsaturated cycloalkyl, saturated and partially unsaturated
heterocyclyl,
cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl,
arylalkyl,
heteroarylalkyl, and heterocyclylalkyl;
R9 is selected from the group consisting of alkyl, alkyl-OH, haloalkyl,
alkenyl, alkynyl,
acyl, saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated
heterocyclyl, wherein said alkyl, alkenyl, alkynyl, acyl, cycloalkyl,
heterocyclyl are
optionally substituted by one or more groups independently selected from the
group
consisting of halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, alkoxyl,
acyl, saturated
and partially unsaturated cycloalkyl, saturated and partially unsaturated
heterocyclyl,
cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl,
arylalkyl,
heteroarylalkyl, and heterocyclylalkyl;
Rio and Rii are each independently selected from the group consisting of
hydrogen,
alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl,
saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated heterocyclyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or
heterocyclylalkyl, wherein said
alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,
cycloalkylalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl are optionally
substituted with
one or more groups independently selected from alkyl, alkyl-OH, haloalkyl,
alkenyl, alkynyl,
heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partially unsaturated
cycloalkyl,
saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl; or
Rio and Rii together with the atom to which they are attached form a 3 to 10
membered
saturated or partially unsaturated heterocyclyl ring optionally containing one
or more
additional heteroatoms selected from N, 0, S, SO, SO2 and NR12, wherein said
heterocyclyl
ring is optionally substituted with one or more groups independently selected
from the group
consisting of oxo, halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl,
saturated and
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partially unsaturated cycloalkyl, saturated and partially unsaturated
heterocyclyl,
cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl,
arylalkyl,
heteroarylalkyl, and heterocyclylalkyl;
R12 is selected from the group consisting of hydrogen, alkyl, alkyl-OH,
haloalkyl,
saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated heterocyclyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl, wherein
said alkyl, alkyl-OH,
haloalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, and
heterocyclylalkyl are optionally substituted with one or more groups
independently selected
from halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, saturated and
partially
unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl,
cycloalkylalkyl,
cyano, nitro, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and
heterocyclylalkyl;
n is 0, 1 or 2;
n1 is 0, 1 or 2.
The following description of embodiments applies to compounds of any of
Formula (I),
Formula (II), and Formula (III), unless otherwise specifically indicated.
In some embodiments, each of X2, X3, X4, and X5 is CH.
In some embodiments, Xi is CH.
In some embodiments, Xi is N.
In some embodiments of compounds of Formula (I), one of X6 and X7 is CH, and
the
other is N. In some embodiments of compounds of Formula (II), one of X6 and X7
is CH, and
the other is N.
In some embodiments, Ri is selected from hydrogen, N(R7)(R8), 0(R9), or
saturated or
partially unsaturated hetercyclyl optionally substituted by acyl.
In some embodiments, Ri is N(R7)(R8), and R7 and Rs are each independently
selected
from hydrogen, alkyl, alkyl-OH, haloalkyl, acyl, saturated or partially
unsaturated cycloalkyl,
saturated or partially unsaturated heterocyclyl, wherein said alkyl, alkyl-OH,
haloalkyl, acyl
cycloalkyl, and heterocyclyl are optionally substituted with one or more
groups
independently selected from alkyl, alkenyl, alkynyl, heteroalkyl,
heteroalkenyl, heteroalkynyl,
alkylamino, saturated and partially unsaturated cycloalkyl, saturated and
partially unsaturated
heterocyclyl optionally substituted by alkyl, aryl, and heteroaryl.
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In some embodiments, Ri is N(R7)(R8), R7 is hydrogen, and R8 is saturated or
partially
unsaturated cycloalkyl substituted by alkyl.
In some embodiments, Ri is N(R7)(R8), R7 is hydrogen, and R8 is
4,4-dimethy1-4,5-dihydrooxazol-2-yl.
In some embodiments, Ri is N(R7)(R8), R7 is hydrogen, and R8 is acyl
substituted by
alkylamino or saturated and partially unsaturated heterocyclyl substituted by
alkyl.
In some embodiments, Ri is N(R7)(R8), R7 is hydrogen, and Rs
is(dimethyamino)but-2-ene-carbonyl or (1-methyl-pyrrolidin-2-y1)-acryloyl.
In some embodiments, Ri is 0(R9), and R9 is selected from the group consisting
of alkyl,
acyl, saturated or partially unsaturated cycloalkyl, saturated or partially
unsaturated
heterocyclyl, wherein said alkyl, cycloalkyl, and heterocyclyl are optionally
substituted by
one or more groups independently selected from the group consisting of
halogen, alkyl,
alkenyl, alkynyl, acyl, and alkoxyl.
In some embodiments, Ri is 0(R9), and R9 is selected from the group consisting
of
C1_6a1ky1, C1-6 acy1,3 to 6 membered saturated or partially unsaturated
cycloalkyl, 3 to 6
membered saturated or partially unsaturated heterocyclyl, wherein said alkyl,
acyl, cycloalkyl,
and heterocyclyl are optionally substituted by one or more groups
independently selected
from halogen, alkyl, or alkoxyl.
In some embodiments, Ri is 0(R9), and R9 is selected from methyl, ethyl,
isopropyl,
piperazinylcarbonyl, cyclopropyl, or tetrahydrofuranyl, each of which is
optionally
substituted by one or more fluor or methyl.
In some embodiments, Ri is partially unsaturated hetercyclyl optionally
substituted by
acyl. In some embodiments, Ri is partially unsaturated hetercyclyl substituted
by acryloyl.
In some embodiments, Ri is tetrahydropyridyl substituted by acryloyl.
In some embodiments, Ri is 0(R9), R9 is selected from the group consisting of
Ci_6 alkyl,
3 to 6 membered saturated or partially unsaturated cycloalkyl, 3 to 6 membered
saturated or
partially unsaturated heterocyclyl, wherein said alkyl, cycloalkyl, and
heterocyclyl are
optionally substituted by one or more groups independently selected from
halogen, alkyl, or
alkoxyl, L is 0, and R2 is selected from saturated or partially unsaturated
cycloalkyl and
saturated or partially unsaturated heterocyclyl, wherein said cycloalkyl and
heterocyclyl are
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optionally substituted with one or more groups independently selected from the
group
consisting of halogen, alkyl, saturated or partially unsaturated cycloalkyl,
and N(Rio)(Rii).
In certain embodiments, Ri is 0(R9), R9 is C1-6 alkyl, L is 0, and R2 is
selected from C4-6
saturated cycloalkyl or 5 to 6 membered saturated heterocyclyl, wherein said
C4-6 saturated
cycloalkyl and 5 to 6 membered saturated heterocyclyl are optionally
substituted with one or
more groups independently selected from the group consisting of halogen,
alkyl, saturated or
partially unsaturated cycloalkyl, and N(Rio)(Rii).
In some embodiments, R2 is optionally substituted with one or more of groups
selected
from methyl, fluoro, cyclopropyl and dimethylamino. In certain embodiments, R2
is
substituted with one or more methyl groups. In certain embodiments, R2 is
substituted with
one or more fluoro groups. In certain embodiments, R2 is substituted with one
or more
cyclopropyl groups. In certain embodiments, R2 is substituted with one or more
dimethylamino groups. In certain embodiments, R2 is substituted with one or
more methyl
groups and one or more fluoro groups.
In some embodiments, L is N(R6), and R2 and R6 together with the nitrogen atom
to
which they are attached form a 3 to 10 membered saturated or partially
unsaturated
heterocyclyl ring optionally containing one or more additional heteroatoms
selected from N,
0 and S, wherein said 3 to 10 membered heterocyclyl ring is optionally
substituted with one
or more groups independently selected from the group consisting of halogen,
cyano, nitro,
carboxy, carbamoyl, alkyl, alkenyl, alkynyl, haloalkyl, saturated and
partially unsaturated
cycloalkyl, and N(Rio)(Rii).
In some embodiments, L is N(R6), and R2 and R6 together with the nitrogen atom
to
which they are attached form a 4 to 9 membered saturated heterocyclyl ring
optionally
containing one or more additional heteroatoms selected from N, 0 and S,
wherein said 4 to 9
membered saturated heterocyclyl ring is optionally substituted with one or
more groups
independently selected from the group consisting of halogen, alkyl, haloalkyl,
saturated and
partially unsaturated cycloalkyl, and N(Rio)(Rii).
In some embodiments, the phrase "R2 and R6 together with the nitrogen atom to
which
they are attached form a 4 to 9 membered saturated heterocyclyl ring" refers
to a 4 to 9
membered monocyclic heterocyclic ring formed from R2 and R6 together with the
nitrogen
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atom to which they are attached. In certain embodiments, such phrase refers to
a 4 to 9
membered spirocyclic ring formed from R2 and R6 together with the nitrogen
atom to which
they are attached. In certain embodiments, such phrase refers to a 4 to 9
membered fused
ring formed from R2 and R6 together with the nitrogen atom to which they are
attached.
In some embodiments, L is N(R6), and R2 and R6 together with the nitrogen atom
to
which they are attached form:
0 N
) ---, ,---- ----, N ,--- ----) ,-
N N , N , , N ,
N 0 N
Cx N C ) ) p N 0
K X
,
P
/ P
N
N '
N N 1
1
I -I- -I-
/ __________________________ \
N I ,
N 0
P
N ,or ,
N
each of which is optionally substituted with one or more groups independently
selected from
the group consisting of halogen, alkyl, and N(Rio)(Rii), wherein p is 1, 2 or
3, and q is 1, 2 or
3. In certain embodiments, p is 1 or 2. In certain embodiments, p is 1. In
certain
embodiments, p is 2. In certain embodiments, q is 1 or 2. In certain
embodiments, q is 1. In
certain embodiments, q is 2.
In some embodiments, the heterocyclyl ring formed by R2 and R6 together with
the
nitrogen atom to which they are attached is substituted with one or more
groups selected
from fluoro, methyl, 2-fluoroethy1,2,2-difluoroethyl, cyclopropyl, or
dimethylamino. In
certain embodiments, said heterocyclyl ring is substituted with one or more
fluor groups.
In certain embodiment, said heterocyclyl ring is substituted with one or more
methyl groups.
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In certain embodiments, said heterocyclyl ring is substituted with one or more
2-fluoroethyl.
In certain embodiments, said heterocyclyl ring is substituted with one or more
2,2-difluoroethyl. In certain embodiments, said heterocyclyl ring is
substituted with one or
more cyclopropyl. In certain embodiments, said heterocyclyl ring is
substituted with one or
more dimethylamino. In certain embodiment, said heterocyclyl ring is
substituted with
fluoro and methyl.
In some embodiments, L is 0, and R2 is selected from saturated or partially
unsaturated
cycloalkyl and saturated or partially unsaturated heterocyclyl, wherein said
cycloalkyl and
heterocyclyl are optionally substituted with one or more groups independently
selected from
the group consisting of halogen, alkyl, saturated or partially unsaturated
cycloalkyl, and
N(R10)(R11).
In some embodiments, L is 0, and R2 is selected from C4_6 saturated cycloalkyl
or 5 to 6
membered saturated heterocyclyl, wherein said C4_6 saturated cycloalkyl and 5
to 6
membered saturated heterocyclyl are optionally substituted with one or more
groups
independently selected from the group consisting of halogen, alkyl, saturated
or partially
unsaturated cycloalkyl, and N(R10)(R11).
In some embodiments, L is 0, and R2 is selected from cyclobutyl, cyclopentyl,
cyclohexyl, pyrrolidinyl, or piperidinyl, each of which is optionally
substituted with one or
more groups independently selected from the group consisting of halogen,
alkyl, saturated or
partially unsaturated cycloalkyl, and N(Rio)(R11).
In some embodiments, L is N(R6), Ri is selected from the group consisting of
halogen,
cyano, nitro, amino, hydroxyl, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl,
heteroalkyl,
heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl,
saturated or
partially unsaturated heterocyclyl, aryl, N(R7)(R8), and 0(R9), and R2 and R6
together with
the nitrogen atom to which they are attached form a 4 to 9 membered saturated
heterocyclyl
ring optionally containing one or more additional heteroatoms selected from N,
0 and S,
wherein said 4 to 9 membered saturated heterocyclyl ring is optionally
substituted with one
or more groups independently selected from the group consisting of halogen,
alkyl, alkyl-OH
haloalkyl, saturated and partially unsaturated cycloalkyl, and N(Rio)(R11).
In certain embodiments, L is N(R6), Ri is N(R7)(R8), and R2 and R6 together
with the
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nitrogen atom to which they are attached form a 4 to 9 membered saturated
heterocyclyl ring
optionally containing one or more additional heteroatoms selected from N, 0
and S, wherein
said 4 to 9 membered saturated heterocyclyl ring is optionally substituted
with one or more
groups independently selected from the group consisting of halogen, alkyl,
haloalkyl,
saturated and partially unsaturated cycloalkyl, and N(Rio)(Rii). In certain
embodiments, R7
is hydrogen, and Rs is saturated or partially unsaturated cycloalkyl
substituted by alkyl. In
certain embodiments, R7 is hydrogen, and R8 is 4,4-dimethy1-4,5-dihydrooxazol-
2-yl.
In certain embodiments, L is N(R6), Ri is 0(R9), R9 is selected from the group
consisting of C1-6 alkyl, 3 to 6 membered saturated or partially unsaturated
cycloalkyl, 3 to 6
membered saturated or partially unsaturated heterocyclyl, wherein said alkyl,
cycloalkyl, and
heterocyclyl are optionally substituted by one or more groups independently
selected from
halogen, alkyl, or alkoxyl, and R2 and R6 together with the nitrogen atom to
which they are
attached form a 4 to 9 membered saturated heterocyclyl ring optionally
containing one or
more additional heteroatoms selected from N, 0 and S, wherein said 4 to 9
membered
saturated heterocyclyl ring is optionally substituted with one or more groups
independently
selected from the group consisting of halogen, alkyl, haloalkyl, saturated and
partially
unsaturated cycloalkyl, and N(Rio)(Ri1).
In certain embodiments, L is N(R6), Ri is 0(R9), R9 is selected from methyl,
ethyl,
isopropyl, cyclopropyl, or tetrahydrofuranyl, each of which is optionally
substituted by one
or more fluor , and R2 and R6 together with the nitrogen atom to which they
are attached
form a 4 to 9 membered saturated heterocyclyl ring optionally containing one
or more
additional heteroatoms selected from N, 0 and S, wherein said 4 to 9 membered
saturated
heterocyclyl ring is optionally substituted with one or more groups
independently selected
from the group consisting of halogen, alkyl, haloalkyl, saturated and
partially unsaturated
cycloalkyl, and N(Rio)(Rii).
In some embodiments, R3 is halogen.
In certain embodiments, R3 is chloro.
In some embodiments, R3 is C1-6 alkyl.
In certain embodiments, R3 is methyl.
In some embodiments, R4 is hydrogen.
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In a further aspect, the present disclosure provides a compound of Formula
(IVa), (IVb),
(IVc), (IVd), (IVe), (IVf), (IVg), (IVh), or (IVi) below:
R4
R3 \ N.'
R2 .
L HN
R1-õ.__.---1.--z----õ.G
I
N N
(IVa)
R4
R3
R2 . N N¨N
L HN
R1---,,..õ--kõ-,
I
N N
(IVb)
R4
R2 .
L HN
R1G
I
N N
(IVC)
R4
R3 NN)
R2 .
L HN
R1-..õ_
I
N N
(IVd)
R4
E4----..rNs
, N
R3
R2
L HN
R1G
I
N N
(IVe)
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R4
R2L R3IçJ NN'
N
NN
HN
G
(IVf)
R4
EN
R3
R2, .NN
N
L HN
N
(IVg)
R4
E
R3
R2
L HN
N
(IVh)
R4
R2 L R3JJ NN
HN
N N-,91
( IVi)
or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester
thereof, wherein G, L,
E, Ri, R2, R3 and R4 have the meanings as defined in Formula (I) and various
embodiments
thereof.
In some embodiments of Formula (I), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf),
(IVg),
(IVh), (IVi), L is selected from 0 or N(R6); Ri is 0(R9), N(R7)(R8), or
partially unsaturated
heterocyclyl optionally substituted by acyl; R2 is selected from C4_6
saturated cycloalkyl or 4
to 6 membered saturated heterocyclyl, wherein said C4-6 saturated cycloalkyl
and 4 to 6
membered saturated heterocyclyl are optionally substituted with one or more
groups
independently selected from the group consisting of halogen, alkyl, and
N(Rio)(Rii), orR2
and R6 together with the nitrogen atom to which they are attached form a 4 to
9 membered
saturated monocyclic, spirocyclic or fused heterocyclyl ring optionally
containing one or
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more additional heteroatoms selected from N, 0 and S, wherein said 4 to 9
membered
saturated monocyclic, spirocyclic or fused heterocyclyl ring is optionally
substituted with
one or more groups independently selected from the group consisting of
halogen, alkyl,
haloalkyl, saturated and partially unsaturated cycloalkyl, and N(Rio)(Rii); R3
is selected from
halogen or alkyl; R4 and R5 are hydrogen; R7 and R8 are each independently
selected from
hydrogen, acyl, or saturated or partially unsaturated heterocyclyl, wherein
said acyl and
heterocyclyl are optionally substituted with one or more groups selected from
alkyl,
alkylamino, saturated and partially unsaturated heterocyclyl; R9 is selected
from the group
consisting of alkyl, acyl, C3-7 saturated or partially unsaturated cycloalkyl,
and 4 to 6
membered saturated or partially unsaturated heterocyclyl, wherein said alkyl,
acyl, cycloalkyl,
and heterocyclyl are optionally substituted by one or more groups
independently selected
from halogen, alkyl, acyl, and alkoxyl; and Rio and Rii are each independently
an alkyl.
In a further aspect, the present disclosure provides a compound of Formula
(Va), (Vb),
(Vc), (Vd), (Ve), (Vf), (Vg) or (Vh):
R4
N
R3
R2 L HN
R1NN ,G
(Va)
R4
N
R3 N
R2 L HN NN
R1
NNJ IG
(Vb)
R4
N
R3
R2, L HN
G
N
(Vc)
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R4
E ,\e, ,
N \\
R2 , L HN NN
R1
I
N i\i
(Vd)
R4
E
N ----)
R2 , N
R3
L HN
R1-...õ-----1--., ...,...G
I
N r\i
(Ve)
R4
E t n
R2 , L HN 1\1---L--- N
R3
R1--,------------, ..,..G
I
N r\i
(Vf)
R4
E
m - N
11 \
\ ----
R2 L HN
R3
R1---,õ..---õ,,,_õ-------, ....õ..G
I
N r\i
(Vg)
R4
m - N
Eto
R2 L HN
R3 N
R1,,,_,,,,,,,,,_,--G
I
N N
(Vh)
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or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester
thereof, wherein G, L,
E, R1, R2, R3 and R4 have the meanings as defined in Formula (II) and various
embodiments
thereof.
In some embodiments of Formula (II), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg)
or (Vh),
L is selected from 0 or N(R6); Ri is 0(R9), N(R7)(R8), or partially
unsaturated heterocyclyl
optionally substituted by acyl; R2 is selected from C4-6 saturated cycloalkyl
or 4 to 6
membered saturated heterocyclyl, wherein said C4-6 saturated cycloalkyl and 4
to 6
membered saturated heterocyclyl are optionally substituted with one or more
groups
independently selected from the group consisting of halogen, alkyl, and
N(Rio)(Rii); orR2
and R6 together with the nitrogen atom to which they are attached form a4 to 9
membered
saturated monocyclic, spirocyclic or fused heterocyclyl ring optionally
containing one or
more additional heteroatoms selected from N, 0 and S, wherein said 4 to 9
membered
saturated monocyclic, spirocyclic or fused heterocyclyl ring is optionally
substituted with
one or more groups independently selected from the group consisting of
halogen, alkyl,
haloalkyl, saturated and partially unsaturated cycloalkyl, and N(Rio)(Rii);R3
is selected from
halogen or alkyl; R4 and R5 are hydrogen; R7 and R8 are each independently
selected from
hydrogen, acyl, or saturated or partially unsaturated heterocyclyl, wherein
said acyl and
heterocyclyl are optionally substituted with one or more groups selected from
alkyl,
alkylamino, saturated and partially unsaturated heterocyclyl; R9 is selected
from the group
consisting of alkyl, acyl, C3-7 saturated or partially unsaturated cycloalkyl,
and 4 to 6
membered saturated or partially unsaturated heterocyclyl, wherein said alkyl,
acyl, cycloalkyl,
and heterocyclyl are optionally substituted by one or more groups
independently selected
from halogen, alkyl, acyl, and alkoxyl; andRio and Rii are each independently
an alkyl.
In a further aspect, the present disclosure provides a compound of Formula
(VIa), (VIb),
(Vic), (VId):
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R4
N
R3 N
R2,
L HN N
R1
(VIa)
R4
N"
R I-\
R2,, N N
L HN
R1
'G
(VIb)
R4
E N
R3
R2,, N N
L HN
R1
'G
(VIC)
R4
NI- N
R3 E
L HN
R1
(VId)
a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof,
wherein L is
selected from 0 or N(R6); R2 is selected from C4_6 saturated cycloalkyl or 4
to 6 membered
saturated heterocyclyl, wherein said C4-6 saturated cycloalkyl and 4 to 6
membered saturated
heterocyclyl are optionally substituted with one or more groups independently
selected from
the group consisting of halogen, alkyl, and N(Rio)(Rii); or R2 and R6 together
with the
nitrogen atom to which they are attached form a 4 to 9 membered saturated
monocyclic,
spirocyclic or fused heterocyclyl ring optionally containing one or more
additional
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heteroatoms selected from N, 0 and S, wherein said 4 to 9 membered saturated
monocyclic,
spirocyclic or fused heterocyclyl ring is optionally substituted with one or
more groups
independently selected from the group consisting of halogen, alkyl, haloalkyl,
saturated and
partially unsaturated cycloalkyl, and N(Rio)(Rii); wherein Rio and Rii are
each
independently an alkyl.
In a further aspect, the present disclosure provides a compound or a solvate,
hydrate,
stereoisomer, or a pharmaceutically salt or ester thereof, the compound
selected from the
group consisting of:
(R)-N-(4-([ 1,2,4]triazolo[ 1, 5 -c]pyrimidin-7-yloxy)-3 -methylpheny1)-5-
((3,3 -difluoro- 1 -
methylpiperidin-4-yl)oxy)-6-methoxypyrido[3 ,4-d]pyrimidin-4-amine;
(S)-N-(4-([ 1,2,4]triazolo[ 1,5 -c]pyrimidin-7-y1 oxy)-3 -methylpheny1)-5-
((3,3 -difluoro- 1 -
methylpiperidin-4-yl)oxy)-6-methoxypyrido[3 ,4-d]pyrimidin-4-amine;
(R)-N-(4-([ 1,2,4]triazolo[ 1, 5 -c]pyrimidin-7-yloxy)-3 -methylpheny1)-5-
((3,3 -difluoro- 1 -
methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3 ,4-d]pyrimidin-4-amine;
(S)-N-(4-([ 1,2,4]triazolo[ 1,5 -c]pyrimidin-7-y1 oxy)-3 -methylpheny1)-5-
((3,3 -difluoro- 1 -
methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3 ,4-d]pyrimidin-4-amine;
(R)-N-(4-([ 1,2,4]triazolo[ 1, 5 -c]pyrimidin-7-yloxy)-3 -methylpheny1)-5-
((3,3 -difluoro- 1 -
methylpiperidin-4-yl)oxy)pyrido[3 ,4-d]pyrimidin-4-amine;
(S)-N-(4-([ 1,2,4]triazolo[ 1,5 -c]pyrimidin-7-y1 oxy)-3 -methylpheny1)-5-
((3,3 -difluoro- 1 -
methylpiperidin-4-yl)oxy)pyrido[3 ,4-d]pyrimidin-4-amine;
(R)-N-(4-([ 1,2,4]triazolo[ 1, 5 -c] pyrimi din-7-yloxy)-3 -chloropheny1)-
543,3 -difluoro- 1 -
methylpiperidin-4-yl)oxy)-6-methoxypyrido[3 ,4-d]pyrimidin-4-amine;
(S)-N-(4-([ 1,2,4]triazolo[ 1,5 -c]pyrimidin-7-y1 oxy)-3 -chloropheny1)-5
,3 -difluoro- 1 -
methylpiperidin-4-yl)oxy)-6-methoxypyrido[3 ,4-d]pyrimidin-4-amine;
(R)-N-(4-([ 1,2,4]triazolo[ 1, 5 -c]pyrimidin-7-yloxy)-3 -methylpheny1)-5-
((3,3 -difluoro- 1 -
methylpiperidin-4-yl)oxy)-6-(methoxy-d3 )pyrido[3 ,4-d]pyrimidin-4-amine;
(S)-N-(4-([ 1,2,4]triazolo[ 1,5 -c]pyrimidin-7-y1 oxy)-3 -methylpheny1)-5-
((3,3 -difluoro- 1 -
methylpiperidin-4-yl)oxy)-6-(methoxy-d3 )pyrido[3 ,4-d]pyrimidin-4-amine;
N-(4-([ 1,2,4]triazolo[ 1, 5 -c] pyrimi din-7-yloxy)-3 -m ethyl pheny1)-6-m
ethoxy-5 -(( 1 -m eth
ylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine;
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N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-5-(3-
(dimethylamino)a
zetidin-1-y1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-(
methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
(methyl-d3)piperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-(
methyl-d3)piperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-543,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro-1-(m
ethyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-543,3-
difluoro-1-(m
ethyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro-1-iso
propylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-543,3-
difluoro-1-iso
propylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-5-((1-
cyclopropy1-3,3
-difluoropiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-541-
cyclopropy1-3,3
-difluoropiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-543,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;
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(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro-1-(m
ethyl-d3)piperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-543,3-
difluoro-1-(m
ethyl-d3)piperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-isopropoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-543,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-isopropoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-6-
(cyclopropylmetho
xy)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-
amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-6-
(cyclopropylmethox
y)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-6-
cyclopropoxy-5-((3,
3-difluoro-1-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-6-
cyclopropoxy-5-((3,
3-difluoro-1-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-(2,2,2-trifluoroethoxy)pyrido[3,4-d]pyrimidin-4-
amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-543,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-(2,2,2-trifluoroethoxy)pyrido[3,4-d]pyrimidin-4-
amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-(difluoromethoxy)pyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-543,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-(difluoromethoxy)pyrido[3,4-d]pyrimidin-4-amine;
N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-6-methoxy-5-((1-
methylp
iperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine;
N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-6-methoxy-5-
morpholino
pyrido[3,4-d]pyrimidin-4-amine;
N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-6-methoxy-5-(4-
methylpi
perazin-l-yl)pyrido[3,4-d]pyrimidin-4-amine;
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cis-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-54(3-fluoro-1-
methyl
piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
trans-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-543-fluoro-
1-meth
ylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-54(4,4-
difluoro-1-me
thylpyrrolidin-3-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-544,4-
difluoro-1-me
thylpyrrolidin-3-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-5-(3-
(dimethylamino)pyrr
olidin-1-y1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-5-(4-
(dimethylamino)-3,3
-difluoropyrrolidin-1-y1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-6-methoxy-5-(5-
methy1-8
-oxa-2,5-diazaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-4-amine;
N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-6-methoxy-5-(2-
methy1-2,
6-diazabicyclo[3.2.0]heptan-6-yl)pyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-5-(7-fluoro-5-
methy1-
2,5-diazaspiro[3.4]octan-2-y1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-5-(7-fluoro-5-
methy1-
2,5-diazaspiro[3.4]octan-2-y1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-5-(7,7-difluoro-5-
methy1-
2,5-diazaspiro[3.4]octan-2-y1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-b]pyridazin-
7-ylox
y)-3-methylpheny1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-54(3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-b]pyridazin-
7-ylox
y)-3-methylpheny1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-7-yloxy)-3-methylpheny1)-543,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
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(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-a]pyridin-7-
yloxy)-
3-methylpheny1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-54(3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-a]pyridin-7-
yloxy)-
3-methylpheny1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-c]pyrimidin-
7-ylox
y)-3-methylpheny1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-54(3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-c]pyrimidin-
7-ylox
y)-3-methylpheny1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-b]pyridazin-7-yloxy)-3-methylpheny1)-543,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-b]pyridazin-7-yloxy)-3-methylpheny1)-543,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-
(tetrazolo[1,
5-c]pyrimidin-7-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;
(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-
(tetrazolo[1,
5-c]pyrimidin-7-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-
(tetrazolo[1,
5-a]pyridin-7-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;
(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-
(tetrazolo[1,
5-a]pyridin-7-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylpheny1)-54(3,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylpheny1)-543,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-chloropheny1)-5-((3,3-
difluoro-1-met
hylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-chloropheny1)-5-((3,3-
difluoro-1-met
hylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylpheny1)-54(3,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;
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(S)-N-(4-([ 1,2,4]triazolo[ -a]pyridin-6-y1 oxy)-3 -methylpheny1)-5 43,3 -
difluoro-1 -me
thylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([ 1,2,4]triazolo[ 1, 5 -a]pyridin-6-yloxy)-3 -methylpheny1)-5 -((3
,3 -difluoro- 1 -me
thylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([ 1,2,4]triazolo[ -a]pyridin-6-y1 oxy)-3 -methylpheny1)-5 43,3 -
difluoro-1 -me
thylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([ 1,2,4]triazolo[ 1, 5 -a]pyri din-6-yloxy)-3 -methylpheny1)-5 -((3
,3 -difluoro- 1-(m
ethyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([ 1,2,4]triazolo[ -a]pyri din-6-yloxy)-3 -methyl pheny1)-5 43,3 -
difluoro-1 -(m
ethyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-5-((3,3 -difluoro- 1 -methyl piperi din-4-yl)oxy)-6-methoxy-N-(3 -methyl-4-
(pyrazol o [ 1,
-a]pyri din-6-y1 oxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;
(S)-5-((3,3 -difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy-N-(3 -methyl -4-
(pyrazol o [ 1,
5 -a]pyri din-6-y1 oxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(3 -chl oro-4-(pyrazolo [ 1,5 -a]pyri din-6-yloxy)pheny1)-5 -((3,3 -
difluoro- 1 -methylpi
peridin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(3 -chloro-4-(pyrazolo[ 1,5 -a]pyridin-6-y1 oxy)pheny1)-5 -((3,3 -
difluoro- -methylpi
peridin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-5-((3,3 -difluoro- 1 -methyl piperi din-4-yl)oxy)-6-ethoxy-N-(3 -methyl-4-
(pyrazol o [ 1,5
-a]pyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;
(N)-5-((3,3 -difluoro-l-methylpiperidin-4-yl)oxy)-6-ethoxy-N-(3 -methyl -4-
(pyrazol o [ 1,
5 -a]pyri din-6-y1 oxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;
(R)-5-((3,3 -difluoro- 1 -methyl piperi din-4-yl)oxy)-6-(methoxy-d3 )-N-(3 -
methyl-4-(pyraz
olo[ 1,5 -a]pyridin-6-y1 oxy)phenyl)pyrido[3 ,4-d]pyrimidin-4-amine;
(S)-5-((3,3 -difluoro- 1 -methylpiperi din-4-yl)oxy)-6-(methoxy-d3 )-N-(3 -
methyl-4-(pyraz
olo[ 1,5 -a]pyridin-6-y1 oxy)phenyl)pyrido[3 ,4-d]pyrimidin-4-amine;
(R)-5-((3,3 -difluoro- 1-(methyl-d3 )piperi din-4-yl)oxy)-6-methoxy-N-(3 -
methyl-4-(pyraz
olo[ 1,5 -a]pyridin-6-y1 oxy)phenyl)pyrido[3 ,4-d]pyrimidin-4-amine;
(S)-5-((3,3 -difluoro- 1 -(methyl -d3 )piperi din-4-yl)oxy)-6-methoxy-N-(3 -
methyl-4-(pyraz
olo[ 1,5 -a]pyridin-6-y1 oxy)phenyl)pyrido[3 ,4-d]pyrimidin-4-amine;
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(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-
(pyrazolo[1,
5-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;
(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-
(pyrazolo[1,
5-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(3-chloro-4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)pheny1)-543,3-difluoro-1-
methy
1piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(3-chloro-4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)pheny1)-5-((3,3-difluoro-1-
methyl
piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-ethoxy-N-(3-methyl-4-
(pyrazolo[1,5
-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;
(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-ethoxy-N-(3-methyl-4-
(pyrazolo[1,5
-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)-N-(3-methyl-4-
(pyraz
olo[1,5-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;
(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)-N-(3-methyl-4-
(pyraz
olo[1,5-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;
(R)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxy-N-(3-methy1-4-
(pyraz
olo[1,5-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;
(S)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxy-N-(3-methy1-4-
(pyraz
olo[1,5-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-
(pyrazolo[1,
5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine;
(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-
(pyrazolo[1,
5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine;
(R)-N-(3-chloro-4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)pheny1)-543,3-difluoro-1-
methy
1piperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine;
(S)-N-(3-chloro-4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)pheny1)-5-((3,3-difluoro-1-
methyl
piperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine;
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-ethoxy-N-(3-methyl-4-
(pyrazolo[1,5
-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine;
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(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-ethoxy-N-(3-methyl-4-
(pyrazolo[1,5
-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine;
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)-N-(3-methyl-4-
(pyraz
olo[1,5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine;
(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)-N-(3-methyl-4-
(pyraz
olo[1,5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine;
(R)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxy-N-(3-methy1-4-
(pyraz
olo[1,5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine;
(S)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxy-N-(3-methy1-4-
(pyraz
olo[1,5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-(
methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
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(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-methoxyquinazolin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-methoxyquinazolin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-chloropheny1)-543,3-
difluoro-1-
methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-chloropheny1)-543,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-methoxyquinazolin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-(methoxy-d3)quinazolin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-(methoxy-d3)quinazolin-4-amine;
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
(methyl-d3)piperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine;
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-(
methyl-d3)piperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine;
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylpheny1)-54(3,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylpheny1)-543,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-chloropheny1)-5-((3,3-
difluoro-1-met
hylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-chloropheny1)-5-((3,3-
difluoro-1-met
hylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylpheny1)-54(3,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;
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(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylpheny1)-543,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylpheny1)-543,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylpheny1)-543,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-(m
ethyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylpheny1)-543,3-
difluoro-1-(m
ethyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylpheny1)-543,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-chloropheny1)-543,3-
difluoro-1-
methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-chloropheny1)-543,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylpheny1)-543,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylpheny1)-543,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylpheny1)-543,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;
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(R)-4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3 -methylphenyl)amino)-5 -
((3 ,3 -difl
uoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy- 1,7-naphthyri dine-3 -
carbonitrile;
(S)-4-((4-([ 1,2,4]triazolo[ 1, 5 -c]pyrimidin-7-yloxy)-3 -methylphenyl)amino)-
5 -((3 ,3 -difl
uoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy- 1,7-naphthyri dine-3 -
carbonitrile;
(R)-4-((4-([ 1,2,4]triazolo[ 1,5 -a]pyri din-7-yloxy)-3 -methyl phenyl)amino)-
5 -((3 ,3 -difluor
o- 1 -methyl piperi din-4-yl)oxy)-6-methoxy- 1, 7-naphthyri dine-3 -
carbonitrile;
(S)-4-((4-([ 1,2,4]triazolo[ 1, 5 -a]pyridin-7-yloxy)-3 -methylphenyl)amino)-5-
((3,3 -difluor
o- 1 -methyl piperi din-4-yl)oxy)-6-methoxy- 1, 7-naphthyri dine-3 -
carbonitrile;
(R)-4-((4-([1,2,4]triazolo[1,5-b]pyridazin-7-yloxy)-3 -methylphenyl)amino)-5 -
((3 ,3 -difl
uoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy- 1,7-naphthyri dine-3 -
carbonitrile;
(S)-4-((4-([ 1,2,4]triazolo[ 1, 5 -b]pyridazin-7-yloxy)-3 -methylphenyl)amino)-
5-((3,3 -diflu
oro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy- 1,7-naphthyri dine-3 -
carbonitrile;
(R)-5-((3,3 -difluoro- 1 -methyl piperi din-4-yl)oxy)-6-methoxy-4-((3 -methyl -
4-(tetrazol o [
1,5 -c]pyrimidin-7-yloxy)phenyl)amino)- 1, 7-naphthyridine-3 -carbonitrile;
(S)-5-((3,3 -difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy-4-((3 -methyl-4-
(tetrazol o [ 1,
-c]pyrimidin-7-yloxy)phenyl)amino)- 1,7-naphthyridine-3 -carbonitrile;
(R)-5-((3,3 -difluoro- 1 -methyl piperi din-4-yl)oxy)-6-methoxy-4-((3 -methyl -
4-(tetrazol o [
1,5 -a]pyri din-7-yloxy)phenyl)amino)- 1, 7-naphthyri dine-3 -carbonitrile;
(S)-5-((3,3 -difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy-4-((3 -methyl-4-
(tetrazol o [ 1,
5 -a]pyri din-7-y1 oxy)phenyl)amino)-1,7-naphthyridine-3 -carbonitrile;
(R)-4-((4-([ 1,2,4]triazolo[ 1,5 -a]pyri din-6-yloxy)-3 -methyl phenyl)amino)-
5 -((3 ,3 -difluor
o- 1 -methyl piperi din-4-yl)oxy)-6-methoxy- 1, 7-naphthyri dine-3 -
carbonitrile;
(S)-4-((4-([ 1,2,4]triazolo[ 1, 5 -a]pyridin-6-yloxy)-3 -methylphenyl)amino)-5-
((3,3 -difluor
o- 1 -methyl piperi din-4-yl)oxy)-6-methoxy- 1, 7-naphthyri dine-3 -
carbonitrile;
(R)-4-((4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3 -methylphenyl)amino)-5 -
((3 ,3 -difl
uoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy- 1,7-naphthyri dine-3 -
carbonitrile;
(S)-4-((4-([ 1,2,4]triazolo[ 1, 5 -a]pyrimidin-6-yloxy)-3 -methylphenyl)amino)-
5 -((3 ,3 -difl
uoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy- 1,7-naphthyri dine-3 -
carbonitrile;
(R)-4-((4-([ 1,2,4]tri azol o [4,3 -a]pyridin-6-yloxy)-3 -methyl phenyl)amino)-
5 -((3 ,3 -difluor
o- 1 -methyl piperi din-4-yl)oxy)-6-methoxy- 1, 7-naphthyri dine-3 -
carbonitrile;
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(S)-4-((4-([ 1 ,2,4]tri azol o [4, 3 -a] pyri din-6-y1 oxy)-3 -
methylphenyl)amino)-5-((3 ,3 -difluor
o- 1 -m ethyl pi p eri di n-4-yl)oxy)-6-m ethoxy- 1, 7-naphthyri di ne-3 -
carbonitrile;
(R)-4-((4-([ 1 ,2,4]tri azol o [4,3 -a] pyrimi din-6-y1 oxy)-3 -
methylphenyl)amino)-5 -((3 ,3 -difl
uoro- 1 -m ethyl pi p eri di n-4-yl)oxy)-6-m ethoxy- 1 ,7-naphthyri dine-3 -
carbonitrile;
(S)-4-((4-([ 1 ,2,4]tri azol o [4, 3 -a] pyrimi din-6-y1 oxy)-3 -
methylphenyl)amino)-5 -((3 ,3 -difl
uoro- 1 -m ethyl pi p eri di n-4-yl)oxy)-6-m ethoxy- 1 ,7-naphthyri dine-3 -
carbonitrile;
(R)-5 -((3,3 -di fluoro- 1 -m ethyl pi p eri di n-4-yl)oxy)-6-m ethoxy-4 -((3 -
methyl -4-(pyrazolo[
1,5 -a] pyrimi din-6-y1 oxy)phenyl)amino)- 1, 7-naphthyri dine-3 -
carbonitrile;
(S)-5 -((3 , 3 -di fluoro- 1 -m ethyl pi p eri di n-4-y1 )oxy)-6-m ethoxy-4-
((3 -m ethy1-4-(pyrazol o [ 1,
-a] pyri mi din-6-y1 oxy)phenyl)amino)- 1 ,7-naphthyri dine-3 -carbonitrile;
(R)-5 -((3,3 -di fluoro- 1 -m ethyl pi p eri di n-4-yl)oxy)-6-m ethoxy-4 -((3 -
methyl -4-(pyrazolo[
1,5 -a] pyri di n-6-yloxy)phenyl )ami no)- 1, 7-naphthyri di ne-3 -
carbonitrile;
(S)-5 -((3 , 3 -di fluoro- 1 -m ethyl pi p eri di n-4-y1 )oxy)-6-m ethoxy-4-
((3 -m ethy1-4-(pyrazol o [ 1,
5 -a] pyri din-6-y1 oxy)phenyl)amino)- 1 ,7-naphthyri dine-3 -carbonitrile;
(R)-4-((4-([ 1 ,2,4]tri azol o [1 , 5 -a]pyrimi din-6-y1 oxy)-3 -
methylphenyl)amino)-5 -((3 ,3 -difl
uoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxyquinoline-3 -carbonitrile;
(S)-4-((4-([ 1 ,2,4]tri azol o [ 1, 5 -a] pyrimi din-6-y1 oxy)-3 -
methylphenyl)amino)-5 -((3 ,3 -difl
uoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxyquinoline-3 -carbonitrile;
(R)-4-((4-([ 1 ,2,4]tri azol o [4,3 -a] pyrimi din-6-y1 oxy)-3 -
methylphenyl)amino)-5 -((3 ,3 -difl
uoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxyquinoline-3 -carbonitrile;
(S)-4-((4-([ 1 ,2,4]tri azol o [4, 3 -a] pyrimi din-6-y1 oxy)-3 -
methylphenyl)amino)-5 -((3 ,3 -difl
uoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxyquinoline-3 -carbonitrile;
(R)-5 -((3,3 -di fluoro- 1 -m ethyl pi p eri di n-4-yl)oxy)-6-m ethoxy-4 -((3 -
methyl -4-(pyrazolo[
1,5 -a] pyrimi din-6-y1 oxy)phenyl)amino)quinoline-3 -carbonitrile;
(S)-5 -((3 , 3 -di fluoro- 1 -m ethyl pi p eri di n-4-y1 )oxy)-6-m ethoxy-4-
((3 -m ethy1-4-(pyrazol o [ 1,
5 -a] pyri mi din-6-y1 oxy)phenyl)amino)quinoline-3 -carbonitrile;
N-(4-((4-([ 1 ,2,4]tri az ol o [ 1 , 5 -a] pyri di n-7-yloxy)-3 -m ethyl
phenyl)ami no)-5 -(3 -(di m ethyl
amino)azeti din- 1 -yl )pyri do [3 ,4-d]pyrimi din-6-y1)-4-(dimethyl amino)but-
2-enami de.
Exemplary compounds of the present disclosure are set forth in Table 1 below.
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Table 1
Cmpd
Compound Structure and Name
No.
F
N F
N ,, .-.N
''0 HN N
OAN
1 I
N4-:,,N-)
(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-54(3,3-
diflu
oro-l-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
N F
N N-N
OLN
2 I
N,-,;-,,e1
(S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-5-((3,3-
diflu
oro-l-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
N-/ F
N -. N-N
''0 HN
N
3 I
N,,-,N--)
(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-54(3,3-
diflu
oro-l-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine
F
N F
"0 HN N -.. N-N
-..,_,Ø..,_,..õ.AN
4 I
N.,,,7,,el
(S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-5-((3,3-
diflu
oro-l-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine
F
N F
'0 HN N ,. N---N
---''''
N ,-7" -. N-ii
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(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-54(3,3-
diflu
oro-l-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine
F
N
HN
6
(S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-5-((3,3-
diflu
oro-l-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine
F
"0 HN N N-
CI N
7
N
(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-chloropheny1)-543,3-
difluo
ro-l-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
"0 HN CI NN
8
N
(S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-chloropheny1)-5-((3,3-
difluo
ro-l-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
NLF
HN N
9 CD3" N
(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-54(3,3-
diflu
oro-l-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine
N7/ F
HN 10 N
CD3
61
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(S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-5-((3,3-
diflu
oro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine
N
11
N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-6-methoxy-54(1
-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine
N HN N
12
N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-5-(3-(dimethyla
mino)azetidin-1-y1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
0 CD3,N F
HN
OLN
13
(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-54(3,3-
diflu
oro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
CD3,N./\11F
HN
14
(S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-5-((3,3-
diflu
oro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
D3C,N7-\ F F N
15 0 HN
CD3"-C)-N
62
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(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-54(3,3-
diflu
oro-1-(methyl-d3)piperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-a
mine
D3C,N,-/F F
HN
N
16 N
(S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-5-((3,3-
diflu
oro-1-(methyl-d3)piperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-a
mine
F
HN
17
N
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
0 HN
18
N N%)
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-543,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
CD3, NF F
IHN N
19
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro
-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
63
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CD3,NF F 0
0 HN
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-543,3-
difluoro
-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
HN
21
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-543,3-
difluoro
-1-isopropylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
N
HN
22
NN
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-543,3-
difluoro
-1-isopropylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
HN N
23
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-541-cycloprop
y1-3,3-difluoropiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
0
HN
24
N
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-5-((1-
cycloprop
y1-3,3-difluoropiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
64
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F 0
'''0 HN N
25 CD3' N
N
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine
N7/ F
HN NN
26 CD3 N
N
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-543,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine
D3C,N,./F F
"O HN N
,D3 N
27 N el
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro
-1-(methyl-d3)piperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amin
F
"0 HN
CD3"-C)N
28 N N)
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-543,3-
difluoro
-1-(methyl-d3)piperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amin
F
N
HN
29
N
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(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-isopropoxypyrido[3,4-d]pyrimidin-4-amine
F
"0 HN
N
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-543,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-isopropoxypyrido[3,4-d]pyrimidin-4-amine
F
ON
A HN
31 N
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-6-
(cyclopropyl
methoxy)-54(3,3-difluoro-1-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-
amine
F 0
0 HN
A\O
N
32 N
NJ
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-6-
(cyclopropyl
methoxy)-54(3,3-difluoro-1-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-
amine
F
HN
33 \iON
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-6-
cyclopropoxy
-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine
66
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F 0
HN
34 \iON
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-6-
cyclopropoxy
-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine
F 0
0 HN
1
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-(2,2,2-trifluoroethoxy)pyrido[3,4-d]pyrimidin-4-
a
mine
F
"0 HN
F3C.õ-ON
1
36
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-543,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-(2,2,2-trifluoroethoxy)pyrido[3,4-d]pyrimidin-4-
a
mine
0
F
HN
37 F
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-(difluoromethoxy)pyrido[3,4-d]pyrimidin-4-amin
NF
HN
38
F
67
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(S)-N-(4-([ 1,2,4]triazolo[ 1, 5 -a]pyridin-7-yloxy)-3 -methylpheny1)-5 -((3
,3 -difluoro
- 1 -methylpiperidin-4-yl)oxy)-6-(difluoromethoxy)pyrido[3 ,4-d]pyrimidin-4-
amin
HN
39
N-(4-([ 1,2,4]tri azol o [ 1, 5 -a]pyri din-7-yloxy)-3 -methylpheny1)-6-
methoxy-5 -((1 -m
ethylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine
HN
0N
N-(4-([ 1,2,4]tri azol o [ 1, 5 -a]pyri din-7-yloxy)-3 -methylpheny1)-6-
methoxy-5-morp
holinopyrido[3,4-d]pyrimidin-4-amine
41
N-(4-([ 1,2,4]tri azol o [ 1, 5 -a]pyri din-7-yloxy)-3 -methylpheny1)-6-
methoxy-5 -(4-me
thylpiperazin- 1 -yl)pyrido[3 ,4-d]pyrimidin-4-amine
F
,N-Nr
HN
42
cis mixture
cis-N-(4-([ 1,2,4]tri azol o [ 1,5 -a]pyri din-7-yloxy)-3 -methyl phenyl)-5-
((3 -fluoro- 1 -
methylpiperidin-4-yl)oxy)-6-methoxypyrido[3 ,4-d]pyrimidin-4-amine
HN
43
N trans mixture
68
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trans-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-543-fluoro-
1
-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
ON
'0 HN
44
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-544,4-
difluoro
-1-methylpyrrolidin-3-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
0 HN
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-544,4-
difluoro
-1-methylpyrrolidin-3-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
-N
N-N
N HN
46
N
N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-5-(3-
(dimethylamin
o)pyrrolidin-1-y1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
/
-N r
N HN
47
NN
N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-5-(4-
(dimethylamin
o)-3,3-difluoropyrrolidin-1-y1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
69
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0
N HN
48 OJN
N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-6-methoxy-5-(5-me
thy1-8-oxa-2,5-diazaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-4-amine
<N >N
49
N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-6-methoxy-5-(2-me
thy1-2,6-diazabicyclo[3.2.0]heptan-6-yl)pyrido[3,4-d]pyrimidin-4-amine
.Nr
N N -N
N
NJ
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-5-(7-fluoro-5-
m
ethyl-2,5-diazaspiro[3.4]octan-2-y1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
N N
51
o'rL)N
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-5-(7-fluoro-5-
methy1-2,5-diazaspiro[3.4]octan-2-y1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
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N HN
52
N-(4-([ 1,2,4]tri azol o [ 1, 5 -a]pyri din-7-yloxy)-3 -methylpheny1)-5-(7,7-
difluoro-5-m
ethyl-2, 5 -diazaspiro[3 .4] octan-2-y1)-6-methoxypyrido[3 ,4-d]pyrimidin-4-
amine
F
HNNNi
53
= ,N,!)
(R)-5-((3 ,3 -difluoro- 1 -methylpiperidin-4-yl)oxy)-N-(4-(imidazo[ 1,2-
b]pyridazin-
7-yloxy)-3 -methylpheny1)-6-methoxypyri do [3 ,4-d]pyrimi din-4-amine
0 HN
N N2
54
(S)-5-((3,3 -difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-
b]pyridazin-
7-yloxy)-3 -methylpheny1)-6-methoxypyri do [3 ,4-d]pyrimi din-4-amine
F
HN
(R)-N-(4-([ 1,2,4]tri azol o [4,3 -a]pyridin-7-yloxy)-3 -methyl pheny1)-5 -((3
,3 -difluoro
- 1 -methylpiperidin-4-yl)oxy)-6-methoxypyrido[3 ,4-d]pyrimidin-4-amine
F
HN
56
0)LN
NNJ
71
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(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-7-yloxy)-3-methylpheny1)-543,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
HN
57
(R)-543,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-a]pyridin-7-
yloxy)-3-methylpheny1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
HN N
58
(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-a]pyridin-7-
y
loxy)-3-methylpheny1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
HN N
59
(R)-543,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-c]pyrimidin-
7-yloxy)-3-methylpheny1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
HN N
(S)-543,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-c]pyrimidin-
7-yloxy)-3-methylpheny1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
61 HN
N
72
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(R)-N-(4-([1,2,4]triazolo[1,5-b]pyridazin-7-yloxy)-3-methylpheny1)-5-((3,3-
diflu
oro-l-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
N F
"0 HN N-N--1\1
0))N
62 I
NN)
(S)-N-(4-([1,2,4]triazolo[1,5-b]pyridazin-7-yloxy)-3-methylpheny1)-543,3-
difluo
ro-l-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
N F
,N
HN Nõ,,,,, N-N'
ON
63 I
NN-,:-I
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-
(tetra
zolo[1,5-c]pyrimidin-7-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
F
N F
,N
."0 HN 1\1N-N'
ON
64 I
N.--23--.N,-
(S)-5-((3,3-difluoro-l-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-
(tetra
zolo[1,5-c]pyrimidin-7-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
F
N F
,N
''0 HN -'----,--õ_õ....N-N'
0j)N
65 I
NN-P1
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-
(tetra
zolo[1,5-a]pyridin-7-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
F
N F
,N
N-N'
66
OAN
I
NN.i
73
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(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-
(tetra
zolo[1,5-a]pyridin-7-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
F
F
',0 HN
ON
67 I
N1\1=J
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylpheny1)-54(3,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
0 HN -----------N
01N
68 I
NN-2-i
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylpheny1)-543,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
N F
''0 HN CI ''-'..---N
ON
69 I
NN-J
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-chloropheny1)-54(3,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
NF
HN CI .*-----N
ON
70 I
Nõ,--- N--)'
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-chloropheny1)-5-((3,3-
difluoro-
1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
F
71
N
I
NN-]
74
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(R)-N-(4-([ 1,2,4]triazolo[ 1,5 -a]pyridin-6-yloxy)-3 -methylpheny1)-5 -((3 ,3
-difluoro
- 1 -methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3 ,4-d]pyrimidin-4-amine
F
HN
72
N i\r)
(S)-N-(4-([ 1,2,4]triazolo[ 1, 5-a]pyridin-6-yloxy)-3 -methylpheny1)-543,3 -
difluoro
- 1 -methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3 ,4-d]pyrimidin-4-amine
F
"O
73
N IN()
(R)-N-(4-([ 1,2,4]triazolo[ 1,5 -a]pyridin-6-yloxy)-3 -methylpheny1)-5 -((3 ,3
-difluoro
- 1 -methylpiperidin-4-yl)oxy)-6-(methoxy-d3 )pyrido[3 ,4-d]pyrimidin-4-
amine
F N N
HN
74 D3C,oy
(S)-N-(4-([ 1,2,4]triazolo[ 1, 5-a]pyridin-6-yloxy)-3 -methylpheny1)-543,3 -
difluoro
- 1 -methylpiperidin-4-yl)oxy)-6-(methoxy-d3 )pyrido[3 ,4-d]pyrimidin-4-
amine
D3C,NF F
'''0 HN
OAN
Nr,J
(R)-N-(4-([ 1,2,4]triazolo[ 1,5 -a]pyridin-6-yloxy)-3 -methylpheny1)-5 -((3 ,3
-difluoro
- 1 -(methyl-d3 )piperidin-4-yl)oxy)-6-
methoxypyrido[3 ,4-d]pyrimidin-4-amine
D3C,N F N N
HN
76
N
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(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylpheny1)-543,3-
difluoro
-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
/ HN
OLN
77
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-(pyra
zolo[1,5-a]pyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
F
HN
78
(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-(pyra
zolo[1,5-a]pyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
UF N_N
/", HN CI
79
NN
(R)-N-(3-chloro-4-(pyrazolo[1,5-a]pyridin-6-yloxy)pheny1)-543,3-difluoro-1-me
thylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
0 HN CI
(S)-N-(3-chloro-4-(pyrazolo[1,5-a]pyridin-6-yloxy)pheny1)-543,3-difluoro-1-me
thylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
HN
81
N
,<")
76
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(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-ethoxy-N-(3-methyl-4-(pyraz
olo[1,5-a]pyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
F
"0 HN
82
(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-ethoxy-N-(3-methy1-4-
(pyrazo
lo[1,5-alpyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
iii''0 HN
D3C,oN
83
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)-N-(3-methyl-4-
(pyrazolo[1,5-a]pyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
F N
O
HN
84 D3C,o)TN
NN
(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)-N-(3-methy1-4-
(pyrazolo[1,5-a]pyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
D3C,N/F F
HN
85 1
(R)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxy-N-(3-methy1-4-
(pyrazolo[1,5-a]pyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
77
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D3C,NF F
O
HN
86 1
(S)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxy-N-(3-methy1-4-
(pyrazolo[1,5-a]pyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
ON
'i0 HN
0*N 87
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-(pyra
zolo[1,5-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
HN
88
(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-(pyra
zolo[1,5-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
FF
HN CI
89
(R)-N-(3-chloro-4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)pheny1)-5-((3,3-difluoro-1-
methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
N
HN CI -N
(S)-N-(3-chloro-4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)pheny1)-543,3-difluoro-1-
methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
78
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F
`.-''0 HN
N
91 I
NN)
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-ethoxy-N-(3-methyl-4-(pyraz
olo[1,5-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
F
N F 0..õ,,,---.. .m_N
Nj
92 I
Nõ,----,,N-ii
(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-ethoxy-N-(3-methy1-4-
(pyrazo
lo[1,5-alpyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
F
N F
":õ...)
"O HN N
-
93 D3CID N
NN-)
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)-N-(3-methyl-4-
(pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
F
N F
"0 HN JO
N
,
94 D3CC1N 1
N,,,' 'N,-I
(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)-N-(3-methy1-4-
(pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
F
D3C, N F
*'/O HN N
ON
95 I
NN)
(R)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxy-N-(3-methy1-4-
(pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
79
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D3C,N F ON_N
HN
0)N
96
N
(S)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxy-N-(3-methy1-4-
(pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine
NF
\
HN
0
N
97
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-(pyra
zolo[1,5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine
HN
0
N
98
N
(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-(pyra
zolo[1,5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine
HN CI
0
N
99
(R)-N-(3-chloro-4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)pheny1)-5-((3,3-difluoro-1-
methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine
F N
\
"0 HN CI
0
100
(S)-N-(3-chloro-4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)pheny1)-543,3-difluoro-1-
methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine
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F 0 N N\
HN
101 N
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-ethoxy-N-(3-methyl-4-(pyraz
olo[1,5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine
0, N
F -\
HN
102 N
(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-ethoxy-N-(3-methy1-4-
(pyrazo
lo[1,5-alpyrimidin-6-yloxy)phenyl)quinazolin-4-amine
F
HN
D3C,0
103 N
1\1.
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)-N-(3-methyl-4-
(pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine
F
"0 HN
D3C,0
104 N
(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)-N-(3-methy1-4-
(pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine
D3 C, N F N
-\
*'/O HN
0
N
105
(R)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxy-N-(3-methy1-4-
(pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine
81
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D3C,NF F
HN
0
106
(S)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-y1)oxy)-6-methoxy-N-(3-methyl-4-
(pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine
F
0 HNNN
OJLN
107
NN
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-543,3-diflu
oro-l-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
"0 HNNN
OyAN
108
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-54(3,3-
diflu
oro-l-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
0 HN CI NN
109
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-543,3-diflu
oro-l-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
"0 HN CI NN
OyN110
NNJ
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-54(3,3-
diflu
oro-l-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
82
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F
="O NN
N
111
(R)-N-(4-([ 1,2,4]triazolo[ 1,5 -a]pyrimidin-6-yloxy)-3 -methylpheny1)-5 -((3
,3 -diflu
oro- 1 -methylpiperi din-4-yl)oxy)-6-ethoxypyri do [3 ,4-d]pyrimidin-4-amine
F
"0 HN -1\1
112
N
(S)-N-(4-([ 1,2,4]triazolo[ 1,5 -a]pyrimidin-6-y1 oxy)-3 -methylpheny1)-5 -((3
,3 -diflu
oro- 1 -methylpiperi din-4-yl)oxy)-6-ethoxypyri do [3 ,4-d]pyrimidin-4-amine
F
NN
113 D3C,oyN
(R)-N-(4-([ 1,2,4]triazolo[ 1,5 -a]pyrimidin-6-yloxy)-3 -methylpheny1)-5 -((3
,3 -diflu
oro- 1 -methylpiperidin-4-yl)oxy)-6-(methoxy-d3 )pyrido[3 ,4-d]pyrimidin-4-
amine
F
0 HNNN
114 D3C,o'N
N
(S)-N-(4-([ 1,2,4]triazolo[ 1,5 -a]pyrimidin-6-y1 oxy)-3 -methylpheny1)-5 -((3
,3 -diflu
oro- 1 -methylpiperidin-4-yl)oxy)-6-(methoxy-d3 )pyrido[3 ,4-d]pyrimidin-4-
amine
D3C, N F N N
HN
0)N
115
(R)-N-(4-([ 1,2,4]triazolo[ 1,5 -a]pyrimidin-6-yloxy)-3 -methylpheny1)-5 -((3
,3 -diflu
oro- 1 -(methyl -d3 )piperidin-4-yl)oxy)-6-methoxypyrido[3 ,4-d]pyrimidin-4-
amine
83
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F
HN NN
O
116 LN
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-54(3,3-
diflu
oro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
0 NN
117 0 N
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-543,3-diflu
oro-l-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine
F , N
"0 HNNN
0
118 N
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-54(3,3-
diflu
oro-l-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine
N
0 HN CI NN
0
N
119
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-chloropheny1)-543,3-
difluo
ro-l-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine
F
"0 HN CI NN
120 0 N
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-chloropheny1)-543,3-
difluo
ro-l-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine
84
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"O HN NN
121 N
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-543,3-diflu
oro-l-methylpiperidin-4-yl)oxy)-6-ethoxyquinazolin-4-amine
F
0 HN -1\1
122 N
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-543,3-diflu
oro-l-methylpiperi din-4-yl)oxy)-6-ethoxypyri do [3,4-d]pyrimidin-4-amine
F
N
HNNN
D3C,0
123 N
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-543,3-diflu
oro- 1 -methylpiperidin-4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine
F
0 HNNN
õ,0
124 N
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-543,3-diflu
oro- 1 -methylpiperidin-4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine
D3C, N F N N
HN NN
0
N
125
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-543,3-diflu
oro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine
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F 0 N N
HN NN
0
126 TELTJ
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylpheny1)-54(3,3-
diflu
oro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine
HN
0)N
127
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylpheny1)-54(3,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
NF
0 HN
128
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylpheny1)-54(3,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
HN CI
OLN
129
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-chloropheny1)-5-((3,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
HN CI
OLN
130
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-chloropheny1)-5-((3,3-
difluoro-
1-methylpiperidin-4-y1)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
86
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F
'''0 HN
131 1
N
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylpheny1)-54(3,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine
F
HN
132 1
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylpheny1)-54(3,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine
F
HN
133 D3C N
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylpheny1)-54(3,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine
F
0 HNN
134 D3C N
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylpheny1)-54(3,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine
D3C,N -\/F F
HN
135
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylpheny1)-54(3,3-
difluoro
-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
87
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D3C,N,---/F F
0 HN Lz''-'N'N
ON
136 I
NN-,-)
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylpheny1)-54(3,3-
difluoro
-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
N F ON,
N
'''0 HN N ---1\1'
ON
137 I
NN-)
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylpheny1)-543,3-diflu
oro-l-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
N F
N
N i\l'
0-AN
138 I
NN.-J
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylpheny1)-54(3,3-
diflu
oro-l-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
N F
N
' '10 HN CI N --1\i'
OyN
139 I
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-chloropheny1)-543,3-
difluo
ro-l-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
N F ON,
N
HN CI N---------N1
0-AN
140 I
N.,---N-)
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-chloropheny1)-543,3-
difluo
ro-l-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
88
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N FF ON
''0 HN N N
141 I
N,,,----.Nj
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylpheny1)-543,3-diflu
oro-l-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine
F
N F
N
''"---NO HN N'-'1\l'
142 I
N 1\1,-)"
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylpheny1)-543,3-
difluoro
-1-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine
F
N F ON__,..
N
''0 HN N---r\l'
143 D3C0 1 ' N
Nõ,----N,:-1
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylpheny1)-543,3-diflu
oro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine
F
N F ON____
0 HN NINI'N
144 D3C0 1 ' N
N N)
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylpheny1)-543,3-diflu
oro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine
F
D3C,N.7._LF ON,
''''0 HN N N
ON
145 I
N-i-N.')"
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylpheny1)-543,3-diflu
oro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine
89
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D3C,NF F
N
HN '1\1
146
(S)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylpheny1)-54(3,3-
diflu
oro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine
F
HN N N-1\1
147
(R)-44(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)amino)-54(3,
3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-
carbonitri
le
0
F
HN N N-N//
148
NN-
(S)-4-((4-([
3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-
carbonitri
le
F
HN
149
(R)-444-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5-((3,3-
difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-
carbonitrile
HN
150
N
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(S)-4-((4-([ 1,2,4]triazolo[1, 5 -a]pyridin-7-yloxy)-3 -methylphenyl)amino)-5-
((3,3 -
difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy- 1 ,7-naphthyri dine-3 -
carbonitrile
F 0
HN N-1\1-1\1/
0 CN
151 N
(R)-4-((4-([ 1,2,4]triazolo[1, 5 -b]pyridazin-7-yloxy)-3 -methylphenyl)amino)-
5-((3,
3 -difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy- 1, 7-naphthyri dine-3 -
carbonitri
le
HN N-1\1-1\i/
0 CN
152 N
(S)-4-((4-([ 1,2,4]triazolo[ 1,5 -b]pyridazin-7-y1 oxy)-3 -methylphenyl)amino)-
5-((3,
3 -difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy- 1, 7-naphthyri dine-3 -
carbonitri
le
0
F
,N
HN
153
N
(R)-5-((3,3 -difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy-4-((3 -methyl-4-
(tetr
azolo[1, 5 -c]pyrimidin-7-y1 oxy)phenyl)amino)-1, 7-naphthyridine-3 -
carbonitrile
NLF
, N
HN
CN
154
(S)-5-((3,3 -difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy-4-((3 -methyl-4-
(tetra
zolo[ 1,5 -c]pyrimidin-7-yloxy)phenyl)amino)-1, 7-naphthyridine-3 -
carbonitrile
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F
N F
, N
'10 HN '-..,,,N-N'
155 I
N,,N,',
(R)-5-((3,3 -difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy-4-((3 -methyl-4-
(tetr
azol o [1, 5 -a]pyri din-7-yloxy)phenyl)amino)- 1,7-naphthyri dine-3 -
carbonitrile
F
N F
, N
"0
O CN
156 -- -.
I
N N
(S)-5-((3,3 -difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy-4-((3 -methyl-4-
(tetra
zol o [1, 5 -a]pyri din-7-yloxy)phenyl)amino)- 1,7-naphthyri dine-3 -
carbonitrile
F
'''0 HN ''/--z----N
157 I
N,,,-- ,N,--''
(R)-444-([ 1,2,4]triazolo[ 1, 5 -a]pyridin-6-yloxy)-3 -methylphenyl)amino)-5 -
((3 ,3 -
difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy- 1 ,7-naphthyri dine-3 -
carbonitrile
F
N F
HN '`,--"------'N
O CN
158
I
N--'= e
(S)-444-([ 1,2,4]triazolo[1, 5 -a]pyridin-6-yloxy)-3 -methylphenyl)amino)-5 -
((3 ,3 -
difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy- 1 ,7-naphthyri dine-3 -
carbonitrile
F
N F
'',0 HN N N
O CN
--- \
I
159 N N
(R)-444-([ 1,2,4]triazolo[1, 5 -a]pyrimidin-6-yloxy)-3 -methylphenyl)amino)-5 -
((3 ,
3 -difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy- 1, 7-naphthyri dine-3 -
carbonitri
le
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F
0 HN N N
I
160
(S)-4-((4-([ 1,2,4]triazolo[ 1,5 -a]pyrimidin-6-y1 oxy)-3 -methylphenyl)amino)-
5-((3,
3 -difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy- 1, 7-naphthyri dine-3 -
carbonitri
le
F
N F
N
''0 HN ,--"-z--NI'
O CN
161
I
N.õ-,e
(R)-444-([1,2,4]triazolo[4,3 -a]pyridin-6-yloxy)-3 -methylphenyl)amino)-5-
((3,3 -
difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy- 1 ,7-naphthyri dine-3 -
carbonitrile
F
N F ON,_
N
"
''.---------N1'0 HN
O CN
162 --- -,,
I
N N
(S)-4-((4-([1,2,4]triazolo[4,3 -a]pyridin-6-yloxy)-3 -methylphenyl)amino)-5-
((3,3 -
difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy- 1 ,7-naphthyri dine-3 -
carbonitrile
F
F ON,
N
''CD HN N l\l'
O CN
\ \
1
163 N N
(R)-4-((4-([1,2,4]triazolo[4,3 -a]pyrimidin-6-yloxy)-3 -methylphenyl)amino)-5 -
((3 ,
3 -difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy- 1, 7-naphthyri dine-3 -
carbonitri
le
F
N F ON,___
N
164 HN
O CN
---
I
N.,-;:-N:---
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(S)-4-((4-([1,2,4]triazolo[4,3 -a]pyrimidin-6-yloxy)-3 -methylphenyl)amino)-5-
((3,
3 -difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy- 1, 7-naphthyri dine-3 -
carbonitri
le
F
0 HN
O CN
165
(R)-5-((3,3 -difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy-4-((3 -methyl-4-
(pyr
azolo[1, 5 -a]pyrimidin-6-y1 oxy)phenyl)amino)-1,7-naphthyridine-3 -
carbonitrile
F N_N
0 HN
O CN
166
(S)-5-((3,3 -difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy-4-((3 -methyl-4-
(pyra
zolo[ 1,5 -a]pyrimidin-6-yloxy)phenyl)amino)-1, 7-naphthyridine-3 -
carbonitrile
F
'''0 HN
CN
167
N
(R)-5 ,3 -
difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy-4-((3 -methyl-4-(pyr
azol o [1, 5 -a]pyri din-6-yloxy)phenyl)amino)- 1,7-naphthyri dine-3 -
carbonitrile
F
HN
O CN
168
(S)-5-((3,3 -difluoro- 1 -methylpiperi din-4-yl)oxy)-6-methoxy-4-((3 -methyl-4-
(pyra
zol o [1, 5 -a]pyri din-6-yloxy)phenyl)amino)- 1,7-naphthyri dine-3 -
carbonitrile
F
HN
169
CN
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(R)-44(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)amino)-54(3,
3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinoline-3-carbonitrile
N FF (D. _,7-, N _
'.NN'N
0 CN
170
--
N
(S)-4-((4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)amino)-5-
((3,
3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinoline-3-carbonitrile
F
N F
' 'f0 HN N i\l'N
O CN
171
--
N
(R)-44(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylphenyl)amino)-54(3,
3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinoline-3-carbonitrile
F
N F
N
'------.'"0 HN N l\l'
O CN
\
172
..,
N
(S)-4-((4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylphenyl)amino)-5-
((3,
3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinoline-3-carbonitrile
F
N F
- ''0
O CN
,-
173
N
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-4-((3-methyl-4-(pyr
azolo[1,5-a]pyrimidin-6-yloxy)phenyl)amino)quinoline-3-carbonitrile
F
N F
174
O CN
..-
--
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(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-4-((3-methyl-4-
(pyra
zolo[1,5-a]pyrimidin-6-yloxy)phenyl)amino)quinoline-3-carbonitrile
N N
I N
175 0 NNJ
N-(4-((4-([ 1,2,4]triazolo[1, 5 -a]pyridin-7-yloxy)-3 -methylphenyl)amino)-5 -
(3 -(di
methylamino)azetidin-l-yl)pyrido[3,4-d]pyrimidin-6-y1)-4-(dimethylamino)but-2-
enamide
Compounds provided herein are described with reference to both generic
formulae and
specific compounds. In addition, compounds of the present disclosure may exist
in a
number of different forms or derivatives, all within the scope of the present
disclosure.
These include, for example, tautomers, stereoisomers, racemic mixtures,
regioisomers, salts,
prodrugs, solvated forms, different crystal forms or polymorphs, and active
metabolites.
The compounds of present disclosure can comprise one or more asymmetric
centers,
and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or
diastereomers.
Thus, inventive compounds and compositions thereof may be in the form of an
individual
enantiomer, diastereomer or geometric isomer, or may be in the form of a
mixture of
stereoisomers. In certain embodiments, the compounds of the present disclosure
are
enantiopure compounds. In certain embodiments, mixtures of enantiomers or
diastereomers
are provided.
The term "enantiomer" refers to two stereoisomers of a compound which are
non-superimposable mirror images of one another. The term "diastereomer"
refers to a pair
of optical isomers which are not mirror images of one another. Diastereomers
have
different physical properties, e.g. melting points, boiling points, spectral
properties, and
reactivities.
Furthermore, certain compounds, as described herein may have one or more
double
bonds that can exist as either the Z or E isomer, unless otherwise indicated.
The present
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disclosure additionally encompasses the compounds as individual isomers
substantially free
of other isomers and alternatively, as mixtures of various isomers, e.g.,
racemic mixtures of
enantiomers. In addition to the above-mentioned compounds per se, this
disclosure also
encompasses compositions comprising one or more compounds.
As used herein, the term "isomers" includes any and all geometric isomers and
stereoisomers. For example, "isomers" include cis- and trans-isomers, E- and Z-
isomers,
R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic
mixtures thereof,
and other mixtures thereof, as falling within the scope of the invention. For
instance, a
stereoisomer may, in some embodiments, be provided substantially free of one
or more
corresponding stereoisomers, and may also be referred to as "stereochemically
enriched".
Where a particular enantiomer is preferred, it may, in some embodiments be
provided
substantially free of the opposite enantiomer, and may also be referred to as
"optically
enriched". "Optically enriched", as used herein, means that the compound is
made up of a
significantly greater proportion of one enantiomer. In certain embodiments,
the compound
is made up of at least about 90% by weight of a preferred enantiomer. In other
embodiments, the compound is made up of at least about 95%, 98%, or 99% by
weight of a
preferred enantiomer. Preferred enantiomers may be isolated from racemic
mixtures by any
method known to those skilled in the art, including chiral high pressure
liquid
chromatography (HPLC) and the formation and crystallization of chiral salts or
prepared by
asymmetric syntheses. See, for example, Jacques, et al., Enantiomers,
Racemates and
Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al.,
Tetrahedron 33:2725
(1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY,
1962); Wilen,
S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel,
Ed., Univ. of
Notre Dame Press, Notre Dame, IN 1972).
The compounds of the present disclosure may also exist in different tautomeric
forms,
and all such forms are embraced within the scope of the present disclosure.
The term
"tautomer" or "tautomeric form" refers to structural isomers of different
energies which are
interconvertible via a low energy barrier. For example, proton tautomers (also
known as
prototropic tautomers) include interconversions via migration of a proton,
such as keto-enol,
amide-imidic acid, lactam-lactim, imine-enamine isomerizations and annular
forms where a
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proton can occupy two or more positions of a heterocyclic system (for example,
1H- and
3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H-
and 2H-
pyrazole). Valence tautomers include interconversions by reorganization of
some of the
bonding electrons. Tautomers can be in equilibrium or sterically locked into
one form by
appropriate substitution. Compounds of the present disclosure identified by
name or
structure as one particular tautomeric form are intended to include other
tautomeric forms
unless otherwise specified.
The compounds of the present disclosure also include prodrugs, active
metabolic
derivatives (active metabolites), active intermediates, solvates, hydrates,
stereoisomers, and
their pharmaceutically acceptable salts and esters.
As used herein, the term "prodrugs" refers to compounds or pharmaceutically
acceptable salts thereof which, when metabolized under physiological
conditions or when
converted by solvolysis, yield the desired active compound. Prodrugs include,
without
limitation, esters, amides, carbamates, carbonates, ureides, solvates, or
hydrates of the active
compound. Typically, the prodrug is inactive, or less active than the active
compound, but
may provide one or more advantageous handling, administration, and/or
metabolic properties.
For example, some prodrugs are esters of the active compound; during
metabolism, the ester
group is cleaved to yield the active drug. Also, some prodrugs are activated
enzymatically
to yield the active compound, or a compound which, upon further chemical
reaction, yields
the active compound. Prodrugs may proceed from prodrug form to active form in
a single
step or may have one or more intermediate forms which may themselves have
activity or
may be inactive. Preparation and use of prodrugs is discussed in T. Higuchi
and V. Stella,
"Pro-drugs as Novel Delivery Systems", Vol. 14 of the A.C.S. Symposium Series,
and in
Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American
Pharmaceutical
Association and Pergamon Press, 1987, both of which are hereby incorporated by
reference
in their entirety.
As used herein, the term "metabolite", e.g., active metabolite overlaps with
prodrug as
described above. Thus, such metabolites are pharmacologically active compounds
or
compounds that further metabolize to pharmacologically active compounds that
are
derivatives resulting from metabolic process in the body of a subject. For
example, such
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metabolites may result from oxidation, reduction, hydrolysis, amidation,
deamidation,
esterification, deesterification, enzymatic cleavage, and the like, of the
administered
compound or salt or prodrug. Of these, active metabolites are such
pharmacologically
active derivative compounds. For prodrugs, the prodrug compound is generally
inactive or
of lower activity than the metabolic product. For active metabolites, the
parent compound
may be either an active compound or may be an inactive prodrug.
Prodrugs and active metabolites may be identified using routine techniques
know in the
art. See, e.g., Bertolini et al, 1997, J Med Chem 40:2011-2016; Shan et al., J
Pharm Sci
86:756-757; Bagshawe, 1995, Drug Dev Res 34:220-230; Wermuth, supra.
As used herein, the term "active intermediate" refers to intermediate compound
in the
synthetic process, which exhibits the same or essentially the same biological
activity as the
final synthesized compound.
Compounds of the present disclosure can be formulated as or be in the form of
pharmaceutically acceptable salts. Unless specified to the contrary, a
compound provided
herein includes pharmaceutically acceptable salts of such compound.
As used herein, the term "pharmaceutically acceptable" indicates that the
substance or
composition is compatible chemically and/or toxicologically, with the other
ingredients
comprising a formulation, and/or the subjects being treated therewith.
As used herein, the term "pharmaceutically acceptable salt", unless otherwise
indicated,
includes salts that retain the biological effectiveness of the free acids and
bases of the
specified compound and that are not biologically or otherwise undesirable.
Contemplated
pharmaceutically acceptable salt forms include, but are not limited to, mono,
bis, tris, tetrakis,
and so on. Pharmaceutically acceptable salts are non-toxic in the amounts and
concentrations at which they are administered. The preparation of such salts
can facilitate the
pharmacological use by altering the physical characteristics of a compound
without
preventing it from exerting its physiological effect. Useful alterations in
physical properties
include lowering the melting point to facilitate transmucosal administration
and increasing
the solubility to facilitate administering higher concentrations of the drug.
Pharmaceutically acceptable salts include acid addition salts such as those
containing
sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate,
acetate, citrate,
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lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-
toluenesulfonate,
cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be
obtained from
acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid,
sulfamic acid,
acetic acid, citric acid, lactic acid, tartaric acid, malonic acid,
methanesulfonic acid,
ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
cyclohexylsulfamic acid,
fumaric acid, and quinic acid.
Pharmaceutically acceptable salts also include basic addition salts such as
those
containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine,
t-butylamine,
ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium,
potassium,
sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as
carboxylic
acid or phenol are present. For example, see Remington's Pharmaceutical
Sciences, 19thed.,
Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; "Handbook of
Pharmaceutical Salts:
Properties, Selection, and Use" by Stahl and Wermuth, Wiley-VCH, Weinheim,
Germany,
2002. Such salts can be prepared using the appropriate corresponding bases.
Pharmaceutically acceptable salts can be prepared by standard techniques. For
example, the free-base form of a compound can be dissolved in a suitable
solvent, such as an
aqueous or aqueous-alcohol solution containing the appropriate acid and then
isolated by
evaporating the solution. Thus, if the particular compound is a base, the
desired
pharmaceutically acceptable salt may be prepared by any suitable method
available in the art,
for example, treatment of the free base with an inorganic acid, such as
hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or
with an organic
acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric
acid, malonic
acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl
acid, such as
glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric
acid or tartaric
acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid,
such as benzoic
acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or
ethanesulfonic acid,
or the like.
Similarly, if the particular compound is an acid, the desired pharmaceutically
acceptable
salt may be prepared by any suitable method, for example, treatment of the
free acid with an
inorganic or organic base, such as an amine (primary, secondary or tertiary),
an alkali metal
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hydroxide or alkaline earth metal hydroxide, or the like. Illustrative
examples of suitable
salts include organic salts derived from amino acids, such as L-glycine, L-
lysine, and
L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic
amines, such as
hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, and inorganic
salts derived
from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,
aluminum and
lithium.
As used herein, "pharmaceutically acceptable esters" refers to esters which
hydrolyzed
in vivo and include those that break down readily in human body to leave the
parent
compound or a salt thereof. Such esters act as a prodrug as defined herein.
The esters can be
formed with an amine, hydroxyl, or carboxyl side chain on the compounds
described herein.
For example, if a disclosed compound contains an alcohol functional group, an
ester can be
formed by the replacement of the hydrogen atom of the alcohol group with an
acidic group
such as, including, but not limited to, carboxylic acids, phosphoric acids,
phosphinic acids,
sulfinic acids, sulfonic acids and boronic acids groups.
It is also to be understood that the compounds of present disclosure can exist
in
unsolvated forms, solvated forms (e.g., hydrated forms), and solid forms
(e.g., crystal or
polymorphic forms), and the present disclosure is intended to encompass all
such forms.
As used herein, the term "solvate" or "solvated form" refers to solvent
addition forms
that contain either stoichiometric or non stoichiometric amounts of solvent.
Some
compounds have a tendency to trap a fixed molar ratio of solvent molecules in
the crystalline
solid state, thus forming a solvate. If the solvent is water the solvate
formed is a hydrate;
and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates
are formed by
the combination of one or more molecules of water with one molecule of the
substance in
which the water retains its molecular state as H20. Examples of solvents that
form solvates
include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO,
ethyl acetate,
acetic acid, and ethanolamine.
As used herein, the terms "crystal form", "crystalline form", "polymorphic
forms" and
"polymorphs" can be used interchangeably, and mean crystal structures in which
a compound
(or a salt or solvate thereof) can crystallize in different crystal packing
arrangements, all of
which have the same elemental composition. Different crystal forms usually
have different
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X-ray diffraction patterns, infrared spectral, melting points, density
hardness, crystal shape,
optical and electrical properties, stability and solubility. Recrystallization
solvent, rate of
crystallization, storage temperature, and other factors may cause one crystal
form to
dominate. Crystal polymorphs of the compounds can be prepared by
crystallization under
different conditions.
The present disclosure is also intended to include includeall isotopes of
atoms in the
compounds. Isotopes of an atom include atoms having the same atomic number but
different
mass numbers. For example, unless otherwise specified, hydrogen, carbon,
nitrogen, oxygen,
phosphorous, sulphur, fluorine, chlorine, bromide or iodine in the compounds
of present
disclosure are meant to also include their isotopes, such as but not limited
to 1H, 2H, 3H, nc,
12c, 13C, 14C, 14N, 15N, 160, 170, 180, 3113 3213 325, 335,345, 365, 17F,
r 35C1, 37C1, 79Br, 81Br,
1271 and 1311. In some embodiments, hydrogen includes protium, deuterium and
tritium. In
some embodiments, carbon includes 12C and 13C.
SYNTHESIS OF THE COMPOUNDS
Synthesis of the compounds provided herein, including pharmaceutically
acceptable
salts thereof, are illustrated in the synthetic schemes in the examples. The
compounds
provided herein can be prepared using any known organic synthesis techniques
and can be
synthesized according to any of numerous possible synthetic routes, and thus
these schemes
are illustrative only and are not meant to limit other possible methods that
can be used to
prepare the compounds provided herein. Additionally, the steps in the Schemes
are for better
illustration and can be changed as appropriate. The embodiments of the
compounds in
examples were synthesized for the purposes of research and potentially
submission to
regulatory agencies.
The reactions for preparing compounds of the present disclosure can be carried
out in
suitable solvents, which can be readily selected by one skilled in the art of
organic synthesis.
Suitable solvents can be substantially non-reactive with the starting
materials (reactants), the
intermediates, or products at the temperatures at which the reactions are
carried out, e.g.
temperatures that can range from the solvent's freezing temperature to the
solvent's boiling
temperature. A given reaction can be carried out in one solvent or a mixture
of more than one
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solvent. Depending on the particular reaction step, suitable solvents for a
particular reaction
step can be selected by one skilled in the art.
Preparation of compounds of the present disclosure can involve the protection
and
deprotection of various chemical groups. The need for protection and
deprotection, and the
selection of appropriate protecting groups, can be readily determined by one
skilled in the art.
The chemistry of protecting groups can be found, for example, in T. W. Greene
and P. G. M.
Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New
York (1999),
which is incorporated herein by reference in its entirety.
Reactions can be monitored according to any suitable method known in the art.
For
example, product formation can be monitored by spectroscopic means, such as
nuclear
magnetic resonance spectroscopy (e.g. 'H or 13C), infrared spectroscopy,
spectrophotometry
(e.g. UV-visible), mass spectrometry, or by chromatographic methods such as
high
performance liquid chromatography (HPLC), liquid chromatography-mass
spectroscopy
(LCMS), or thin layer chromatography (TLC). Compounds can be purified by one
skilled in
the art by a variety of methods, including high performance liquid
chromatography (HPLC)
("Preparative LC-MS Purification: Improved Compound Specific Method
Optimization"
Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem.
2004, 6(6),
874-883, which is incorporated herein by reference in its entirety), and
normal phase silica
chromatography.
The structures of the compounds in the examples are characterized by nuclear
magnetic
resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR
chemical shift (6) is given in the unit of 10' (ppm). 1H-NMR spectra is
recorded in CDC13,
CD3OD or DMSO-d6 solutions (reported in ppm) on a Varian instrument (400 MHz),
using
tetramethylsilane (TMS) as the reference standard (0.0 ppm).
MS measurement is carried out using Shimadzu 2010 Mass Spectrometer or Agilent
6110A MSD or 1969A TOF mass spectrometer using electrospray, chemical and
electron
impact ionization methods from a range of instruments.
TLC measurement is carried out using Yantai Huanghai H5GF254 silica gel or
Anhui
Liang Chen Gui Yuan plates. The silica gel plates used for TLC are 0.15mm-
0.2mm. The
silica gel plates used for separating and purifying products by TLC are 0.4mm-
0.5mm.
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Column chromatography was done on a Biotage system (Manufacturer: Dyax
Corporation) having a silica gel column or on a silica SepPak cartridge
(Waters).
The known starting materials of the present disclosure can be synthesized by
using or
according to the known methods in the art, or can be purchased from commercial
suppliers
such as Aldrich Chemical Company, Adamas-beta, TCI or Accela ChemBio Co., Ltd,
and
were used without further purification unless otherwise indicated.
Tetrahydrofuran (THF),
N,N-dimethylformamide (DMF), dichloromethane (DCM), dichloroethane (DCE),
dioxane
and 1,1,2,2-tetrachloroethane were purchased from Aldrich in Sure seal bottles
and used as
received.
Unless otherwise specified, the reactions of the present disclosure were all
done under a
positive pressure of nitrogen or argon or with a drying tube in anhydrous
solvents, and the
reaction flasks were typically fitted with rubber septa for the introduction
of substrates and
reagents via syringe. Glassware was oven dried and/or heat dried.
For illustrative purposes, the following shows general synthetic route for
preparing the
compounds of the present disclosure as well as key intermediates. For a more
detailed
description of the individual reaction steps, see the Examples section below.
Those skilled
in the art will appreciate that other synthetic routes may be used to
synthesize the inventive
compounds. Although specific starting materials and reagents are depicted in
the Schemes
and discussed below, other starting materials and reagents can be easily
substituted to provide
a variety of derivatives and/or reaction conditions. In addition, many of the
compounds
prepared by the methods described below can be further modified in light of
this disclosure
using conventional chemistry well known to those skilled in the art.
USE OF COMPOUNDS
The compounds of the present disclosure (as used herein, "a compound of the
present
disclosure" or "compounds of the present disclosure" refers to any compound of
Formula (I),
Formula (II) and Formula (III), as well as the various more specific
embodiments thereof as
described herein, as well as solvates, hydrates, stereoisomers, or
pharmaceutically salts or
esters thereof) show inhibitory activity against type I receptor tyrosine
kinase, in particular
HER2.
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As used herein, the term "inhibitory activity against type I receptor tyrosine
kinase"
refers to a decrease in the activity of type I receptor tyrosine kinase as a
direct or indirect
response to the presence of a compound of the present disclosure, or a
solvate, hydrate,
stereoisomer, or a pharmaceutically salt or ester thereof, relative to the
activity of type I
receptor tyrosine kinase in the absence of compounds of the present
disclosure. Such a
decrease in activity may be due to the direct interaction of the compound of
the present
disclosure with type I receptor tyrosine kinase, or due to the interaction of
the compound of
the present disclosure, with one or more other factors that in turn affect
activity of type I
receptor tyrosine kinase. For example, the compounds of the present disclosure
may
decrease activity of type I receptor tyrosine kinase by directly binding to
the type I receptor
tyrosine kinase, by causing (directly or indirectly) another factor to
decrease type I receptor
tyrosine kinase activity, or by (directly or indirectly) decreasing the amount
of type I receptor
tyrosine kinase present in the cell or organism.
In some embodiments, the compounds of the present disclosure are selective
inhibitors
for HER2 over other type I receptor tyrosine kinases, such as wild type EGFR
(wt-EGFR).
As used herein, the term "selective inhibitor of HER2" or "selectively
inhibitsHER2"
means that a provided compound inhibits HER2 in at least one assay described
herein (e.g.,
biochemical or cellular) over other type I receptor tyrosine kinases, such as
wt-EGFR. In
some embodiments, the term "selective inhibitor of HER2 over EGFR" or
"selectively
inhibitsHER2 over EGFR" means that a provided compound has the IC50 for wt-
EGFR at
least 10 fold higher, at least 20 fold higher, at least 30 fold higher, at
least 40 fold higher, at
least 50 fold higher, at least 60 fold higher, at least 70 fold higher, at
least 80 fold higher, at
least 90 fold higher, at least 100 fold higher, at least 200 fold higher, at
least 300 fold higher,
at least 400 fold higher, at least 500 fold higher, at least 600 fold higher,
at least 700 fold
higher, at least 800 fold higher, at least 900 fold higher, at least 1000 fold
higher, at least
2000 fold higher than the IC50 for HER2, as determined by assays described
herein.
Accordingly, there is provided compounds of the present disclosure which are
highly
potent HER2 inhibitors and are highly selective for HER2 relative to EGFR.
Such
compounds would allow treatment of cancers which can be treated by inhibiting
HER2, for
example cancers which express or overexpress HER2, in a relatively selective
manner,
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thereby minimizing potential side effects associated with the inhibition of
other kinases such
as EGFR.
In some embodiments, the compounds of the present disclosure are not P-
glycoprotein
(Pgp) substrates, nor ATP-binding cassette sub-family G member 2 (ABCG2, or
BCRP)
substrates. As used herein, the term "Pgp substrate" means that a given
compound is
susceptible to transportation back into the intestinal lumen (in the case of
Pgp distributed in
intestinal epithelium), bile ducts (in the case of Pgp distributed in liver
cells), urinar filtrate
(in the case of Pgp distributed in the cells of the proximal tubule of the
kidney), capillaries
(in the case of Pgp distributed in the capillary endothelial cells composing
the blood-brain
barrier and blood-testis barrier) and the like, by Pgp. As used herein, the
term "BCRP
substrate" means that a given compound is blocked from being absorption at the
apical
membrane of the intestine, the blood-testis barrier, the blood-brain barrier,
and the
membranes of hematopoietic progenitor and other stem cells, in particular the
blood-brain
barrier, by BCRP. Therefore, there is provided compounds which demonstrate
good brain
penetration in subjects, allowing for applications in treating both
extracranial cancers and
metastatic cancer, such as brain metastases.
In some embodiments, the Pgp and BCRP susceptibility of a compound can be
evaluated by MDCK-MDR1 Pgp permeability assay and Caco-2 BCRP permeability
assay,
respectively, as described in detail in Example section below. In some
embodiments, the
compounds of the present disclosure show low Pgp susceptibility with a MDCK-
Pgp efflux
ratio (MDCK-Pgp ER) of less than about 5, less than about 4, less than about
3, less than
about 2, less than about 1.
In some embodiments, the compounds of the present disclosure are capable of in
vivo
brain penetration, as determined by mouse SOA study described in detail in
Example section
below. In some embodiments, the compounds of the present disclosure show a
brain to
blood concentration ratio Kp of greater than about 0.1, greater than about
0.15, greater than
about 0.2, greater than about 0.25, greater than about 0.3, greater than about
0.35, greater
than about 0.4, greater than about 0.45, greater than about 0.5.
Accordingly, there is provided compounds of the present disclosure that are
capable of
crossing blood-brain barrier, without the need of any agent for facilitating
the blood-brain
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barrier entry. Such compounds would allow treatment of metastatic cancer, such
as brain
metastases, in particular brain metastases of breast cancer.
In some embodiments, the compounds of the present disclosure show low hERG
inhibition, as determined by hEGR inhibition assay described in detail in
Example section
below. In some embodiments, the compounds of the present disclosure show a
hERG
inhibition IC50 of greater than about 2 uM, greater than about 3 uM, greater
than about 4 uM,
greater than about 5 [NI, greater than about 6 uM, greater than about 7 uM,
greater than
about 8 [NI, greater than about 9 uM, greater than about 10 uM. This indicates
the
compounds provided herein have low risk of cardiac toxicity in vivo.
As a result of their inhibitory activity against type I receptor tyrosine
kinase (optionally
selective HER2 inhibitory activity), the compounds of the present disclosure
are useful in
therapy, for example in the treatment of diseases or medical conditions
mediated at least in
part by one or more type I receptor tyrosine kinases, including cancer.
As used herein, the term "cancer" is intended to encompass both non-metastatic
cancer
and metastatic cancer. In this context, treating cancer involves treatment of
both primary
tumors and tumor metastases.
As used herein, the term "therapy" is intended to have its normal meaning of
dealing
with a disease in order to entirely or partially relieve one, some or all of
its symptoms, or to
correct or compensate for the underlying pathology, thereby achieving
beneficial or desired
clinical results. For purposes of this disclosure, beneficial or desired
clinical results include,
but are not limited to, alleviation of symptoms, diminishment of extent of
disease, stabilized
(i.e., not worsening) state of disease, delay or slowing of disease
progression, amelioration or
palliation of the disease state, and remission (whether partial or total),
whether detectable or
undetectable. "Therapy" can also mean prolonging survival as compared to
expected
survival if not receiving it. Those in need of therapy include those already
with the condition
or disorder as well as those prone to have the condition or disorder or those
in which the
condition or disorder is to be prevented. The term "therapy" also encompasses
prophylaxis
unless there are specific indications to the contrary. The terms "therapeutic"
and
"therapeutically" should be interpreted in a corresponding manner.
As used herein, the term "prophylaxis" is intended to have its normal meaning
and
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includes primary prophylaxis to prevent the development of the disease and
secondary
prophylaxis whereby the disease has already developed and the patient is
temporarily or
permanently protected against exacerbation or worsening of the disease or the
development
of new symptoms associated with the disease.
The term "treatment" is used synonymously with "therapy". Similarly the term
"treat"
can be regarded as "applying therapy" where "therapy" is as defined herein.
In some embodiments, the compounds of the present disclosure possess
anti-cell-proliferation properties, which are believed to arise from their
type I receptor
tyrosine kinase inhibitory activity. Accordingly, the compounds of the present
disclosure
are expected to be useful in the treatment of diseases or conditions mediated
alone or in part
by type I receptor tyrosine kinases, i.e. the compounds may be used to produce
an
anti-proliferative effect mediated alone or in part by inhibiting type I
receptor tyrosine
kinases. In some embodiments, such disease or condition treated by providing
an
anti-proliferative effect is type I receptor tyrosine kinase sensitive
cancers, including but not
limited to breast cancer, lung cancer, colon cancer, rectum cancer, stomach
cancer, prostate
cancer, bladder cancer, pancreas cancer and ovary cancer, or other cell-
proliferation diseases
such as psoriasis.
Therefore, in one aspect, there is provided a compound of the present
disclosure for use
in therapy.
In some embodiments, there is provided a compound of the present disclosure
for use as
a medicament.
In some embodiments, there is provided a compound of the present disclosure
for use in
the treatment of diseases or conditions mediated alone or in part by type I
receptor tyrosine
kinases.
In some embodiments, there is provided a compound of the present disclosure
for use in
the manufacture of a medicament for the treatment of type I receptor tyrosine
kinase-associated diseases or conditions.
In some embodiments, there is provided a compound of the present disclosure
for use in
the manufacture of a medicament for the treatment of HER2-associated diseases
or
conditions.
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In some embodiments, there is provided a compound of the present disclosure
for use in
the manufacture of a medicament for the treatment of cancer.
PHARMACEUTICAL COMPOSITION
The present disclosure provides pharmaceutical compositions comprising one or
more
compound of the present disclosure. In some embodiments, the pharmaceutical
composition comprises one or more compounds of the present disclosure and at
least one
pharmaceutically acceptable excipient.
A "pharmaceutical composition", as used herein, is a formulation containing
the
compounds of the present disclosure in a form suitable for administration to a
subject. In
some embodiments, the pharmaceutical composition is in bulk or in unit dosage
form. The
unit dosage form is any of a variety of forms, including, for example,
tablets, capsules, pills,
powders, granules, sachets, cachets, lozenges, suspensions, emulsions,
solutions, syrups,
aerosols (as a solid or in a liquid medium), spray, ointment, paste, cream,
lotion, gel, patch,
inhalant, or suppository. The quantity of active ingredient (e.g., a
formulation of the
disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose
of composition
is a therapeutically effective amount and is varied according to the
particular treatment
involved. One skilled in the art will appreciate that it is sometimes
necessary to make
routine variations to the dosage depending on the age and condition of the
patient. The
dosage will also depend on the route of administration. A variety of routes
are
contemplated, including oral, pulmonary, rectal, parenteral, transdermal,
subcutaneous,
intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual,
intrapleural,
intrathecal, intranasal, and the like. Dosage forms for the topical or
transdermal
administration of a compound of this invention include powders, sprays,
ointments, pastes,
creams, lotions, gels, solutions, patches and inhalants. In some embodiments,
the
compound of the present disclosure is mixed under sterile conditions with a
pharmaceutically
acceptable excipient, and with any preservatives, buffers or propellants that
are required.
As used herein, the term "pharmaceutically acceptable excipient" means an
excipient
that is useful in preparing a pharmaceutical composition that is generally
safe, non-toxic and
neither biologically nor otherwise undesirable, and includes excipient that is
acceptable for
veterinary use as well as human pharmaceutical use. A "pharmaceutically
acceptable
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excipient" as used in the specification and claims includes both one and more
than one such
excipient. The term "pharmaceutically acceptable excipient" also encompasses
"pharmaceutically acceptable carrier" and "pharmaceutically acceptable
diluent".
The particular excipient, carrier, or diluent or used will depend upon the
means and
purpose for which the compounds of the present disclosure is being applied.
Solvents are
generally selected based on solvents recognized by persons skilled in the art
as safe (GRAS)
to be administered to a mammal. In general, safe solvents are non-toxic
aqueous solvents
such as water and other non-toxic solvents that are soluble or miscible in
water. Suitable
aqueous solvents include water, ethanol, propylene glycol, polyethylene
glycols (e.g., PEG
400, PEG 300), etc. and mixtures thereof. Acceptable excipients, diluents, and
carriers, and
stabilizers are nontoxic to recipients at the dosages and concentrations
employed, and include
buffers such as phosphate, citrate and other organic acids; antioxidants
including ascorbic
acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium
chloride;
hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol,
butyl or
benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol;
resorcinol;
cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about
10 residues)
polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins;
hydrophilic
polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine,
asparagine,
histidine, arginine, or lysine; monosaccharides, disaccharides and other
carbohydrates
including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars
such as
sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as
sodium; metal
complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as
TWEENTm,
PLURONICSTM or polyethylene glycol (PEG).
The composition may also comprise one or more stabilizing agents, surfactants,
wetting
agents, lubricating agents, emulsifiers, suspending agents, preservatives,
antioxidants,
opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming
agents,
flavoring agents and other known additives to provide an elegant presentation
of the drug
(i.e., a compound of the present disclosure or pharmaceutical composition
thereof) or aid in
the manufacturing of the pharmaceutical product (i.e., medicament). The active
pharmaceutical ingredients may also be entrapped in microcapsules prepared,
for example,
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by coacervation techniques or by interfacial polymerization, for example,
hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate)
microcapsules, respectively, in colloidal drug delivery systems (for example,
liposomes,
albumin microspheres, microemulsions, nano-particles and nanocapsules) or in
macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical
Sciences
16th edition, Osol, A. Ed. (1980). A "liposome" is a small vesicle composed of
various
types of lipids, phospholipids and/or surfactant which is useful for delivery
of a drug (such as
the compounds disclosed herein and, optionally, a chemotherapeutic agent) to a
mammal.
The components of the liposome are commonly arranged in a bilayer formation,
similar to
the lipid arrangement of biological membranes.
The pharmaceutical compositions of compounds of the present disclosure may be
in the
form of a sterile injectable preparation, such as a sterile injectable aqueous
or oleaginous
suspension. This suspension may be formulated according to the known art using
those
suitable dispersing or wetting agents and suspending agents which have been
mentioned
above. The sterile injectable preparation may also be a sterile injectable
solution or
suspension in a non-toxic parenterally acceptable diluent or solvent, such as
a solution in
1,3-butanediol or prepared as a lyophilized powder. Among the acceptable
vehicles and
solvents that may be employed are water, Ringer's solution and isotonic sodium
chloride
solution. In addition, sterile fixed oils may conventionally be employed as a
solvent or
suspending medium. For this purpose any bland fixed oil may be employed
including
synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid
may likewise be
used in the preparation of injectables.
Compositions suitable for parenteral administration include aqueous and
nonaqueous
sterile injection solutions which may contain anti-oxidants, buffers,
bacteriostats and solutes
which render the formulation isotonic with the blood of the intended
recipient; and aqueous
and non-aqueous sterile suspensions which may include suspending agents and
thickening
agents.
The pharmaceutical compositions of the present disclosure may also be in a
form
suitable for oral use(for example as tablets, lozenges, hard or soft capsules,
aqueous or oily
suspensions, emulsions, dispersible powders or granules, syrups or elixirs),
for topical use
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(for example as creams, ointments, gels, or aqueous or oily solutions or
suspensions), for
administration by inhalation (for example as a finely divided powder or a
liquid aerosol), for
administration by insufflation (for example as a finely divided powder)
Suitable pharmaceutically-acceptable excipients for a tablet formulation
include, for
example, inert diluents such as lactose, sodium carbonate, calcium phosphate
or calcium
carbonate, granulating and disintegrating agents such as corn starch or
alginic acid; binding
agents such as starch; lubricating agents such as magnesium stearate, stearic
acid or talc;
preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-
oxidants, such as
ascorbic acid. Tablet formulations may be uncoated or coated either to modify
their
disintegration and the subsequent absorption of the active ingredient within
the
gastrointestinal tract, or to improve their stability and/or appearance, in
either case using
conventional coating agents and procedures well known in the art.
Formulations for oral use may be in the form of hard gelatin capsules in which
the
active ingredient is mixed with an inert solid diluent, for example, calcium
carbonate,
calcium phosphate or kaolin, or as soft gelatin capsules in which the active
ingredient is
mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions generally contain the active ingredient in finely powdered
form
together with one or more suspending agents, such as sodium
carboxymethylcellulose,
methylcellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinyl-
pyrrolidone,
gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin
or condensation
products of an alkylene oxide with fatty acids (for example polyoxethylene
stearate), or
condensation products of ethylene oxide with long chain aliphatic alcohols,
for example
heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with
partial esters
derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
monooleate, or
condensation products of ethylene oxide with partial esters derived from fatty
acids and
hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous
suspensions
may also contain one or more preservatives (such as ethyl or propyl p-
hydroxybenzoate,
anti-oxidants (such as ascorbic acid), coloring agents, flavoring agents,
and/or sweetening
agents (such as sucrose, saccharine or aspartame).
Oily suspensions may be formulated by suspending the active ingredient in a
vegetable
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oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a
mineral oil (such as liquid
paraffin). The oily suspensions may also contain a thickening agent such as
beeswax, hard
paraffin or cetyl alcohol. Sweetening agents such as those set out above, and
flavoring agents
may be added to provide a palatable oral preparation. These compositions may
be preserved
by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous
suspension by
the addition of water generally contain the active ingredient together with a
dispersing or
wetting agent, suspending agent and one or more preservatives. Suitable
dispersing or
wetting agents and suspending agents are exemplified by those already
mentioned above.
Additional excipients such as sweetening, flavoring and coloring agents, may
also be present.
The pharmaceutical compositions of the present disclosure may also be in the
form of
oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive
oil or arachis oil,
or a mineral oil, such as for example liquid paraffin or a mixture of any of
these. Suitable
emulsifying agents may be, for example, naturally-occurring gums such as gum
acacia or
gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin,
esters or partial
esters derived from fatty acids and hexitol anhydrides (for example sorbitan
monooleate) and
condensation products of the said partial esters with ethylene oxide such as
polyoxyethylene
sorbitan monooleate. The emulsions may also contain sweetening, flavoring and
preservative
agents.
Syrups and elixirs may be formulated with sweetening agents such as glycerol,
propylene glycol, sorbitol, aspartame or sucrose, and may also contain a
demulcent,
preservative, flavoring and/or coloring agent.
Suppository formulations may be prepared by mixing the active ingredient with
a
suitable non-irritating excipient that is solid at ordinary temperatures but
liquid at the rectal
temperature and will therefore melt in the rectum to release the drug.
Suitable excipients
include, for example, cocoa butter and polyethylene glycols. Formulations
suitable for
vaginal administration may be presented as pessaries, tampons, creams, gels,
pastes, foams or
spray formulations containing in addition to the active ingredient such
carriers as are known
in the art to be appropriate.
Topical formulations, such as creams, ointments, gels and aqueous or oily
solutions or
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suspensions, may generally be obtained by formulating an active ingredient
with a
conventional, topically acceptable, vehicle or diluent using conventional
procedures well
known in the art.
Formulations for transdermal administration may be in the form of those
transdermal
skin patches that are well known to those of ordinary skill in the art.
Formulations suitable for intrapulmonary or nasal administration have a
particle size for
example in the range of 0.1 to 500 microns (including particle sizes in a
range between 0.1
and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns,
etc.), which
is administered by rapid inhalation through the nasal passage or -by
inhalation through the
mouth so as to reach the alveolar sacs. Suitable formulations include aqueous
or oily
solutions of the active ingredient. Formulations suitable for aerosol or dry
powder
administration may be prepared according to conventional methods and may be
delivered
with other therapeutic agents such as compounds heretofore used in the
treatment or
prophylaxis disorders as described below.
The pharmaceutical composition (or formulation) for application may be
packaged in a
variety of ways depending upon the method used for administering the drug. For
example,
an article for distribution can include a container having deposited therein
the pharmaceutical
composition in an appropriate form. Suitable containers are well known to
those skilled in
the art and include materials such as bottles (plastic and glass), sachets,
ampoules, plastic
bags, metal cylinders, and the like. The container may also include a tamper-
proof
assemblage to prevent indiscreet access to the contents of the package. In
addition, the
container has deposited thereon a label that describes the contents of the
container. The
label may also include appropriate warnings. The compositions may also be
packaged in
unit-dose or multi-dose containers, for example sealed ampoules and vials, and
may be stored
in a freeze-dried (lyophilized) condition requiring only the addition of the
sterile liquid
carrier, for example water, for injection immediately prior to use.
Extemporaneous
injection solutions and suspensions are prepared from sterile powders,
granules and tablets of
the kind previously described.
In another aspect, there is also provided veterinary compositions comprising a
compound of the present disclosure together with a veterinary carrier.
Veterinary carriers
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are materials useful for the purpose of administering the composition and may
be solid,
liquid or gaseous materials which are otherwise inert or acceptable in the
veterinary art and
are compatible with the active ingredient. These veterinary compositions may
be
administered parenterally, orally or by any other desired route.
As used herein, the term "therapeutically effective amount" refers to an
amount of a
pharmaceutical agent to treat, ameliorate, or prevent an identified disease or
condition, or to
exhibit a detectable therapeutic or inhibitory effect. The effect can be
detected by any assay
method known in the art. The precise effective amount for a subject will
depend upon the
subject's body weight, size, and health; the nature and extent of the
condition; the rate of
administration; the therapeutic or combination of therapeutics selected for
administration;
and the discretion of the prescribing physician. Therapeutically effective
amounts for a
given situation can be determined by routine experimentation that is within
the skill and
judgment of the clinician.
In some embodiments, the pharmaceutical compositions can be formulated so that
a
dosage of between 0.001-500 mg/kg body weight/day, for example, 0.01-400 mg/kg
body
weight/day, 0.01-300 mg/kg body weight/day, 0.1-200 mg/kg body weight/day, 0.1-
150
mg/kg body weight/day, 0.1-100 mg/kg body weight/day, 0.5-100 mg/kg body
weight/day,
0.5-80 mg/kg body weight/day, 0.5-60 mg/kg body weight/day, 0.5-50 mg/kg body
weight/day, 1-50 mg/kg body weight/day, 1-40 mg/kg body weight/day of the
compounds of
the present disclosure can be administered. In some instances, dosage levels
below the
lower limit of the aforesaid range may be more than adequate, while in other
cases still larger
doses may be employed without causing any harmful side effect, provided that
such larger
doses are first divided into several small doses for administration throughout
the day. For
further information on routes of administration and dosage regimes, see
Chapter 25.3 in
Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of
Editorial
Board), Pergamon Press 1990, which is specifically incorporated herein by
reference.
In some embodiments, the pharmaceutical compositions comprise one or more
compounds of the present disclosure, as a first active ingredient, and further
comprise a
second active ingredient.
In some embodiments, the second active ingredient of the pharmaceutical
combination
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formulation or dosing regimen has complementary activities to the compound of
the present
disclosure such that they do not adversely affect each other. Such ingredients
are suitably
present in combination in amounts that are effective for the purpose intended.
In certain embodiments, the second active ingredient can be any anti-tumor
agent
known in the art. The anti-tumor agent can be selected from the following
categories:
(i) antiproliferative/anti-neoplastic drugs and combinations thereof, such as
TKIs (such
as lapatinib, neratinib and afatinib); DNA alkylating agents (for example
cisplatin, oxaliplatin,
carboplatin, cyclophosphamide, nitrogen mustards like ifosfamide,
bendamustine, melphalan,
chlorambucil, busulphan, temozolamide and nitrosoureas like carmustine);
antimetabolites
(for example capecitabine, gemcitabine and antifolates such as
fluoropyrimidines like
5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside,
and hydroxyurea);
anti-tumour antibiotics (for example anthracyclines like adriamycin,
bleomycin, doxorubicin,
liposomal doxorubicin, pirarubicin, daunomycin, valrubicin, epirubicin,
idarubicin,
mitomycin-C, dactinomycin, amrubicin and mithramycin); antimitotic agents (for
example
vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and
taxoids like taxol
and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for
example
epipodophyllotoxins like etoposide and teniposide, amsacrine, irinotecan,
topotecan and
camptothecin); inhibitors of DNA repair mechanisms such as CHK kinase; DNA-
dependent
protein kinase inhibitors; inhibitors of poly (ADP-ribose) polymerase (PARP
inhibitors,
including olaparib); and Hsp90 inhibitors such as tanespimycin and
retaspimycin, inhibitors
of ATR kinase (such as AZD6738); and inhibitors of WEE 1 kinase (such as
AZD1775/MK-1775);
(ii) cytostatic agents such as antiestrogens (for example, tamoxifen,
toremifene,
raloxifene, droloxifene and iodoxyfene); estrogen receptor down regulators
(for example,
fulvestratrant); antiandrogens (for example, bicalutamide, flutamide,
nilutamide, cyproxerone
acetate and CASODEXTM
(4'-cyano-3-(4-fluorophenylsulphony1)-2-hydroxy-2-methy1-3'-
(trifluoromethyl)propionanili
de)); LHRH antagonists or LHRH agonists (for example, goserelin, leuporelin
and buserelin);
progestogens (for example, megestrol acetate); aromatase inhibitors (for
example,
asanastrozole, letrozole, vorazole and exemestane); inhibitors of 5a-reductase
such as
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finasteride; and p38 inhibitors such as those disclosed in U.S. Publication
Nos.
2004/0176325, 2004/0180896, and 2004/0192635;
(iii) agents which inhibit cancer cell invasion (for example,
metalloproteinase inhibitors
like marimastat and inhibitors of urokinase plasminogne activator receptor
function);
(iv) inhibitors of growth factor function such as growth factor antibodies,
growth factor
receptor antibodies (for example, the anti-ErbB2 antibody such astrastumuzab
[HERCEPTINTm] and the anti-ErbB1 antibody cetuximab [C225]), antibody drug
conjugates
(for example, T-DM1), farnesyl transferase inhibitors, tyrosine kinase
inhibitors and
serine-threonine kinase inhibitors (for example, inhibitors of the epidermal
growth factor
family tyrosine kinases such as
N-(3-chloro-4-fluoropheny1)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-
amine
(gefitinib, ZD1839), N-(3-ethynylpheny1)-6,7-bis(2-methoxyethoxy)quinazolin-4-
amine
(erlotinib, OSI-774) and
6-acrylamido-N-(3-chloro-4-fluoropheny1)-7-(3-mopholinopropoxy)quinazolin-4-
amine (CI
1033)); inhibitors of the platelet-derived growth factor family; inhibitors of
the hepatocyte
growth factor family; and MEK inhibitors such as PD325901 and compounds such
as those
disclosed in U.S. Patent Publication 2004/0116710;
(v) antiangiogenic agents such as those which inhibit the effects of vascular
endothelial
growth factor, such as but not limited to, the anti-vascular endothelial cell
growth factor
antibody bevacizumab, a VEGF receptor tyrosine kinase inhibitor such as
vandetanib
(ZD6474), sorafenib, vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-
013736),
pazopanib (GW 786034) and cediranib (AZD2171); compounds such as those
disclosed in
International Patent Applications W097/22596, WO 97/30035, WO 97/32856 and WO
98/13354; and compounds that work by other mechanisms (for example linomide,
inhibitors
of integrin av133 function and angiostatin), or inhibitors of angiopoietins
and their receptors
(Tie-1 and Tie-2), inhibitors of PLGF, inhibitors of delta- like ligand (DLL-
4);
(vi) vascular damaging agents such as Combretastatin A4 and compounds
disclosed in
PCT Publication Nos. WO 99/02166, WO 0/40529, WO 00/41669, WO 01/92224, WO
02/04434, and WO 02/08213;
(vii) antisense therapies (for example, those which are directed to the
targets listed
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above such as ISIS 2503, and anti-ras antisense);
(viii) gene therapy approaches, including for example GVAXTM, approaches to
replace
aberrant genes such as aberrant p53 or aberrant BRCAI or BRCA2, GDEPT (gene-
directed
enzyme pro-drug therapy) approaches such as those using cytosine deaminase,
thymidine
kinase or a bacterial nitroreductase enzyme and approaches to increase patient
tolerance to
chemotherapy or radiotherapy such as multi-drug resistance gene therapy;
(ix) interferon;
(x) immunotherapy approaches, including, but not limited to, ex-vivo and in-
vivo
approaches to increase the immunogenicity of patient tumour cells, such as
transfection with
cytokines such as interleukin 2, interleukin 4 or granulocyte -macrophage
colony stimulating
factor; approaches to decrease T-cell anergy or regulatory T-cell function;
approaches that
enhance T-cell responses to tumours, such as blocking antibodies to CTLA4 (for
example
ipilimumab and tremelimumab), B7H1, PD-1 (for example BMS-936558 or AMP-514),
PD-Li (for example MEDI4736) and agonist antibodies to CD137; approaches using
transfected immune cells such as cytokine-transfected dendritic cells;
approaches using
cytokine-transfected tumour cell lines, approaches using antibodies to tumour
associated
antigens, and antibodies that deplete target cell types (e.g., unconjugated
anti-CD20
antibodies such as Rituximab, radiolabeled anti-CD20 antibodies Bexxar and
Zevalin, and
anti-CD54 antibody Campath); approaches using anti-idiotypic antibodies;
approaches that
enhance Natural Killer cell function; and approaches that utilize antibody-
toxin conjugates
(e.g. anti-CD33 antibody Mylotarg); immunotoxins such as moxetumumabpasudotox;
agonists of toll-like receptor 7 or toll-like receptor 9;
(xi) efficacy enhancers, such as leucovorin.
Accordingly, there is provided pharmaceutical composition comprising a
compound of
the present disclosure, and at least one additional anti-tumor agent.
In some embodiment, the additional anti-tumour agent is selected from the
group
consisting of TKIs (such as lapatinib, neratinib and afatinib), anti-HER2
agents (for example,
monoclonal antibodies such as Trastuzumab, ADCs such as T-DM1) and combination
thereof. In some embodiments, the additional anti-tumour agent includes
capecitabine,
anti-HER2 antibodies, and T-DM1. In some embodiments, there is one additional
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anti-tumour agent. In some embodiments, there are two additional anti-tumour
agents. In
some embodiments, there are three or more additional anti-tumour agents.
In some embodiments, the amount of additional anti-tumour agent present in the
composition of the present disclosure can be no more than the amount that
would normally
be administered in a composition comprising that anti-tumour agent as the only
active agent.
In certain embodiments, the amount of the additional anti-tumor agent in the
composition of
the present disclosure will range from about 50% to 100% of the amount
normally present in
a composition comprising that anti-tumor agent as the only therapeutically
active agent.
The compound(s) of the present disclosure and the second active ingredient(s),
may be
administered together in a unitary pharmaceutical composition or separately
and, when
administered separately this may occur simultaneously or sequentially in any
order. Such
sequential administration may be close in time or remote in time. The amounts
of the
compound(s) of the present disclosure and the second agent(s) and the relative
timings of
administration will be selected in order to achieve the desired combined
therapeutic effect
Suitable dosages for any of the above co-administered agents are those
presently used
and may be lowered due to the combined action (synergy) of the newly
identified agent and
other chemotherapeutic agents or treatments.
As used herein, the term "combination" refers to simultaneous, separate or
sequential
administration. In some embodiments, "combination" refers to simultaneous
administration.
In some embodiments, "combination" refers to separate administration. In some
embodiments, "combination" refers to sequential administration. Where the
administration
is sequential or separate, the delay in administering the second component
should not be such
as to lose the beneficial effect of the combination.
Therefore, in another aspect, there is provided a compound of the disclosure
in
combination with one or more active ingredients such as anti-tumor agents
listed above.
In a further aspect, there is provided a pharmaceutical composition comprising
a
compound of the present disclosure in combination with one or more active
ingredients such
as anti-tumor agents listed above, in association with a pharmaceutically
acceptable
excipient.
In a further aspect, there is provided a kit comprising a compound of the
present
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disclosure in combination with one or more anti-tumour agents listed above.
In a further aspect, there is provided a kit comprising:
(a) a compound of the present disclosure in a first unit dosage form;
(b) an anti-tumour agent selected from those listed above in a second unit
dosage form;
and
(c) container for containing the first and second unit dosage forms.
METHOD FOR TREATMENT
In a further aspect, there is provided a method of treating type I receptor
tyrosine
kinase-associated diseases or conditions in a subject in need thereof, which
comprises
administering to the subject a therapeutically effective amount of a compound
of the present
disclosure, or a pharmaceutical composition of the present disclosure, owning
to the type I
receptor tyrosine kinase inhibitory activity, non-Pgp and non-BCRP
susceptibility and brain
penetration capability of the compounds of the present disclosure.
As used herein, the term "subject in need thereof' is a subject having a type
I receptor
tyrosine kinase-associated disease or condition (e.g., cancer), or a subject
having an increased
risk of developing a type I receptor tyrosine kinase-associated disease or
condition (e.g.,
cancer) relative to the population at large. In the case of cancer, a subject
in need thereof
can have a precancerous condition. A "subject" includes a warm-blooded animal.
In some
embodiments, the warm-blooded animal is a human.
In this context, the term "therapeutically effective amount" refers to an
amount of a
compound of the present disclosure which is effective to provide "therapy" in
a subject, or to
"treat" a type I receptor tyrosine kinase-associated disease or disorder in a
subject. In the
case of cancer, the therapeutically effective amount may cause any of the
changes observable
or measurable in a subject as described in the definition of "therapy",
"treatment" and
"prophylaxis" above. For example, the effective amount can reduce the number
of cancer
or tumour cells; reduce the overall tumour size; inhibit or stop tumour cell
infiltration into
peripheral organs including, for example, the soft tissue and bone; inhibit
and stop tumour
metastasis; inhibit and stop tumour growth; relieve to some extent one or more
of the
symptoms associated with the cancer; reduce morbidity and mortality; improve
quality of life;
or a combination of such effects. An effective amount may be an amount
sufficient to
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decrease the symptoms of a disease responsive to inhibition of type I receptor
tyrosine kinase
activity. For cancer therapy, efficacy in-vivo can, for example, be measured
by assessing
the duration of survival, time to disease progression (TTP), the response
rates (RR), duration
of response, and/or quality of life. As
recognized by those skilled in the art, effective
amounts may vary depending on route of administration, excipient usage, and co-
usage with
other agents. For
example, where a combination therapy is used, the amount of the
compound of the present disclosure described in this specification and the
amount of the
other pharmaceutically active agent(s) are, when combined, jointly effective
to treat a
targeted disorder in the animal patient. In this context, the combined amounts
are in a
"therapeutically effective amount" if they are, when combined, sufficient to
decrease the
symptoms of a disease responsive to inhibition of type I receptor tyrosine
kinase activity as
described above.
In generally, "therapeutically effective amount" may be determined by one
skilled in the
art by, for example, starting with the dosage range described in this
specification for the
compound of the present disclosure and an approved or otherwise published
dosage range(s)
of the other pharmaceutically active compound(s).
In some embodiments, the type I receptor tyrosine kinase-associated disease or
condition is abnormal cell growth or hyperproliferative disorder. The terms
"abnormal cell
growth" and "hyperproliferative disorder" are used interchangeably in this
application.
"Abnormal cell growth", as used herein, refers to cell growth that is
independent of normal
regulatory mechanisms (e.g., loss of contact inhibition).
This includes, for example, the
abnormal growth of: (1) tumor cells (tumors) that proliferate by expressing a
mutated
tyrosine kinase or over-expression of a receptor tyrosine kinase; (2) benign
and malignant
cells of other proliferative diseases in which aberrant tyrosine kinase
activation occurs; (3)
any tumors that proliferate by receptor tyrosine kinases; (4) any tumors that
proliferate by
aberrant serine/threonine kinase activation; and (5) benign and malignant
cells of other
proliferative diseases in which aberrant serine/threonine kinase activation
occurs.
In certain embodiments, abnormal cell growth in cancer. According, there is
provided
a methods of treating cancer in a subject in need thereof, which comprises
administering to
the subject a therapeutically effective amount of a compound of the present
disclosure, or a
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pharmaceutical composition of the present disclosure.
In some embodiment, the cancer is a HER2-expressing cancer, a HER2-
overexpressing
cancer, or a HER ligand overexpressing cancer.
A "HER2-expressing cancer" is one that involves cancer cells or tumor cells
having
HER2 protein present at their cell surface. A "HER2-overexpressing cancer" is
one which has
significantly higher levels of a HER receptor, such as HER2, at the cell
surface of a cancer or
tumor cell, compared to a noncancerous cell of the same tissue type. Such
overexpression
may be caused by gene amplification or by increased transcription or
translation.
A "HER-ligand overexpressing cancer" is one which produces significantly
higher
levels of the HER2 ligand compared to a noncancerous cell of the same tissue
type. "HER
ligand" as used herein refers to a polypeptide which binds to and/or activates
a HER receptor.
Examples include, without limitation, epidermal growth factor (EGF),
transforming growth
factor alpha (TGF-alpha); amphiregulin; betacellulin; heparin-binding
epidermal growth
factor (HB-EGF); a heregulin; epiregulin; neuregulin-2 (NRG-2); NRG-3; NRG-4
or cripto
(CR-1). HER ligands which bind EGFR include EGF, TGF-.alpha., amphiregulin,
betacellulin, HB-EGF and epiregulin.
HER receptor or HER ligand expression or overexpression may be determined in a
diagnostic or prognostic assay by evaluating increased levels of the HER
protein present on
the surface of a cell (e.g. via an immunohistochemistry assay; IHC).
Alternatively, or
additionally, one may measure levels of HER-encoding nucleic acid in the cell,
e.g. via
fluorescent in situ hybridization (FISH; see W098/45479 published October,
1998), southern
blotting, or polymerase chain reaction (PCR) techniques, such as real time
quantitative PCR
(RT-PCR). One may also study HER receptor overexpression by measuring shed
antigen (e.g.,
HER extracellular domain) in a biological fluid such as serum (see, e.g., U.S.
Pat. No.
4,933,294 issued Jun. 12, 1990; W091/05264 published Apr. 18, 1991; U.S. Pat.
No.
5,401,638 issued Mar. 28, 1995; and Sias et al. J. Immunol. Methods 132: 73-80
(1990)).
Aside from the above assays, various in vivo assays are available to the
skilled practitioner.
For example, one may expose cells within the body of the patient to an
antibody which is
optionally labeled with a detectable label, e.g. a radioactive isotope, and
binding of the
antibody to cells in the patient can be evaluated, e.g. by external scanning
for radioactivity or
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by analyzing a biopsy taken from a patient previously exposed to the antibody.
HER receptor or HER ligand expression or overexpression may be determined in a
diagnostic or prognostic assay by evaluating increased levels of the HER or
levels of the
HER ligand in a biological sample (such as cancer cell) from the subject to be
treated.
Various methods can be used. For example, the test biological sample can be
exposed to an
anti-HER2 antibody which binds to and detects the expressed HER2 protein.
Alternatively,
HER2 can also be detected at nucleic acid expression level, using methods such
as qPCR,
reverse transcriptase PCR, microarray, SAGE, FISH, and the like. One may also
study
HER receptor overexpression by measuring shed antigen (e.g., HER extracellular
domain) in
a biological fluid such as serum (see, e.g., U.S. Pat. No. 4,933,294;
W091/05264; U.S. Pat.
No. 5,401,638; and Sias et al. J. Immunol. Methods 132: 73-80 (1990)). In some
embodiments, the test sample is derived from a cancer cell or tissue, or tumor
infiltrating
immune cells.
In certain embodiments, the cancer is selected from the group consisting of
lung cancer,
bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck,
cutaneous or
intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of
the anal region,
stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma, of the
fallopian tubes,
carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the
vagina, carcinoma
of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small
intestine,
cancer of the endocrine system, cancer of the thyroid gland, cancer of the
parathyroid gland,
cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra,
cancer of the penis,
prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of
the bladder,
cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal
pelvis, neoplasms
of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors,
brain stem
glioma, pituitary adenoma, or a combination of one or more of the foregoing
cancer.
In some embodiments, the cancer is metastatic cancer. In some embodiments, the
metastatic cancer comprises metastases of the central nervous system. In
some
embodiments, the metastases of the central nervous system comprise brain
metastases. In
some embodiments, the metastases of the central nervous system comprise
leptomeningeal
metastases. "Leptomeningeal metastases" occur when cancer spreads to the
meninges, the
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layers of tissue that cover the brain and the spinal cord.
Metastases can spread to the
meninges through the blood or they can travel from brain metastases, carried
by the
cerebrospinal fluid (CSF) that flows through the meninges. In certain
embodiments, the
metastatic cancer is breast cancer brain metastases.
Accordingly, in a further aspect, there is provided a method of treating
breast cancer
brain metastases in a subject in need thereof, which comprises administering
to the subject a
therapeutically effective amount of a compound of the present disclosure, or a
pharmaceutical composition of the present disclosure.
The method of treating type I receptor tyrosine kinase-associated diseases or
conditions
described in this specification may be used as a monotherapy. As used herein,
the term
"monotherapy" refers to the administration of a single active or therapeutic
compound to a
subject in need thereof. In some embodiments, monotherapy will involve
administration of
a therapeutically effective amount of one of the compounds of the present
disclosure to a
subject in need of such treatment.
Depending upon the particular diseases or conditions to be treated, the method
of
treating type I receptor tyrosine kinase-associated diseases or conditions
described in this
specification may involve, in addition to administration of the compound of
the present
disclosure, one or more additional therapies, for example, conventional
surgery, radiotherapy,
chemotherapy, or a combination of such additional therapies. As used herein,
the term
"combination therapy" refers to the administration of a combination of
multiple active
compounds.
The additional therapies, such as additional anti-tumor agents, may be
administered
separately from the compounds of the present disclosure, as part of a multiple
dosage
regimen. Alternatively, these additional therapies may be part of a single
dosage form,
mixed with the compounds of the present disclosure in a single composition.
In some embodiments, the compounds of the present disclosure may be
administered
simultaneously, sequentially or separately to treatment with the conventional
surgery,
radiotherapy or chemotherapy.
Radiotherapy may include one or more of the following categories of therapy:
(i)
external radiation therapy using electromagnetic radiation, and intraoperative
radiation
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therapy using electromagnetic radiation; (ii) internal radiation therapy or
brachytherapy;
including interstitial radiation therapy or intraluminal radiation therapy; or
(iii) systemic
radiation therapy, including but not limited to iodine 131 and strontium 89.
Chemotherapy may include anti-tumor agents known in the art, for example,
antineoplastic agents, cytostatic agents, antiangiogenic agents, immunotherapy
approaches,
efficacy enhancers, and the like described in this specification.
Therefore, in one aspect, there is provided a method of treating type I
receptor tyrosine
kinase-associated diseases or conditions in a subject in need thereof, wherein
the compound
of the present disclosure is administered simultaneously, separately or
sequentially with one
or more additional anti-tumour agents.
In some embodiments, the one or more additional anti-tumour agents include
capecitabine, anti-HER2 antibodies, and T-DM1.
In some embodiments, the type I receptor tyrosine kinase-associated disease or
condition is a HER2-associated disease or condition. In some embodiments, the
type I
receptor tyrosine kinase-associated disease or condition is cancer. In some
embodiments,
the HER2-associated disease or condition includes breast cancer, gastric
cancer, mCRC,
NSCLC or metastasis thereof. In certain embodiments, the amounts of the
compound of the
present disclosure and the one or more additional anti-tumour agents are
jointly effective in
producing an anti-cancer effect.
In a further aspect, there is provided a method of treating breast cancer
brain metastases
in a subject in need thereof, wherein the compound of the present disclosure
is administered
simultaneously, separately or sequentially with one or more additional anti-
tumour agents.
EXAMPLES
For the purpose of illustration, the following examples are included. However,
it is to be
understood that these examples do not limit the invention and are only meant
to suggest a
method of practicing the present disclosure. Persons skilled in the art will
recognize that
the chemical reactions described may be readily adapted to prepare a number of
other
compounds of the present disclosure, and alternative methods for preparing the
compounds
of the present disclosure are deemed to be within the scope of the present
disclosure. For
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example, the synthesis of non-exemplified compounds according to the present
disclosure
may be successfully performed by modifications apparent to those skilled in
the art, e.g., by
appropriately protecting interfering groups, by utilizing other suitable
reagents known in the
art other than those described, and/or by making routine modifications of
reaction conditions.
Alternatively, other reactions disclosed herein or known in the art will be
recognized as
having applicability for preparing other compounds of the present disclosure.
The following abbreviations have been used in the examples:
AcOH acetic acid
AcONa sodium acetate
aq. aqueous
Boc20 di-tert-butyl dicarbonate
CH2C12 dichloromethane
Cs2CO3 cesium carbonate
DCE dichloroethane
DCM dichloromethane
DHP 3,4-Dihydro-2H-pyran
DIEA or DIPEA diisopropylethylamine
DMA N,N-dimethylacetamide
D1VIF N,N-dimethylformamide
DMSO dimethyl sulfoxide
Et0H ethanol
Et3N triethylamine
Et0Ac ethyl acetate
HCHO formaldehyde
HCOOH formic acid
H2SO4 Sulfuric acid
hr(s) hour(s)
IPA isopropyl alcohol
K2CO3 potassium carbonate
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KOtBu or tBuOK potassium tert-butoxide
LDA lithium diisopropyl amide
LiA1H4 lithium aluminium hydride
MeCN acetonitrile
Mel methyl iodide
Me0H methanol
NaBH(OAc)3 sodium triacetoxyborohydride
NaH sodium hydride
NaHCO3 sodium bicarbonate
NaOH sodium hydroxide
Na2SO4 sodium sulfate
NH4C1 ammonium chloride
NH4OH ammonium hydroxide
Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
Pd(OAc)2 palladium(II) acetate
PE petroleum ether
P0C13 phosphoric trichloride
PPTS Pyridinium p-toluenesulfonate
Tol toluene
Ts0H p-toluenesulfonic acid
TEA triethylamine
THF tetrahydrofuran
TFA trifluoroacetic acid
TFAA trifluoroacetic anhydride
Xant-phos 9,9-dimethy1-4,5-bis(diphenylphosphino)xanthene
Examples 1-175
Compounds and Synthesis
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It is understood as used herein, the compounds in the following examples are
also referred to
by the corresponding example numbers.
Example 1
(R)-N-(4-(11,2,41triazolo[1,5-clpyrimidin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro-1-m
ethylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F 0 F 0 Ph
F Na0Me CO2
Mel FII\d'
Ph ,
LDA, THF
,Br N
2 3
KCO3 DMF Br Br N .8r
Pd2(dba)3, Xantphos
Cs2CO3, dioxane
F 0
F 0 F OH
OH
HCI 0.-- HN= NH2
N N 2-methoxyethanol KOtBu, DMSO N
N H2
NF
Ph Ph
F
N F
POCI3
CII N
DIPEA, To 0,
IPA
N -
N N
Step 1: 5-bromo-3-fluoro-2-methoxypyridine
N Br
To a solution of 5-bromo-2,3-difluoropyridine (10 g, 51.5 mmol) in methanol
(150 mL) was
added Me0Na (15 mL, 77.3 mol, 30% in methanol) at 0 C. The mixture was
stirred at 25 C
for 12 hrs. The reaction mixture was concentrated, diluted with water (50 mL),
extracted with
Et0Ac (100 mL x2). The combined organic layers were washed with brine, dried
over
anhydrous Na2SO4, filtered and concentrated to dryness. The residue was
purified by column
chromatography on silica gel (PE:Et0Ac = 40: 1) to give desired product (10 g,
94% yield)
as a yellow oil. MS (ESI) m/z: 206 (M+H)+.
Step 2: 5-bromo-3-fluoro-2-methoxyisonicotinic acid
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F 0
IOH
NBr
To a solution of 5-bromo-3-fluoro-2-methoxypyridine (9 g, 43.7 mmol) in THF
(100 mL)
was added LDA (28.4 mL, 56.81 mmol, 2.0 M in THF) drop-wise at -78 C under N2
atmosphere and the mixture was stirred at -78 C for 1 hr. Then the mixture
was degassed
and purged with CO2. The mixture was stirred at -78 C for 1 hr. The mixture
was quenched
with saturated ammonium chloride solution (50 mL), diluted with water (100
mL), adjusted
to ph = 3 with diluted hydrochloric acid (1 M), extracted with Et0Ac (100 mL
x2). The
combined organic layers were washed with brine, dried over anhydrous Na2SO4,
filtered and
concentrated to give desired product (8.9 g, 81% yield) as a white solid. MS
(ESI) m/z: 250
(M+H)+.
Step 3: methyl 5-bromo-3-fluoro-2-methoxyisonicotinate
F 0
oI
NBr
To a solution of 5-bromo-3-fluoro-2-methoxyisonicotinic acid (8.9 g, 36 mmol)
and K2CO3
(9.96 g, 72 mmol) in DMF (100 mL) was added Mel (10.2 g, 72 mmol). The mixture
was
stirred at 25 C for 12 hrs. The mixture was diluted with Et0Ac (400 mL) and
washed with
EA (200 mL x3). The organic layer was washed with brine, dried over anhydrous
Na2SO4,
filtered and concentrated to give a residue. The residue was purified by
column
chromatography on silica gel (PE:Et0Ac = 20: 1) to give desired product (8.4
g, 89% yield)
as a yellow oil. MS (ESI) m/z: 264 (M+H)+.
Step 4: methyl 5-((diphenylmethylene)amino)-3-fluoro-2-methoxyisonicotinate
F 0
Ph Ph
To a solution of methyl 5-bromo-3-fluoro-2-methoxyisonicotinate (3 g, 11.4
mmol) in
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dioxane (100 mL) was added diphenylmethanimine (3.1g, 17.1mmol), Pd2(dba)3
(522mg,
0.57 mmol), Xantphos (660 mg, 1.14 mmol) and Cs2CO3 (7.43 g, 22.8 mmol). The
mixture
was stirred at 100 C for 12 hrs under N2. The mixture was filtered and
concentrated to give
desired product (12 g, crude). MS (ESI) m/z: 365 (M+H)+.
Step 5: methyl 5-amino-3-fluoro-2-methoxyisonicotinate
F 0
0
N
NH2
To a solution of methyl 5-((diphenylmethylene)amino)-3-fluoro-2-
methoxyisonicotinate(5 g,
13.7 mmol) in THF/H20(120 mL/12 mL) was added diluted hydrochloric acid (30
mL, 1M).
The mixture was stirred at 25 C for 12 hrs. The mixture was adjusted pH = 7
with saturated
sodium bicarbonate solution, extracted with Et0Ac (100 mLx2). The combined
organic
layers were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated to
give a residue. The was purified by column chromatography on silica gel
(PE:Et0Ac = 20: 1)
to give desired product (4.5 g, 57% yield) as a yellow solid. MS (ESI) m/z:
201 (M+H)+.
Step 6: 5-fluoro-6-methoxypyrido[3,4-cl]pyrimidin-4-ol
F OH
ON
N
To a solution of methyl 5-amino-3-fluoro-2-methoxyisonicotinate (2 g, 10 mmol)
in
methoxyethanol (10 mL) was added sodium acetate (2.46 g, 30 mmol) and
formimidamide
hydrochloride (3.2 g, 40 mmol). The mixture was stirred at 120 C for 12 hrs.
The mixture
was diluted with water (50 mL), extracted with Et0Ac (100 mL x2). The combined
organic
layers were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated to
give a residue. The was purified by chromatography on silica gel (DCM:Me0H =
100: 1) to
give desired product (1.3 g, 60% yield) as a white solid. MS (ESI) m/z: 196
(M+H)+.
Step 7:
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(R)-54(3,3-difluoro-1-methylpiperidin-4-y1)oxy)-6-methoxypyrido[3,4-
dlpyrimidin-4-ol
F
OH
ON
A solution of 5-fluoro-6-methoxypyrido[3,4-d]pyrimidin-4-ol (800 mg, 4.1
mmol),
(R)-3,3-difluoro-1-methylpiperidin-4-ol (1.23 g, 8.2 mmol) and potassium tert-
butoxide (918
mg, 8.2 mmol) in dimethyl sulfoxide (5 mL) was stirred at 160 C for 2 hrs.
The mixture was
diluted with water (20 mL), adjusted pH = 8 with diluted hydrochloric acid
(1M), and
extracted with DCM/Me0H (5:1, 50 mLx2). The combined organic layers were
washed with
brine, dried over anhydrous Na2SO4, filtered and concentrated to give a
residue. The residue
was triturated with PE/Et0Ac (10:1, 30 mL) to give desired product (900 mg,
67% yield) as
a white solid. MS (ESI) m/z: 327 (M+H)+.
Step 8:
(R)-4-chloro-54(3,3-difluoro-l-methylpiperidin-4-y1)oxy)-6-methoxypyrido[3,4-
d]pyrim
idine
F
CI
ON
To a solution of P0C13 (564.3 mg, 3.68 mmol) and DIPEA (475.6 mg, 3.68 mmol)
in toluene
(10 mL) was
added
(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-
d]pyrimidin-4-ol
(300 mg, 0.92 mmol) at 85 C. The mixture was stirred at 85 C for 3 hrs. The
mixture was
concentrated, diluted with Et0Ac (20 mL), and washed with saturated sodium
bicarbonate
solution (20 mL). The organic layer was washed with brine, dried over
anhydrous Na2SO4,
filtered and concentrated to give desired product (400 mg, crude). MS (ESI)
m/z: 345
(M+H)+.
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Step
9:(R)-N-(4-(11,2,41triazolo11,5-c]pyrimidin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro-1-
methylpiperidin-4-yl)oxy)-6-methoxypyrido13,4-d]pyrimidin-4-amine
F ON
0 HN
N
A solution of
(R)-4-chl oro-5-((3,3 -difluoro-l-methyl piperi din-4-yl)oxy)-6-methoxypyri do
[3,4-d]pyrimi din
e (400 mg, 1.16 mmol) and 4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-
methylaniline (280
mg, 1.16 mmol) in isopropanol (5 mL) was stirred at 65 C for 1 hr. The
mixture was
concentrated to give a residue. The residue was purified by prep-TLC (DCM:Me0H
= 15:1)
to give desired product (54 mg, 16% yield) as a white solid. '1-1 NMR (400
MHz, CDC13) 6
9.95 (s, 1H), 9.20 (d, J = 1.2 Hz, 1H), 8.72 (s, 1H), 8.60 (s, 1H), 8.33 (s,
1H), 7.87 (s, 1H),
7.82-7.73 (m, 1H), 7.11 (d, J = 8.8 Hz, 1H), 6.89 (d, J= 0.8 Hz, 1H), 4.95-
4.79 (m, 1H), 4.15
(s, 3H), 3.21 (s, 1H), 2.97 (d, J = 12.4 Hz, 1H), 2.42-2.33 (m, 4H), 2.29-2.25
(m, 4H),
2.23-2.09 (m, 2H). MS (ESI) m/z: 550 (M+H)+.
Example 7
(R)-N-(4-(11,2,41triazolo11,5-c]pyrimidin-7-yloxy)-3-chloropheny1)-54(3,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
OH
CICI
0
N2H4 H20 CI N,NH2 trimethoxymethane 01 .r-N\ 02N CI ,
NN N N NN.N K2CO3,
02N N
N
MeCN
NF
CI
0
o
diti N N-
Fe, NH4CI 0 HN CI N
1111
IPA/H20 H2N ci N IPA
N
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Step 1: 4-chloro-6-hydrazinylpyrimidine
N N
To a solution of 4,6-dichloropyrimidine (20 g, 135.1 mmol) in Et0H (160 mL)
was added
hydrazine (26 mL, 50 wt%) drop-wisely at 45 C for 1 hr. After addition, the
mixture was
stirred at 50 C for 2 hrs. The mixture was filtered and the solid was washed
with water to
give desired product (18.2 g, 94% yield) as yellow solid. MS (ESI) m/z: 145
(M+H)+.
Step 2: 7-chloro-11,2,41triazolo14,3-clpyrimidine
CI
N N-
N
The solution of 4-chloro-6-hydrazinylpyrimidine (18.2 g, 126.4 mmol) in
trimethoxymethane
(100 mL) was stirred at 90 C overnight. The mixture was concentrated to
dryness and the
residue was diluted with saturated aq.NaHCO3 (100 mL), extracted with Et0Ac
(100 mL x2).
The combined organic phases were washed with brine, dried over Na2SO4,
filtered and
concentrated. The residue was purified by column chromatography on silica gel
(PE: Et0Ac
= 5: 1) to give the desired product (14 g, 72% yield) as yellow solid. MS
(ESI) m/z: 155
(M+H)+.
Step 3: 7-(2-chloro-4-nitrophenoxy)-11,2,41triazolo[1,5-clpyrimidine
0
N N-
02N CI N
To a solution of 2-chloro-4-nitrophenol (2 g, 13 mmol) in MeCN (30 mL) was
added K2CO3
(4.5 g, 32.6 mmol) at 0 C and the mixture was stirred at rt for 15 min. Then
7-chloro-[1,2,4]triazolo[4,3-c]pyrimidine (2.2 g, 16.4 mmol) was added and the
resulting
mixture was stirred at 60 C for 72 hrs. The mixture was filtered and the
filtrate was
concentrated to dryness. The residue was triturated with Me0H (50 mL) and
filtered to give
the desired product (0.22 g, 6% yield) as brown solid. MS (ESI) m/z: 292
(M+H)+.
Step 4: 4-(11,2,41triazolo11,5-clpyrimidin-7-yloxy)-3-chloroaniline
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N N-
H2N CI N
To a solution of 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[4,3-c]pyrimidine
(0.22 g, 0.76
mmol) in propan-2-ol (5 mL) was added Fe powder (212 mg, 3.8 mmol), NH4C1 (190
mg,
3.8 mmol) and water (1 mL). The reaction was stirred at 85 C for 1 hr. The
mixture was
cooled and filtered, the filtrate was concentrated and diluted with saturated
aq. NaHCO3 (10
mL), extracted with DCM (10 mL x2). The combined organic layers were washed
with brine,
dried over Na2SO4, filtered and concentrated. The residue was purified by
column
chromatography on silica gel (DCM: Me0H = 20: 1) to give the desired product
(120 mg,
72% yield) as yellow solid. MS (ESI) m/z: 262 (M+H)+.
Step 5:
(R)-N-(4-(11,2,41triazolo[1,5-clpyrimidin-7-yloxy)-3-chloropheny1)-54(3,3-
difluoro-1-me
thylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
HN CI N N-N1
N
A solution of 4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-chloroaniline (100
mg, 0.38
mmol) and
(R)-4-chl oro-5-((3,3 -difluoro-l-m ethyl pip eri din-4-yl)oxy)-6-m ethoxypyri
do [3 ,4-d] pyrimi din
e (131 mg, 0.38 mmol ) in IPA (3 mL) was stirred at 65 C for 1 hr. The
reaction mixture was
poured into ice water and the pH was adjusted to 7-8 with NaHCO3 slowly. After
extraction
with DCM (10 mL x2), the combined organic layers were dried over anhydrous
Na2SO4 and
filtered. The filtrate was concentrated to dryness and the residue was
purified by prep-TLC
(DCM: Me0H = 15: 1) to give the desired product (66 mg, 30% yield) as white
solid.
1H-NMIR (400 MHz, DMSO-d6) 6 9.85 (s, 1H), 9.70 (d, J= 1.2 Hz, 1H), 8.78 (s,
1H), 8.63 (d,
J = 4.0 Hz, 2H), 8.29 (d, J = 2.4 Hz, 1H), 7.82 (d, J= 8.7 Hz, 1H), 7.46 (dd,
J= 18.0, 5.0 Hz,
2H), 5.23 (s, 1H), 4.12 (s, 3H), 3.17 (s, 1H), 2.73 (s, 2H), 2.51 (s, 4H),
2.47-2.37 (m, 1H),
2.20 (s, 1H). MS (ESI) m/z: 570 (M+H)+.
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Example 12
N-(4-(11,2,41triazolo[1,5-c] pyrimidin-7-yloxy)-3-methylpheny1)-5-(3-
(dimethylamino)aze
tidin-1-y1)-6-methoxypyrido [3,4-d] pyrimidin-4-amine
F " \N---CNH =SO ) 0 N o
POCI3 N OH __ N CI H2N N HN
Nj t-BuOK, DIMS N DIPEA, To IPA 0
N
N N;-J NNN
Step 1: 5-13-(dimethylamino)azetidin-1-y11-6-methoxypyrido13,4-dlpyrimidin-4-
ol
N OH
NNJ
A mixture of 5-fluoro-6-methoxypyrido[3,4-d]pyrimidin-4-ol (200 mg, 1.02
mmol),
N,N-dimethylazetidin-3-amine (275 mg, 2.75 mmol) and t-BuOK (538 mg, 4.81
mmol)
in DMSO (3 mL) was stirred at 160 C for 2 hrs. The mixture was concentrated
to dryness
under reduced pressure and the residue was purified by flash chromatography
(eluted with
DCM: Me0H= 20: 1) to give desired product (108 mg, 28% yield) as yellow solid.
MS (ESI)
m/z: 276 (M+H)+.
Step 2:
1-(4-chloro-6-methoxypyrido [3,4-d] pyrimidin-5-y1)-N,N-dimethylazetidin-3-
amine
N CI
0)N
To a mixture of P0C13 (0.1 mL, 1.17 mmol) and DIPEA (0.26 mL, 1.56 mmol) in
toluene (3
mL) was added 5 -[3 -(dimethyl amino)azeti din-l-yl] -6-methoxypyri do [3 ,4-
cl] pyrimi din-4-ol
(108 mg, 0.39 mmol) at 85 C and the mixture was stirred at 85 C for 3 hrs.
The mixture
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was concentrated to dryness and the residue was neutralized with ice-cooled
saturated aq.
NaHCO3 solution. The mixture was extracted with Et0Ac (5 mL x2) and the
combined
organic layers were washed with brine, dried over anhydrous Na2SO4, filtered
and
concentrated to dryness to give desired product (100 mg, 87% yield). MS (ESI)
m/z: 294
(M+H)+.
Step 3:
N-(4-(11,2,41triazolo[1,5-clpyrimidin-7-yloxy)-3-methylpheny1)-5-(3-
(dimethylamino)aze
tidin-l-y1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
N HN N
A
mixture
of
1-(4-chl oro-6-m ethoxypyri do [3 ,4-cl] pyrimi din-5 -y1)-N,N-dim ethyl az
eti din-3 -amine (100
mg, 0.34 mmol) and 4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylaniline
(82 mg,
0.34 mmol) in IPA (3 mL) was stirred at 65 C for 1 hr. The mixture was
concentrated to
dryness and the residue was purified by prep-TLC (DCM: Me0H = 15: 1) twice to
give
desired product (3 mg, 1.77% yield) as white solid. 1H-NMIR (400 MHz, DMSO-d6)
6 9.66 (d,
J= 1.2 Hz, 1H), 8.75 (s, 1H), 8.58 (s, 1H), 8.50 (s, 1H), 8.14 (s, 1H), 8.05
(s, 1H), 7.24 (d, J
= 8.7 Hz, 1H), 7.12 (d, J= 1.1 Hz, 1H), 4.12 (s, 3H), 3.91-3.83 (m, 1H), 3.08
(s, 2H), 2.26 (s,
6H), 2.21 (s, 3H), 2.03 ¨ 1.96 (m, 2H). MS (ESI) m/z: 499 (M+H)+.
The following compounds were prepared according to the above described methods
using different starting materials.
Ex# Structure Name
MS
m/z
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(S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimi
F
N.LF 0.-õ,______,N
din-7-yloxy)-3-methylpheny1)-5-((3,3
HN N N ,. -
-,--- N 550(M
2 N -difluoro-l-methylpiperidin-4-yl)oxy)
0L +H)+
I -6-methoxypyrido[3,4-d]pyrimidin-4-
NN,I,
amine
(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimi
F
N F 0.,--:--\r-N
din-7-yloxy)-3-methylpheny1)-5-((3,3
'0 HN N N
.,. -
',--- N 564(M
3 -difluoro-1-methylpiperidin-4-yl)oxy)
+H)+
I N N -6-ethoxypyrido[3,4-d]pyrimidin-4-a
.7,,-)
mine
F (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimi
N F
..*0
din-7-yloxy)-3-methylpheny1)-5-((3,3
N -..,.N-1 564(M
4 ''-'-- HN -difluoro-l-methylpiperidin-4-yl)oxy)
+H)+
I -6-ethoxypyrido[3,4-d]pyrimidin-4-a
mine
F
N.LF 0,,,,,,_______N (R)-N-(4-
([1,2,4]triazolo[1,5-c]pyrimi 520
NN-N din-7-yloxy)-3-methylpheny1)-5-((3,3
.-7-. HN
"/0 (M+H)
N -difluoro-l-methylpiperidin-4-yl)oxy)
-')- --
I +
N,),,-,-,N-.) pyrido[3,4-d]pyrimidin-4-amine
F
-N,,,----... j F 0N1 (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimi 520
"=,..---N,0 HN 6 N N- din-7-yloxy)-3-methylpheny1)-5-((3,3
--,-- N N -difluoro-l-methylpiperidin-4-yl)oxy) (M+H)
I +
N.7%-..N--) pyrido[3,4-d]pyrimidin-4-amine
F (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimi
0
'N '.7--F õ-%\iõ,-.N
din-7-yloxy)-3-chloropheny1)-5-((3,3- 570
N -N. N
8 HN CI ''''. -N difluoro-1-methylpiperidin-4-
yl)oxy)- (M+H)
--'oN
I 6-methoxypyrido[3,4-d]pyrimidin-4-a +
N--N-I
mine
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F (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimi
0
N F y\iõ-N\
din-7-yloxy)-3-methylpheny1)-5-((3,3 553
HN 1\1N-N//
9 -difluoro-l-methylpiperidin-4-yl)oxy) (M+H)
...----.-....õ-------...,
CD3o 1 N -6-(methoxy-d3)pyrido[3,4-d]pyrimid +
in-4-amine
F (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimi
0,,r,r,N
N F
0 HN N ,,N
10- din-7-yloxy)-3-methylpheny1)-5-((3,3
553
-difluoro-l-methylpiperidin-4-yl)oxy) (M+H)
CD3-"o'irN -6-(methoxy-d3)pyrido[3,4-d]pyrimid +
1\rl-
in-4-amine
=-.N, 0õ,,,;__N
N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-
514
N-, N-N
7-yloxy)-3-methylpheny1)-6-methoxy
11 (M+H)
N -5-((1-methylpiperidin-4-yl)oxy)pyrid
I +
NN-,') o[3,4-d]pyrimidin-4-amine
(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimi
C D3, N .,--/F F
din-7-yloxy)-3-methylpheny1)-5-((3,3 553
HN N,_N-N
13 -difluoro-1-(methyl-d3)piperidin-4-y1) (M+H)
ON
I oxy)-6-methoxypyrido[3,4-d]pyrimidi +
Ne-i
n-4-amine
(S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimi
C D3, N.,--/F F
/'`=0 HN N,_,-, N-N din-7-yloxy)-3-methylpheny1)-5-((3,3 553
14 -difluoro-1-(methyl-d3)piperidin-4-y1) (M+H)
ON
I oxy)-6-methoxypyrido[3,4-d]pyrimidi +
N ,,,--- lei
n-4-amine
F D3C,N (R)-N-(4-([1,2,4]triazolo[1,5-
c]pyrimi
____F 0.,,,,,,,,<;,N
/*',0 HN N,,.,-,. N-N din-7-yloxy)-3-methylpheny1)-5-((3,3 556
15 -difluoro-1-(methyl-d3)piperidin-4-
y1) (M+H)
CD3-- "(N oxy)-6-(methoxy-d3)pyrido[3,4-d]pyr +
NN-J
imidin-4-amine
D3C,F 0 (S)-N-(4-([1,2,4]triazolo[1,5-
c]pyrimi
N F
..--;*rN din-7-yloxy)-3-methylpheny1)-5-((3,3 556
0 HN
16 -difluoro-1-(methyl-d3)piperidin-4-
y1) (M+H)
N oxy)-6-(methoxy-d3)pyrido[3,4-d]pyr +
NN,J
imidin-4-amine
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(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridi
n-7-yloxy)-3-methylpheny1)-543,3-d 549
N- N
17 HN ifluoro-l-methylpiperidin-4-yl)oxy)-6
(M+H)
-methoxypyrido[3,4-d]pyrimidin-4-a +
mine
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin
N
-7-yloxy)-3-methylpheny1)-543,3-dif 549
HN N-N
18 luoro-l-methylpiperidin-4-yl)oxy)-6-
(M+H)
methoxypyrido[3,4-d]pyrimidin-4-am +
me
Example 2
White solid. 41-NIVIR (400 MHz, DMSO-d6) 6 9.92 (s, 1H), 9.66 (d, J= 1.0 Hz,
1H), 8.70 (s,
1H), 8.58 (s, 1H), 8.54 (s, 1H), 7.82 (d, J= 2.0 Hz, 1H), 7.73 (d, J= 8.8 Hz,
1H), 7.23 (d, J=
8.7 Hz, 1H), 7.19 (s, 1H), 5.10-4.92 (m, 1H), 4.09 (s, 3H), 3.14 (s, 1H), 2.82
(m, 1H),
2.47-2.35 (m, 1H), 2.20 (m, 8H), 2.01-1.86 (m, 1H).
Example 3
White solid. 41 NMR (400 MHz, CDC13) 6 9.96 (s, 1H), 9.20 (d, J = 1.2 Hz, 1H),
8.70 (s,
1H), 8.60 (s, 1H), 8.33 (s, 1H), 7.87 (s, 1H), 7.79 (d, J= 8.6 Hz, 1H), 7.11
(d, J= 8.8 Hz, 1H),
6.89 (d, J= 1.2 Hz, 1H), 4.93-4.80 (m, 1H), 4.65-4.51 (m, 2H), 3.21 (s, 1H),
2.98 (s, 1H),
2.42 - 2.30 (m, 5H), 2.26 (s, 3H), 2.23 - 2.13 (m, 2H), 1.50 (t, J= 6.8 Hz,
3H).
Example 5
White solid. 41-NIVIR (400 MHz, DMSO-d6) 6 9.89 (s, 1H), 9.66 (d, J= 1.1 Hz,
1H), 8.86 (s,
1H), 8.75 (s, 1H), 8.66 (s, 1H), 8.59 (s, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.72
(dd, J = 8.8, 2.4
Hz, 1H), 7.25 (d, J= 8.7 Hz, 1H), 7.19 (d, J= 1.1 Hz, 1H), 5.53 ¨5.26 (m, 1H),
3.24 (s, 1H),
2.85 (d, J= 11.4 Hz, 1H), 2.57 (d, J= 11.8 Hz, 1H), 2.36 (dd, J= 24.5, 10.3
Hz, 2H), 2.30 (s,
3H), 2.20 (s, 3H), 1.98 (d, J= 8.9 Hz, 1H).
Example 9
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White solid. 1H-NIVIR (400 MHz, DMSO-d6) 6 9.92 (s, 1H), 9.66 (d, J= 1.0 Hz,
1H), 8.70 (s,
1H), 8.58 (s, 1H), 8.53 (s, 1H), 7.81 (s, 1H), 7.73 (d, J= 8.9 Hz, 1H), 7.23
(d, J= 8.7 Hz,
1H), 7.18 (d, J= 0.9 Hz, 1H), 5.08 ¨ 4.91 (m, 1H), 3.13 (d, J= 7.3 Hz, 1H),
2.82 (d, J= 12.0
Hz, 1H), 2.48 ¨2.37 (m, 1H), 2.20 (m, 8H), 1.94 (dd, J= 21.9, 9.8 Hz, 1H).
Example 11
White solid. 1H-NMIR (400 MHz, DMSO-d6) 6 10.08 (s, 1H), 9.66 (d, J= 1.1 Hz,
1H), 8.67
(s, 1H), 8.58 (s, 1H), 8.53 (s, 1H), 7.89 (s, 1H), 7.79 (d, J= 8.3 Hz, 1H),
7.25 (d, J= 8.7 Hz,
1H), 7.18 (s, 1H), 4.67 (m, 1H), 4.07 (s, 3H), 2.83 (m, 2H), 2.13-2.26 (m,
10H), 1.84 (m,
2H).
Example 17
(R)-N-(4-(11,2,41triazolo11,5-alpyridin-7-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-meth
ylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
NH, [10 F
1111 :H2 DMFDMA, IPA 0 TTFHAAF ON N
02N
NLF
NaH, DMF 02N lir NH2OH.HCI
HO 02N 02N
"o CI
N - Pd/C, H2 HN
Et0H H2N IPA Ni N
Step!: 4-(2-methyl-4-nitrophenoxy)pyridin-2-amine
H2
02N
To a solution of 2-aminopyridin-4-ol (1 g, 9.0 mmol) in DMF (20 mL) was added
NaH (1.1 g,
27 mmol, 60% dispersion in mineral oil) at 0 C under N2 atmosphere and the
mixture was
stirred at 0 C for 1 hr. Then 1-fluoro-2-methyl-4-nitrobenzene (1.4 g, 9.0
mmol) was added
and the resulting mixture was stirred at 25 C for 16 hrs. The resulting
mixture was diluted
with water (30 mL), extracted with Et0Ac (30 mL x2). The combined organic
layers were
washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to
dryness. The
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residue was purified by chromatography on silica gel (PE: Et0Ac= 3: 1) to give
desired
product (500 mg, 22% yield) as yellow solid. MS (ESI) m/z: 246 (M+H)+.
Step 2: (E)-N-hydroxy-N'-14-(2-methy1-4-nitrophenoxy)pyridin-2-
yllmethanimidamide
02N N
To a solution of 4-(2-methyl-4-nitrophenoxy)pyridin-2-amine (300 mg, 1.2 mmol)
in IPA (5
mL) was added DMF-DMA (0.24 mL, 1.8 mmol) and the mixture was stirred at 80 C
for 2
hrs. Hydroxylamine hydrochloride (170 mg, 2.47 mmol) was added and the
resulting mixture
was stirred at 50 C for 2 hrs. The mixture was concentrated to dryness and
the residue was
purified by chromatography on silica gel (DCM: Me0H= 20: 1) to give desired
product (150
mg, 42% yield) as yellow oil. MS (ESI) m/z: 298 (M+H)+.
Step 3: 7-(2-methy1-4-nitrophenoxy)-11,2,41triazolo11,5-al pyridine
02N
To a solution of
(E)-N-hydroxy-N'44-(2-methy1-4-nitrophenoxy)pyri din-2-yl] methanimi dami de
(150 mg,
0.52 mmol) in THF (3 mL) was added TFAA (164 mg, 0.78 mmol) at 0 C and the
reaction
mixture was stirred at 25 C for 18 hrs. The reaction mixture was concentrated
to dryness and
the residue was purified by chromatography on silica gel (DCM: Me0H= 10: 1) to
give
desired product (100 mg, 71% yield) as white solid. MS (ESI) m/z: 271 (M+H)+.
Steps 4-5:
(R)-N-(4-(11,2,41triazolo11,5-al pyridin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro-1-meth
ylpiperidin-4-yl)oxy)-6-methoxypyrido [3,4-d] pyrimidin-4-amine
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F
HN
The crude product was prepared in a similar fashion to Examples 1 and 7, which
was purified
by prep-TLC (DCM: Me0H = 20: 1) to give desired product as white solid. 'H-
NMR(400
MHz, DMSO-d6) 6 9.95 (s, 1H), 8.94 (d, J= 7.5 Hz, 1H), 8.71 (s, 1H), 8.55 (s,
1H), 8.39 (s,
1H), 7.88 (d, J= 2.2 Hz, 1H), 7.79 (dd, J= 8.7, 2.4 Hz, 1H), 7.26 (d, J = 8.7
Hz, 1H), 7.03
(dd, J = 7.5, 2.6 Hz, 1H), 6.83 (d, J = 2.5 Hz, 1H), 5.00 (ddd, J= 17.0, 11.1,
5.5 Hz, 1H),
4.10 (s, 3H), 3.15 (s, 1H), 2.83 (d, J= 11.5 Hz, 1H), 2.47-2.37 (m, 1H), 2.20
(m, 8H), 1.95
(dt, J = 11.4, 7.9 Hz, 1H). MS (ESI) m/z: 549 (M+H)+.
Example 19
(R)-N-(4-(11,2,41triazolo11,5-al pyridin-7-yloxy)-3-methylpheny1)-5-03,3-
difluoro-1-(met
hyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido [3,4-d] pyrim idin-4-amine
F OH
D F
3C- N HC I
13 c -N DHP/PPTS LIAID4
,
'0H NF
DCM '0THP THF 90TH p Me0H ,,0H t-
BuOK, DMSO
D3C D3C. nal N
0 POCI3, DIPEA ci H2N HN
toluene IPA
N
Step 1: (4R)-tert-butyl 3,3-difluoro-4-((tetrahydro-211-pyran-2-
yl)oxy)piperidine
-1-carboxylate
BocN FF
To a solution of tert-butyl (4R)-3,3-difluoro-4-hydroxypiperidine-1-
carboxylate (500 mg,
2.11 mmol) in DCM (10 mL) was added PPTS (106 mg, 0.42 mmol) and the mixture
was
stirred at 25 C for 16 hrs. The mixture was concentrated to dryness and the
residue was
purified by column (elute with PE: Et0Ac= 10: 1) to give desired product (700
mg, 103%
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yield) as colorless oil. MS (ESI) m/z: 322 (M+H)+.
Step 2: (4R)-3,3-difluoro-1-(methyl-d3)-4-((tetrahydro-211-pyran-2-
yl)oxy)piperidine
D3C, F
'''OTHP
To a solution of tert-butyl (4R)-3,3-difluoro-4-(oxan-2-yloxy)piperidine-1-
carboxylate (400
mg, 1.25 mmol) in THF (10 mL) was added LiAlD4 (157 mg, 3.73mmo1) in portions
at 0 C
and the mixture was stirred at 70 C for 16 hrs. The reaction mixture was
quenched by
drop-wise addition of water (0.15 mL) followed by aq. NaOH solution (15% wt,
0.15 mL)
and water (0.45 mL) at 0 C. The mixture was filtered and the filter cake was
washed with
Et0Ac (5 mL x3). The filtrate was washed with brine, dried over Na2SO4,
filtered and
concentrated to dryness. The residue was purified by silica gel chromatography
(eluted with
PE: Et0Ac= 5: 1) to give desired product (200 mg ,67% yield) as colorless oil.
MS (ESI) m/z:
239 (M+H)+.
Step 3: (R)-3,3-difluoro-1-(methyl-d3)piperidin-4-ol
D3C,N/F F
To a solution of
(4R)-4-({4-chl oro-6-methoxypyri do [3 ,4-cl] pyrimi din-5 -yl }oxy)-3 ,3 -
difluoro-1-(D3)methylpip
eridine (200 mg, 0.84 mmol) in Me0H (2 mL) was added 2N aq.HC1 (2 mL) and the
mixture
was stirred at 30 C for 2 hrs. The mixture was basified with saturated aq.
NaHCO3 solution
and extracted with chloroform/IPA (5 mL x3, 3/1, v/v). The combined organic
layers were
washed with brine, dried over Na2SO4, filtered and concentrated to dryness.
The residue was
purified by silica gel chromatography (eluted with DCM: Me0H = 30: 1) to give
desired
product (100 mg, 77% yield) as white solid. MS (ESI) m/z: 155 (M+H)+.
Steps 4-6:
(R)-N-(4-(11,2,41triazolo11,5-al pyridin-7-yloxy)-3-methylpheny1)-5-03,3-
difluoro-1-(met
hyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido [3,4-d] pyrim idin-4-amine
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D3CNF F
HN
N
The crude product was prepared in a similar fashion to Example 1, which was
purified by
prep-TLC (DCM: Me0H= 15: 1) twice to give title product as white solid. 'H-NMR
(400
MHz, DMSO-d6) 6 9.96 (s, 1H), 8.93 (d, J= 7.4 Hz, 1H), 8.71 (s, 1H), 8.55 (s,
1H), 8.39 (s,
1H), 7.89 (d, J= 2.2 Hz, 1H), 7.79 (dd, J= 8.8, 2.4 Hz, 1H), 7.26 (d, J= 8.7
Hz, 1H), 7.04
(dd, J= 7.5, 2.6 Hz, 1H), 6.83 (d, J= 2.5 Hz, 1H), 5.00 (m, 1H), 4.10 (s, 3H),
3.20-3.07 (m,
1H), 2.82 (m, 1H), 2.40 (M, 1H), 2.26-2.08 (m, 5H), 2.05-1.86 (m, 1H). MS
(ESI) m/z: 552
(M+H)+.
Example 21
(R)-N-(4-(11,2,41triazolo11,5-al pyridin-7-yloxy)-3-methylpheny1)-54(3,3-
difluoro-1-isopr
opylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
Boc, 0
F OH
OH
FH OH TFA OH
- N t-BuOK, DMSO DCM NaBH(OAc)3,
DCE/THF
N
0
P C13 ________ A) a H2N-- N-N HN
DIPEA, tol IPA
N N
N N
Step 1: tert-butyl
(R)-3,3-difluoro-44(4-hydroxy-6-rnethoxypyrido[3,4-d1pyrimidin-5-
y1)oxy)piperidine4-
carboxylate
BocNFF
OH
N N-)
A mixture of 5-fluoro-6-methoxypyrido[3,4-d]pyrimidin-4-ol (400 mg, 2.05
mmol),
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tert-butyl (R)-3,3-difluoro-4-hydroxypiperidine-1-carboxylate (486 mg, 2,0
mmol) and
t-BuOK (453 mg, 4.1 mmol) in DMSO (10 mL) was stirred at 160 C for 2 hrs. The
mixture
was concentrated to dryness under reduced pressure and the residue was
purified by flash
chromatography (eluted with PE: Et0Ac:::: 3: 1) to give desired product (400
mg, 47% yield)
as white solid. MS (ESI) m/z: 413 (M+H)+.
Step 2: (R)-5-((3,3-difluoropiperidin-4-yDoxy)-6-methoxypyridoi3,4-dipyrimidin-
4-o1
HN
OH
ON
N
To a solution of
(R)-3,3-difluoro-44(4-hy droxy-6-methoxypyri do[3,4-d]pyrimidi n-5-
yl)oxy)piperidine-l-car
boxylate(400 mg, 0.97 mmol) in DCM (10 mL) was added TFA (1 mL) and the
mixture was
stirred at 25 C for 18 hrs. The mixture was concentrated to dryness and the
residue was
basified with saturated aq.NaHCO3 solution and extracted with DCM (5 mL x3).
The
combined organic layers were washed with brine, dried over Na2SO4, filtered
and
concentrated to dryness to give desired product (200 mg, 66% yield). MS (ESI)
miz: 313
(M+H)+.
Step 3:
(11)-54(3,3-ditluoro-1-isopropylpiperidin-4-yl)oxy)-6-methoxypyridop,4-
dlpyrimidin-4-
01
OH
ON
To a solution of
(R)-5-((3,3-difluoropiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-ol
(200 mg, 0.64
mmol) in DCE (10 mL)/THF (1 mL) was added propan-2-one (0,2 mL, 2.7 mmol) and
the
mixture was stirred at room temperature for 1 how-. NaBH(OAc)3 (65 mg, 1.9
mmol) was
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added to the mixture in small portions at 0 0C and the resulting mixture was
stirred at r.t. for
another 2 hrs. The reaction mixture was quenched with water (10 mL) and
extracted with
DCM/Nle0H (5 mL x3, 10/1, v/v). The combined organic layers were washed with
brine,
dried over Na2SO4, filtered and concentrated to dryness. The residue was
purified by
chromatography on silica gel (eluted with DCM: Me0H = 30: 1) to give the title
compound
(150 mg, 66(Y0 yield) as yellow solid. MS (ES1) in/z: 355 (M+H)t
Steps 4-5:
(R)-N-(4-(11,2,41triazolo11,5-alpyridin-7-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-isopr
opylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F
HN
ON
The crude product was prepared in a similar fashion to Example 1, which was
purified by
prep-TLC (DCM: Me0H= 20: 1) to give desired product as white solid. 11-1-NAIR
(400 MHz,
DMSO-d6) 6 10.00 (s, 1H), 8.98 (d, J= 7.5 Hz, 1H), 8.75 (d, J = 3.6 Hz, 1H),
8.59 (s, 1H),
8.44 (s, 1H), 7.95 (s, 1H), 7.79 (t, J= 15.9 Hz, 1H), 7.31 (d, J= 8.7 Hz, 1H),
7.09 (dd, J =
7.5, 2.6 Hz, 1H), 6.88 (d, J= 2.5 Hz, 1H), 5.14-4.88 (m, 1H), 4.15 (s, 3H),
3.21-3.10 (m, 1H),
2.87 (dd, J= 12.9, 6.7 Hz, 2H), 2.71-2.61 (m, 1H), 2.43 (t, J= 11.4 Hz, 1H),
2.26 (s, 4H),
1.92 (dd, J= 21.7, 9.7 Hz, 1H), 1.00 (d, J= 6.5 Hz, 6H). MS (ESI) m/z: 577
(M+H)+.
Example 23
(R)-N-(4-(11,2,41triazolo[1,5-alpyridin-7-yloxy)-3-methylpheny1)-5-((1-
cyclopropyl-3,3-
difluoropiperidin-4-y1)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F F
õN
j µ( 1,11 fF
"0 OH TMSO "Cr
''"-) '0 OH pod', .0 CI 112N HN"
0, NaBH3CN, DCE/THF ,0, DIPEA, tol IPA
N
7 1 11.
N
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Step 1:
(R)-54(1-cyclopropy1-3,3-difluoropiperidin-4-yl)oxy)-6-methoxypyrido [3,4-d]
py rim id in
-4-ol
N F
OH
To a mixture of
(R)-5-((3,3-difluoropiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-ol
(200 mg, 0.64
mmol) in Me0H (10 mL) was added (1-ethoxycyclopropoxy)trimethylsilane (0.25
mL, 1.2
mmol) and AcOH (3.8 mg, 0.06 mmol) and the mixture was stirred at rt for 1 hr.
Then
NaBH3CN (64 mg, 1.9 mmol) was added and the mixture was stirred at rt for
another 2 hrs.
The reaction mixture was diluted with water (10 mL) and extracted with DCWMe0H
(10
mL x3, 10/1, v-/v). The combined organic layers were dried over Na2SO4,
filtered and
concentrated to dryness. The residue was purified by chromatography on silica
gel (eluted
with DCM: Me0H = 30: 1) to give the title compound (150 mg, 66% yield) as
yellow solid.
MS (ESI) m/z: 353 (M+H)-f.
Steps 2-3:
(R)-N-(4-(11,2,41triazolo11,5-alpyridin-7-yloxy)-3-methylpheny1)-5-((1-
cyclopropyl-3,3-
difluoropiperidin-4-yDoxy)-6-methoxypyrido13,4-dlpyrimidin-4-amine
NF F
HN
The crude product was prepared in a similar fashion to Example 1, which was
purified by
prep-TLC (DCM: Me0H = 15: 1) to give desired product as white solid. 'H-NMIt
(400 MHz,
DMSO-d6) 6 9.90 (s, 1H), 8.92 (d, J= 7.5 Hz, 1H), 8.69 (s, 1H), 8.53 (s, 1H),
8.38 (s, 1H),
7.89 (d, J = 2.4 Hz, 1H), 7.73 (dd, J = 8.8, 2.5 Hz, 1H), 7.24 (d, J= 8.7 Hz,
1H), 7.02 (dd, J=
7.5, 2.6 Hz, 1H), 6.81 (d, J = 2.5 Hz, 1H), 5.00 (ddd, J= 21.0, 11.1, 5.5 Hz,
1H), 4.09 (s, 3H),
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3.25-3.16 (m, 1H), 2.98 (d, J= 11.9 Hz, 1H), 2.73 (dd, J= 30.2, 12.0 Hz, 1H),
2.51 (s, 1H),
2.19 (s, 4H), 1.92-1.80 (m, 1H), 1.77 (d, J= 3.1 Hz, 1H), 0.49 ¨ 0.27 (m, 4H).
MS (ESI) m/z:
575 (M+H)+.
Example 37
(R)-N-(4-(11,2,41triazolo11,5-alpyridin-7-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-meth
ylpiperidin-4-yl)oxy)-6-(difluoromethoxy)pyrido[3,4-d]pyrimidin-4-amine
NH
0 0 -JI. .-õ F
0
F ' [i
'-,s ,,
F 9 F 0 "-/' OH F 0 1-'7. Fy0 1
TMSCI, Nal
c). F F , F.0, 0, ___________ F
____________________________ 0-y---y0"-- N
Na2SO4, ACN I II Pd2(dba)3, Xantphos
MeCN F I
Br N --,
Br Cs2CO3, dioxane
oc
F F
AcOH 'NThi¨F
F 0 F OH
HNNH2
HCI
. F 0 '0 OH
THF __ ' F-,1---0 1 --, _________ o--- y 1 --- 'N
t-BuOK I
2-methoxyethanol DIPEA, Tol
F N----J
NH2 Na0Ac 1\1` DMSO Fy0.õTi õa .,,õN
F N ---' N------1
F F ilk 0
-'N'-'17----F 11 T r"r---- ,-N------/-F
H2N -'..' Lk-' N L'"''' ''o HN
F 0, IPA F 0
'-- ' N
F N ..., ) F IV
N
Step 1: methyl 5-bromo-3-fluoro-2-oxo-1,2-dihydropyridine-4-carboxylate
F 0
O=,,(y'
HN,,.r;--,Br
To a solution of methyl 5-bromo-3-fluoro-2-methoxyisonicotinate (2 g, 7.5
mmol) in CH3CN
(40 mL) was added TMSC1 (2.9 mL, 22.7 mmol) and NaI (3.4 g, 22.7 mmol) and the
mixture
was stirred at 85 C for 2 hrs. The reaction mixture was concentrated under
reduced pressure
to give crude product, which was purified by chromatography on silica gel
(DCM: Me0H =
20: 1) to give desired product (1.8 g, 95% yield). MS (ESI) m/z: 250 (M+H)+.
Step 2: methyl 5-bromo-2-(difluoromethoxy)-3-fluoropyridine-4-carboxylate
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F 0
F ,Br
To a solution of methyl 5-bromo-3-fluoro-2-oxo-1,2-dihydropyridine-4-
carboxylate (500 mg,
2.0 mmol) in CH3CN (10 mL) was added 2,2-difluoro-2-(fluorosulfonyl)acetic
acid (1.0 g,
6.0 mmol) and Na2SO4 (252 mg, 1.7 mmol) and the mixture was stirred at 70 C
for 3 hrs.
The reaction mixture was concentrated under reduced pressure to dryness and
the residue
was purified by chromatography on silica gel (PE: Et0Ac = 10: 1) to give
desired product
(370 mg, 61% yield). MS (ESI) m/z: 300 (M+H)+.
Steps 3-8:
(R)-N-(4-(11,2,41triazolo11,5-alpyridin-7-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-meth
ylpiperidin-4-yl)oxy)-6-(difluoromethoxy)pyrido[3,4-d]pyrimidin-4-amine
F 0
'0 HN
FOLJ
N
F
The crude product was prepared in a similar fashion to Example 1, which was
purified by
prep-TLC (DCM: Me0H = 15: 1) twice to give desired product as white solid.1H-
NMR(400
MHz, DMSO-c16) 6 9.85 (s, 1H), 8.93 (d, J = 7.5 Hz, 1H), 8.75 (s, 1H), 8.66
(s, 1H), 8.39 (s,
1H), 8.15 (s, 1H), 7.96-7.53 (m, 3H), 7.27 (d, J = 8.7 Hz, 1H), 7.04 (dd, J =
7.5, 2.6 Hz, 1H),
6.83 (d, J = 2.5 Hz, 1H), 4.90 (ddd, J = 20.2, 11.2, 5.5 Hz, 1H), 3.17 (d, J =
5.3 Hz, 1H), 2.87
(d, J = 11.7 Hz, 1H), 2.41 (dd, J = 29.3, 12.3 Hz, 1H), 2.23 (m, 7H), 2.15 (d,
J = 12.1 Hz, 1H),
2.10-1.96 (m, 1H). MS (ESI) m/z: 585 (M+H)+.
The following compounds were prepared according to the above described methods
using different starting materials.
Ex# Structure Name
MS
mlz
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F
N ./--.F (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin 549
-7-yloxy)-3-methylpheny1)-5((3,3-difl
HN
18 (M+H)
ON uoro-l-methylpiperidin-4-yl)oxy)-6-m
I +
N -7---N--ii ethoxypyrido[3,4-d]pyrimidin-4-amine
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin
CD3 /
,NF F
0 HN ,_,.N....N -7-yloxy)-3-methylpheny1)-54(3,3-difl 552
20 uoro-1-(methyl-d3)piperidin-4-yl)oxy) (M+H)
ON
I -6-methoxypyrido[3,4-d]pyrimidin-4-a +
mine
F (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin
N ' 0 ...,,,..N
-7-yloxy)-3-methylpheny1)-54(3,3-difl
F 577
22 '0 HN
uoro-1-isopropylpiperidin-4-yl)oxy)-6 (M+H)
ON
-methoxypyrido[3,4-d]pyrimidin-4-am +.
I
me
&,N F
F (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin
0 HN ,,,N.s. -7-yloxy)-3-methylpheny1)-54(1-((1 575
24 propy1-3,3-difluoropiperidin-4-yl)oxy) (M+H)
ON
I -6-methoxypyrido[3,4-d]pyrimidin-4-a
+
NN,-21 mine
F (R)-N-(4-([1,2,4]triazolo[1,5-
a]pyridin
N F
''()
-7-yloxy)-3-methylpheny1)-54(3,3-((3,3 552
-,-..,,-N
HN N
25 uoro-l-methylpiperidin-4-yl)oxy)-6-(
(M+H)
N methoxy-d3)pyrido[3,4-d]pyrimidin-4- +
N- J
-,N,
amine
F (S)-N-(4-([1,2,4]triazolo[1,5-
a]pyridin
HN ,,,,N1--
-7-yloxy)-3-methylpheny1)-54(3,3-difl 552
-N
0
26 uoro-l-methylpiperidin-4-yl)oxy)-6-(
(M+H)
CD3'-o'rrN methoxy-d3)pyrido[3,4-d]pyrimidin-4- +
NN-.9-'1
amine
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin
D3C,N,---F F 0 ...õ,_____<-7,..õ___N
N -7-yloxy)-3-methylpheny1)-5((3,3-difl
555
."0 HN
27 uoro-1-(methyl-d3)piperidin-4-yl)oxy)
(M+H)
CD3--o'il N -6-(methoxy-d3)pyrido[3,4-d]pyrimidi +
NN n-4-amine
n-4-amine
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F (S)-N-(4-([1,2,4]triazolo[1,5-
a]pyridin
D3C,N,..-----õ7 F 0..õ,......N
N -7-yloxy)-3-methylpheny1)-5((3,3-difl
555
0 HN -,-N
28 uoro-1-(methyl-d3)piperidin-4-yl)oxy)
(M+H)
CD3---C)N -6-(methoxy-d3)pyrido[3,4-d]pyrimidi
+
N=-.1\1-;"J
n-4-amine
F (R)-N-(4-([1,2,4]triazolo[1,5-
a]pyridin
F
-7-yloxy)-3-methylpheny1)-5((3,3-difl 577
O HN
29 uoro-l-methylpiperidin-4-yl)oxy)-6-is
(M+H)
N
I opropoxypyrido[3,4-d]pyrimidin-4-am +
N-)
me
F (S)-N-(4-([1,2,4]triazolo[1,5-
a]pyridin
N F
0 HN ,,,N,.,1 -7-yloxy)-3-methylpheny1)-
54(3,3-difl 577
30 uoro-l-methylpiperidin-4-yl)oxy)-6-is
(M+H)
N
I opropoxypyrido[3,4-d]pyrimidin-4-am +
N Ni
me
F (R)-N-(4-([1,2,4]triazolo[1,5-
a]pyridin
N F
',0 HN -----...:...-N
-7-yloxy)-3-methylpheny1)-6-(cyclopr 589
31 opylmethoxy)-5-((3,3-difluoro-1-meth
(M+H)
'L\O
'N= ' N
I ylpiperidin-4-yl)oxy)pyrido[3,4-
d]pyri +
NN-ri
midin-4-amine
F (S)-N-(4-([1,2,4]triazolo[1,5-
a]pyridin
N F (:)._,r,-._õ_____N
N -7-yloxy)-3-methylpheny1)-6-(cyclopr
589
A 0 HN
32 opylmethoxy)-5-((3,3-difluoro-1-meth
(M+H)
L-OL
.N. ' N
I ylpiperidin-4-yl)oxy)pyrido[3,4-
d]pyri +
NN-;=-1
midin-4-amine
F (R)-N-(4-([1,2,4]triazolo[1,5-
a]pyridin
N F
',0 HN .õõ..¨N-N
-7-yloxy)-3-methylpheny1)-6-cyclopro 575
33 poxy-5-((3,3-difluoro-1-methylpiperid (M+H)
0
N in-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-
+
amine
F (S)-N-(4-([1,2,4]triazolo[1,5-
a]pyridin
N F 0.,,,-,,.<__N
-7-yloxy)-3-methylpheny1)-6-cyclopro 575
0 HN
34 poxy-5-((3,3-difluoro-1-methylpiperid
(M+H)
v'oN in-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-
+
NN,521
amine
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F (R)-N-(4-([1,2,4]triazolo[1,5-
a]pyridin
N F
0 HN .,,,,,,._,N_.._ -7-yloxy)-3-methylpheny1)-
54(3,3-((3,3 617
35 uoro-l-methylpiperidin-4-yl)oxy)-6-(2 (M+H)
F3C0õ,-LN
I ,2,2-trifluoroethoxy)pyrido[3,4-
d]pyri +
NN,-;-1
midin-4-amine
F (S)-N-(4-([1,2,4]triazolo[1,5-
a]pyridin
'N F
HN ,N
-7-yloxy)-3-methylpheny1)-54(3,3-difl 617
"0 .,,,-N
36 uoro-l-methylpiperidin-4-yl)oxy)-6-(2 (M+H)
F3CON
I ,2,2-trifluoroethoxy)pyrido[3,4-
d]pyri +
NN-)
midin-4-amine
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin
-.N=-iF F 0,,,,,..õ___N
-7-yloxy)-3-methylpheny1)-54(3,3-((3,3 585
HN N-N
38 uoro-l-methylpiperidin-4-yl)oxy)-6-(d
(M+H)
N
I ifluoromethoxy)pyrido[3,4-d]pyrimidi
+
F NN
n-4-amine
-..N,,--,, \ N-(4-([1,2,4]triazolo[1,5-a]pyridin-
7-y
513
L"---0 HN m// '-''''''N loxy)-3-methylpheny1)-6-methoxy-54
39 (M+H)
ON 1-methylpiperidin-4-yl)oxy)pyrido[3,4
I -d]pyrimidin-4-amine +
0 o'-7M----JI{N\ N-(4-
([1,2,4]triazolo[1,5-a]pyridin-7-y 485
,N-
1\F-HN i\j //
loxy)-3-methylpheny1)-6-methoxy-5-
40 (M+H)
0))N morpholinopyrido[3,4-d]pyrimidin-4-a
I +
N;-.J mine
I
N 0../-1_,..õ-N\ N-(4-
([1,2,4]triazolo[1,5-a]pyridin-7-y 497
-_,N-r\l/ loxy)-3-methylpheny1)-6-methoxy-54
41 'N-.HN (M+H)
0
N 4-methylpiperazin-1-yl)pyrido[3,4-d]p
1 +
yrimidin-4-amine
N.õ../---,N)
Example 18
White solid. 'H-NIVIR (400 MHz, DMSO-d6) 6 9.94 (s, 1H), 8.93 (d, J= 7.5 Hz,
1H), 8.69 (s,
1H), 8.54 (s, 1H), 8.38 (s, 1H), 7.87 (d, J= 2.2 Hz, 1H), 7.78 (dd, J= 8.7,
2.3 Hz, 1H), 7.25
(d, J = 8.7 Hz, 1H), 7.02 (dd, J = 7.5, 2.6 Hz, 1H), 6.82 (d, J= 2.5 Hz, 1H),
5.11-4.90 (m,
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1H), 4.09 (s, 3H), 3.20-3.06 (m, 1H), 2.88-2.76 (m, 1H), 2.47-2.35 (m, 1H),
2.25-2.14 (m,
8H), 2.00-1.88 (m, 1H).
Example 25
White solid. 1H-NIVIR(400 MHz, DMSO-d6) 6 9.99 (s, 1H), 8.98 (d, J= 7.5 Hz,
1H), 8.75 (s,
1H), 8.59 (s, 1H), 8.44 (s, 1H), 7.94 (t, J= 6.4 Hz, 1H), 7.82 (ddd, J= 9.1,
7.2, 2.8 Hz, 1H),
7.31 (d, J= 8.7 Hz, 1H), 7.08 (dd, J= 7.5, 2.6 Hz, 1H), 6.88 (d, J= 2.5 Hz,
1H), 5.18-4.94
(m, 1H), 3.20 (dt, J= 10.9, 4.9 Hz, 1H), 2.87 (d, J= 11.4 Hz, 1H), 2.49 (dd,
J= 29.8, 12.2
Hz, 1H), 2.25 (m, 8H), 2.06-1.93 (m, 1H).
Example 29
White solid. 11-1-NIVIR (400 MHz, DMSO-d6) 6 9.95 (s, 1H), 8.93 (d, J= 7.5 Hz,
1H), 8.69 (s,
1H), 8.54 (s, 1H), 8.39 (s, 1H), 7.89 (d, J= 2.2 Hz, 1H), 7.80 (d, J= 8.7 Hz,
1H), 7.26 (d, J=
8.7 Hz, 1H), 7.04 (dd, J= 7.5, 2.6 Hz, 1H), 6.82 (d, J= 2.5 Hz, 1H), 5.48
¨5.37 (m, 1H),
4.91 (dd, J= 21.4, 10.8 Hz, 1H), 3.15 (s, 1H), 2.87 (d, J= 11.2 Hz, 1H), 2.44
¨ 2.32 (m, 1H),
2.23 (d, J= 14.4 Hz, 8H), 2.00 (d, J= 8.2 Hz, 1H), 1.45 (d, J= 6.2 Hz, 3H),
1.41 (d, J= 6.1
Hz, 3H).
Example 31
White solid. 11-1-NIVIR (400 MHz, DMSO-d6) 6 9.97 (s, 1H), 8.93 (d, J= 7.5 Hz,
1H), 8.66 (s,
1H), 8.54 (s, 1H), 8.39 (s, 1H), 7.89 (d, J= 2.3 Hz, 1H), 7.80 (dd, J= 8.8,
2.5 Hz, 1H), 7.26
(d, J= 8.7 Hz, 1H), 7.03 (dd, J= 7.5, 2.6 Hz, 1H), 6.82 (d, J= 2.5 Hz, 1H),
5.08-4.97 (m,
1H), 4.38 (dd, J= 10.9, 7.2 Hz, 1H), 4.28 (dd, J= 10.9, 7.5 Hz, 1H), 3.18 (s,
1H), 2.88 (d, J
= 10.9 Hz, 1H), 2.42-2.31 (m, 2H), 2.25 (s, 3H), 2.21 (s, 4H), 2.08-2.00 (m,
1H), 1.35 (m, J=
12.6, 7.9, 5.0 Hz, 1H), 0.64-0.58 (m, 2H), 0.48-0.39 (m, 2H).
Example 33
White solid. 11-1-NIVIR (400 MHz, DMSO-d6) 6 9.96 (s, 1H), 8.99 (d, J= 7.5 Hz,
1H), 8.79 (s,
1H), 8.62 (s, 1H), 8.44 (s, 1H), 7.93 (s, 1H), 7.84 (d, J= 8.4 Hz, 1H), 7.31
(d, J= 8.7 Hz,
1H), 7.09 (dd, J= 7.4, 2.4 Hz, 1H), 6.88 (d, J= 2.3 Hz, 1H), 4.95-4.75 (m,
1H), 4.55 (d, J=
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3.1 Hz, 1H), 3.18 (s, 1H), 2.89 (d, J= 11.1 Hz, 1H), 2.53-2.42 (m, 1H), 2.29
(s, 3H), 2.26 (s,
3H), 2.20 (s, 1H), 2.06¨ 1.97 (m, 1H), 1.29 (s, 1H), 0.88 (dd, J= 38.8, 7.3
Hz, 4H).
Example 35
White solid. 11-1-NMR (400 MHz, CD30D) 6 8.63 (d, J= 7.5 Hz, 1H), 8.52 (s,
1H), 8.42 (s,
1H), 8.18 (s, 1H), 7.76 (d, J= 2.4 Hz, 2H), 7.10-7.05 (m, 1H), 6.96 (dd, J=
7.5, 2.6 Hz, 1H),
6.71 (d, J= 2.4 Hz, 1H), 5.01 (q, J= 8.7 Hz, 2H), 4.85 (m, 1H), 3.16 ¨ 3.06
(m, 1H), 2.89 (d,
J= 12.1 Hz, 1H), 2.37-2.22 (m, 5H), 2.14 (m, 4H), 2.05 (dd, J= 12.4, 3.5 Hz,
1H).
Example 39
white solid. 11-1-NMIt (400 MHz, CD30D) 6 8.74 (d, J = 7.5 Hz, 1H), 8.62 (s,
1H), 8.47 (s,
1H), 8.28 (s, 1H), 7.91 (d, J= 2.3 Hz, 1H), 7.86 (dd, J= 8.6, 2.5 Hz, 1H),
7.21 (d, J= 8.7 Hz,
1H), 7.07 (dd, J= 7.5, 2.6 Hz, 1H), 6.79 (d, J= 2.4 Hz, 1H), 4.82 (s, 1H),
4.14 (s, 3H), 3.12
(d, J= 12.1 Hz, 2H), 2.57-2.42 (m, 5H), 2.24 (m, 5H), 2.05-1.94 (m, 2H).
Example 40
11-1-NMR (400 MHz, DMSO-d6) 6 13.48 (s, 1H), 8.94 (d, J= 7.5 Hz, 1H), 8.82 (s,
1H), 8.53
(s, 1H), 8.39 (s, 1H), 8.02 (d, J= 2.3 Hz, 1H), 7.88 (dd, J= 8.7, 2.5 Hz, 1H),
7.29 (d, J= 8.7
Hz, 1H), 7.05 (dd, J= 7.5, 2.6 Hz, 1H), 6.82 (d, J= 2.5 Hz, 1H), 4.09 (s, 3H),
4.01 (d, J= 9.7
Hz, 2H), 3.81 (t, J= 11.0 Hz, 2H), 3.70 (dd, J= 11.6, 8.8 Hz, 2H), 2.99 (d, J=
11.1 Hz, 2H),
2.23 (s, 3H).
Example 41
White solid. 11-1-NMIt (400 MHz, DMSO-d6) 6 13.59 (s, 1H), 8.94 (d, J= 7.5 Hz,
1H), 8.80
(s, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 8.02-7.95 (m, 2H), 7.32-7.26 (m, 1H),
7.04 (dd, J = 7.5,
2.6 Hz, 1H), 6.83 (d, J= 2.3 Hz, 1H), 4.07 (s, 3H), 3.70 (m, 2H), 2.99-3.01
(d, J = 11.8 Hz,
2H), 2.92-2.95 (d, J= 11.8 Hz, 2H), 2.34 (d, J= 12.2 Hz, 5H), 2.23 (s, 3H).
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Example 42
cis-N-(4-(11,2,41triazolo11,5-alpyridin-7-yloxy)-3-methylpheny1)-5-((3-fluoro-
1-methylpi
peridin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
F Boc.,r,----
..1.,,F
C1)2 TFAA Boc¨N OH t.--'' "0
'- _________ CNOOH (CO3 DCM __ - 'o -*===
NH2
TEA, DCM N ,,0,,,,L,
N'----;-----' Br
HN-----..õ,,,F
TFA L,-----',0 CH20 , ''''.0 BocNH2 1"----.'0 TFA
DCM ..õ0 ...,... CN
,T,...la
Br NaBH(OAc)3
I
Br xantphos, Pd2(dba); DCM
Cs2CO3, dioxane ,,..0,1,---L, õCN
1
N's---"NHBoc
DCE/THF ' --- Y-L---
NCNHN2
-'N-----)''µF L
DMFDMA is 0.....---..,1_,N --.N.-----..... '
--1-1\1 o-Cr--N'>
'''0
--"" 0 HN
H2N
õCN
1 HOAc ' N -"-.3-iy''N
N,,-..----.N---------.N.- I
N-)
I
Step 1: 5-bromo-3-fluoro-2-methoxypyridine-4-carboxamide
F 0
N H2
I
N Br
To a solution of 5-bromo-3-fluoro-2-methoxypyridine-4-carboxylic acid (4 g,
16.0 mmol) in
DCM (40 mL) was added oxalyl chloride (2.7 mL, 32.0 mmol) and DMF (62 mg, 0.80
mmol)
at 0 C and the mixture was stirred at 25 C for 2 hrs. The mixture was
concentrated under
reduced pressure to give a residue. The residue was dissolved in DCM (40 mL)
and
NH3NIe0H solution (30 mL, 120 mmol, 4 M in Me0H) was added. The resulting
mixture
was stirred at 25 C for 2 hrs. The reaction mixture was filtered and the
filtrate was
concentrated to dryness. The residue was purified by chromatography on silica
gel (DCM:
Me0H = 10: 1) to give desired product (2.8 g, 70% yield). MS (ESI) m/z: 249
(M+H)+.
Step 2: 5-bromo-3-fluoro-2-methoxyisonicotinonitrile
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OCN
N Br
To a mixture of 5-bromo-3-fluoro-2-methoxypyridine-4-carboxamide (2 g, 8.0
mmol), TEA
(3.3 mL, 24.0 mmol) in DCM (20 mL) was added TFAA (3.3 g, 16.0 mmol) drop-
wisely at 0
C and the reaction mixture was stirred at 25 C for 12 hrs. The reaction
mixture was
concentrated to dryness and the residue was purified by chromatography on
silica gel (PE:
Et0Ac = 10: 1) to give desired product (1.5 g, 80% yield) as yellow solid.
Step 3: cis-tert-butyl
44(5-bromo-4-cyano-2-methoxypyridin-3-yl)oxy)-3-fluoropiperidine-1-carboxylate
F
N Br
To a solution of tert-butyl cis-3-fluoro-4-hydroxypiperidine-1-carboxylate
(284 mg, 1.3
mmol) in THF (5 mL) was added NaH (104 mg, 2.6 mmol, 60% dispersion in mineral
oil) at
0 C under N2 atmosphere and the mixture was stirred at 0 C for 1 hr. Then
5-bromo-3-fluoro-2-methoxyisonicotinonitrile (300 mg, 1.3 mmol) was added and
the
reaction mixture was stirred at 25 C for 18 hrs. The mixture was diluted with
water (20 mL),
extracted with Et0Ac(20 mL x2). The combined organic layers were washed with
brine,
dried over anhydrous Na2SO4, filtered and concentrated to give crude product.
The residue
was purified by chromatography on silica gel (PE: Et0Ac = 10: 1) to give
desired product
(200 mg, 36% yield) as yellow solid. MS (ESI) m/z: 430 (M+H)+.
Step 4: cis-5-bromo-34(3-fluoropiperidin-4-yl)oxy)-2-methoxyisonicotinonitrile
F
HN ,õ
N Br
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To a solution of cis-tert-butyl 4-((5-bromo-4-cyano-2-methoxypyridin-3-yl)oxy)-
3-
fluoropiperidine-1-carboxylate (200 mg, 0.46 mmol) in DCM (2 mL) was added TFA
(1 mL)
and the mixture was stirred at 25 C for 18 hrs. The mixture was concentrated
to dryness and
the residue was basified with saturated aq.NaHCO3 solution and extracted with
DCM (5 mL
x3). The combined organic layers were washed with brine, dried over Na2SO4,
filtered and
concentrated to dryness to give desired product (150 mg, 98% yield). MS (ESI)
m/z:
330(M+H)+.
Step 5:
5-bromo-3-{1(35,4R)-3-fluoro-1-methylpiperidin-4-ylloxy}-2-methoxypyridine-4-
carbon
itrile
õF
N '
N Br
To a solution of
5-bromo-3-((cis-3-fluoro-1-methylpiperidin-4-yl)oxy)-2-
methoxyisonicotinonitrile (150 mg,
0.45 mmol) in DCE/THF (5 mL, 5/1, v/v) was added formaldehyde (1 mL, 37% wt in
water)
and the mixture was stirred at rt for 1 hr. NaBH(OAc)3 (46 mg, 1.3 mmol) was
added to the
mixture in small portions at 0 C and the resulting mixture was stirred at rt
for another 2 hrs.
The reaction mixture was quenched with water (10 mL) and extracted with
DCM/Me0H (5
mL x3, 10/1, v/v). The combined organic layers were washed with brine, dried
over Na2SO4,
filtered and concentrated to dryness. The residue was purified by
chromatography on silica
gel (eluted with DCM: Me0H = 30: 1) to give the title compound (100 mg, 64%
yield) as
yellow solid. MS (ESI) m/z: 344 (M+H)+.
Step 6: tert-butyl
(4-cyano-5-((cis-3-fluoro-1-methylpiperidin-4-yl)oxy)-6-methoxypyridin-3-
yl)carbamate
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F
To a solution of
5-bromo-3- { [(3 S,4R)-3-fluoro-1-methylpiperidin-4-yl]oxy} -2-methoxypyridine-
4-carbonitrile (100 mg, 0.29 mmol) in 1,4-dioxane (5 mL) was added BocNH2 (68
mg, 0.58
mmol ), Pd2(dba)3 (13 mg, 0.015 mmol), XantPhos (17 mg, 0.030 mmol) and Cs2CO3
(189
mg, 0.58 mmol). The mixture was degassed under N2 atmosphere and stirred under
N2
atmosphere at 100 C for 16 hrs. The mixture was filtered and the filtrate was
concentrated to
dryness. The residue was purified by chromatography on silica gel (DCM: Me0H =
20: 1) to
give desired product (100 mg, 90% yield) as yellow solid. MS (ESI) m/z: 381
(M+H)+.
Step 7:
5-amino-3-((cis-3-fluoro-l-methylpiperidin-4-yl)oxy)-2-
methoxyisonicotinonitrile
s, F
N '
OCN
NH2
To a solution of tert-butyl
(4-cyano-5-((cis-3-fluoro-1-methylpiperidin-4-yl)oxy)-6-methoxypyridin-3-
yl)carbamate
(100 mg, 0.26 mmol) in DCM (2 mL) was added diluted TFA (1 mL) and the mixture
was
stirred at 25 C for 16 hrs. The mixture was basified with saturated aq.NaHCO3
solution to
pH=7 and extracted with Et0Ac (30 mL x2). The combined organic layers were
washed with
brine, dried over anhydrous Na2SO4, filtered and concentrated to give desired
product (70 mg,
95% yield) as yellow oil. MS (ESI) m/z: 281 (M+H)+.
Step 8:
(E)-N'-(4-cyano-5-((cis-3-fluoro-l-methylpiperidin-4-yl)oxy)-6-methoxypyridin-
3-y1)-N,
N-dimethylformimidamide
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OCN
To a solution of
5-amino-3-((cis-3-fluoro-1-methylpiperidin-4-yl)oxy)-2-
methoxyisonicotinonitrile (70 mg,
0.25 mmol) in THF (1 mL) was added DMF-DMA (1 mL) and the mixture was stirred
at
70 C for 16 hrs. The mixture was concentrated to dryness and the residue was
purified by
chromatography on silica gel (DCM: Me0H = 10: 1) to give desired product (50
mg, 59%
yield) as yellow solid. MS (ESI) m/z: 336 (M+H)+.
Step 9:
cis-N-(4-(11,2,41triazolo11,5-alpyridin-7-yloxy)-3-methylpheny1)-5-((3-fluoro-
1-methylpi
peridin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
HN
NN
To a solution of
(E)-N'-(4-cyano-5-((cis-3-fluoro-1-methylpiperidin-4-yl)oxy)-6-methoxypyridin-
3-y1)-N,N-d
imethylformimidamide (50 mg, 0.15 mmol) in AcOH (2 mL) was added
4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (36 mg, 0.15 mmol)
and the
mixture was stirred at 100 C for 16 hrs. The mixture was basified with
saturated aq.NaHCO3
solution to pH=7 and extracted with DCM (10 mL x2). The combined organic
layers were
washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to
dryness. The
residue was purified by chromatography on silica gel (DCM: Me0H = 10: 1) to
give desired
product (14 mg, 17% yield) as yellow solid. 'H-NIVIR(400 MHz, DMSO-d6) 6 10.13
(s, 1H),
8.92 (d, J= 7.5 Hz, 1H), 8.68 (s, 1H), 8.53 (s, 1H),8.38 (s, 1H), 7.88 (d, J =
2.2 Hz, 1H), 7.78
(dd, J = 8.7, 2.4 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H), 7.02 (dd, J= 7.5, 2.6 Hz,
1H), 6.82 (d, J=
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2.5 Hz, 1H), 5.12 (d, J= 50.4 Hz, 1H), 4.95-4.85 (m, 1H), 4.07 (s, 3H),3.16-
3.08 (m, 1H),
2.83-2.77 (s, 1H), 2.34-2.25 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 2.08-1.97
(m, 2H),1.86-1.78
(m, 1H). MS (ESI) m/z: 531 (M+H)+.
Example 44
(R)-N-(4-(11,2,41triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-5-((4,4-
difluoro-1-
methylpyrrolidin-3-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
Example 45
(S)-N-(4-(11,2,41-triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-5-((4,4-
difluoro-1-
methylpyrrolidin-3-y1)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
0
'10 HN 0 HN
The racemic product was prepared using similar procedure as in Example 42 give
the
desired product as a white solid, which was subsequently separated by chiral
SFC to give two
isomers.
(R)-N-(4-([1,2,4]tri az ol o [1,5-a]pyri din-7-yloxy)-3 -methyl pheny1)-544,4-
difluoro-l-met
hylpyrrolidin-3-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine as white
solid. 'H-NIVIR
(400 MHz, DMSO-d6) 6 10.12 (s, 1H), 8.94 (d, J= 7.5 Hz, 1H), 8.71 (s, 1H),
8.56 (s, 1H),
8.39 (s, 1H), 7.98 ¨ 7.81 (m, 2H), 7.25 (d, J= 8.7 Hz, 1H), 7.04 (dd, J = 7.5,
2.6 Hz, 1H),
6.81 (d, J= 2.3 Hz, 1H), 5.55 (d, J= 9.0 Hz, 1H), 4.10 (s, 3H), 3.23 (d, J =
11.6 Hz, 2H),
2.87 ¨ 2.70 (m, 2H), 2.30 (s, 3H), 2.22 (s, 3H). MS (ESI) m/z: 549 (M+H)+.
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-544,4-
difluoro-1-met
hylpyrrolidin-3-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine as white
solid. 'H-NIVIR
(400 MHz, DMSO-d6) 6 10.12 (s, 1H), 8.94 (d, J= 7.5 Hz, 1H), 8.71 (s, 1H),
8.56 (s, 1H),
8.36 (d, J= 20.8 Hz, 1H), 7.97-7.79 (m, 2H), 7.25 (d, J= 8.8 Hz, 1H), 7.04
(dd, J= 7.5, 2.6
Hz, 1H), 6.82 (t, J= 5.1 Hz, 1H), 5.55 (d, J= 9.4 Hz, 1H), 4.10 (s, 3H), 3.32-
3.17 (m, 2H),
2.90-2.69 (m, 2H), 2.32 (d, J= 13.0 Hz, 3H), 2.22 (s, 3H). MS (ESI) m/z: 549
(M+H)+.
SFC condition: Column: ChiralPak AD, 250x21.2 mm ID., 5 p.m; Mobile phase: A
for
CO2 and B for Methanol (0.1% NH4OH); Gradient: B 20%; Flow rate: 50 mL /min;
Column
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temperature: 35 C.
Example 50
(S)-N-(4-(11,2,41triazolo11,5-al pyridin-7-yloxy)-3-methylpheny1)-5-(7-fluoro-
5-methyl-
2,5-diazaspiro [3.4] octan-2-y1)-6-methoxypyrido [3,4-d] pyrimidin-4-amine
Example 51
(R)-N-(4-(11,2,41triazolo11,5-al pyridin-7-yloxy)-3-methylpheny1)-5-(7-fluoro-
5-m ethyl-
2,5-diazas piro [3.4] octan-2-y1)-6-methoxypyrido [3,4-d] pyrimidin-4-amine
,N
NNJ
N HN N HN
N
The racemic product was prepared using similar procedure as in Example 42 give
the
desired product as a white solid, which was subsequently separated by chiral
SFC to give two
isomers.
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-5-(7-fluoro-5-
methy1-
2,5-diazaspiro[3.4]octan-2-y1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine as
yellow solid.
'H-NMR (400 MHz, DMSO-d6) 6 9.00 (d, J= 7.5 Hz, 1H), 8.83 (s, 1H), 8.54 (s,
1H), 8.45 (s,
1H), 7.95 (d, J= 6.6 Hz, 2H), 7.34 (d, J= 9.3 Hz, 1H), 7.11 (dd, J = 7.5, 2.6
Hz, 1H), 6.89 (d,
J= 2.4 Hz, 1H), 5.23 ¨ 5.43 (d, J= 56.2 Hz, 1H), 4.50 ¨4.73 (m, 2H), 4.24 (s,
3H), 3.59 ¨
3.97 (m, 4H), 2.91 ¨3.15 (m, 2H), 2.72 (s, 3H), 2.29 (s, 3H). MS (ESI) m/z:
542 (M+H)+.
(R)-N-(4-([1,2,4]tri az ol o [1,5-a]pyri din-7-yloxy)-3 -methyl pheny1)-5-(7-
fluoro-5-methyl -
2,5-diazaspiro[3.4]octan-2-y1)-6-methoxypyrido[3,4-d]pyrimidin-4-amine as
yellow solid.
'H-NMR (400 MHz, DMSO-d6) 6 9.00 (d, J= 7.5 Hz, 1H), 8.83 (s, 1H), 8.54 (s,
1H), 8.45 (s,
1H), 7.95 (d, J= 6.5 Hz, 2H), 7.34 (d, J= 9.3 Hz, 1H), 7.11 (dd, J = 7.5, 2.6
Hz, 1H),
6.87-6.89 (d, J= 2.4 Hz, 1H), 5.21-5.40 (d, J= 55.7 Hz, 1H), 4.63-4.69 (m,
2H), 4.22 (s, 3H),
3.74-3.98 (m, 4H), 2.92-3.14 (m, 2H), 2.71 (s, 3H), 2.29 (s, 3H). MS (ESI)
m/z: 542 (M+H)+.
SFC condition: Column: ChiralPak AD, 250x21.2 mm ID., 5 p.m; Mobile phase: A
for
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CO2 and B for Methanol (0.1% NH4OH); Gradient: B 30%; Flow rate: 50 mL /min;
Column
temperature: 35 C.
The following compounds were prepared according to the above described methods
using different starting materials.
Ex# Structure Name
MS
nth
-..N...õ.F o--;----N\ trans-N-(4-
([1,2,4]triazolo[1,5-a]pyridi
m // 531
/'='0 HN ,' 'NI n-7-yloxy)-3-methylpheny1)-5((3-fluo
43
(M+H)
ON ro-1-methylpiperidin-4-yl)oxy)-6-met
I +
N ,,!,,,--- ,Nr) trans mixture hoxypyrido[3,4-d]pyrimidin-4-amine
/
¨N N-(4-([1,2,4]triazolo[1,5-a]pyridin-
7-y
512
*,_,,,N-N loxy)-3-methylpheny1)-5-(3-(dimethyl
46 N HN
(M+H)
O
N amino)pyrrolidin-l-y1)-6-methoxypyri
+
I do[3,4-d]pyrimidin-4-amine
/ ¨N F N-(4-([1,2,4]triazolo[1,5-a]pyridin-
7-y
',õ,N-N loxy)-3-methylpheny1)-5-(4-(dimethyl
548
47 N HN amino)-3,3-difluoropyrrolidin-1-y1)-
6- (M+H)
ON
methoxypyrido[3,4-d]pyrimidin-4-ami +
I
ne
o.------õ,
N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-y
loxy)-3-methylpheny1)-6-methoxy-54 540
=,,,õ..N N -
48 N HN 5-methyl-8-oxa-2,5-diazaspiro[3.5]no
(M+H)
ON nan-2-yl)pyrido[3,4-d]pyrimidin-4-am
+
I
N.--.- ,N--ii me
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N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-y
loxy)-3-methylpheny1)-6-methoxy-54 510
49 N HN
2-methyl-2,6-diazabicyclo[3.2.0]hepta (M+H)
OLN
n-6-yl)pyrido[3,4-d]pyrimidin-4-amin +
N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-y
loxy)-3-methylpheny1)-5-(7,7-difluoro 560
52 N HN
-5-methyl-2,5-diazaspiro[3.4]octan-2- (M+H)
y1)-6-methoxypyrido[3,4-d]pyrimidin- +
4-amine
Example 43
White solid. 1H-NIVIR (400 MHz, DMSO-d6) 6 9.96 (s, 1H), 8.94 (d, J= 7.4 Hz,
1H), 8.68 (s,
1H), 8.53 (s, 1H), 8.39 (s, 1H), 7.91 (s, 1H), 7.82 (d, J= 8.6 Hz, 1H), 7.26
(d, J= 8.6 Hz,
1H), 7.04 (m, 1H), 6.83 (d, J= 2.3 Hz, 1H), 4.93 (m, 1H), 4.58 (m, 1H), 4.08
(s, 3H), 3.12
(m, 1H), 2.76 (m, 1H), 2.22 (s, 7H), 2.13-1.99 (m, 2H), 1.97-1.85 (m, 1H).
Example 46
Yellow solid.41-NMIt (400 MHz, DMSO-d6) 6 8.92 (d, J= 6.8 Hz, 1H), 8.77 (s,
1H), 8.51 (s,
1H), 8.37 (s, 1H), 8.18 (s, 1H), 7.99 (s, 2H), 7.25 (s, 1H), 7.04 (s, 1H),
6.79 (s, 1H), 4.07 (s,
3H), 3.86 (s, 2H), 3.29-3.15 (m, 2H), 2.94 (m, 1H), 2.23 (m, 11H).
Example 47
Light yellow solid. 11-1-NMIt (400 MHz, DMSO-d6) 6 12.64 (d, J = 29.2 Hz, 1H),
8.93 (d, J =
7.4 Hz, 1H), 8.86 (s, 1H), 8.56 (s, 1H), 8.38 (s, 1H), 7.97 (s, 1H), 7.93-7.78
(m, 1H), 7.28 (d,
J= 8.9 Hz, 1H), 7.03 (dd, J= 7.4, 2.2 Hz, 1H), 6.80 (d, J = 2.5 Hz, 1H), 4.11
(d, J = 10.8 Hz,
3H), 4.05-3.75 (m, 2H), 3.74-3.68 (m, 2H), 3.55-3.38 (m, 1H), 2.36 (s, 3H),
2.33 (s, 3H),
2.21 (s, 3H).
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Example 48
Light yellow solid. 'H-NMIR (400 MHz, DMSO-d6) 6 12.64 (d, J = 29.2 Hz, 1H),
8.93 (d, J =
7.4 Hz, 1H), 8.86 (s, 1H), 8.56(s, 1H), 8.38 (s, 1H), 7.97 (s, 1H), 7.91-7.82
(m, 1H), 7.28 (d,
J= 8.9 Hz, 1H), 7.03 (dd, J= 7.4, 2.2 Hz,1H), 6.80 (d, J= 2.5 Hz, 1H), 4.11
(d, J = 10.8 Hz,
3H), 4.05-3.75 (m, 2H), 3.73-3.36 (m, 4H), 2.41-2.28(m, 7H), 2.21 (s, 3H).
Example 53
(R)-5-((3,3-difluoro-1-m ethylpiperidin-4-yl)oxy)-N-(4-(imidazo [1,2-b]
pyridazin-7-yloxy)
-3-methylpheny1)-6-methoxypyrido [3,4-d] pyrimidin-4-amine
CI BocNH2,t-BuONa,
Na0Me Xant-Phos,Pd(0A02 TFA
,
Me0H dioxane,120 C N. N.Boc dioxnae
CI N N
HO 0
ON HBr 02N Fe,NH4CI
N-N-J K CO3, DMF 02N
N ---F
CI
0
,N
NN "O HN NN
IPA
Step 1:3-chloro-5-methoxypyridazine
To a solution of 3,5-dichloropyridazine (9 g, 60.4 mmol) in Me0H (60 mL) was
added
Na0Me (12 mL, 30% wt) and the mixture was stirred at rt for 3 hrs. The mixture
was
evaporated under reduced pressure to dryness below 25 C. The residue was
dissolved in
water (50 mL) and extracted with Et0Ac (50 mL x3). The combined organic layers
were
washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and
concentrated
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to dryness. The residue was purified by column chromatography on silica gel
(PE: Et0Ac =
10: 1) to give desired product (8.3 g, 95% yield) as white solid. MS (ESI)
m/z: 145 (M+H)+.
Step 2:tert-butyl (5-methoxypyridazin-3-yl)carbamate
N
NkNBoC
To a solution of 3-chloro-5-methoxypyridazine (6.0 g, 41.5 mmol) in 1,4-
dioxane (180 mL)
was added tert-butyl carbamate (9.7 g, 83.0 mmol), t-BuONa (12.0 g, 125 mmol),
XantPhos
(2.40 g, 4.12 mmol) and Pd(OAc)2 (0.93 g, 4.2 mmol). The mixture was degassed
under N2
atmosphere for three times and stirred at 120 C for 7 hrs. The mixture was
filtered and the
filtrate was concentrated to dryness. The residue was purified by column
chromatography on
silica gel (DCM: Me0H = 50: 1 to 30: 1) to give desired product (300 mg, 6%
yield) as dark
yellow oil. MS (ESI) m/z: 226 (M+H)+.
Step 3:5-methoxypyridazin-3-amine
H2NN:N
To a solution of tert-butyl (5-methoxypyridazin-3-yl)carbamate (300 mg, 2.66
mmol) in
DCM (15 mL) was added TFA (15 mL) and the mixture was stirred at rt for 16
hrs. The
mixture was concentrated to dryness and the residue was basified with
saturated aq. NaHCO3
solution and extracted with DCM (5 mL x3). The combined organic layers were
washed with
brine, dried over Na2SO4, filtered and concentrated to dryness. The residue
was purified by
column chromatography on silica gel (DCM: Me0H = 10: 1) to give desired
product (200
mg, 60% yield) as brown oil. MS (ESI) m/z: 126 (M+H)+.
Step 4: 7-methoxyim idazo 11,2-131 pyridazine
To a solution of 5-methoxypyridazin-3-amine (200 mg, 1.60 mmol) in 1,4-dioxane
(5 mL)
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was added 2-chloroacetaldehyde (0.12 mL, 1.92 mmol) and the mixture was
stirred at 90 C
for 4 hrs. The mixture was concentrated to dryness and the residue was
purified by column
chromatography on silica gel (DCM: Me0H = 20: 1) to give desired product (300
mg, 94%
yield) as pink oil. MS (ESI) m/z: 150 (M+H)+.
Step 5: imidazo 11,2-131 pyridazin-7-ol
HO
The mixture of 7-methoxyimidazo[1,2-b]pyridazine (300 mg, 2.0 mmol) and
pyridine
hydrochloride (1.16 g, 10.06 mmol) was stirred at 120 C for 8 hrs. The
mixture was
concentrated to dryness and the residue was purified by column chromatography
on silica gel
(DCM: Me0H = 20: 1 to 10: 1) to give desired product (100 mg, 37% yield) as
pink oil. MS
(EST) m/z: 136 (M+H)+.
Step 6: 7-(2-methyl-4-nitrophenoxy)imidazo 11,2-131 pyridazine
02N NNi
To a solution of imidazo[1,2-b]pyridazin-7-ol (100 mg, 0.74 mmol) in DMF (5
mL) was
added K2CO3 (204 mg, 1.48 mmol) and 1-fluoro-2-methyl-4-nitrobenzene (115 mg,
0.74
mmol) and the mixture was stirred at 100 C for 2 hrs. The mixture was diluted
with Et0Ac
(10 mL), washed with saturated aq.NH4C1 (5 mL x3) and brine, dried over
Na2SO4, filtered
and evaporated to dryness. The residue was purified by column chromatography
on silica gel
(PE: Et0Ac = 3: 1) to give desired product (80 mg, 40% yield) as yellow oil.
MS (ESI) m/z:
271 (M+H)+.
Step 7:4-(imidazo11,2-131pyridazin-7-yloxy)-3-methylaniline
H2N NNi
To a solution of 7-(2-methy1-4-nitrophenoxy)imidazo[1,2-b]pyridazine (80 mg,
0.30 mmol)
in i-PrOH (4 mL) and water (0.5 mL) was added Fe (84 mg, 1.50 mmol) and NH4C1
(161 mg,
3.00 mmol) and the mixture was stirred at 80 C for 1 hr. The mixture was
filtered and the
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filtrate was evaporated to dryness. The residue was purified by column
chromatography on
silica gel (DCM: Me0H = 30: 1) to give desired product (50 mg, 62% yield) as
yellow solid.
MS (ESI) m/z: 241 (M+H)+.
Step 8:
(R)-54(3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-b]pyridazin-
7-yloxy)
-3-methylpheny1)-6-methoxypyrido13,4-d]pyrimidin-4-amine
F
HN N-Nj
A solution of (R)-4-chloro-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-
methoxypyrido[3,4-d]pyrimidine (72 mg, 0.21 mmol) and
4-(imidazo[1,2-b]pyridazin-7-yloxy)-3-methylaniline (50 mg, 0.21 mmol) in
isopropanol (3
mL) was stirred at 65 C for 1 hr. The mixture was concentrated. The residue
was purified by
prep-TLC (DCM: Me0H = 15: 1) to give desired product (25 mg, 22% yield) as
yellow solid.
1H-NMR (400 MHz, DMSO-d6) 6 9.94 (s, 1H), 8.71 (s, 1H), 8.65 (d, J= 2.7 Hz,
1H), 8.55 (s,
1H), 8.22 (s, 1H), 7.88 (d, J= 2.3 Hz, 1H), 7.76 (dd, J= 8.7, 2.5 Hz, 1H),
7.66 (d, J= 1.3 Hz,
1H), 7.25 (m, 1H), 7.13 (m, 1H), 5.08 ¨ 4.93 (m, 1H), 4.10 (s, 3H), 3.15 (m,
1H), 2.82 (m,
1H), 2.46 ¨ 2.32 (m, 1H), 2.26 (s, 3H), 2.24 (s, 3H), 2.20 (m, 2H), 1.97 (m,
1H). MS (ESI)
m/z: 549 (M+H)+.
Example 55
(R)-N-(4-(11,2,41triazolo14,3-a]pyridin-7-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-
methylpiperidin-4-y1)oxy)-6-methoxypyrido13,4-d]pyrimidin-4-amine
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H2N,N
0
OBr
0 con. HCI ONNH __________ -0N
PhB(OH)2,Na0Bu-t cat. Tos0H
BINAP,Pd(OAc)2,tol
Py.HC HONO2N ,1\1 Fe
/ 1\1O2N Ni _______
H2N
K2CO3, DMF
CI
HN
IPA
1\1N
Step 1: 1-(diphenylmethylene)-2-(3-methoxyphenyl)hydrazine
Hc
0 N,N
jj
To a solution of 2-bromo-4-methoxypyridine (2 g, 10.63 mmol) in toluene (20
mL) was
added (diphenylmethylidene)hydrazine (2.30 g, 11.70 mmol), Na0Bu-t (1.43 g,
14.89 mmol),
BINAP (0.13 g, 0.21 mmol), PhB(OH)2 (16.21 mg, 0.13 mmol) and Pd(OAc)2 (0.05
g, 0.21
mmol). The mixture was degassed and stirred under N2 atmosphere at 100 C for
16 hrs. The
mixture was diluted with Et0Ac (10 mL), washed with water and brine, dried
over
anhydrous Na2SO4, filtered and concentrated to dryness. The residue was
purified by
chromatography on silica gel (PE: Et0Ac = 3: 1) to afford the crude compound
(2.7 g, 83%
yield) as white solid. MS (ESI) m/z: 303 (M+H)+.
Step 2: 2-hydraziny1-4-methoxypyridine
imki n2
A solution of 242-(diphenylmethylidene)hydrazin-1-y1]-4-methoxypyridine (2.70
g, 8.90
mmol) in concentrated aq.HC1 (27 mL) was stirred at 60 C overnight. The
mixture was
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concentrated to dryness and the residue was alkalified by adding saturated aq.
NaHCO3
solution to pH = 8. The mixture was extracted with Et0Ac (10 mL x2) and the
combined
organic layers were concentrated to dryness to give desired product (500 mg,
40% yield) as
yellow solid. MS (ESI) m/z: 140 (M+H)+.
Step 3: 7-methoxy-11,2,41triazolo14,3-alpyridine
N --//N
To a solution of 2-hydraziny1-4-methoxypyridine (500 mg, 3.59 mmol) in
trimethoxymethane
(5 mL) was added Ts0H (682.67 mg, 3.59 mmol) at 0 C and the mixture was
stirred at rt
overnight. The mixture was concentrated under vacuum to give the residue,
which was
purified by flash chromatography (DCM: Me0H = 10: 1) to give desired product
(100 mg,
18% yield) as yellow solid. MS (ESI) m/z: 150 (M+H)+.
Step 4: 11,2,41triazolo 14,3-al pyridin-7-ol
A mixture of 7-methoxy-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.67 mmol) and
pyridine
hydrochloride (387 mg, 3.35 mmol) was stirred at 120 C for 4 hrs. The mixture
was
concentrated to dryness and the residue was purified by flash chromatography
(DCM: Me0H
= 20: 1 to 10: 1) to give [1,2,4]triazolo[4,3-a]pyridin-7-ol (45 mg, 49%
yield) as pink oil. MS
(ESI) m/z: 136 (M+H)+.
Steps 5-7:
(R)-N-(4-(11,2,41triazolo14,3-alpyridin-7-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-meth
ylpiperidin-4-yl)oxy)-6-methoxypyrido [3,4-d] pyrimidin-4-amine
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HN
OLN
The crude product was prepared in a similar fashion to Example 53, which was
purified by
Prep-TLC (DCM: Me0H = 20: 1) to give desired product as white solid.1H-NMR
(400 MHz,
CD30D) 6 9.05 (d, J= 0.8 Hz, 1H), 8.62 (s, 1H), 8.51-8.45 (m, 2H), 7.88-7.81
(m, 2H), 7.18
(dd, J = 7.4, 2.0 Hz, 1H), 6.98 (dd, J = 7.5, 2.3 Hz, 1H), 6.67-6.63 (m, 1H),
5.04 (ddd, J=
19.9, 11.2, 5.6 Hz, 1H), 4.15 (s, 3H), 3.22-3.13 (m, 1H), 2.95 (d, J = 12.5
Hz, 1H), 2.54-2.43
(m, 1H), 2.35 (s, 3H), 2.30 (d, J= 11.7 Hz, 2H), 2.25 (s, 3H), 2.07 (dd, J =
14.8, 11.3 Hz,
1H). MS (ESI) m/z: 549 (M+H)+.
Example 57
(R)-5((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo 11,2-al pyridin-
7-yloxy)-3
-methylpheny1)-6-methoxypyrido [3,4-d] pyrimidin-4-amine
02N
0
HON Pd/C, H2
HO H2
dioxane NaH, DMF JJLõ.N Et0H
02N
F
CI
F 0
HN
H2N IPA NNJ
Step 1: imidazo[1,2-alpyridin-7-ol
To a solution of 2-aminopyridin-4-ol (500 mg, 4.5 mmol) in 1,4-dioxane (10 mL)
was added
2-chloroacetaldehyde (2.1 mL, 13.6 mmol) and the mixture was stirred at 100 C
for 18 hrs.
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The mixture was concentrated to dryness. The residue was purified by
chromatography on
silica gel (DCM: Me0H= 10: 1) to give imidazo[1,2-a]pyridin-7-ol (150 mg , 24%
yield) as
colorless oil. MS (ESI) m/z: 135 (M+H)+.
Step 2: 7-(2-methy1-4-nitrophenoxy)imidazo11,2-al pyridine
O2 N-
To a solution of imidazo[1,2-a]pyridin-7-ol (100 mg, 0.7 mmol) in DMF (5 mL)
was added
NaH (19 mg, 2.1 mmol, 60% dispersion in mineral oil) at 0 C under N2
atmosphere and the
mixture was stirred at 0 C for 1 hr. Then 2-fluoro-1-methy1-4-nitrobenzene
(115 mg, 0.7
mmol) was added and the reaction mixture was stirred at 25 C for 18 hrs. The
mixture was
diluted with water (20 mL), extracted with Et0Ac (10 mL x 2). The combined
organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated
to give
crude product. The residue was purified by chromatography on silica gel (PE:
Et0Ac= 10: 1)
to give desired product (70 mg, 35% yield) as yellow solid. MS (ESI) m/z: 270
(M+H)+.
Steps 3-4:
(R)-5-((3,3-difluoro- 1-m ethylpiperidin-4-yl)oxy)-N-(4-(imidazo 11,2-al
pyridin-7-yloxy)-3
-methylpheny1)-6-methoxypyrido [3,4-d] pyrimidin-4-amine
F
HN N
OAN
The crude product was prepared in a similar fashion to Example 53, which was
purified by
prep-TLC (DCM: Me0H = 15: 1) to give desired product as white solid. 'H-
NIVIR(400 MHz,
DMSO-c16) 6 9.92 (s, 1H), 8.70 (s, 1H), 8.55 (d, J= 7.3 Hz, 2H), 8.18 (s, 1H),
7.84 (s, 2H),
7.75 (dd, J = 8.6, 2.3 Hz, 1H), 7.44 (s, 1H), 7.18 (d, J = 8.7 Hz, 1H), 6.80
(dd, J= 7.4, 2.4 Hz,
1H), 6.57 (d, J= 2.3 Hz, 1H), 5.09-4.88 (m, 1H), 4.09 (s, 3H), 3.14 (s, 1H),
2.82 (d, J = 11.9
Hz, 1H), 2.40 (dd, J= 31.6, 19.3 Hz, 1H), 2.21 (m, 8H), 2.02-1.86 (m, 1H). MS
(ESI) m/z:
548 (M+H)+.
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The following compounds were prepared according to the above described methods
using different starting materials.
Ex# Structure Name
MS
nth
F
N F -..,---N\ (S)-5-((3,3-difluoro-1-
methylpiperidin- miz:
4-yl)oxy)-N-(4-(imidazo[1,2-b]pyridazi 549
N
54 HN
0)N n-7-yloxy)-3-methylpheny1)-6-methoxy
(M+H)
I
N,,,,,--;,-,,Nr) pyrido[3,4-d]pyrimidin-4-amine +
F
na/z:
N F 0.õ;,--,,_::,N, (S)-N-(4-
([1,2,4]triazolo[4,3-a]pyridin-
56
N--,N 7-yloxy)-3-methylpheny1)-5-((3,3-diflu 549
Or)N oro-l-methylpiperidin-4-yl)oxy)-6-meth (M+H)
I
N i\r-J oxypyrido[3,4-d]pyrimidin-4-amine +
F N ./--F 0 N (S)-54(3,3-difluoro-1-methylpiperidin-
na/z:
N-1 58 HN
4-yl)oxy)-N-(4-(imidazo[1,2-a]pyridin- 548
ON 7-yloxy)-3-methylpheny1)-6-methoxypy
(M+H)
1
Nr) rido[3,4-d]pyrimidin-4-amine +
-,,N.------,iF F 0.,,,õ4õ,;N (R)-5-((3,3-
difluoro-1-methylpiperidin- 549
N -,,,N---) 4-yl)oxy)-N-(4-(imidazo[1,2-c]pyrimidi
59 '''0 HN (M+H)
0)N n-7-yloxy)-3-methylpheny1)-6-methoxy
I +
N--) pyrido[3,4-d]pyrimidin-4-amine
F
N.LF 0 .õ......õ4-..-..õ_N (S)-5-((3,3-difluoro-1-
methylpiperidin- 549
0 HN N.- ft) 4-yl)oxy)-N-(4-(imidazo[1,2-c]pyrimidi
60 (M+H)
0-)N n-7-yloxy)-3-methylpheny1)-6-methoxy
I +
NN) pyrido[3,4-d]pyrimidin-4-amine
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F
N F 0_,_,.,,,,,,,,,_,N (R)-N-(4-
([1,2,4]triazolo[1,5-b]pyridazi 550
- n-7-yloxy)-3-methylpheny1)-543,3-difl
61 '/O HN N _ NI N N (M+H)
uoro-l-methylpiperidin-4-yl)oxy)-6-met O
1 +
NN-,) hoxypyrido[3,4-d]pyrimidin-4-amine
F
N F 0,__,,-;_________N (S)-N-(4-
([1,2,4]triazolo[1,5-b]pyridazi 550
--, HN N _N- n-7-yloxy)-3-methylpheny1)-543,3-difl
N
62 N (M+H)
uoro-l-methylpiperidin-4-yl)oxy)-6-met O
1 +
NN-,) hoxypyrido[3,4-d]pyrimidin-4-amine
F
N F ,N, (R)-5-((3,3-difluoro-1-methylpiperidin-
551
N
63 ''0 HN
NN' - ' 4-yl)oxy)-6-methoxy-N-(3-methyl-4-(te
-'-'' -,-N
O
N (M+H)
trazolo[1,5-c]pyrimidin-7-yloxy)phenyl
I +
N...-7.2N-.)" )pyrido[3,4-d]pyrimidin-4-amine
F 0
N F ,r\____-_-N,N (S)-543,3-difluoro-1-methylpiperidin-
551
NN-N' 4-yl)oxy)-6-methoxy-N-(3-methyl-4-(te
64 (M+H)
ON trazolo[1,5-c]pyrimidin-7-yloxy)phenyl
I +
N.N-.) )pyrido[3,4-d]pyrimidin-4-amine
F
N/ F ON, (R)-5-((3,3-difluoro-1-
methylpiperidin- 550
,N
HN N-N' 4-yl)oxy)-6-methoxy-N-(3-methy1-4-(te
65 (M+H)
trazolo[1,5-a]pyridin-7-yloxy)phenyl)py
---o'N +
N ,'' N,N-) rido[3,4-d]pyrimidin-4-amine
F
N/ F 0,,,,,,,_____:_N, (S)-
543,3-difluoro-1-methylpiperidin- 550
,N
0 HN N-N' 4-yl)oxy)-6-methoxy-N-(3-methy1-4-
(te
66 (M+H)
ON trazolo[1,5-a]pyridin-7-
yloxy)phenyl)py
I +
N.,i,,N-ii rido[3,4-d]pyrimidin-4-amine
F
N F 0 ,õ ,N.._N (R)-N-
(4-([1,2,4]triazolo[1,5-a]pyridin- 549
1;) HN ',-,r------"N 6-yloxy)-3-methylpheny1)-
543,3-diflu
67 (M+H)
N oro-l-methylpiperidin-4-yl)oxy)-6-meth
O
1 +
N-----' N-,)' oxypyrido[3,4-d]pyrimidin-4-amine
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F
N F xx (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-
549
0 HN `,,-.1---N/ 6-yloxy)-3-methylpheny1)-54(3,3-diflu
68 (M+H)
ON oro-l-methylpiperidin-4-yl)oxy)-6-meth
I +
N.-) oxypyrido[3,4-d]pyrimidin-4-amine
F
N F (:)N-N (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin- 569
''0 HN ci '-'õ-^'N 6-yloxy)-3-chloropheny1)-543,3-difluo
69 (M+H)
0--N ro-l-methylpiperidin-4-yl)oxy)-6-metho
I +
N,,-----.N--.) xypyrido[3,4-d]pyrimidin-4-amine
F
N F ()N-N (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin- 569
0 HN CI ''''-----N 6-yloxy)-3-chloropheny1)-543,3-
difluo
70 (M+H)
ON ro-l-methylpiperidin-4-yl)oxy)-6-metho
I +
N--)' xypyrido[3,4-d]pyrimidin-4-amine
F
N F ()-,-i-N-N (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-
563
0 HN '=,,,,,^--N 6-yloxy)-3-methylpheny1)-54(3,3-
diflu
71 (M+H)
N oro-l-methylpiperidin-4-yl)oxy)-6-etho
I +
N,2,-----,,N,) xypyrido[3,4-d]pyrimidin-4-amine
F
N F -,-,%- N - (S)-N-(4-([1,2,4]triazolo[1,5-
a]pyridin- 563
"0 HN '=,,,,,^--N 6-yloxy)-3-methylpheny1)-54(3,3-
diflu
72 (M+H)
N oro-l-methylpiperidin-4-yl)oxy)-6-etho
I +
N,2,-----,,N,) xypyrido[3,4-d]pyrimidin-4-amine
F (R)-N-(4-([1,2,4]triazolo[1,5-
a]pyridin-
NF 0,,,N___N
6-yloxy)-3-methylpheny1)-54(3,3-diflu 552
N
73 L'-'-- ' ' '0 HN' oro-1-methylpiperidin-4-yl)oxy)-6-(met
(M+H)
-0
N hoxy-d3)pyrido[3,4-d]pyrimidin-4-amin +
e
F (S)-N-(4-([1,2,4]triazolo[1,5-
a]pyridin-
N 0,,,,,N_N
F
6-yloxy)-3-methylpheny1)-54(3,3-diflu 552
"0 HN N
74 oro-1-methylpiperidin-4-yl)oxy)-6-(met
(M+H)
-0,,õ,¨õ,,,
D3C 1 ' N hoxy-d3)pyrido[3,4-d]pyrimidin-4-amin
+
e
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(R)-N-(4-([1,2,4]tri azol o [1,5-a]pyri din-
D3C, N F
6-yloxy)-3-methylpheny1)-5-((3,3-diflu 552
75 HN oro-1-(methyl-d3)piperidin-4-yl)oxy)-6-
(M+H)
methoxypyrido[3,4-d]pyrimidin-4-amin +
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-
D3C,NF F
6-yloxy)-3-methylpheny1)-5-((3,3-diflu 552
76 HN oro-1-(methyl-d3)piperidin-4-yl)oxy)-6-
(M+H)
methoxypyrido[3,4-d]pyrimidin-4-amin +
Example 59
Yellow solid. 1H-NIVIR (400 MHz, DMSO-d6) 6 9.91 (s, 1H), 9.28 (d, J= 1.2 Hz,
1H), 8.70
(s, 1H), 8.53 (s, 1H), 7.97 (s, 1H), 7.80 (s, 1H), 7.71 (d, J= 8.9 Hz, 1H),
7.57 (d, J= 1.4 Hz,
1H), 7.17 (d, J= 8.7 Hz, 1H), 6.81 (s, 1H), 5.01 (s, 1H), 4.09 (s, 3H), 3.15
(s, 1H), 2.80 (s,
1H), 2.43 ¨2.32 (m, 1H), 2.21 (t, J= 12.0 Hz, 8H), 1.94 (d, J= 7.7 Hz, 1H).
Example 67
White solid. 1H-NIVIR (400 MHz, DMSO-d6) 6 9.95 (s, 1H), 8.93 (d, J= 7.5 Hz,
1H), 8.71 (s,
1H), 8.55 (s, 1H), 8.39 (s, 1H), 7.88 (d, J= 2.3 Hz, 1H), 7.82-7.72 (m, 1H),
7.26 (d, J= 8.7
Hz, 1H), 7.03 (dd, J= 7.5, 2.6 Hz, 1H), 6.82 (d, J= 2.5 Hz, 1H), 5.11-4.93 (m,
1H), 4.10 (s,
3H), 3.17 (s, 1H), 2.83 (s, 1H), 2.35 (d, J= 13.3 Hz, 1H), 2.28-2.15 (m, 8H),
1.99-1.90 (m,
1H).
Example 77
(R)-5((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-
(pyrazolo[1,
5-a] pyridin-6-yloxy)phenyl)pyrido [3,4-d] pyrimidin-4-amine
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NO2
HO,õ7-,õN-N 02N
0 /
0, 0
s NH2 .-- n=== NO2
HBr/H20 ____________________________________________________
I ,
DMF
02N K2CO3,DMF K2CO3, DCM
0 NH202N
0
F is N-N,
S0,
\ Fe, NH4CI = 0 N-N\ __ NNJ ,,0 HN
=
02N IPA/H20 H2N IPA "'=
N
Step 1: 1-amino-3-methoxypyridin-1-ium 2,4-dinitrobenzen-1-olate
NO2
i+) 0
NH202N
A suspension of 3-methoxypyridine (2.77 mL, 27.49 mmol) and
0-(2,4-dinitrophenyl)hydroxylamine (3.55 mL, 30.24 mmol) in DCM (150 mL) was
stirred
at rt for 18 hrs. After addition of MTBE, the resulting precipitate was
filtered and the filter
cake was dried under vacuum to give desired product (5.50 g, 64% yield) as
yellow solid.
MS (ESI) m/z: 125 (M+H)+.
Step 2: methyl 6-methoxypyrazolo11,5-alpyridine-3-carboxylate
0 /
0
---/
N-N
0
To a solution of 1-amino-3-methoxypyridin-1-ium 2,4-dinitrobenzen-1-olate (5
g, 16.22
mmol) in DMF (50 mL) was added K2CO3 (3.14 g, 22.70 mmol) and methyl prop-2-
ynoate
(1.52 mL, 17.03 mmol) at 0 C. The resulting mixture was stirred at rt under
N2 atmosphere
overnight. The reaction mixture was diluted with Et0Ac (50 mL), washed with
water and
brine, dried over Na2SO4, filtered and concentrated to dryness. The residue
was purified by
flash chromatography (PE: Et0Ac = 5: 1) to afford the title compound (560 mg,
16% yield)
as yellow solid. 1H-NMIR (400 MHz, CDC13) 6 8.31 (s, 1H), 8.10 (d, J = 1.8 Hz,
1H),
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8.06-8.01 (m, 1H), 7.20 (dd, J= 9.6, 2.2 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H).
MS (ESI) m/z:
207 (M+H)+.
Step 3:Pyrazolo[1,5-a] pyridin-6-ol
NI\
A solution of methyl 4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (560 mg,
2.71 mmol)
in aq.HBr (10 mL, 40% wt) was stirred at 100 C overnight. The mixture was
alkalified by
adding saturated aq.NaOH solution to pH = 8 and extracted with Et0Ac (10 mL
x2). The
combined organic layers were washed with brine, dried over Na2SO4, filtered
and
concentrated to dryness. The filtrate was concentrated and the residue was
purified by flash
chromatography (DCM: Me0H = 10: 1) to afford the title compound (160 mg, 43%
yield) as
yellow solid. MS (ESI) m/z: 135 (M+H)+.
Steps 4-6:
(R)-5((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-
(pyrazolo[1,
5-a] pyridin-6-yloxy)phenyl)pyrido [3,4-d] pyrimidin-4-amine
ON_N
HN
The crude product was prepared in a similar fashion to Example 53, which was
purified by
prep-TLC (DCM: Me0H = 20: 1) to give desired product as yellow solid. 'H-NMR
(400
MHz, DMSO-c16) 6 9.83 (s, 1H), 8.69 (s, 1H), 8.51 (s, 1H), 8.38 ¨ 8.32 (m,
1H), 7.96 (d, J =
2.3 Hz, 1H), 7.77 (dd, J= 9.4, 5.9 Hz, 2H), 7.65 (dd, J = 8.7, 2.4 Hz, 1H),
7.14 (dd, J = 9.6,
2.1 Hz, 1H), 7.02 (d, J= 8.8 Hz, 1H), 6.65 (d, J = 1.9 Hz, 1H), 5.08 ¨4.96 (m,
1H), 4.09 (s,
3H), 3.32 ¨ 3.28 (m, 1H), 2.91 (s, 1H), 2.47 (s, 1H), 2.25 (d, J= 44.2 Hz,
8H), 1.96 (d,
11.7 Hz, 1H). MS (ESI) m/z: 548 (M+H)+.
The following compounds were prepared according to the above described methods
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using different starting materials.
Ex# Structure Name
MS
nth
F
N F N-N (S)-5-((3,3-difluoro-1-methylpiperidin-
548
0 HN ',.--0-- 4-yl)oxy)-6-methoxy-N-(3-methyl-4-(p
78 (M+H)
0)-N yrazolo[1,5-a]pyridin-6-yloxy)phenyl)p
I +
N,,,,---.N--) yrido[3,4-d]pyrimidin-4-amine
F
N F .N__N\ (R)-N-(3-chloro-4-(pyrazolo[1,5-a]pyri
568
(sr."'ID HN CI '''---L--) din-6-yloxy)pheny1)-5-
((3,3-difluoro-1-
79 (M+H)
ON methylpiperidin-4-yl)oxy)-6-methoxypy
I +
N--ii rido[3,4-d]pyrimidin-4-amine
F
N F N___N (S)-N-(3-chloro-4-(pyrazolo[1,5-
a]pyrid 568
80 HN CI
'',,=,- .---0¨ \ in-6-yloxy)pheny1)-5-((3,3-difluoro-1-m
"0 OLN ethylpiperidin-4-yl)oxy)-6-methoxypyri
(M+H)
I +
Nel do[3,4-d]pyrimidin-4-amine
F
NF N___N\ (R)-5-((3,3-difluoro-1-
methylpiperidin-
562
/'''0 HN '=,.--=:----. -) 81 4-yl)oxy)-6-ethoxy-N-(3-methyl-4-(pyr N
azolo[1,5-a]pyridin-6-yloxy)phenyl)pyri (M+H)
I +
N..,;.-,e1 do[3,4-d]pyrimidin-4-amine
F
NLF N___N\ (S)-5-((3,3-difluoro-1-
methylpiperidin-
562
82 HN
,.--.:---- -) 4-yl)oxy)-6-ethoxy-N-(3-methy1-4-(pyr
"0 N azolo[1,5-a]pyridin-6-yloxy)phenyl)py
(M+H)
ri
I +
N-,-) do[3,4-d]pyrimidin-4-amine
-----..JF F 0-,,,N-N (R)-
5-((3,3-difluoro-1-methylpiperidin- 551
N
',0 HN 4-yl)oxy)-6-(methoxy-d3)-N-(3-methyl-
83 (M+H)
4-(pyrazolo[1,5-a]pyridin-6-yloxy)phen
D3C-oI N +
-..N.-.) yl)pyrido[3,4-d]pyrimidin-4-amine
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F
F 0,..õ<.,,-----,N___N (S)-5-((3,3-difluoro-1-
methylpiperidin- 551
0 HN , 4-yl)oxy)-6-(methoxy-d3)-N-(3-methyl-
84 (M+H)
4-(pyrazolo[1,5-a]pyridin-6-yloxy)phen
N +
N1ei yl)pyrido[3,4-d]pyrimidin-4-amine
D3C,NFF 85 (R)-5-((3,3-difluoro-1-(methyl-
d3)piper 551
/','0 HN ''N..----'-----"") idin-4-yl)oxy)-6-methoxy-N-(3-
methyl-
ON 4-(pyrazolo[1,5-a]pyridin-6-yloxy)phen
(M+H)
I +
N,,,,;--,.N-,() yl)pyrido[3,4-d]pyrimidin-4-amine
D3C,NFF 86 (S)-5-((3,3-difluoro-1-(methyl-
d3)piperi 551
0 HN '-N.õ.--"---"") din-4-yl)oxy)-6-methoxy-N-(3-methy1-4 ON -
(pyrazolo[1,5-a]pyridin-6-yloxy)pheny (M+H)
I +
N,,,,;--,.N-,() 1)pyrido[3,4-d]pyrimidin-4-amine
Example 87
(R)-5((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-
(pyrazolo[1,
5-a]pyrimidin-6-yloxy)phenyl)pyrido13,4-d]pyrimidin-4-amine
F
Br-,,..õ,,,,,-..,,. N_N\
KOH HO,,,,, N_N 02N rõ. ,..--õ,.0 ..,õ_,,,--
,,, N_N Fe, NH4CI .
*'--N--L--) Me0H, refl; ''',-N---1-, K2CO3, DMF 02N .,,,p,.., .õ1,---j
IPA/H20
N
F
N F
CI F
0*LN N F
L"-----'10 HN N
PA, 65 C
H2N ..NL----')
I 1
NNi
Step 1:pyrazolo11,5-alpyrimidin-6-ol
HON_N\
N
To a solution of 6-bromopyrazolo[1,5-a]pyrimidine (2 g, 0.01 mol) in Me0H (50
mL) was
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added KOH (3.4 g, 0.06 mol) at 0 C. After addition, the mixture was stirred
at 65 C for 3
hrs. The solvent was removed and the residue was diluted with water, adjusted
pH to 1 with
con.HC1. The mixture was extracted with Et0Ac (20 mL x2) and the combined
organic
layers were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated to
dryness to give desired product (1 g, 73% yield) as yellow solid. MS (ESI)
m/z: 136 (M+H)+.
Steps 2-4:
(R)-5((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4-
(pyrazolo[1,
5-a]pyrimidin-6-yloxy)phenyl)pyrido113,4-d]pyrimidin-4-amine
ON_N
HN
The crude product was prepared in a similar fashion to Example 53, which was
purified by
purified by column chromatography on silica gel (eluted with DCM: Me0H = 20:
1) to give
desired product as yellow solid. 11-1-NMIt (400 MHz, DMSO-d6) 6 9.86 (s, 1H),
8.96 (dd, J =
2.6, 0.9 Hz, 1H), 8.68 (s, 1H), 8.60 (d, J= 2.6 Hz, 1H), 8.50 (s, 1H), 8.20
(d, J= 2.4 Hz, 1H),
7.79 (d, J = 2.4 Hz, 1H), 7.63 (dd, J = 8.8, 2.5 Hz, 1H), 7.07 (d, J= 8.8 Hz,
1H), 6.79 (dd, J
= 2.4, 0.9 Hz, 1H), 5.06-4.89 (m, 1H), 4.08 (s, 3H), 3.17-3.06 (m, 1H), 2.80
(d, J= 11.1 Hz,
1H), 2.47-2.37 (m, 1H), 2.34 (d, J= 9.6 Hz, 3H), 2.24-2.11 (m, 5H), 1.97-1.85
(m, 1H). MS
(ESI) m/z: 549 (M+H)+.
The following compounds were prepared according to the above described methods
using different starting materials.
Ex# Structure Name
MS
mlz
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F
N F N-N\ (S)-54(3,3-difluoro-l-methylpiperidin-
549
88
HN "-N-^.----)- 4-yl)oxy)-6-methoxy-N-(3-methy1-4-(p 0-)N
yrazolo[1,5-a]pyrimidin-6-yloxy)phenyl (M+H)
I +
N-;---,,el )pyrido[3,4-d]pyrimidin-4-amine
F
N F N___N (R)-N-(3-chloro-4-(pyrazolo[1,5-a]pyri
569
Ci HN CI '1\1 ------) midin-6-yloxy)pheny1)-
54(3,3-difluoro-
89 (M+H)
0 N 1-methylpiperidin-4-yl)oxy)-6-methoxy
I +
N,----.N--.2-1 pyrido[3,4-d]pyrimidin-4-amine
F
.-.N,------õ" F 0.,,y--..õ.. .NõN (S)-N-(3-chloro-4-
(pyrazolo[1,5-a]pyri 569
HN CI 'I\I'-'sz-----) midin-6-yloxy)pheny1)-
54(3,3-difluoro-
90 (M+H)
ON 1-methylpiperidin-4-yl)oxy)-6-methoxy
I +
N...----,Ni--)- pyrido[3,4-d]pyrimidin-4-amine
F
N F N___N (R)-5-((3,3-difluoro-1-methylpiperidin-
563
''C. HN "N,--'-------) 4-yl)oxy)-6-ethoxy-N-(3-
methy1-4-(pyr
91 (M+H)
N azolo[1,5-a]pyrimidin-6-yloxy)phenyl)p
I +
N ---- .N,-:i yrido[3,4-d]pyrimidin-4-amine
F
N F N___N (S)-54(3,3-difluoro-l-methylpiperidin-
563
"0 HN '1\1-----). \ 4-yl)oxy)-6-ethoxy-N-(3-methy1-4-(pyr
92 (M+H)
N azolo[1,5-a]pyrimidin-6-yloxy)phenyl)p
I +
N ---- .N,-:i yrido[3,4-d]pyrimidin-4-amine
F
N./ F N, - \N\ (R)-5-((3,3-
difluoro-1-methylpiperidin- 552
''0 HNN)'------/ 4-yl)oxy)-6-(methoxy-d3)-N-(3-
methyl -
93 (M+H)
4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)ph
N +
N N-) enyl)pyrido[3,4-d]pyrimidin-4-amine
F
N F N__ N
(S)-54(3,3-difluoro-1-methylpiperidin- 552
4-yl)oxy)-6-(methoxy-d3)-N-(3-methyl -
94 (M+H)
4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)ph
N +
N N-) enyl)pyrido[3,4-d]pyrimidin-4-
amine
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D3C,N,,--FF
0.õ7--N_N (R)-5-((3,3-difluoro-1-(methyl-d3)piper 552
''---."10 HN '--N.------z---) idin-4-yl)oxy)-6-methoxy-N-(3-
methyl-
0
N 4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)ph (M+H)-)
I +
N el enyl)pyrido[3,4-d]pyrimidin-4-amine
O D3CI\IF F N_N (S)-5-((3,3-
difluoro-1-(methyl-d3)piperi 552
' \
HN N--' ----''') din-4-yl)oxy)-6-methoxy-N-(3-
methy1-4
96
(M+H)
0-)N -(pyrazolo[1,5-a]pyrimidin-6-yloxy)phe
I +
N el nyl)pyrido[3,4-d]pyrimidin-4-amine
F
.N,.--.-,/ F m ¨ 0,,,,-,,_N (R)-5-((3,3-
difluoro-1-methylpiperidin- 548
97 \
''0 HN `N-j-) 4-yl)oxy)-6-methoxy-N-(3-methy1-4-(p 0
yrazolo[1,5-a]pyrimidin-6-yloxy)phenyl (M+H)
--- ' N +
N-) )quinazolin-4-amine
F
N F
N_N (S)-5-((3,3-difluoro-1-methylpiperidin- 548
,,..)
98 4-yl)oxy)-6-methoxy-N-(3-methyl-4-(p
N 04 H)
O yrazolo[1,5-a]pyrimidin-6-yloxy)phenyl
+
N<--J )quinazolin-4-amine
F
N F 0õ,,,, N _ N\) (R)-
N-(3-chloro-4-(pyrazolo[1,5-a]pyri 568
99 ''0 HN CI 'N ------=.-- midin-6-yloxy)pheny1)-
5-((3,3-difluoro-
N
O 1-methylpiperidin-4-yl)oxy)-6-methoxy (M+H)
N<%i quinazolin-4-amine
F
N F 0õ,,,, m _ N) (S)-
N-(3-chloro-4-(pyrazolo[1,5-a]pyri 568
100 "0 HNCI
i'i \
'N --------- midin-6-yloxy)pheny1)-5-((3,3-difluoro-
N
O 1-methylpiperidin-4-yl)oxy)-6-methoxy (M+H)
..- '
N-;) quinazolin-4-amine
F
.N,--/ F 0,,,,,,-;_N1_, (R)-5-((3,3-difluoro-1-methylpiperidin-
_.., m 562
101 4-yl)oxy)-6-ethoxy-N-(3-methyl-4-(pyr
(M H)
0
azolo[1,5-a]pyrimidin-6-yloxy)phenyl)q
+
N<>I uinazolin-4-amine
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F
N.------,i F 0-,,,N-N (S)-5-((3,3-difluoro-1-
methylpiperidin-
,,,,.....) 562
N ' 4-yl)oxy)-6-ethoxy-N-(3-methyl-4-(pyr
102
(M+H)
' N azolo[1,5-a]pyrimidin-6-yloxy)phenyl)q
+
NI') uinazolin-4-amine
F
N.LF N-N\ (R)-5-((3,3-difluoro-1-methylpiperidin-
551
''0 HN N--'0--- 4-yl)oxy)-6-(methoxy-d3)-N-(3-
methyl-
103
(M+H)
D3C-0 N 4-(pyrazolo[1,5-alpyrimidin-6-yloxy)ph
' +
1\l'i enyl)quinazolin-4-amine
F
N-./ F 0-,,/,`-- N-N (S)-5-((3,3-difluoro-1-
methylpiperidin- 551
_ ji
4-yl)oxy)-6-(methoxy-d3)-N-(3-methyl-
104
(M+H)
D3C_0 N 4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)ph
+
Nr) enyl)quinazolin-4-amine
D3C,N,õ/F F 0.,,,_7-- N - N\ (R)-54(3,3-difluoro-1-(methyl-
d3)piper 551
''0 HN N -'-'--- idin-4-yl)oxy)-6-methoxy-N-(3-
methyl-
105
(M+H)
0 4-(pyrazolo[1,5-alpyrimidin-6-yloxy)ph
- +
,' N
enyl)quinazolin-4-amine
D3C,N,õ/F F 0.,,,_7--N-N\ (S)-5-((3,3-difluoro-1-(methyl-
d3)piperi 551
HN -'N "----) din-4-yl)oxy)-6-methoxy-N-(3-methy1-4
106
(M+H)
0 -(pyrazolo[1,5-a]pyrimidin-6-yloxy)phe
+
nyl)quinazolin-4-amine
Example 107
(R)-N-(4-(11,2,41triazolo11,5-alpyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-1-m
ethylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine
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Br
KOH HO,
N---\\ 02N
elrNH2 _________
AcOH, 80 C, --N Me0H,65 C, N K2CO3, DMF,
N-N 02N
NN
100 C
CI
F
NF N_N
Fe
/0 HNNN
NH4CI, H2N NN IPA, 65 C
IPA/H20,
85 C NNJ
Step 1: 5-bromo-3-fluoro-2-methoxypyridine
BrN_N
N-
To a solution of 4H-1,2,4-triazol-3-amine (2 g, 23.78 mmol) in AcOH (20 mL)
was added
2-bromopropanedial (3.59 g, 23.78 mmol) at rt and the mixture was stirred at
80 C for 7 hrs.
The reaction mixture was concentrated to dryness and diluted with Et0Ac (30
mL). The
solution was washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated to
dryness to give 6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine (1.09 g, 23% yield)
as white solid.
MS (ESI) m/z: 197 (M+H)+.
Step 2: 11,2,41triazolo[1,5-a] pyrimidin-6-ol
N_N
To a solution of 6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine (0.9 g, 4.5 mmol) in
Me0H (5 mL)
was added KOH (1.52 g, 27.14 mmol) and the mixture was stirred at 65 C
overnight. The
reaction mixture was concentrated to dryness, diluted with water (20 mL),
adjusted pH value
to 1-2 with 1M aq. HC1 and extracted with IPA/DCM (20 mL x 3, 3/1, v/v). The
combined
organic layers were washed with brine, dried over anhydrous Na2SO4, filtered
and
concentrated to dryness. The residue was purified by column chromatography
silica gel
(DCM: Me0H = 30: 1) to give [1,2,4]triazolo[1,5-a]pyrimidin-6-ol (330 mg, 53%
yield) as
yellow solid. MS (ESI) m/z: 136 (M+H)+.
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Steps
3-5:(R)-N-(4-(11,2,41triazolo11,5-alpyrimidin-6-yloxy)-3-methylpheny1)-5-((3,3-
difluoro-
1-methylpiperidin-4-y1)oxy)-6-methoxypyrido13,4-d]pyrimidin-4-amine
F
0
HN NN
0)N
The crude product was prepared in a similar fashion to Example 53, which was
purified by
column chromatography silica gel (DCM: Me0H = 20: 1) and prep-TLC (PE: Et0Ac=
1: 3)
to give desired product as white solid. 1H-NMIR (400 MHz, DMSO-d6) 6 9.84 (s,
1H), 9.31 (d,
J= 2.8 Hz, 1H), 8.93 (d, J= 2.8 Hz, 1H), 8.69 (d, J= 13.9 Hz, 2H), 8.53 (s,
1H), 7.83 (d, J =
2.3 Hz, 1H), 7.65 (d, J= 8.9 Hz, 1H), 7.13 (d, J= 8.8 Hz, 1H), 4.98-5.08 (m,
1H), 4.10 (s,
3H), 2.22-2.36 (m, 6H), 2.50 (s, 3H), 2.37 (s, 3H). MS (ESI) m/z: 549 (M+H)+.
The following compounds were prepared according to the above described methods
using different starting materials.
Ex# Structure Name
MS
mlz
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi
0 HN din-6-yloxy)-3-methylpheny1)-5-((3,3-
550
108 N N difluoro-l-methylpiperidin-4-yl)oxy)-
(M+H)
6-methoxypyrido[3,4-d]pyrimidin-4-a +
mine
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi
0 HN din-6-yloxy)-3-methylpheny1)-5-((3,3-
570
CI
109 difluoro-l-methylpiperidin-4-yl)oxy)-
(M+H)
6-methoxypyrido[3,4-d]pyrimidin-4-a +
mine
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F (S)-N-(4-([1,2,4]triazolo[1,5-
a]pyrimi
N.1--F 0,,,,;;;N.N_N
din-6-yloxy)-3-methylpheny1)-5-((3,3- 570
110 "0 HN CI N N difluoro-1-methylpiperidin-4-
yl)oxy)- (M+H)
ON
I 6-methoxypyrido[3,4-d]pyrimidin-4-a
+
NN,%i
mine
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi
N F
-,õ/F 0,....,4><:-----N_ N
din-6-yloxy)-3-methylpheny1)-5-((3,3- 564
'''(:) HN N-'N
111 difluoro-1-methylpiperidin-4-yl)oxy)-
(M+H)
N
I 6-ethoxypyrido[3,4-d]pyrimidin-4-ami
+
NN,%i
ne
F (S)-N-(4-([1,2,4]triazolo[1,5-
a]pyrimi
N.1--F 0,,,,;N_N
din-6-yloxy)-3-methylpheny1)-5-((3,3- 564
"0 HN -',-N,,--:-----N
112 difluoro-1-methylpiperidin-4-yl)oxy)-
(M+H)
N
I 6-ethoxypyrido[3,4-d]pyrimidin-4-ami
+
ne
F (R)-N-(4-([1,2,4]triazolo[1,5-
a]pyrimi
N F
',0 HN N ,,k
'' N din-6-yloxy)-3-methylpheny1)-5-((3,3-
553
113 difluoro-l-methylpiperidin-4-yl)oxy)-
(M+H)
N 6-(methoxy-d3)pyrido[3,4-d]pyrimidin +
N1\rJ
-4-amine
F (S)-N-(4-([1,2,4]triazolo[1,5-
a]pyrimi
N F
0 HN N din-6-yloxy)-3-methylpheny1)-5-((3,3-
553
-1\1
114 difluoro-l-methylpiperidin-4-yl)oxy)-
(M+H)
N 6-(methoxy-d3)pyrido[3,4-d]pyrimidin +
N1\rJ
-4-amine
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi
D3C, N,.--FF 0.....,------N__N
din-6-yloxy)-3-methylpheny1)-5-((3,3- 553
HN N-1\1
115 difluoro-1-(methyl-d3)piperidin-4-
yl)o (M+H)
Or)N
I xy)-6-methoxypyrido[3,4-d]pyrimidin-
+
NN 4-amine
4-amine
(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi
D3C,N,.-/F 0.....,------N__N
din-6-yloxy)-3-methylpheny1)-5-((3,3- 553
0 HN N'---INI
116 difluoro-1-(methyl-d3)piperidin-4-yl)o (M+H)
Oy-N
I xy)-6-methoxypyrido[3,4-d]pyrimidin-
+
N,_.,-,%=,,N1
4-amine
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F
= F ,,,,,<.= N - (R)-N-(4-
([1,2,4]triazolo[1,5-a]pyrimi 549
',0 HN N-1\1 din-6-yloxy)-3-methylpheny1)-5-
((3,3-
117
(M+H)
O difluoro-l-methylpiperidin-4-yl)oxy)-
.,- ' N +
6-methoxyquinazolin-4-amine
F
= F 0,,,,õ.-N-N (S)-N-(4-
([1,2,4]triazolo[1,5-a]pyrimi 549
0 HN N-1\1 din-6-yloxy)-3-methylpheny1)-5-
((3,3-
118
(M+H)
O difluoro-l-methylpiperidin-4-yl)oxy)-
N +
N:-J 6-methoxyquinazolin-4-amine
F
= F ,,,,,<.= N - (R)-N-(4-
([1,2,4]triazolo[1,5-a]pyrimi 569
119
',0 HN CI N-:-.-1\1 din-6-yloxy)-3-
chloropheny1)-543,3- 0 difluoro-l-methylpiperidin-4-yl)oxy)-
(M+H)
N +
N:-J 6-methoxyquinazolin-4-amine
F
N F 0,,__<.N...N (S)-N-(4-
([1,2,4]triazolo[1,5-a]pyrimi 569
120 OHN CI N.----.1\1 din-6-yloxy)-3-chloropheny1)-543,3-
(M+H)
O difluoro-l-methylpiperidin-4-yl)oxy)-
+
6-methoxyquinazolin-4-amine
F
N F 0,_.,<N... (R)-N-(4-([1,2,4]triazolo[1,5-
a]pyrimi 564
"NN din-6-yloxy)-3-methylpheny1)-5-((3,3-
121
(M+H)
N difluoro-l-methylpiperidin-4-yl)oxy)-
1 +
N,4-',,,,\I-i 6-ethoxyquinazolin-4-amine
F (S)-N-(4-([1,2,4]triazolo[1,5-
a]pyrimi
--.N.---..... j F 0õ,õ,..---.. .N_N
0 HN ,N,,,._,,, din-6-yloxy)-3-methylpheny1)-
5-((3,3-
564
122 difluoro-l-methylpiperidin-4-yl)oxy)-
(M+H)
N 6-ethoxypyrido[3,4-d]pyrimidin-4-ami +
ne
F
(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi 552
',0 HN "r\i.''.---N din-6-yloxy)-3-
methylpheny1)-5-((3,3-
123
(M+H)
D3C,0 difluoro-l-methylpiperidin-4-yl)oxy)-
' N +
N 6-(methoxy-d3)quinazolin-4-amine
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F
N F 0,,,_7-;=,,N_N (S)-N-(4-([1,2,4]triazolo[1,5-
a]pyrimi 552
N ---------N din-6-yloxy)-3-methylpheny1)-5-((3,3-
124
(M+H)
D3C,0 difluoro-l-methylpiperidin-4-yl)oxy)-
' N +
N 6-(methoxy-d3)quinazolin-4-amine
D3C.,N---/F F O., N... (R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi 552
0 HN N -------N din-6-yloxy)-3-methylpheny1)-5-((3,3-
125
(M+H)
0 difluoro-1-(methyl-d3)piperidin-4-yl)o
N +
N xy)-6-methoxyquinazolin-4-amine
D3C.,N---/F F O., N,..N\\ (S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi 552
HN 7 din-6-yloxy)-3-methylpheny1)-5-((3,3- 04 H)
126
0 difluoro-1-(methyl-d3)piperidin-4-yl)o
+
N xy)-6-methoxyquinazolin-4-amine
F
N.F (:)-,/7-N-- (R)-N-(4-([1,2,4]triazolo[4,3-
a]pyridin 549
N'N -6-yloxy)-3-methylpheny1)-54(3,3-((3 127 (M+H)
ON uoro-l-methylpiperidin-4-yl)oxy)-6-m
I +
N.,..7--i\r--J ethoxypyrido[3,4-d]pyrimidin-4-amine
F
N.F ON__.- (S)-N-(4-([1,2,4]triazolo[4,3-
a]pyridin 549
0 HN -,õ,-1-'----N'N -6-yloxy)-3-
methylpheny1)-54(3,3-((3 128 (M+H)
ON uoro-l-methylpiperidin-4-yl)oxy)-6-m
I +
N Nr.:-J ethoxypyrido[3,4-d]pyrimidin-4-amine
F
N.F CI-N,N-- (R)-N-(4-([1,2,4]triazolo[4,3-
a]pyridin 569
N
''CD HN CI 1<--N1' -6-yloxy)-3-
chloropheny1)-543,3-((3 129 (M+H)
OAN uoro-l-methylpiperidin-4-yl)oxy)-6-m
I +
N ,,/,--, lei ethoxypyrido[3,4-d]pyrimidin-4-amine
.---,,F
N / F ON____. (S)-N-(4-([1,2,4]triazolo[4,3-
a]pyridin 569
N
"0 HN CI 'N"-.-1.----NI' -6-yloxy)-3-chloropheny1)-
5((3,3-difl
130
(M+H)
OAN uoro-l-methylpiperidin-4-yl)oxy)-6-m
I +
N,,...,%---,N ethoxypyrido[3,4-d]pyrimidin-4-amine
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F
N F (31N--- (R)-N-(4-([1,2,4]triazolo[4,3-
a]pyridin 564
HN 1\l'INI -6-Yloxy)-3-methylpheny1)-54(3,3-
((3 131 (M+H)
N uoro-l-methylpiperidin-4-yl)oxy)-6-et
I +
N,--N,J hoxypyrido[3,4-d]pyrimidin-4-amine
F
N F 0, ,,'=
--- 1\1"- (S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin 564
"0 HN 1\l'INI -6-Yloxy)-3-methylpheny1)-54(3,3-
((3 132 (M+H)
N uoro-l-methylpiperidin-4-yl)oxy)-6-et
I +
Nõ,-i,,N.%-i hoxypyrido[3,4-d]pyrimidin-4-amine
F (R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin
N F N ,,,,_,
' \
HN \,N -6-yloxy)-3-methylpheny1)-54(3,3-difl
552
133 uoro-l-methylpiperidin-4-yl)oxy)-6-(
(M+H)
,
D3CC1 1 ' N methoxy-d3)pyrido[3,4-d]pyrimidin-4- +
N.,=,,,N-)
amine
F (S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin
N F N ,,,,_,
' \
0 HN \,N -6-yloxy)-3-methylpheny1)-54(3,3-
difl 552
134 uoro-l-methylpiperidin-4-yl)oxy)-6-( (M+H)
,
D3CC1 1 ' N methoxy-d3)pyrido[3,4-d]pyrimidin-4- +
N.,=,,,N-)
amine
D3C,NFF
(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin
0_õ ,--,,
----- N
',0 HN N,N -6-yloxy)-3-methylpheny1)-54(3,3-((3,3
552
135 uoro-1-(methyl-d3)piperidin-4-yl)oxy) (M+H)
0
1 ' N -6-methoxypyrido[3,4-d]pyrimidin-4-a
+
NN-)
mine
D3C N/FF (S)-N-(4-([1,2,4]triazolo[4,3-
a]pyridin
,
0 HN ,,,,,,,N,N -6-yloxy)-3-methylpheny1)-54(3,3-difl
552
136 uoro-1-(methyl-d3)piperidin-4-yl)oxy) (M+H)
0
1 ' N -6-methoxypyrido[3,4-d]pyrimidin-4-a
+
NN-)
mine
F (R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimi
NF IN õ,__,
- \\
N din-6-yloxy)-3-methylpheny1)-5-((3,3- 550
0 HN 1\l'
N
137 N difluoro-l-methylpiperidin-4-yl)oxy)-
(M+H)
I 6-methoxypyrido[3,4-d]pyrimidin-4-a +
N,,,----.N.
mine
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F (S)-N-(4-([1,2,4]triazolo[4,3-
a]pyrimi
NF IN n,,\
--- \\
N din-6-yloxy)-3-methylpheny1)-5-((3,3- 550
HN 1\l'
N
138 difluoro-l-methylpiperidin-4-yl)oxy)- (M+H)
ON
I 6-methoxypyrido[3,4-d]pyrimidin-4-a
+
NN,4J
mine
F (R)-N-(4-([1,2,4]triazolo[4,3-
a]pyrimi
N F ON,
j,_ ,N din-6-yloxy)-3-chloropheny1)-543,3-
((3,3 570
'-''''ID HN CI N N
139 difluoro-l-methylpiperidin-4-yl)oxy)- (M+H)
OyN
I 6-methoxypyrido[3,4-d]pyrimidin-4-a
+
NN-)
mine
F (S)-N-(4-([1,2,4]triazolo[4,3-
a]pyrimi
NF IN n,,\
\\
N din-6-yloxy)-3-chloropheny1)-543,3- 570
HN CI
140 N difluoro-l-methylpiperidin-4-yl)oxy)- (M+H)
0-)
I 6-methoxypyrido[3,4-d]pyrimidin-4-a
+
N,,---,-Ni
mine
F (R)-N-(4-([1,2,4]triazolo[4,3-
a]pyrimi
N F ()N-- din-6- 564
1 N din-3-methylpheny1)-5-((3,3-
'0 HN -- ,-"---:----ki'
N .µ
141 difluoro-l-methylpiperidin-4-yl)oxy)-
(M+H)
N
I 6-ethoxypyrido[3,4-d]pyrimidin-4-ami
+
ne
F
N F IN õ,,\
--- \\N (S)-N-(4-([1,2,4]triazolo[4,3-
a]pyridin 564
142
0 HN 'N-,"--N' -6-yloxy)-3-methylpheny1)-5((3,3-difl N uoro-
l-methylpiperidin-4-yl)oxy)-6-et (M+H)
I +
N,--j-N.J" hoxypyrido[3,4-d]pyrimidin-4-amine
F (R)-N-(4-([1,2,4]triazolo[4,3-
a]pyrimi
N F IN ,,,,\
-' \\
N din-6-yloxy)-3-methylpheny1)-5-((3,3- 553
.=--'''''0 N HN
143 difluoro-l-methylpiperidin-4-yl)oxy)-
(M+H)
õ_,,-,
D3C,...0 1 '- ' N 6-(methoxy-d3)pyrido[3,4-d]pyrimidin +
NN--->i
-4-amine
F (S)-N-(4-([1,2,4]triazolo[4,3-
a]pyrimi
N F IN ,,,,\
-' \\
N din-6-yloxy)-3-methylpheny1)-5-((3,3- 553
0 HN
N
144 difluoro-l-methylpiperidin-4-yl)oxy)- (M+H)
-
D3C0 1 "- ' N 6-(methoxy-d3)pyrido[3,4-d]pyrimidin +
NN-1"
-4-amine
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(R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimi
D3C,N..,-/FF IN ______,
-- \
\N din-6-yloxy)-3-methylpheny1)-5-((3,3- 553
-N,---------N'
145 0 HN difluoro-1-methylpiperidin-4-yl)oxy)-
(M+H)
0.,?L.N 6-(methoxy-d3)pyrido[3,4-d]pyrimidin
+
-4-amine
F (S)-N-(4-([1,2,4]triazolo[4,3-
a]pyrimi
D3C,N,,-/ F 0.õ,,,,,,,,N 553
---\ din-6-yloxy)-3-methylpheny1)-5-((3,3-
- N --1:------ N'
146 "0 HN difluoro-1-methylpiperidin-4-yl)oxy)-
(M+H)
6-(methoxy-d3)pyrido[3,4-d]pyrimidin +
-4-amine
Example 147
(R)-44(4-(11,2,41triazolo[1,5-clpyrimidin-7-yloxy)-3-methylphenyl)amino)-5-
((3,3-difluo
ro-l-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile
F
F ''N -----
Z--F
F 0 F 0 F OH N---'`/----F
DMFDMA ,-0 , 0.--- 1. n-BuLi, MeCN,
THF. ,.0 CN 'OH
."---'. 0 1 = ,,O,,,,
,,J-CN
I
t-BuOK,DMS0 II
N---
F F 0
O 1_,_-_N
On,.:N ''N".--1--F Eft
N -, N-
-,,-----' ' ------ N
'0 CI N ''''. '0 HN ''"-
POCI3 H2N igril
' 01,,,,CN
--- ---, 0
-' ,. CN
I IPA
NI N----
N "--- N---
Step 1:
methyl (E)-3-fluoro-2-methoxy-5-(((methylamino)methylene)amino)isonicotinate
F 0
I
N ,,-,.1\(---,N.--
H
A solution of methyl 5-amino-3-fluoro-2-methoxyisonicotinate (260 mg, 1.30
mmol) in
D1VIF-DMA (5 mL) was stirred at 70 C for 2 hrs. The mixture was concentrated
to dryness
and the residue was purified by silica gel column (PE: acetone = 3: 1 to 1: 1)
to give desired
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product (300mg, 90% yield) as yellow oil. MS (ESI) m/z: 242 (M+H)+.
Step 2:5-fluoro-4-hydroxy-6-methoxy-1,7-naphthyridine-3-carbonitrile
F OH
0 CN
N
To a solution of acetonitrile (0.15 mL, 2.85 mmol) in THF (5 mL) was added n-
BuLi (0.9 mL,
2.24 mmol, 2.5 M) at ¨78 C. After stirring at this temperature for 10 min, a
solution of
methyl (E)-3-fluoro-2-methoxy-5-(((methylamino)methylene)amino)isonicotinate
(260 mg,
1.02 mmol) in THF (2 mL) was added drop-wisely and the resulting mixture was
stirred at rt
for 16 hrs. After the mixture was cooled to -78 C, AcOH (1 mL) was added, and
the mixture
was stirred for 2 hrs. The mixture was basified with aq.NaHCO3 and extracted
with DCM (5
mL x 3). The combined organic layers were washed with water and brine, dried
over Na2SO4,
filtered and evaporated to dryness. The residue was purified by silica gel
column (eluted with
DCM: Me0H = 50: 1 to 30: 1) to give desired product (100 mg, 45% yield) as
yellow solid.
MS (ESI) m/z: 220(M+H)+.
Steps 3-5:
(R)-44(4-(11,2,41triazolo 11,5-c] pyrimidin-7-yloxy)-3-methylphenyl)amino)-
5((3,3-difluo
ro-l-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile
F
N N-
HN N
The crude product was prepared in a similar fashion to Example 1, which was
purified by
prep-TLC (DCM: Me0H= 15: 1) to give desired product as white solid. 1H-NMIt
(400 MHz,
DMSO-c16) 6 10.00 (s, 1H), 9.71 (d, J= 1.1 Hz, 1H), 8.81 (s, 1H), 8.56 (s,
1H), 8.44 (s, 1H),
7.43 (s, 1H), 7.37-7.21 (m, 2H), 6.98 (d, J = 1.1 Hz, 1H), 4.99 (m, 1H), 4.11
(s, 3H), 3.12 (s,
1H), 2.80 (m, 1H), 2.44-2.30 (m, 1H), 2.17 (m, 8H), 1.93 (m, 1H). MS (ESI)
m/z: 574
(M+H)+.
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The following compounds were prepared according to the above described methods
using different starting materials.
Ex# Structure Name
MS
nth
F (S)-444-([1,2,4]triazolo[1,5-
c]pyrimidi
N 1--F
N N
n-7-yloxy)-3-methylphenyl)amino)-5-((
HN 574
,,,,,,,-N
148 0CN 3,3-difluoro-l-methylpiperidin-4-
yl)oxy (M+H)
--- \ \
I )-6-methoxy-1,7-naphthyridine-3-carbo
+
N, N
nitrile
F (R)-444-([1,2,4]triazolo[1,5-a]pyridin-
N F
m 7-yloxy)-3-methylphenyl)amino)-5-((3, 573
'-'---*"/0 HN -----..:-õ,õõ. - - N
149 3-difluoro-1-methylpiperidin-4-yl)oxy)- (M+H)
0-.LõCN
I 6-methoxy-1,7-naphthyridine-3-carboni
+
NN
trile
F (S)-4-((4-([1,2,4]triazolo[1,5-
a]pyridin-
N F
0 HN ----,,,..õ..... N- N
7-yloxy)-3-methylphenyl)amino)-5-((3, 573
150 3-difluoro-1-methylpiperidin-4-yl)oxy)-
(M+H)
I 6-methoxy-1,7-naphthyridine-3-carboni
+
N N
trile
F (R)-444-([1,2,4]triazolo[1,5-
b]pyridazi
N F
n-7-yloxy)-3-methylphenyl)amino)-5-(( 574
151 AD HN N-N - N 3,3-difluoro-1-methylpiperidin-4-
yl)oxy (M+H)
I )-6-methoxy-1,7-naphthyridine-3-carbo
+
NN
nitrile
F (S)-444-([1,2,4]triazolo[1,5-
b]pyridazi
N .7---F
''''() ,.N n-7-yloxy)-3-methylphenyl)amino)-5-((
574
- m
HN N
152 0CN 3,3-difluoro-l-methylpiperidin-4-
yl)oxy (M+H)
.-' \ \
I )-6-methoxy-1,7-naphthyridine-3-carbo
+
NN
nitrile
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F (R)-5-((3,3 -difluoro- 1 -methylpiperi
din-
N F 0 Ns
, N 4-yl)oxy)-6-methoxy-4-((3 -methyl-4-(te 575
N_N¨N'
153 L'="'*'/O HN trazol o [ 1,5 -c]pyrimi din-7-
yloxy)phenyl (M+H)
I )amino)- 1,7-naphthyri dine-3 -
carbonitril +
N N
e
F (S)-5-((3 ,3 -difluoro- 1 -
methylpiperidin-
N F Or--\_-___-N,
N 4-yl)oxy)-6-methoxy-4-((3 -methy1-4-(te 575
Nõ,,,, N-N"
0 HN
154 trazol o [ 1,5 -c]pyrimi din-7-
yloxy)phenyl (M+H)
I )amino)- 1,7-naphthyri dine-3 -
carbonitril +
e
F
N F Ns (R)-543,3 -difluoro- 1 -methylpiperi
din- 574
HN *-----. N ---N'
,N
4-yl)oxy)-6-methoxy-4-((3 -methy1-4-(te
155
(M+H)
0 CN trazol o [ 1,5 -a]pyri din-7-
yloxy)phenyl)a
I +
N N mino)-1,7-naphthyridine-3 -carbonitrile
F
N.F 0 ..õ....õ.. _______Ns (S)-
5-((3,3 -difluoro- 1 -methylpiperidin- 574
0 HN -.,,N¨NN 4-yl)oxy)-6-methoxy-4-((3 -
methy1-4-(te
156
(M+H)
0 CN trazol o [ 1,5 -a]pyri din-7-
yloxy)phenyl)a
-,
I +
N N mino)-1,7-naphthyridine-3 -
carbonitrile
F (R)-4-((4-([ 1,2,4]triazolo[ 1,5 -
a]pyridin-
N F ,N_N
6-yloxy)-3 -methylphenyl)amino)-5-((3, 573
(D,
157 HN 3 -difluoro- 1 -methyl piperi din-4-
yl)oxy)- (M+H)
,,OCN
I 6-methoxy- 1,7-naphthyri dine-3 -
carboni +
true
F (S)-4-((4-([1,2,4]triazolo[1, 5 -
a]pyridin-
N F 0..õ<õ; ----., ,N_N
0 HN ,__,,f\i 6-yloxy)-3 -
methylphenyl)amino)-5-((3, 573
158 3 -difluoro- 1 -methyl piperi din-4-
yl)oxy)- (M+H)
I 6-methoxy- 1,7-naphthyri dine-3 -
carboni +
true
F (R)-4-((4-([ 1,2,4]triazolo[1, 5 -
a]pyrimidi
N F N__N
n-6-yloxy)-3 -methyl phenyl)amino)-5 -((
HN N N 574
159 3,3 -difluoro- 1 -methylpiperi din-4-
yl)oxy (M+H)
I )-6-methoxy- 1,7-naphthyri dine-3 -
carbo +
N N nitrile
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F (S)-4-((4-([1,2,4]triazolo[1,5-
a]pyrimidi
N F 0õ, N
--- NI' -
n-6-y1 oxy)-3 -methyl phenyl)amino)-5-(( 574
N'10 HN --1\1
N
160 3,3 -difluoro-l-methylpiperi din-4-yl)oxy (M+H)
O- -L
I )-6-methoxy-1,7-naphthyri dine-3 -carb
o +
N N
nitrile
F (R)-4-((4-([1,2,4]triazolo[4,3-
a]pyridin-
N F
0 HN ,NN,N 6-yloxy)-3-methylphenyl)amino)-5-
((3, 573
161 3 -difluoro-l-methyl piperi din-4-
yl)oxy)- (M+H)
O CN
I 6-methoxy-1,7-naphthyri dine-3 -carb oni +
N N
true
F (S)-4-((4-([1,2,4]triazolo[4,3-
a]pyridin-
N F 0.,,,--. it .,\
N \\
N 6-yloxy)-3-methylphenyl)amino)-5-((3, 573
'...."0 HN 1\l'
162 3 -difluoro-l-methyl piperi din-4-
yl)oxy)- (M+H)
_õ.0CN
I 6-methoxy-1,7-naphthyri dine-3 -carb oni +
N ,-N
true
F (R)-4-((4-([1,2,4]triazolo[4,3 -a]pyrimidi
0, ,,-
N ./---F -.'" N
----N n-6-y1 oxy)-3 -methyl phenyl)amino)-5-(( 574
HN 1\l'
N
163 3,3 -difluoro-l-methylpiperi din-4-
yl)oxy (M+H)
O CN
.'
I )-6-methoxy-1,7-naphthyri dine-3 -carb o +
N ,N
nitrile
F (S)-4-((4-([1,2,4]triazolo[4,3 -
a]pyrimidi
NF 0, õ,-.-.
---"- N -----N n-6-y1 oxy)-3 -methyl phenyl)amino)-5-(( 574
,---------Kr
HN N -
164 3,3 -difluoro-l-methylpiperi din-4-
yl)oxy (M+H)
I )-6-methoxy-1,7-naphthyri dine-3 -carb o +
N ,N
nitrile
F (R)-5-((3,3 -difluoro-l-methylpiperi
din-
N F
0 4-yl)oxy)-6-methoxy-4-((3 -methyl -4-(p 573
165 0 HN N yrazolo[1,5-a]pyrimidin-6-yloxy)phenyl
(M+H)
O CN
\ \
I )amino)-1,7-naphthyri dine-3 -
carbonitril +
N ,N
e
F (S)-5-((3,3-difluoro-1-methylpiperidin-
N F
4-yl)oxy)-6-methoxy-4-((3 -methyl -4-(p 573
'..4.0 HN N
166 yrazolo[1,5-a]pyrimidin-6-yloxy)phenyl
(M+H)
O CN
\ \
I )amino)-1,7-naphthyri dine-3 -
carbonitril +
N N
e
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F
N F 0,_,,,,,N,..N (R)-543,3-difluoro-1-
methylpiperidin- 572
',0 HN 4-yl)oxy)-6-methoxy-4-((3-methyl-4-(p
167
(M+H)
O CN yrazolo[1,5-a]pyridin-6-
yloxy)phenyl)a
7-
I +
N N mino)-1,7-naphthyridine-3-carbonitrile
,,,--,2*
F
N F 0,_,,,,,,--.N_N (S)-543,3-difluoro-1-
methylpiperidin- 572
0 HN 4-yl)oxy)-6-methoxy-4-((3-methy1-4-(p
168
(M+H)
yrazolo[1,5-a]pyridin-6-yloxy)phenyl)a
I +
N mino)-1,7-naphthyridine-3-carbonitrile
N
F
N F 0,,,,,x; N _ N (R)-4-((4-
([1,2,4]triazolo[1,5-a]pyrimidi 573
''(:) HN 'N----------N n-6-yloxy)-3-methylphenyl)amino)-5-((
169
(M+H)
O CN 3,3-difluoro-l-methylpiperidin-4-
yl)oxy
7 +
7 N )-6-methoxyquinoline-3-carbonitrile
-----, iF
N F 0,,,,,,%=,õ ,N_N (S)-444-
([1,2,4]triazolo[1,5-a]pyrimidi 573
I-
0 HN i\r---z-N n-6-yloxy)-3-methylphenyl)amino)-5-((
170
(M+H)
O CN 3,3-difluoro-l-methylpiperidin-4-
yl)oxy
+
7 N )-6-methoxyquinoline-3-carbonitrile
F
NZ--F N---i\I (R)-4-((4-([1,2,4]triazolo[4,3-a]pyrimidi
573
0 HN 'N------------N1 n-6-yloxy)-3-methylphenyl)amino)-5-((
171
(M+H)
O CN 3,3-difluoro-l-methylpiperidin-4-
yl)oxy
+
7 N )-6-methoxyquinoline-3-carbonitrile
F
N.LF IC)-7-`N--N (S)-444-([1,2,4]triazolo[4,3-a]pyrimidi
573
0 HN N-^"-N' n-6-yloxy)-3-methylphenyl)amino)-5-((
172
(M+H)
O CN 3,3-difluoro-l-methylpiperidin-4-
yl)oxy
7 +
7 )-6-methoxyquinoline-3-carbonitrile
N
0õ,,,,N _N (R)-543,3-difluoro-l-methylpiperidin- 572
'''---
/F
N F
___.i
',0 HN N 4-yl)oxy)-6-methoxy-4-((3-methyl-4-(p
173
(M+H)
O CN yrazolo[1,5-alpyrimidin-6-
yloxy)phenyl
7 +
7 N )amino)quinoline-3-carbonitrile
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(S)-5-((3,3-difluoro-1-methylpiperidin- 572
0
174 HN 4-yl)oxy)-6-methoxy-4-((3-methyl-4-(p
(M+H)
0 CN yrazolo[1,5-a]pyrimidin-6-yloxy)phenyl
)amino)quinoline-3-carbonitrile
N-(444-([1,2,4]triazolo[1,5-a]pyridin-7
40 -yloxy)-3-methylphenyl)amino)-5-(3-(di
594
175 N N // methylamino)azetidin-1-yl)pyrido[3,4-d
(M+H)
]pyrimidin-6-y1)-4-(dimethylamino)but- +
0
2-enamide
Example 176
Biological Assays
Assay a) BT474 cellular assay (HER2 inhibition)
Inhibition of phosphor HER2 was determined by enzyme-linked immunosorbent
assay
(ELISA) in BT474 cells. BT474 cell line was purchased from ATCC (catalog
number
HTB-20). Human Phospho-ErbB2 ELISA kit was purchased from R&D systems (catalog
number DYC1768).
Day 1:
When the cells reach 70-90%confluence, cells were trypsinized and re-
suspended. 5000
cells per well were seeded to a 384-well plate. The plate was incubated at 37
C with 5%
CO2for 24 hours. ELISA plate was coated with 2 g/m1 capture antibody, which
was
incubated at 4 C overnight.
Day 2:
25n1 compounds was dosed by Echo from source plate and the 384-well plate was
incubated at 37 C for 2 hours.30 1lysis buffer was added to each well and the
384-well plate
was shaken softly at 4 C for30 minutes. The ELISA plate was washed, blocked
and
incubated at room temperature for 1-2 hours. The blocked ELISA plate was
washed and 20 1
cell lysate was transferred from the 384-well plate to the ELISA plate, which
was incubated
overnight at 4 C.
Day3:
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The ELISA plate was washed 3 times.25 1/well detection antibody was added
(diluted 1
by2000 in 1% BSA in PBS). After 2 hours of incubation with detection antibody,
the EL1SA
plate was washed 3times, 25 1/well TMB substrate was added and incubated for
10-15minutes before stop solution was added. Absorbance at 450 nm and 570nm
was read
within 30 minutes after adding the stop solution.
The compounds synthesized in Examples 1-68 are tested in BT474 cellular assay
as
described above. The IC50 results are provided in Table 1 for some exemplary
compounds.
For the other Example compounds for which the results are not shown, all have
an IC50 result
of no more than 1000nM. Some have an IC50 result no more than 300nM, some no
more than
200nM, or no more than 100nM, or even no more than 50nM.
Assay b) NCI H838 cellular assay (wt-EGFR inhibition)
Inhibition of phosphor wt-EGFR was determined by enzyme-linked immunosorbent
assay (ELISA) in NCI H838 cells (ATCC, catalog number CRL-5844). Human
Phospho-EGFR DuoSet IC ELISA kit was purchased from R&D systems (catalog
number
DYC1095).
Day 1:
When the cells reach 70-90% confluence, cells were trypsinized and re-
suspended.
5000 cells per well were seeded to a 384-well plate. The plate was incubated
at 37 C with
5% CO2for 24 hours.
Day 2:
Cell culture medium was replaced with 40 tL FBS-Free RPMI1640. After 2hours of
starvation, the 384-well plate was dosed with 40 nL of compounds by Echo from
source plate
and the 384-well plate was incubated at 37 C with 5% CO2 for 2 hours. After
2hours of
incubation with compounds, EGF (final concentration at 10Ong/m1) was added to
the plate
which was incubated at 37 C with 5% CO2 for 5-10 minutes. Medium was
discarded from
the plate and301,t1/well lysis buffer was added to the plate which was
incubated at 4 C for 10
minutes. The cell lysates can be stored at -80 C in cell plates but must be
thawed at room
temperature for at least 30 minutes prior to use and continuing the assay.
ELISA plate was
coated by diluting capture antibody to 4 pg/m1 with PBS, and 251,t1/well was
dispensed to
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384 well UltraCruz ELISA Plate, which was incubated at 4 C overnight.
Day 3:
After the plates were washed three times with 100111/well of wash buffer, the
plates
were blocked by adding 75 pi of Block Buffer to each well and incubated at
room
temperature for 3 hours. After the plates were washed three times with
100111/well of wash
buffer, 20 pi cell lysate was transferred to the blocked ELISA plate which was
incubated for
2 hours at room temperature. After the plates were washed three times with
100111/well of
wash buffer, 25111/well detection antibody (dilute 1 in 900 in assay buffer)
was added the
plate which was incubated for 2 hours, protected from light. After washed
three times, 25
111/well TMB substrate was added to the ELISA plate which was incubated for
about
10-15min, protected from light before addition of 25111/well stop solution.
Absorbance was
read at 450 nm and 570 nm within 30 minutes.
Results of exemplary compounds of the present disclosure in assays a) and b)
are shown
in Table 2. From Table 2, it can be found that the compounds of the present
disclosure not
only have good inhibition of HER2, they are also very selective for HER2overwt-
EGFR.
For the other Example compounds for which the results are not shown, all have
an IC50
against HER2 of no more than 1000 nM. Some of these compounds have an IC50
against
HER2 of no more than 500 nM, some no more than 400 nM, some no more than 300
nM,
some no more than 200 nM, or no more than 100 nM, or no more than 50 nM, or no
more
than 40 nM, or no more than 30 nM, or no more than 20 nM, or no more than 10
nM, or even
no more than 5 nM. In addition, some of the Example compounds for which the
results are
not shown show IC50 against wt-EGFR of more than 0.5 pM, more than 1 pM, some
more
than 21.tM, more than 3 pM, more than 4 pM, more than 61.tM, more than 81.tM,
or even more
than 10 [NI.
Table 2: HER2 and wt-EGFR inhibition data for exemplary compounds in assays a)-
b)
Example BT474 IC50(nM) 11838 IC50 (pM)
1 20 >10
2 8.4 >10
3 12 >10
109 >10
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7 7.7 4.9
9 6.2 1.9
11 201 7.9
12 29 >10
17 8.1 >10
18 3.6 >10
19 12 >10
21 25 >10
23 31 >10
25 6.0 >10
29 26 >10
31 205 >10
33 63 >10
35 32 >10
37 63 >10
39 144 >10
40 119 >10
41 205 >10
42 36 >10
43 50 >10
44 23 >10
45 16 >10
46 106 >10
47 127 >10
48 11 >10
50 8.2 >10
51 7.6 >10
53 31 >10
55 266 >10
57 4.0 >10
59 15 >10
67 18 >10
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77 31 >10
87 122 >10
107 408 >10
147 251 >10
Example 177
DMPK and hERG inhibition studies
DMPK and hERG inhibition studies were carried out with the compounds of the
present
disclosure as well as Reference compound 1
(2-chloro-N4-(5-((1-methylpiperidin-4-yl)oxy)quinazolin-4-y1)-N1-(pyridin-2-
ylmethyl)benze
ne-1,4-diamine), Reference compound 2 (Neratinib) and Reference compound 3
(ARRY-380,
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylpheny1)-N6-(4,4-dimethy1-
4,5-dihydr
ooxazol-2-yl)quinazoline-4,6-diamine) using the following assays: c): MDCK-
MDR1 Pgp
assessment, d) Caco-2 BCRP assessment, e) mouse SOA study for brain
penetration (Brain
Kp) and f) hERG inhibition assessment.
Assay c): MDCK-MDR1 Pgp assessment
Efflux transport mediated by P-glycoprotein (Pgp) was assessed by MDCK-MDR1
cells.
The final concentrations of test compounds and control compound were at 11.1M.
The
multi-well insert plate was incubated at 37 C for 2 hours.
Assay d): Caco-2 BCRP assessment
Caco-2 cells were used to study efflux transport mediated by BCRP. Rate of
drug
transport by BCRP was determined in the presence and absence of novobiocin, a
strong
inhibitor of BCRP, which was added to both apical and basolateral compartments
at a final
concentration of 3011M. The final concentrations of test compounds and control
compound
were at 11.1M. The multi-well insert plate was incubated at 37 C for 2 hours.
Efflux ratio
(-inhibitod+inhibitor)>2 was considered to be a BCRP substrate.
Assay e) Mouse SOA study for brain penetration
Six non-fasted male balb/c mice (6-8 weeks, 20-25 g)were orally administered
at
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10mg/kg, using a suspension formulation of 1% methylcellulose (MC) in
deionized water.
Brain and blood samples were collected at 0.25, 0.5, 1, 2, 4, 7 hours after
dose. Plasma was
obtained by centrifuging the blood samples for 5 min at 4000g and 4 C. Brain
tissue was
homogenized following addition of four times the volume of phosphate-buffered
saline (pH
7.4). Quantification of the compound in plasma and brain was undertaken by LC-
MS/MS.
Area under the curve (AUC) was determined from 0 to 7 hours in the brain
tissue and
plasma.
Total brain to plasma concentration ratio Kp was determined using the
equation:
Brain Kp=AUC0-7hr brain/AUCO-7hr plasma
Unbound brain to plasma ratio was determined using the equation:
Brain Kp,uu=Kp*fu,brain/fu,plasma
Unbound fraction (fu, plasma) and unbound fraction (fu, brain) were obtained
from in
vitro equilibrium dialysis by using plasma and brain homogenate, respectively.
Assay f): hERG inhibition
Inhibition of hERG channel was conducted in HEK 293 cell line stably
expressing
hERG channel by manual patch clamp.
The compounds synthesized in Examples 1-175 are tested in the above assays c)-
f) for
DMPK and hERG inhibition studies. Results of exemplary compounds of Examples
1, 3,
17, 18, 48, 53, 57, 77, 87, and 107 and Reference compounds 1-3 in assay a),
b), c) and d) are
shown in Table 3.
Table 3: Results of exemplary compounds of Examples and reference compounds 1-
3 in
assay c)-f)
Example No. Pgp ER BCRP ER hERG (IC50) Mouse Kpu,u
Ref. compd. 1 0.57 1.1 <2 M Not determined
Ref. compd. 2 >18.6 1.4 >10 M Too low to
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calculate
Too low to
Ref. compd. 3 23.8 2.1 > 10 [tM
calculate
1 0.82 0.61 > 10 [tM 0.23
3 1.06 0.69 > 10 [tM N/A
17 0.42 0.43 > 10 [tM 0.13
18 0.55 0.47 > 10 [tM 0.12
48 1.3 N/A N/A N/A
53 1.45 N/A > 10 [tM N/A
57 1.62 N/A >5 [tM N/A
77 2.1 N/A > 10 [tM N/A
87 1.22 N/A > 10 [tM N/A
107 1.48 N/A > 10 [tM N/A
From Table 3, it is shown that Reference compound 1 is a strong hERG inhibitor
with
IC50<2 04. In contrast, compounds of Examples do not show hERG liability.
Furthermore, Reference compounds 2 and 3 are strong Pgp substrates and not
brain
penetrable in vivo with Kpu,u that are too low to calculate. In contrast,
compounds of
Examples are not Pgp substrates. Example 1 , 17 and 18 was selected to
evaluate Kpu,u in
mouse SOA study and are further confirmed to be brain penetrable. For the
other Example
compounds in this table or some examples not in this table which the results
of Kpu,u are not
shown, are expected to be capable of brain penetration.
These data demonstrated the compounds of this application have superior brain
barrier
penetration properties when compared to Neratinib and Array380 and predict
drug action on
metastatic tumors in brain.
The foregoing description is considered as illustrative only of the principles
of the
present disclosure. Further, since numerous modifications and changes will be
readily
apparent to those skilled in the art, it is not desired to limit the invention
to the exact
construction and process shown as described above. Accordingly, all suitable
modifications
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and equivalents may be considered to fall within the scope of the invention as
defined by the
claims that follow.
The words "comprise", "comprising", "include", "including", and "includes"
when used
in this specification and in the following claims are intended to specify the
presence of stated
features, integers, components, or steps, but they do not preclude the
presence or addition of
one or more other features, integers, components, steps, or groups thereof.
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