AU2025203211A1

AU2025203211A1 - ErbB RECEPTOR INHIBITORS AS ANTI-TUMOR AGENTS

Info

Publication number: AU2025203211A1
Application number: AU2025203211A
Authority: AU
Inventors: Ziqiang CHENG; Zheng Wang; Ding Zhou
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 2020-03-13
Filing date: 2025-05-06
Publication date: 2025-05-29
Also published as: AU2020435503B2; WO2021179274A1; AU2020435503A1; CA3175102A1

Abstract

Provided herein are novel compounds as inhibitors of type I receptor tyrosine kinases, 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, such as cancer and inflammation, in mammals and especially in humans.

Description

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 HERI), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4) (Reviewed in

Riese and Stem, 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 Cin

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 CancerRes,

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.

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 ofHER2 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 (Kp) <0.01 (Kabraji S. et al. ClinicalCancerResearch. 2018, 3351).

T-DM1, an antibody drug conjugate (ADC), does not cross BBB either with Kp<0.01

(Askoxylakis V, et al. JNCIJNatlCancerInst, 2015, 763-763). Approved tyrosine kinase

inhibitors (TKIs) lapatinib, neratinib and afatinib are strong Pgp substrates, and have poor

brain penetration with Kp of 0.04, 0.079 and <0.08, respectively (Tanaka, Y.et al, Scientific

Reports, 2018, 343; Zhang, Shirong, et al, Acta PharmacologicaSinica, 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 Kp at 0.02-0.05 (Dinkel V, et al. CancerResearch, 2012, 72).

In addition, the evaluation of resected brain metastases has revealed that the BBB was 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):

(R 4) n1 X2 E X1 D

__X_ A R2', X5 X 6-x N L HN X4 7

G ( \, 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;

X1, X2, X3, X4, X5, X 6, 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, SO 2 and N(R);

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)(R), and O(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,

o 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 N(Rio)(Rni);

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

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, S02 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,

heteroarylalkyl, and heterocyclylalkyl;

Rio and Ru are each independently selected from the group consisting of hydrogen,

alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,

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 Ru 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,S02and NR1 2,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; nI is 0, 1 or 2. In some embodiments according to Formula (I), at least one of Xi,X6 andX7 is N. In another aspect, the present disclosure provides compounds of Formula (II): R 4 ) n1

X2 E Xb N A

L HN X4X

) G

)n M ~~* (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;

XI, X2 , X 3 , X4 , X5 , X6 , andX7 are each independently CH or N, with the proviso that

when M is CH, at least one of Xi,X 6 andX7is N; E is 0, NH, or S; L is selected from the group consisting of 0, C(=0), S,SO,S02and N(R6);

R 1 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(R 7)(R), and O(R 9), 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), R2and R6together 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); 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; R7and 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

heteroarylalkyl, and heterocyclylalkyl;

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

heteroarylalkyl, and heterocyclylalkyl;

R12 is selected from the group consisting of hydrogen, alkyl, alkyl-OH, haloalkyl,

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;

nI is 0, 1 or 2.

In some embodiments of the compounds according to Formula (II), at least one of Xi,

X6 and X 7 is N. In some embodiments, X 7 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):

R3 X2 E R2', I-X5 L HN X4

HN

N (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)(R), and O(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 , Y 3 , Y 4 , Y 5, andY 6 is optionally substituted by one or more of groups each independently having the same definition as RI;

L is selected from the group consisting of 0, C(=0), S, SO, S02 and N(R6);

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, haloalkyl, saturated and partially unsaturated cycloalkyl,

and N(Rio)(Rii);

alkoxyl;

R5 is selected from the group consisting of hydrogen, halogen and cyano;

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

additional heteroatoms selected from N, 0, S, SO, S02 and NR1 2 , wherein said heterocyclyl

heteroarylalkyl, and heterocyclylalkyl;

Rio and R1 are each independently selected from the group consisting of hydrogen,

saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl; or

additional heteroatoms selected from N, 0, S, SO, SO 2 and NR1 2 , wherein said heterocyclyl

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;

n is 0, 1 or 2;

and nl 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.

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.

Formula (III), or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof

particular HER2-associated diseases or conditions, wherein the compound is administered

simultaneously, separately or sequentially with radiotherapy.

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.

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 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, 7 5 th Ed., 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 Modem 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

"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" 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, C .61

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 "Ci-2" indicates I to 12, particularly I to 10, particularly I 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 "Cij 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 I Icarbon atoms. In some

embodiments, alkyl groups contain to I Icarbon atoms, I to 10 carbon atoms, I 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, I to 3 carbon atoms, or I to 2 carbon atoms. Examples of alkyl group

include, but are not limited to, methyl, ethyl, I-propyl (n-propyl), 2-propyl (isopropyl),

1-butyl (n-butyl), 2-methyl-i-propyl (i-butyl), 2-butyl (s-butyl), 2-methyl-2-propyl (t-butyl),

i-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl,

2-methyl-i-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,

4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl,

3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, and the like. Examples of"CI12 alkyl" include, but

are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,

undecyl, dodecyl. Examples of "C1.6 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-methyl-2-butyl,

3-methyl-i-butyl, 2-methyl-i-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl,

3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl,

2,3-dimethyl-2-butyl, 3,3-dimethyl-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, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,

alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, 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, alkylsulfmyl, 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, cycloalkylalkyl, 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 2to 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, 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-1-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,

ethynyl,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 I to 12 carbon

atoms. In some embodiments, alkoxy groups contain 1 to 11 carbon atoms. In some

embodiments, alkoxy groups contain Ito 11carbon atoms, Ito 10 carbon atoms, I 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 C 2 -6alkenyl-carbonyl group (e.g., acryloyl), a C 3 .10 cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), a

C3-iocycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), a C6-14 aryl-carbonyl group,

a C 7- 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 Ci-6 alkoxy-carbonyl

group, a C6 - 14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), a

C7-iaralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), a

carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C2-6

alkenyl-carbamoyl group (e.g., diallylcarbamoyl), a mono- or di-C 3 -io cycloalkyl-carbamoyl

group (e.g., cyclopropylcarbamoyl), a mono- or di-C-14 aryl-carbamoyl group (e.g.,

phenylcarbamoyl), a mono- or di-C 7-1 6 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 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-(Ci-2 alkyl)carbamoyl" include, but are not limited to, methylaminocarbonyl and ethylaminocarbonyl. Examples of "N,N-(Ci-12 alkyl)2carbamoyl" include, but are not limited to, dimethylaminocarbonyl and methylethylaminocarbonyl.

As used herein, the terms "cycloalkyl", "carbocyclyl" 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-l-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,

cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and

cyclododecyl.

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, 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-C13 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

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

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 "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 heterocyclyl may contains any oxidized form of carbon, nitrogen or sulfur, and any quaternized form of a basic nitrogen. "Heterocyclyl" 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-yl (nitrogen linked) or pyrrol-3-yl (carbon

linked). Further, a group derived from imidazole maybe imidazol-1-yl (nitrogen linked) or

imidazol-3-yl (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 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-Ci-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 -N02 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 result in stable compounds. When any variable (e.g., R') 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 0-2R 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 R. 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):

(R 4 ) n1 X2 E X1 D

R21, L HN X 5 X6 N-B

L HN 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;

X1, X2, X3, X4, X5, X 6 , andX7 are each independently CH or N;

E is 0, NH, or S; L is selected from the group consisting of 0, C(=O), ,SO,SO2 and N(R); 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)(R), and O(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;

R6 is hydrogen or alkyl; or

when L is N(R6 ), R2 and R6 together with the nitrogen atom to which they are attached

10 membered heterocyclyl ring is optionally substituted with one or more groups

and N(Rio)(Rii);

alkoxyl;

R5 is selected from the group consisting of hydrogen, halogen and cyano;

alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkylamino, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl optionally substituted by alkyl, aryl, and heteroaryl; or

heteroarylalkyl, and heterocyclylalkyl;

saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl; or

Rio and Ri together with the atom to which they are attached form a 3 to 10 membered

additional heteroatoms selected from N, 0, S, SO, SO 2 and NR1 2 , 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;

n is 0, 1 or 2;

nI is 0, 1 or 2.

In some embodiments according to Formula (I), at least one of X1, X6 and X7 is N.

In another aspect, the present disclosure provides compounds of Formula (II):

R 4 ) n1 X2 E XN A

R2,X 5 D~. L HN X X X7

(R ), 1 nM G /

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;

heteroarylalkyl, and heterocyclylalkyl;

n is 0, 1 or 2;

nI is 0, 1 or 2.

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):

R3 X2 L HN X4

(R 1

N (III) or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof, wherein:

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 , Y 3 , Y 4 , Y 5, and Y 6 is optionally substituted by one or more of groups each independently having the same definition as RI;

L is selected from the group consisting of 0, C(=0), S, SO, S02 and N(R6);

R6 is hydrogen or alkyl; or

10 membered heterocyclyl ring is optionally substituted with one or more groups

and N(Rio)(Rii);

alkoxyl;

R5 is selected from the group consisting of hydrogen, halogen and cyano;

by alkyl, aryl, and heteroaryl; or

heteroarylalkyl, and heterocyclylalkyl;

saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl; or

n is 0, 1 or 2;

nI 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 X 2 , X 3 , X 4 , and X5 is CH.

In some embodiments, X1 is CH.

In some embodiments, Xi is N.

In some embodiments of compounds of Formula (I), one of X 6 and X 7 is CH, and the

other is N. In some embodiments of compounds of Formula (II), one of X6 and X 7 is CH, and

the other is N.

In some embodiments, Ri is selected from hydrogen, N(R)(Rs), O(R9), or saturated or

partially unsaturated hetercyclyl optionally substituted by acyl.

In some embodiments, Ri is N(R)(Rs), 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.

In some embodiments, Ri is N(R7 )(Rs), R7 is hydrogen, and Rs is saturated or partially

unsaturated cycloalkyl substituted by alkyl.

In some embodiments, R1 is N(R7)(R), R7 is hydrogen, and Rs is

4,4-dimethyl-4,5-dihydrooxazol-2-yl.

In some embodiments, R 1 is N(R7)(R), R7 is hydrogen, and Rs is acyl substituted by

alkylamino or saturated and partially unsaturated heterocyclyl substituted by alkyl.

In some embodiments, Ri is N(R)(Rs), R7 is hydrogen, and Rs

is(dimethyamino)but-2-ene-carbonyl or (1-methyl-pyrrolidin-2-yl)-acryloyl.

In some embodiments, Ri is O(R9), and R9 is selected from the group consisting of alkyl,

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, R 1 is O(R 9), and R 9 is selected from the group consisting of

C1-6alkyl, Ci-6acyl,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, R 1 is O(R9 ), and R 9 is selected from methyl, ethyl, isopropyl,

piperazinylcarbonyl, cyclopropyl, or tetrahydrofuranyl, each of which is optionally

substituted by one or more fluoro 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 O(R9 ), R 9 is selected from the group consisting of C 1 -6alkyl,

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 R2is 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(Rio)(Rii).

In certain embodiments, Ri is O(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, R 2 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

0 and S, wherein said 3 to 10 membered heterocyclyl ring is optionally substituted with one

carboxy, carbamoyl, alkyl, alkenyl, alkynyl, haloalkyl, saturated and partially unsaturated

cycloalkyl, and N(Rio)(Rn).

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)(Rn).

In some embodiments, the phrase "R2 and R 6 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 R 2 and R6 together with the nitrogen 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(R 6), and R 2 and R6 together with the nitrogen atom to

which they are attached form: O N

N N N N N

P PN N N N p N 0

N N N N N N N N N N N

NN P N 0

, or N 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-fluoroethyl,2,2-difluoroethyl, cyclopropyl, or dimethylamino. In

certain embodiments, said heterocyclyl ring is substituted with one or more fluoro groups.

In certain embodiment, said heterocyclyl ring is substituted with one or more methyl groups.

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 R2is 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(Rio)(Rii). In some embodiments, L is 0, and R2 is selected fromC 4.6 saturated cycloalkyl or 5 to 6 membered saturated heterocyclyl, wherein saidC4-6 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, 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)(Rii). In some embodiments, L is N(R 6), 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)(R), and O(R9), and R2and 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)(Rii). In certain embodiments, L is N(R6 ), Ri is N(R)(Rs), and R2 and R6 -togetherwith 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 certain embodiments, R7 is hydrogen, and Rs is saturated or partially unsaturated cycloalkyl substituted by alkyl. In certain embodiments, R7 is hydrogen, and Rs is 4,4-dimethyl-4,5-dihydrooxazol-2-yl.

In certain embodiments, L is N(R), Ri is O(R), 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 R 6 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)(Rni).

In certain embodiments, L is N(R6), Ri is O(R), R9 is selected from methyl, ethyl,

isopropyl, cyclopropyl, or tetrahydrofuranyl, each of which is optionally substituted by one

or more fluoro, 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)(Rn).

In some embodiments, R3 is halogen.

In certain embodiments, R 3 is chloro.

In some embodiments, R3 is C1.6 alkyl.

In certain embodiments, R3 is methyl.

In some embodiments, R4 is hydrogen.

In a further aspect, the present disclosure provides a compound of Formula (IVa), (IVb),

(IVc), (IVd), (IVe), (I), (IVg), (IVh), or (IVi) below:

R3 N R2 L HN

R,

N (IVa)

R4 E N R3 NN /> R2 L HN R1

N (IVb)

R2 L HWE R,G

N (IVc)

R4

E N N7

L HNE R,

N (IVd)

E N 2,L HNN(:jN

R,

N (IVe)

R4

E N, N R2 L HN R1

N (Ivf)

R4

R2L NN

N (IVg) R4 EN

R2s R3 E ~ /N L HN R1

N (IVh)

E NN R2, R3 N NJ L HN R1

N (IVi) or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof, wherein G, L,

E, Ri, R2, R3 and R4have the meanings as defined in Formula (I)and various embodiments

thereof.

In some embodiments of Formula (I), (IVa), (IVb), (IVc), (IVd), (IVe), (I), (IVg),

(IVh), (IVi), L is selected from 0 or N(R); R1 is O(R), N(R)(R), 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 C 4.6 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 R 6 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 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; R 4 and R5 are hydrogen; R7 and Rs 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; R 9 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 Rn 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):

E N-N R3 RL HN N

N (Va)

E RR4 N

L HN N

N (Vb)

E Q R R3 E N L HN R1

N (Vc)

WO 2021/179274 PCT1CN20201079097

EE R2NL HNN ~NN R, 'G

N (Vd)

NaEN R2 , L R3 LHN R,

N (Ve)

NE NL NN N -

N (Vf)

NE N N -

N (Vg)

NE N-N

R2NL HN ~ N

N (Vh) or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof, wherein G, L,

E, R1, R2, R3 and R 4 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); R is O(R9), N(R)(R), 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 C 4 .6 saturated cycloalkyl and 4 to 6

independently selected from the group consisting of halogen, alkyl, and N(Rio)(RI); 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

saturated monocyclic, spirocyclic or fused heterocyclyl ring is optionally substituted with

haloalkyl, saturated and partially unsaturated cycloalkyl, and N(Rio)(Rii);R 3 is selected from

halogen or alkyl; R 4 and R5 are hydrogen; R7 and Rs 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, C 3 .7 saturated or partially unsaturated cycloalkyl, and 4 to 6

from halogen, alkyl, acyl, and alkoxyl; andRio and Rn are each independently an alkyl.

In a further aspect, the present disclosure provides a compound of Formula (VIa), (VIb),

(VIc), (VId):

R4 E N-N R3> R2 L HN N N R1G

N (VIa)

R4 E N R2 L HN N N

R1G

N (VIb)

R4 E

R2 L HN N N

R1G

N (VIC)

R4 E NN

R2 L HN R1G

N (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 C 4 .6 saturated cycloalkyl and 4 to 6 membered saturated

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 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 Ru 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-methylphenyl)-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-yloxy)-3-methylphenyl)-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-methylphenyl)-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-yloxy)-3-methylphenyl)-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-methylphenyl)-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-yloxy)-3-methylphenyl)-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]pyrimidin-7-yloxy)-3-chlorophenyl)-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-yloxy)-3-chlorophenyl)-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-methylphenyl)-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-yloxy)-3-methylphenyl)-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]pyrimidin-7-yloxy)-3-methylphenyl)-6-methoxy-5-((1-meth ylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine;

N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-(3-(dimethylamino)a

zetidin-1-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-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-methylphenyl)-5-((3,3-difluoro-1-(

methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(methyl-d3)piperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;

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-methylphenyl)-5-((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-methylphenyl)-5-((3,3-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-methylphenyl)-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[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-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-methylphenyl)-5-((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-methylphenyl)-5-((3,3-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-methylphenyl)-5-((1-cyclopropyl-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-methylphenyl)-5-((1-cyclopropyl-3,3

-difluoropiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

thylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;

ethyl-d3)piperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;

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-methylphenyl)-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-methylphenyl)-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-methylphenyl)-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-methylphenyl)-6-cyclopropoxy-5-((3,

3-difluoro-1-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine;

thylpiperidin-4-yl)oxy)-6-(2,2,2-trifluoroethoxy)pyrido[3,4-d]pyrimidin-4-amine;

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-methylphenyl)-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-methylphenyl)-6-methoxy-5-morpholino

pyrido[3,4-d]pyrimidin-4-amine;

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-methoxy-5-(4-methylpi

perazin-1-yl)pyrido[3,4-d]pyrimidin-4-amine; cis-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((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-methylphenyl)-5-((3-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-methylphenyl)-5-((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-methylphenyl)-5-((4,4-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-methylphenyl)-5-(3-(dimethylamino)pyrr

olidin-1-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(4-(dimethylamino)-3,3

-difluoropyrrolidin-1-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-methoxy-5-(5-methyl-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-methylphenyl)-6-methoxy-5-(2-methyl-2,

6-diazabicyclo[3.2.O]heptan-6-yl)pyrido[3,4-d]pyrimidin-4-amine;

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(7-fluoro-5-methyl

2,5-diazaspiro[3.4]octan-2-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(7-fluoro-5-methyl

2,5-diazaspiro[3.4]octan-2-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(7,7-difluoro-5-methyl

2,5-diazaspiro[3.4]octan-2-yl)-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-methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-b]pyridazin-7-ylox

y)-3-methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-7-yloxy)-3-methylphenyl)-5-((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-methylphenyl)-5-((3,3-difluoro-1-me

thylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-a]pyridin-7-yloxy)

3-methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-a]pyridin-7-yloxy)

3-methylphenyl)-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-methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-c]pyrimidin-7-ylox

y)-3-methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(R)-N-(4-([1,2,4]triazolo[1,5-b]pyridazin-7-yloxy)-3-methylphenyl)-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-b]pyridazin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1

methylpiperidin-4-yl)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;

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-methylphenyl)-5-((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-methylphenyl)-5-((3,3-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-chlorophenyl)-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-chlorophenyl)-5-((3,3-difluoro-1-met

hylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

thylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;

thylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylphenyl)-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[1,5-a]pyridin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-(m

ethyl-d3)piperidin-4-yl)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-(pyrazolo[1,

5-a]pyridin-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]pyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;

(R)-N-(3-chloro-4-(pyrazolo[1,5-a]pyridin-6-yloxy)phenyl)-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-yloxy)phenyl)-5-((3,3-difluoro-1-methylpi

peridin-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]pyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;

(N)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-ethoxy-N-(3-methyl-4-(pyrazolo[1,

5-a]pyridin-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]pyridin-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]pyridin-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-methyl-4-(pyraz

olo[1,5-a]pyridin-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-methyl-4-(pyraz

olo[1,5-a]pyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;

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)phenyl)-5-((3,3-difluoro-1-methy

lpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(S)-N-(3-chloro-4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)-5-((3,3-difluoro-1-methyl

piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

-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;

olo[1,5-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;

5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine;

lpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine;

piperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine;

-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine;

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-methylphenyl)-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-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1

methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;

methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;

(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-methylphenyl)-5-((3,3-difluoro-1-(

methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine;

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-chlorophenyl)-5-((3,3-difluoro-1

methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine;

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-chlorophenyl)-5-((3,3-difluoro-1

methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine;

methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;

methylpiperidin-4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine;

(methyl-d3)piperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine;

methyl-d3)piperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine;

(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylphenyl)-5-((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-methylphenyl)-5-((3,3-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-chlorophenyl)-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-chlorophenyl)-5-((3,3-difluoro-1-met

hylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

thylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;

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-methylphenyl)-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-methylphenyl)-5-((3,3-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-methylphenyl)-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-methylphenyl)-5-((3,3-difluoro-1

methylpiperidin-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-chlorophenyl)-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-chlorophenyl)-5-((3,3-difluoro-1

methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;

thylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;

methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;

(R)-4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)amino)-5-((3,3-difi

uoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(S)-4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)amino)-5-((3,3-difl

uoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5-((3,3-difluor

o-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5-((3,3-difluor

o-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(R)-4-((4-([1,2,4]triazolo[1,5-b]pyridazin-7-yloxy)-3-methylphenyl)amino)-5-((3,3-dif

uoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(S)-4-((4-([1,2,4]triazolo[1,5-b]pyridazin-7-yloxy)-3-methylphenyl)amino)-5-((3,3-diflu

oro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-4-((3-methyl-4-(tetrazolo[

1,5-c]pyrimidin-7-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile;

(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-4-((3-methyl-4-(tetrazolo[1,

5-c]pyrimidin-7-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile;

1,5-a]pyridin-7-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile;

5-a]pyridin-7-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile;

(R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylphenyl)amino)-5-((3,3-difluor

o-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylphenyl)amino)-5-((3,3-difluor

o-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(R)-4-((4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)amino)-5-((3,3-dif

uoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(S)-4-((4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)amino)-5-((3,3-dif

uoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(R)-4-((4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylphenyl)amino)-5-((3,3-difluor

o-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(S)-4-((4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylphenyl)amino)-5-((3,3-difluor

o-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(R)-4-((4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylphenyl)amino)-5-((3,3-dif

uoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(S)-4-((4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylphenyl)amino)-5-((3,3-difl

uoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-4-((3-methyl-4-(pyrazolo[

1,5-a]pyrimidin-6-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile;

(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-4-((3-methyl-4-(pyrazolo[1,

5-a]pyrimidin-6-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile;

1,5-a]pyridin-6-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile;

5-a]pyridin-6-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile;

uoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinoline-3-carbonitrile;

(S)-4-((4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)amino)-5-((3,3-difl

uoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinoline-3-carbonitrile;

1,5-a]pyrimidin-6-yloxy)phenyl)amino)quinoline-3-carbonitrile;

5-a]pyrimidin-6-yloxy)phenyl)amino)quinoline-3-carbonitrile;

N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5-(3-(dimethyl

amino)azetidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)-4-(dimethylamino)but-2-enamide.

Exemplary compounds of the present disclosure are set forth in Table 1 below.

Table 1

Cmpd Compound Structure and Name No. FF

N FHN

(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F N F

o HN 2 O NO HN (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

F O N F" HN

3 0 N N (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1I-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine Fo NaF oHN a N

(S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine

N FF N F 0 HN NN-N

N

(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine F NaF -a oH HN N

6 N

(S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine FF

N F HN "0 ci

7 0 N-N

(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-chlorophenyl)-5-((3,3-difluo ro-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine FF

N o HN OF c INNN

8 )

Nt

(S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-chlorophenyl)-5-((3,3-difluo ro-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F N F H "0 HNa- N~N~

9 CD3

(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine Fo N F

C 30 0 N CD '> NN

6

(S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine

NOL~~ - - 0 N>

11 '70"

N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-6-methoxy-5-((1 -methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine N N 0 N

HN N

12 N'

N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-(3-(dimethyla mino)azetidin-1-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine "0 H-N N~ CD3'N O 0H

13 -70~

(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

CD3' N FF H

14 N

N,- ,N (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-diflu -:

oro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

D3CN FFH

Cf N

2N

(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-(methyl-d3)piperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-a mine

FF COHN N

0CD3 > 16 N N (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-(methyl-d3)piperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-a mine F

N OFH "0 HNN -C 17 N N N' (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F

N OF 0OHNN

18 N N (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

CD3'N F HN

'0 HN N _

19 0 N

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

CD3'N F 0

0OHN ~N

0 NW (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

NaF /> 'O HN

21 N

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-isopropylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

'N FF 0,

N oHN

22 N' (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-isopropylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine FN NOLFF 0~~ /> O HN

23 'O

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((1-cycloprop yl-3,3-difluoropiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

N% FF 0,-CrN

O HN

24 )

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((1-cycloprop yl-3,3-difluoropiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

F 0 Na F /N> "o HN

CD3 O NN (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine

N F H ao HNa

26 CD 3 0) Nl N

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine

D3C'N F 0

'0 HNN CD 0 ' 27 C s N

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-(methyl-d3)piperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amin e

D3C'N FF 0

aoHNN

CD 3 N 28

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-(methyl-d3)piperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amin e F

29 "0 HN

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-isopropoxypyrido[3,4-d]pyrimidin-4-amine F 0

N F 0OHNN

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-isopropoxypyrido[3,4-d]pyrimidin-4-amine

O HN O

31 O

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-(cyclopropyl methoxy)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4 amine

F 0

o HN

32

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-(cyclopropyl methoxy)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4 amine F 0 ND F I - "0 HN O

33 Nl

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-cyclopropoxy -5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine

F

N F H> 0OHNN

34 O N N (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-cyclopropoxy -5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine

F-1F 0 ,C r_

'0 HN F 3 C-O- 0 F -NY (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-(2,2,2-trifluoroethoxy)pyrido[3,4-d]pyrimidin-4-a mine

F 0,, N

N O HN N

36 F3CyO

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-(2,2,2-trifluoroethoxy)pyrido[3,4-d]pyrimidin-4-a mine

N F H> "0 HNa F', 0 37 F O N (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-(difluoromethoxy)pyrido[3,4-d]pyrimidin-4-amin e

N F H 38 0 HN '.N~

F 0

F Nx '

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-(difluoromethoxy)pyrido[3,4-d]pyrimidin-4-amin e

N Oa HN

39 0

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-methoxy-5-((1-m ethylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine

>0 >

N)HN N

0-1 N Ny

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-methoxy-5-morp holinopyrido[3,4-d]pyrimidin-4-amine

N~ ~ /0>.

N HN N

41 O >y NN

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-methoxy-5-(4-me thylpiperazin-1-yl)pyrido[3,4-d]pyrimidin-4-amine

"I N XF0 N~

N "0 HN O

42 > N N N cis mixture

cis-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3-fluoro-1 methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

~N F >0 -N N 'O HN 43 O

N trans mixture trans-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3-fluoro-1 -methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F

--N F H -N

NN 44

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((4,4-difluoro -1-methylpyrrolidin-3-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F 0

--N 0 HN

45N

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((4,4-difluoro -1-methylpyrrolidin-3-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

-N N HN O

46 0) Nt

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(3-(dimethylamin o)pyrrolidin-1-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

-N F H N N HN"

47 /O

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(4-(dimethylamin o)-3,3-difluoropyrrolidin-1-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

N HN 48

/ N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-methoxy-5-(5-me thyl-8-oxa-2,5-diazaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-4-amine

NN

N HNaN 49 /

N N

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-methoxy-5-(2-me thyl-2,6-diazabicyclo[3.2.0]heptan-6-yl)pyrido[3,4-d]pyrimidin-4-amine F

-N N g0

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(7-fluoro-5-m ethyl-2,5-diazaspiro[3.4]octan-2-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine ,F

N N 51 '0-

N NY (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(7-fluoro-5 methyl-2,5-diazaspiro[3.4]octan-2-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

F F 0 N> N HN 52 0o

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(7,7-difluoro-5-m ethyl-2,5-diazaspiro[3.4]octan-2-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

N F HN

"0 HN N'

53 0 N N (R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-b]pyridazin 7-yloxy)-3-methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F N F HN

0OHN K- N' 54

(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-b]pyridazin 7-yloxy)-3-methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

N F N

'0 HN

N N (R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F 0 N F N N 56 0 HN

(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine Fo N F HN '0 HN 57 )N

(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-a]pyridin-7 yloxy)-3-methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F 0 r

N F 0OHN 58 '

N (S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-a]pyridin-7-y loxy)-3-methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F N F HN

0OHNa

59 N N)

(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-c]pyrimidin 7-yloxy)-3-methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F

N F HN 0OHNa

N

(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-c]pyrimidin 7-yloxy)-3-methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

61 "0 HN NN O~

(R)-N-(4-([1,2,4]triazolo[1,5-b]pyridazin-7-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

FF

o HN NN

62 O ' N_ N

(S)-N-(4-([1,2,4]triazolo[1,5-b]pyridazin-7-yloxy)-3-methylphenyl)-5-((3,3-difluo ro-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F 0, N F HxNN N "0 HN ~ NNj

63 O NN

(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

N F HN N 'N o HN

64 N N (S)-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

N FFo-z0 -N

N F HN "0 HN

O N N (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 F0N

66 N F HN N

7N

(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

N0 HN

67 O N (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F 0

0 HN N

68 0

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

N OFH "0 HN ci 69 0

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-chlorophenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F

N 0OFHHN'a ci

0 N-N

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-chlorophenyl)-5-((3,3-difluoro 1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

F 0 - i-N

N N

0 HN K\> 71 O4

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine

72 O N N

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine

F 0 N F HN "0o HN '~ N

73 D 3C '

N N (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine F 0 NN F H O0H N "z N

74 D3C'0 N N (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine

D3C' N F F HN -;-'NN

O NN

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine D3, F 0o SD3CN F 76 0 HN > N

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F 0oN N F H

"0 HN

77 -0

(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 0 _ N F

0OHN

78 O

(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 F 0 N F H

"0 HN cI

79 -0 1

(R)-N-(3-chloro-4-(pyrazolo[1,5-a]pyridin-6-yloxy)phenyl)-5-((3,3-difluoro-1-me thylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F 0

0OHN CI

0 N N

(S)-N-(3-chloro-4-(pyrazolo[1,5-a]pyridin-6-yloxy)phenyl)-5-((3,3-difluoro-1-me thylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

-F ~N F 81 0 HN

6N

(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

~N :FF OHN S

82O N

(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-ethoxy-N-(3-methyl-4-(pyrazo lo[1,5-a]pyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine F 0 ~N OFH '0o H N '0 D3C'O 83 Y'N

(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 0o ~N F

NO HN 0 HN

84 D3C'0 N N

(S)-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

D3, F 0 D3C'N F HN

'ON N-N

(R)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4 (pyrazolo[1,5-a]pyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine

D3, F 0 N D3C'N F H

86 0

(S)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4 (pyrazolo[1,5-a]pyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine

N F HN

"0 HN ~ N

87 -0-

N N

(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

N F HN

ao HN a_-N

88 > NN

(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

N F HN

"0 HN CI N

89 O

(R)-N-(3-chloro-4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)-5-((3,3-difluoro-1 methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F

~N OFH 0OHNa GIN

0 N N-N

(S)-N-(3-chloro-4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)-5-((3,3-difluoro-1 methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

F N F HN

"0 H N ~ N

91 N N 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)pyrido[3,4-d]pyrimidin-4-amine F 0

~N OFH 0 HN N

92 N N N (S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-ethoxy-N-(3-methyl-4-(pyrazo lo[1,5-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine

N( -F N ~N OFH "10 H N ~ N 10N 93 D 3C '

N (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 0 NN F H 0:o H N N

94 D3C' N

(S)-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

D3C, N NaOF HNC; -

'10 HNa N

ON

(R)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4 (pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine

D3C'N FO H NaF N

'oHN N

96 N N

(S)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4 (pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine F 0 NN FH

"0 HN ~ N

97 ol:0N N

(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

N F HN

ao HN al NZ

98 O 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

99 ol:0 N F NN

(R)-N-(3-chloro-4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)-5-((3,3-difluoro-1 methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine F N

N0 HNa CI N

100 -OI N

(S)-N-(3-chloro-4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)-5-((3,3-difluoro-1 methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine

F N F HN

"0 H N ~ N

101 1: N 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 F 0

N FHN NN

102 N

(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-ethoxy-N-(3-methyl-4-(pyrazo lo[1,5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine

N( -F N

"0 HN N

103 D 3C '

N_ (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 0o F

NO 0:o H N HN N

104 D 3C N

(S)-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

D3C, N NaOF HNC; -

'10 HNa N

105 0O 5 N

(R)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4 (pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine

D3C'N FO H NaF N

0o HN N

106 IC N

(S)-5-((3,3-difluoro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxy-N-(3-methyl-4 (pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine F o

N OFH 0OHN ~ N N

107 0) N

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

N FF N F> O HN N N

108 0) N

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F0

O HN CI N N

109 0 N t- -.

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F 0

OHNa S CI N N

110 T NN

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

N F NNN

111 O NN

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine Fo N F HN

0OHN ~ N N

112 O) ' N

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine F 0

"O HN N N 10N 113 D 3C N N (R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine F 0 -N N F N O0HNa N N '0 114 D 3C'O NN

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine

D3C'N F HN '10 HN N N

115 '-O N (R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

D3C' FO H Na F NN' 0o HN N N

116 0o NN

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine Fo N F HN

0OHN ~ N N

117 I0

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine

N FF N F> O HN N N

118 -O

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine F0

O HN CI N N

119 0

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-chlorophenyl)-5-((3,3-difluo ro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine F 0

OHNa S CI N N

120 0

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-chlorophenyl)-5-((3,3-difluo ro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine

F -N ~N OFH 0OHN ~ N N

121 O

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-ethoxyquinazolin-4-amine Fo N F HN

0OHN ~ N N

122 OI N)N

"O HN N N

123 D 3C N

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine F 0

O HN N N

124 D 3C'

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine

D3C'N F HN '10 HN N N

125 ~N

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine

D3C' FO H Na F NN' 0o HN N N

126 )o

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine F 0 aF N0 HN N

127 O N

(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F 0

NN N 0OHNa 128 1o

(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F 0

"0 HN cN

129 0 N

(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-chlorophenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

N 0 HN cN

130 0 1o N '

(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-chlorophenyl)-5-((3,3-difluoro 1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

F 0 NFN N "0 HN N

131 O N-N

(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine F0 NFN

o HN N

132 0 N

(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine

"0 HN N

133 D 3C '

N

(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine F 0 NFN N O HN N

134 D 3C'O N N

(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine

D3C' FN NN '0 HN N

135 0N N

(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

D3CFN O NaF N IN 'OHN N'

136 N

(S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F NFN N N0 HN N N

137 O N-N

(R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F 0

o HN N N

138 70 N N (S)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

N FF 0 N

"0 HN CI N N

139 N N N (R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-chlorophenyl)-5-((3,3-difluo ro-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F NaF

0 HNC N N

140 O N-N

(S)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-chlorophenyl)-5-((3,3-difluo ro-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

F NFN

"0 HN N N

141 0

(R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine F NFN N o HN N

142 N (S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro -1-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine F 0 NFN N "0 HN N N

143 D 3C '

N N

(R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine F 0 aF ~ NN

0 HN N N

144 D3C'O N (S)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine

D3C'N F

'10 HN ~ N N

145 N N-N

(R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine

D3CNN FF 0

o HNN N

146 N

(S)-N-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-diflu oro-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine

N F HN "0 H N N

147 N N (R)-4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)amino)-5-((3, 3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitri le FF

N F H 0 HN X N<NN >0 > CN 148 O N (S)-4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)amino)-5-((3, 3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitri le F

N OFH "0 HNN

149 O CN N x _

(R)-4-((4-([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 F A

150 0 HN O0 CN

(S)-4-((4-([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 F

0 HN NN CN 151 N-C N (R)-4-((4-([1,2,4]triazolo[1,5-b]pyridazin-7-yloxy)-3-methylphenyl)amino)-5-((3, 3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitri le

NaF F I NN O 5 o HN N N CN 0 CN 152

(S)-4-((4-([1,2,4]triazolo[1,5-b]pyridazin-7-yloxy)-3-methylphenyl)amino)-5-((3, 3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitri le Fo N FF 0N

0 HN NN

70 CN 153 N (R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-4-((3-methyl-4-(tetr azolo[1,5-c]pyrimidin-7-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile F Na F 0

0 HN N

70 CN 154

(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-4-((3-methyl-4-(tetra zolo[1,5-c]pyrimidin-7-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile

F 0

F HN N

155 ON N __ N_

(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-4-((3-methyl-4-(tetr azolo[1,5-a]pyridin-7-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile F 0 Na F I --

o HN N

156 O CN

(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-4-((3-methyl-4-(tetra zolo[1,5-a]pyridin-7-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile F0N

~N F "0 HN N

157 O CN

(R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylphenyl)amino)-5-((3,3 difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile F

O HN N

158 O oNCCN N (S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylphenyl)amino)-5-((3,3 difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile

N OH F 0 N N N 0 HN N ONN

159 N CN

(R)-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-methoxy-1,7-naphthyridine-3-carbonitri le

F

~N NH F F0 N -N ONN

160 N CN

(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-methoxy-1,7-naphthyridine-3-carbonitri le F0 NFN N0 HN N

161 OoNOCN

N (R)-4-((4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylphenyl)amino)-5-((3,3 difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile F0 N O HNa N

162 O CN

(S)-4-((4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylphenyl)amino)-5-((3,3 difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile F

"0 HN N N

163 O CN

(R)-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-methoxy-1,7-naphthyridine-3-carbonitri le F 0 F N 164 0 HN N N CN

N___ 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-methoxy-1,7-naphthyridine-3-carbonitri le F 0 NN FH

"0 HN N

165 oNCCN 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)-1,7-naphthyridine-3-carbonitrile

N F 0 N OFH o HN '1 N o10 CN 166 N ___ N_

(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)-1,7-naphthyridine-3-carbonitrile F 0 N FN

'0 HN

167 oNCCN N (R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-4-((3-methyl-4-(pyr azolo[1,5-a]pyridin-6-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile F 0 N N aF ONH 0OHN CN 168 N .- N_

(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-4-((3-methyl-4-(pyra zolo[1,5-a]pyridin-6-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile

169 O HN N

ON CN

(R)-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 OFFN N -N N 0 H NN 0 CN 170

(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

N FF 0N ~ N \N 0 HN N -0 ( CN 171 N (R)-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 0

O HN N N -0 ( 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

N O HN '0 HN N O0 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 F N 0 N

174 0 HN N O16 CN

N

(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 0 N>

N NO ~N~N ~ N 175 ON0 N

N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5-(3-(di methylamino)azetidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)-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 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 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. Forexample,such 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, 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, 19hed., 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 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

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 H,2 H,3 H, 1 1 C, 12 14 15 31 32 C, 13c, C, 14N, N, 160, 170, 180, P, , 32s, 33s, 34s, 36s, 1 7F, 19F, 35 C1, 37 C1, 7 9Br, 81Br, and 13 1I. 127I In some embodiments, hydrogen includes protium, deuterium and tritium. In

some embodiments, carbon includes 12 C 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 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.1 H or 13 C), 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 10-6(pm). H-NMR spectra is recorded in CDC 3 ,

CD 30D 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 HSGF254 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.

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 (TIF), 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.

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 theIC5ofor 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 theICofor 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, 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 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 inhibitionIC 5 oof greater than about 2 M, greater than about 3 M, greater than about 4 M, greater than about 5 lM, greater than about 6 M, greater than about 7 M, greater than about 8 lM, greater than about 9 M, greater than about 10 M. 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 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.

the manufacture of a medicament for the treatment of type I receptor tyrosine

kinase-associated diseases or conditions.

the manufacture of a medicament for the treatment ofHER2-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 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 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 TWEEN TM ,

PLURONICSTMor 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, 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

(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, hydroxypropylmethylcellulose, 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 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 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 lyophilizedd) 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 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 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 CASODEX TM (4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-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 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

[HERCEPTIN T M] 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-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine

(gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine

(erlotinib, OSI-774) and

6-acrylamido-N-(3-chloro-4-fluorophenyl)-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 avP3 function and angiostatin), or inhibitors of angiopoietins and their receptors

(Tie-i 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 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), B7HI, PD-i (for example BMS-936558 or AMP-514),

PD-Li (for example MED14736) 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-DMi) and combination

thereof. In some embodiments, the additional anti-tumour agent includes capecitabine,

anti-HER2 antibodies, and T-DMi. In some embodiments, there is one additional 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 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. Insome 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 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 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 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 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 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 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

CH 2C1 2 dichloromethane

Cs2CO3 cesium carbonate

DCE dichloroethane

DCM dichloromethane

DHP 3,4-Dihydro-2H-pyran

DIEA or DIPEA diisopropylethylamine

DMA N,N-dimethylacetamide

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

EtOH ethanol

Et3N triethylamine

EtOAc ethyl acetate

HCHO formaldehyde

HCOOH formic acid

H 2 SO 4 Sulfuric acid

hr(s) hour(s)

IPA isopropyl alcohol

K 2 CO 3 potassium carbonate

KOtBu or tBuOK potassium tert-butoxide

LDA lithium diisopropylamide

LiAlH 4 lithium aluminium hydride

MeCN acetonitrile

Mel methyl iodide

MeOH methanol

NaBH(OAc) 3 sodium triacetoxyborohydride

NaH sodium hydride

NaHCO 3 sodium bicarbonate

NaOH sodium hydroxide

Na2SO4 sodium sulfate

NH4 Cl ammonium chloride

NH4 0 H ammonium hydroxide

Pd2 (dba) 3 tris(dibenzylideneacetone)dipalladium(O)

Pd(OAc) 2 palladium(II) acetate

PE petroleum ether

POCl3 phosphoric trichloride

PPTS Pyridinium p-toluenesulfonate

Tol toluene

TsOH p-toluenesulfonic acid

TEA triethylamine

THF tetrahydrofuran

TFA trifluoroacetic acid

TFAA trifluoroacetic anhydride

Xant-phos 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene

Examples 1-175 Compounds and Synthesis

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-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-m ethylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F F F 0 F Ph O F NaOMe O CO 2 OH Mel O/ HN Ph, LDATHF N B K2 CO3 ,DMF N 'B Pd 2(dba) 3, Xantphos B, Br Cs;COs, dioxane

F F O N F N F FF 0 C F 0 F OH "O 0O YN0 01 H N NH 2 0 _ __

O0N N 15 2-methoxyetHH hanol

" 2 ex anKOtBu, DMSO N

Ph Ph F 0 N F o ND- F />~ Fc POC3 CIH 2N O HN N DIPEA, Tol "N IPA 0Os Nx' N '~ N

Step 1: 5-bromo-3-fluoro-2-methoxypyridine F

N -" Br

To a solution of 5-bromo-2,3-difluoropyridine (10 g, 51.5 mmol) in methanol (150 mL) was added MeONa (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 EtOAc (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:EtOAc = 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

F 0

) OH

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 TIF) 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 EtOAc (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

N Br

To a solution of 5-bromo-3-fluoro-2-methoxyisonicotinic acid (8.9 g, 36 mmol) and K 2 CO3

(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 EtOAc (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:EtOAc = 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

0 N

Ph Ph To a solution of methyl 5-bromo-3-fluoro-2-methoxyisonicotinate (3 g, 11.4 mmol) in dioxane (100 mL) was added diphenylmethanimine (3.lg, 17.1mmol), Pd 2(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 N 2 . 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 1~0 >1'

NH 2

To a solution of methyl 5-((diphenylmethylene)amino)-3-fluoro-2-methoxyisonicotinate(5 g, 13.7 mmol) in THF/H 2 0(120 mL/12 mL) was added diluted hydrochloric acid (30 mL, IM).

The mixture was stirred at 25 °C for 12 hrs. The mixture was adjusted pH = 7 with saturated

sodium bicarbonate solution, extracted with EtOAc (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:EtOAc = 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-d]pyrimidin-4-ol F OH O 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 EtOAc (100 mL x2). The combined organic

give a residue. The was purified by chromatography on silica gel (DCM:MeOH = 100: 1) to

give desired product (1.3 g, 60% yield) as a white solid. MS (ESI) m/z: 196 (M+H)*.

Step 7:

(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-o F

0 OH

N

A solution of 5-fluoro-6-methoxypyrido[3,4-d]pyrimidin-4-ol (800 mg, 4.1 mmol), (R)-3,3-difluoro--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 (IM), and

extracted with DCM/MeOH (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/EtOAc (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-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrim

idine F N FF

'0 C1

N N

To a solution of POCl 3 (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-o

(300 mg, 0.92 mmol) at 85 °C. The mixture was stirred at 85 °C for 3 hrs. The mixture was

concentrated, diluted with EtOAc (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)*.

Step

9:(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1

methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F N F "0 HN'~ NN

N N

A solution of

(R)-4-chloro-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin

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:MeOH = 15:1)

to give desired product (54 mg, 16% yield) as a white solid. 'H NMR (400 MUz, CDC 3) 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-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-chlorophenyl)-5-((3,3-difluoro-1-me

thylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine OH

C NH trimethoxymethane CI 2N CI 0N O N N N N-N K 2C0 3 : 2N C N MeCN F NaF 0 CI IN N F 0

Fe, NH 4CI > N N N O HN IPA/H 2 0 N N N 0 H -I>~~ H 2Na Cl N IPA N

13N

Step 1: 4-chloro-6-hydrazinylpyrimidine H CI N'NH 2 N N

To a solution of 4,6-dichloropyrimidine (20 g, 135.1 mmol) in EtOH (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-[1,2,4]triazolo[4,3-c]pyrimidine

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 EtOAc (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: EtOAc

= 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)-[1,2,4]triazolo[1,5-c]pyrimidine 0 N

0 2N CI

To a solution of 2-chloro-4-nitrophenol (2 g, 13 mmol) in MeCN (30 mL) was added K 2 CO3

(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 MeOH (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-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-chloroaniline

0 N

H 2 NCl NN

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), NH4Cl (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: MeOH = 20: 1) to give the desired product (120 mg,

72% yield) as yellow solid. MS (ESI) m/z: 262 (M+H)*.

Step 5 :

thylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F

"0 HN CN 0 N >

NN

A solution of 4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-chloroaniline (100 mg, 0.38

mmol) and

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 NaHCO 3 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: MeOH = 15: 1) to give the desired product (66 mg, 30% yield) as white solid.

'H-NMR (400 M Uz, DMSO-d) 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)*.

Example 12

N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-(3-(dimethylamino)aze

tidin-1-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

N N NN F OH < 'a OF ON N NH NOH CI H 2N N HN N N N ~ t-BuOK,DMSO O DIPEA, Tol o N IPA O N N Nr A N Nx N N

Step 1: 5-[3-(dimethylamino)azetidin-1-yl]-6-methoxypyrido[3,4-d]pyrimidin-4-o N

N OH O N N

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: MeOH= 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-yl)-N,N-dimethylazetidin-3-amine

N N CI N

To a mixture of POCl 3 (0.1 mL, 1.17 mmol) and DIPEA (0.26 mL, 1.56 mmol) in toluene (3

mL) was added 5-[3-(dimethylamino)azetidin-1-yl]-6-methoxypyrido[3,4-d]pyrimidin-4-ol

(108 mg, 0.39 mmol) at 85 °C and the mixture was stirred at 85 °C for 3 hrs. The mixture was concentrated to dryness and the residue was neutralized with ice-cooled saturated aq.

NaHCO3 solution. The mixture was extracted with EtOAc (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:

tidin-1-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine N 0 N

NHN N N

A mixture

of 1-(4-chloro-6-methoxypyrido[3,4-d]pyrimidin-5-yl)-N,N-dimethylazetidin-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: MeOH = 15: 1) twice to give

desired product (3 mg, 1.77% yield) as white solid. IH-NMR (400 MUz, DMSO-d 6) 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

WO 2021/179274 PCT1CN20201079097

N FF ,T N(S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimi N-/ N F-1

2 0 HN HN K N~ din-7-yloxy)-3-methylphenyl)-5-((3,3 -difluoro-1I-methylpiperidin-4-yl)oxy) 50( 5(

N N amine

F (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimi N ,z F / di n- 7-yl oxy) -3-m ethyl phenyl) -5-((3,3 56( 3 0 H N-difluoro-1I-methylpiperidin-4-yl)oxy)

N mine F 0N(S)-N-(4-([1,2,4]triazolo[ 1, 5-c]pyrimi N/F din-7-yloxy)-3-methylphenyl)-5-((3'3 4 0 HN -difluoro-1I-methylpiperidin-4-yl)oxy)56( S N -6-ethoxypyrido[3,4-d]pyrimidin-4-a +) NX N mine

0 (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrim 5, '0 HNzz N-/ din-7-yloxy)-3-methylphenyl)-5-((3,3 5 N -difluoro-1I-methylpiperidin-4-yl)oxy) (M±H) N -- -- pyrido[3,4-d]pyrimidin-4-amine+ N

N F O-: N> (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimi 520 6z 0 HN />~ di n- 7-yl oxy) -3-m ethyl phenyl) - 5-((3,3 6 HN -difluoro-1I-methylpiperidin-4-yl)oxy) (M+H) N .- pyridoll3,4-d]pyrimidin-4-amine+ ' N' F 0N(S)-N-(4-([1,2,4]tri azol o [1, 5-c] pyrimi Na F jI-C/> din-7-yloxy)-3-chlorophenyl)-5-((3,3- 570

8 0 HN ciNN N difluoro-1I-methylpiperidin-4-yl)oxy)- (M+H) 0N 0-N 6-methoxypyrido[3,4-d]pyrimidin-4-a+ N mine

F N (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimi N F O din-7-yloxy)-3-methylphenyl)-5-((3,3 553

9 0 HN N -difluoro-1-methylpiperidin-4-yl)oxy) (M+H) CD3 O N -6-(methoxy-d3)pyrido[3,4-d]pyrimid

+ N in-4-amine

F N (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimi F O din-7-yloxy)-3-methylphenyl)-5-((3,3 5 0 HN -difluoro-1-methylpiperidin-4-yl)oxy) (M+H) CD N -6-(methoxy-d3)pyrido[3,4-d]pyrimid

+ N -N N ,in-4-amine

N 0 N N-(4-([1,2,4]triazolo[1,5-c]pyrimidin- 514 11 O HNa NZ NN 7-yloxy)-3-methylphenyl)-6-methoxy 0 N -5-((1-methylpiperidin-4-yl)oxy)pyrid N N o[3,4-d]pyrimidin-4-amine

N FF (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimi din-7-yloxy)-3-methylphenyl)-5-((3,3 5 ND3'N F> 13 0 HN -difluoro-1-(methyl-d3)piperidin-4-yl) (M+H)

N oxy)-6-methoxypyrido[3,4-d]pyrimidi

+ N n-4-amine

N F N (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimi CD' F O> din-7-yloxy)-3 -methylphenyl)-5-((3,3 553

14 0 HN -difluoro-1-(methyl-d3)piperidin-4-yl) (M+H) O N oxy)-6-methoxypyrido[3,4-d]pyrimidi +

N N n-4-amine

D N F N (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimi HN' /> din-7-yloxy)-3-methylphenyl)-5-((3,3 556 '0 O HN -difluoro-1-(methyl-d3)piperidin-4-yl) (M+H) CD< 0 > N oxy)-6-(methoxy-d3)pyrido[3,4-d]pyr +

N imidin-4-amine

D 3 CN F (S)-N-(4-([1,2,4]triazolo[1,5-c]pyrimi 556 NN /> din-7-yloxy)-3-methylphenyl)-5-((3,3 16 0 HNN -difluoro-1-(methyl-d3)piperidin-4-yl) (M+H) CD0 N oxy)-6-(methoxy-d3)pyrido[3,4-d]pyr +

N imidin-4-amine

F (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridi N F > n-7-yloxy)-3-methylphenyl)-5-((3,3-d 549 17 0 HN N ifluoro-1-methylpiperidin-4-yl)oxy)-6 (M+H) N -methoxypyrido[3,4-d]pyrimidin-4-a

+ N mine

F N (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin N tF I --- 7-yloxy)-3-methylphenyl)-5-((3,3-dif54 18 0 HN N luoro-1-methylpiperidin-4-yl)oxy)-6- (M+H) N methoxypyrido[3,4-d]pyrimidin-4-am

+ N NNm N ine

Example 2

White solid. IH-NMR (400 MHz, DMSO-d) 69.92 (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. 1H NMR (400 MHz, CDCl3) 69.96 (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. 1H-NMR (400 MHz, DMSO-d) 69.89 (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

White solid. IH-NMR (400 MHz, DMSO-d )6 69.92 (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. 1 H-NMR (400 MHz, DMSO-d) 610.08 (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-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-meth ylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

NH2 F NH 2 0 ~ NH 2 H FA. 0.. N ~N I DMFDMPA -0 HO NaH, DMF 0 2N O N H 2 HH N O2 HO 6' 02 N 0THF F "NF

0 CI F

NN K N N N N O HN Pd/H,0 1) N aI> EtOH H 2N N PA N

Step1:4-(2-methyl-4-nitrophenoxy)pyridin-2-amine 0 NH 2

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 N 2 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 EtOAc (30 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 (PE: EtOAc= 3: 1) to give desired product (500 mg, 22% yield) as yellow solid. MS (ESI) m/z: 246 (M+H)*.

Step2:(E)-N-hydroxy-N'-[4-(2-methyl-4-nitrophenoxy)pyridin-2-yl]methanimidamide H 0 N N'OH

0 2N

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 OC for 2 hrs. The mixture was concentrated to dryness and the residue was

purified by chromatography on silica gel (DCM: MeOH= 20: 1) to give desired product (150

mg, 42% yield) as yellow oil. MS (ESI) m/z: 298 (M+H)*.

Step 3: 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine

0 2N O

To a solution of

(E)-N-hydroxy-N'-[4-(2-methyl-4-nitrophenoxy)pyridin-2-yl]methanimidamide (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: MeOH= 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-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-meth

ylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

F o Na F I/ S"0 HN O

0-1N

The crude product was prepared in a similar fashion to Examples 1 and 7, which was purified

by prep-TLC (DCM: MeOH = 20: 1) to give desired product as white solid. 'H-NMR(400

MVUlz, DMSO-d) 69.95 (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-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-(met hyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F OH

F3C F Fo~ LAJD Fo~ F Boc F DHP/PPTS F LIAI D3CN F HCI D3C'N F N THF OTHP MeOH OH t-BuOK,DMSO OH DCM OTHP

D3C'N FF 0 N( - FN D3C' FF N D3C F 0 N

o toluene IPA 0 N

N N N 'N) N N

Step1:(4R)-tert-butyl3,3-difluoro-4-((tetrahydro-2H-pyran-2-yl)oxy)piperidine -1-carboxylate

F BocN F

'OTHP

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: EtOAc= 10: 1) to give desired product (700 mg, 103% yield) as colorless oil. MS (ESI) m/z: 322 (M+H)*.

Step2:(4R)-3,3-difluoro-1-(methyl-d3)-4-((tetrahydro-2H-pyran-2-yl)oxy)piperidine F D3C'N 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 LiAlD 4 (157 mg, 3.73mmol) 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

EtOAc (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: EtOAc= 5: 1) to give desired product (200 mg,67% yield) as colorless oil. MS (ESI) m/z:

239 (M+H)*.

Step3:(R)-3,3-difluoro-1-(methyl-d3)piperidin-4-ol F

'OH To a solution of

(4R)-4-({4-chloro-6-methoxypyrido[3,4-d]pyrimidin-5-yl}oxy)-3,3-difluoro-1-(D3)methylpip

eridine (200 mg, 0.84 mmol) in MeOH (2 mL) was added 2N aq.HCl (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: MeOH = 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-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-(met hyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

D3C'N F N

O HN NN

The crude product was prepared in a similar fashion to Example 1, which was purified by

prep-TLC (DCM: MeOH= 15: 1) twice to give title product as white solid. 'H-NMR (400

MVUlz, DMSO-d) 69.96 (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-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-isopr opylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine BO F Boc, F F No ,F N FHa 0 ',N --F F OH 0 O Bo 0 OH TFA '0 OH O NH . N t-BuOK, DMSO N DCM O N NaBH(OAc) 3, .. NN'Ill NxN DCE/THF PNN O N

N N

FaF OC13N F2

N

'0 OH O

A mixture of 5-fluoro-6-methoxypyrido[3,4-d]pyrimidin-4-ol (400 mg, 205 rnmol), tert-butyl (R)-3,3-difluoro-4-hydroxypiperidine-I-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: EtOAc= 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-yl)oxy)-6-methoxypyrido[3,4-dpyrimidin-4-o F HN F

'0 OH

N N To a solution of (R)-3,3-difluoro-4-((4-hydroxy-6-methoxypyrido[3,4-d]pyrimidin-5-yl)oxy)piperidine-1-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) m/z: 313 (M+H)*.

Step 3: (R)-5-((3,3-difluoro-1-isopropylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-dpyrimidin-4 01 F N F

'0 OH

N N 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 hour. NaBH(OAc) 3 (65 mg, 1.9 mmol) was added to the mixture in small portions at 0 °C 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/MeOH (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: MeOH = 30: 1) to give the title compound (150 mg, 66% yield) as yellow solid. MS (ESI) m/z: 355 (M+H)*.

Steps 4-5: (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-isopr opylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F 0 N

"0 HN O

N

The crude product was prepared in a similar fashion to Example 1, which was purified by prep-TLC (DCM: MeOH= 20: 1) to give desired product as white solid. H-NMR (400 MHz, DMSO-d) 610.00 (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-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((1-cyclopropyl-3,3 difluoropiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F A -' F7<~~ 0, F F N -'F N F FN '0 OH TMSO OH ------POCl O CI H2N N O HN NaBH3CN,DCEiTHF O GPEAtol O N IPA O N NN N N N N N

Step 1: (R)-5-((1-cyclopropyl-3,3-difluoropiperidin-4-yl)oxy)-6-nethoxypyrido[3,4-dipyrimidin -4-ol

F N F

'0 OH

N 0 _

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 MeOH (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 DCM/MeOH (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: MeOH = 30: 1) to give the title compound (150 mg, 66% yield) as yellow solid.

MS (ESI) m/z: 353 (M+H)+.

Steps 2-3:

difluoropiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine N, FF

O HN O

prep-TLC (DCM: MeOH = 15: 1) to give desired product as white solid. IH-NMR (400 MHz,

DMSO-d) 69.90 (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),

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-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-meth

ylpiperidin-4-yl)oxy)-6-(difluoromethoxy)pyrido[3,4-d]pyrimidin-4-amine

F 0 NH F O FO TMSCLNa F 0 FF FN

FN N MeCN HNa 2SO 4,ACN FO O FPd 2 (dba)F3 ,Xantphos BrBr F N Br Cs 2CO 3 ,dioxane

F O AcOH F OH N F N F HCI F 0 O HN NH2 F 0 N O OH O

F F 2-meoxyethano

, O CIH2c OMO HN HCN F KN NH F ON N P F H0O O1

F "acH NH2 "O~ N- DIIO O F 0 P N

F L) OH F m NN NO cHFO a -

ToF a souino2ehl5boo3ur--methoyisoicotnat (2 gO 7. mmol in A CH3C

Step 1: methyl 5-bromo-3-fluoro-2-oxo-1,2-dihydropyridine-4-carboxylate F 0 0, O

To asolution of methyl 5-bromo-3-fluoro-2-methoxyisonicotinate (2 g,7.5mnol) in CH3 CN (40 mL) was added TMSC1(2.9 mL, 22.7minol) and Nal (3.4 g, 22.7mnol) and the mixture was stirred at 85IC for 2hrs. Thereaction mixture wasconcentrated under reduced pressure to give crude product, which was purified by chromatography on silica gel (DCM: MeGH= 20: 1)to give desired product (1.8 g, 95%oyield). MS (ESI) m/z: 250 (M+H).

Step 2: methyl 5-bromo-2-(difluoromethoxy)-3-fluoropyridine-4-carboxylate

F 0 F 0

F Nx Br

To a solution of methyl 5-bromo-3-fluoro-2-oxo-1,2-dihydropyridine-4-carboxylate (500 mg,

2.0 mmol) in CH 3CN (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: EtOAc = 10: 1) to give desired product

(370 mg, 61% yield). MS (ESI) m/z: 300 (M+H)*.

Steps 3-8: (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-meth

ylpiperidin-4-yl)oxy)-6-(difluoromethoxy)pyrido[3,4-d]pyrimidin-4-amine F o N F HO "10 HNNN F YO-' F NN N

prep-TLC (DCM: MeOH = 15: 1) twice to give desired product as white solid.H-NMR(400

MVUlz, DMSO-d) 69.85 (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

m/z

N FO N (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin

OHN N N~ -7-yloxy)-3-methylphenyl)-5-((3,3-difl

N N uoro-1-methylpiperidin-4-yl)oxy)-6-m N - ethoxypyrido[3,4-d]pyrimidin-4-amine

N3 F N (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin NC t N F -7-yloxy)-3-methylphenyl)-5-((3,3-difl 552

0 HN N uoro-1-(methyl-d3)piperidin-4-yl)oxy) (M+H) 0 N -6-methoxypyrido[3,4-d]pyrimidin-4-a

+ N N mine

F (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin

N> F-7-yloxy)-3-methylphenyl)-5-((3,3-difl 577 22 0 HN uoro-1-isopropylpiperidin-4-yl)oxy)-6 (M+H) SN -methoxypyrido[3,4-d]pyrimidin-4-am

+ F (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin N F N -7-yloxy)-3-methylphenyl)-5-((-cyclo 575

24 0 HN N propyl-3,3-difluoropiperidin-4-yl)oxy) (M+H) N -6-methoxypyrido[3,4-d]pyrimidin-4-a

+ N- mine

F N (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin F O -7-yloxy)-3-methylphenyl)-5-((3,3-dif 552

0 HN uoro-1-methylpiperidin-4-yl)oxy)-6-( (M+H) CO CD N N methoxy-d3)pyrido[3,4-d]pyrimidin-4 N' N amine

F (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin N F -7-yloxy)-3-methylphenyl)-5-((3,3-difl 552

26 0 HN uoro-1-methylpiperidin-4-yl)oxy)-6-( (M+H) CDO N methoxy-d3)pyrido[3,4-d]pyrimidin-4- +

NN N amine

F N (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin D> -7-yloxy)-3-methylphenyl)-5-((3,3-difl 555

27 0 HN N uoro-1-(methyl-d3)piperidin-4-yl)oxy) (M+H) CDf N -6-(methoxy-d3)pyrido[3,4-d]pyrimidi +

N N n-4-amine

F N (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin D3 N F/> -7-yloxy)-3-methylphenyl)-5-((3,3-dif 555

28 0 HN uoro-1-(methyl-d3)piperidin-4-yl)oxy) (M+H) 0 CD{ 'N -6-(methoxy-d3)pyrido[3,4-d]pyrimidi

+ N NN n-4-amine

F (R)-N-(4-([1,2,4 ]triazolo[1,5-a]pyridin N2 F -7-yloxy)-3-methylphenyl)-5-((3,3-dif 577 29 O HN uoro-1-methylpiperidin-4-yl)oxy)-6-is (M+H) ONN opropoxypyrido[3,4-d]pyrimidin-4-am

+ N ine

F (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin N F O -7-yloxy)-3-methylphenyl)-5-((3,3-diI 577

O HN N uoro-1-methylpiperidin-4-yl)oxy)-6-is (M+H) N opropoxypyrido[3,4-d]pyrimidin-4-am

+ Ny N ine

F 0 (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin /> -7-yloxy)-3-methylphenyl)-6-(cyclopr 589 31 0 HN N opylmethoxy)-5-((3,3-difluoro-1-meth (M+H) N ylpiperidin-4-yl)oxy)pyrido[3,4-d]pyri

+ N N midin-4-amine

F 0 (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin N F O -7-yloxy)-3-methylphenyl)-6-(cyclopr 589 32 0 HN N opylmethoxy)-5-((3,3-difluoro-1-meth (M+H)

N ylpiperidin-4-yl)oxy)pyrido[3,4-d]pyri +

N midin-4-amine

F N (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin N / -7-yloxy)-3-methylphenyl)-6-cyclopro 5 33 0 HN N poxy-5-((3,3-difluoro-1-methylpiperid (M+H) 'N in-4-yl)oxy)pyrido[3,4-d]pyrimidin-4- +

N N amine

F N (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin N -7-yloxy)-3-methylphenyl)-6-cyclopro 5 34 0 HN poxy-5-((3,3-difluoro-1-methylpiperid (M+H) N in-4-yl)oxy)pyrido[3,4-d]pyrimidin-4- +

N N amine

F 0 N (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin N F > -7-yloxy)-3-methylphenyl)-5-((3,3-difl 617 0 HN N uoro-1-methylpiperidin-4-yl)oxy)-6-(2 (M+H) F3 C O N,2,2-trifluoroethoxy)pyrido[3,4-d]pyri

+ N midin-4-amine

F 0 (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin N> F -7-yloxy)-3-methylphenyl)-5-((3,3-difl 617

36 0 HN uoro-1-methylpiperidin-4-yl)oxy)-6-(2 (M+H) F3C", O N ,2,2-trifluoroethoxy)pyrido[3,4-d]pyri

+ N midin-4-amine F (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin N> F -7-yloxy)-3-methylphenyl)-5-((3,3-difl 585

38 O HN uoro-1-methylpiperidin-4-yl)oxy)-6-(d (M+H) F N ifluoromethoxy)pyrido[3,4-d]pyrimidi

+ F N N n-4-amine

N0O N N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-y 513 O HN NN loxy)-3-methylphenyl)-6-methoxy-5-((

1-methylpiperidin-4-yl)oxy)pyrido[3,4

+ 0 -N N N d]pyrimidin-4-amine

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-y 485 N HN N loxy)-3-methylphenyl)-6-methoxy-5 O0N morpholinopyrido[3,4-d]pyrimidin-4-a +

N N mine

N 0 N N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-y 497 41 --C NN / loxy)-3-methylphenyl)-6-methoxy-5-( 41 N HN (MH 0 'N 4-methylpiperazin-1-yl)pyrido[3,4-d]p N / yrimidin-4-amine

Example 18

White solid. 'H-NMR (400 MHz, DMSO-d) 69.94 (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,

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. IH-NMR(400 MHz, DMSO-d) 69.99 (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. IH-NMR (400 MHz, DMSO-d )6 69.95 (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. 1H-NMR (400 MHz, DMSO-d) 69.97 (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. IH-NMR (400 MHz, DMSO-d) 69.96 (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

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. IH-NMR (400 MHz, CD 30D) 68.63 (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. 1 H-NMR (400 MHz, CD 30D) 68.74 (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

H-NMR (400 MHz, DMSO-d) 613.48 (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. IH-NMR (400 MHz, DMSO-d) 613.59 (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).

Example 42

cis-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3-fluoro-1-methylpi

peridin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F Boc. F

N N

No~- "O HN F N F N F N Br Brr~ BrN o TFA CH20 O0 BocNH2 O1 TFA L'.O S O C O CN xantphos, Pd2(dba)3 CN DN DCETHF N Cs2CO3, dioxane N NHoc'N DMFDMA NF H7N O HN O

NF C[c O N NN NN

NN 'N'' N N)

CNBr H NH Step 1: 5-bromo-3-fluoro-2-methoxypyridine-4-carboxamide F 0

NH 2

Toasolution of5-bromo-3-fluoro-2-methoxypyridine-4-carboxyic acid(4g,16.0mmol)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

NH 3/MeOH solution (30 mL, 120 mmol, 4 M in MeOH) 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:

MeOH = 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

F O_ CN

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

OC 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:

EtOAc = 10: 1) to give desired product (1.5 g, 80% yield) as yellow solid.

Step 3: cis-tert-butyl

4-((5-bromo-4-cyano-2-methoxypyridin-3-yl)oxy)-3-fluoropiperidine-1-carboxylate

Boc' XF

NC ON

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 N 2 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 EtOAc(20 mL x2). The combined organic layers were washed with brine,

dried over anhydrous Na2SO4, filtered and concentrated to give crude product. The residue

(200 mg, 36% yield) as yellow solid. MS (ESI) m/z: 430 (M+H)*.

Step 4: cis-5-bromo-3-((3-fluoropiperidin-4-yl)oxy)-2-methoxyisonicotinonitrile

HN

"0

Br

To a solution of cis-tert-butyl 4-((5-bromo-4-cyano-2-methoxypyridin-3-yl)oxy)-3

fluoropiperidine--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-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]oxy}-2-methoxypyridine-4-carbon

itrile

0 ON ONC 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/MeOH (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: MeOH = 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

"0 0 'ON CN O" N ~NHBoc

To a solution of

5-bromo-3-{[(3S,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 ), Pd 2(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: MeOH = 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-1-methylpiperidin-4-yl)oxy)-2-methoxyisonicotinonitrile

N ,F '0 O CN

NH 2

To a solution of tert-butyl

(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 EtOAc (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-1-methylpiperidin-4-yl)oxy)-6-methoxypyridin-3-yl)-N,

N-dimethylformimidamide

N ',,\F

'0 CN

N / N N N

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: MeOH = 10: 1) to give desired product (50 mg, 59%

yield) as yellow solid. MS (ESI) m/z: 336 (M+H)*.

Step 9:

peridin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

"0 HN O

O)I N NY To a solution of

(E)-N'-(4-cyano-5-((cis-3-fluoro-1-methylpiperidin-4-yl)oxy)-6-methoxypyridin-3-yl)-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: MeOH = 10: 1) to give desired

product (14 mg, 17% yield) as yellow solid. 'H-NMR(400 MUz, DMSO-d) 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=

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-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((4,4-difluoro-1 methylpyrrolidin-3-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine Example 45 (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((4,4-difluoro-1 methylpyrrolidin-3-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F 0 F 0 FI '__ NF/> -N -N "0 HN 0 /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.

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((4,4-difluoro-1-met

hylpyrrolidin-3-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine as white solid. 'H-NMR

(400 MHz, DMSO-d) 610.12 (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-methylphenyl)-5-((4,4-difluoro-1-met

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 I.D., 5 rm; Mobile phase: A for

CO2 and B for Methanol (0.1% NH40H); Gradient: B 20%; Flow rate: 50 mL /min; Column temperature: 35 °C.

Example 50

2,5-diazaspiro[3.4]octan-2-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

Example 51

2,5-diazaspiro[3.4]octan-2-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

F F

-N0 N -N 0 CrN

N HN N HN O N

isomers.

2,5-diazaspiro[3.4]octan-2-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine as yellow solid.

'H-NMR (400 Mz, DMSO-d) 9.00 (d, J= 7.5 Hz, 1H), 8.83 (s, 1H), 8.54 (s, 1H), 8.45 (s, 6

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)*.

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)*.

CO2 and B for Methanol (0.1% NH40H); 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

m/z

N F O N trans-N-(4-([1,2,4]triazolo[1,5-a]pyridi 531 /I> 43 ' HN N'N n-7-yloxy)-3-methylphenyl)-5-((3-fluo

O "N ro-1-methylpiperidin-4-yl)oxy)-6-met N N- trans mixture hoxypyrido[3,4-d]pyrimidin-4-amine

-N 0 N N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-y 512 loxy)-3-methylphenyl)-5-(3-(dimethyl 46 N HN N(M+H) O NN amino)pyrrolidin-1-yl)-6-methoxypyri do[3,4-d]pyrimidin-4-amine

-N F N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-y F Oloxy)-3-methylphenyl)-5-(4-(dimethyl 548 47 N HN N amino)-3,3-difluoropyrrolidin-1-yl)-6- (M+H) O N methoxypyrido[3,4-d]pyrimidin-4-ami +

N ne

0 N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-y 0 N loxy)-3-methylphenyl)-6-methoxy-5-( 540

48 N HN N 5-methyl-8-oxa-2,5-diazaspiro[3.5]no (M+H)

ON nan-2-yl)pyrido[3,4-d]pyrimidin-4-am +

N N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-y O N loxy)-3-methylphenyl)-6-methoxy-5-( 510

49 NHN N 2-methyl-2,6-diazabicyclo[3.2.0]hepta (M+H) O N n-6-yl)pyrido[3,4-d]pyrimidin-4-amin

+ F F N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-y N - N loxy)-3-methylphenyl)-5-(7,7-difluoro 560

52N HN N -5-methyl-2,5-diazaspiro[3.4]octan-2- (M+H) O N yl)-6-methoxypyrido[3,4-d]pyrimidin-

+ 4-amine

Example 43

White solid. 'H-NMR (400 MHz, DMSO-d) 69.96 (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. IH-NMR (400 MHz, DMSO-d) 68.92 (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. 1H-NMR (400 MHz, DMSO-d) 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).

Example 48

Light yellow solid. 'H-NMR (400 MVz, DMSO-d) 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-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-b]pyridazin-7-yloxy)

-3-methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

CI O BocNH 2 t-BuONa, 0 O NaOMe Xant-Phos,Pd(OAc) 2 TFA C_'-_ O

H2 N dioxnae SMeOH C N'C1 N'N dioxane,120°C NNN IN Boc H2 N N CI N H

HN HK2C03DMF O2N N H2N O F

N rNF)/ 02N FN N'

0 CIF

N N O HN N CI NN

To a solution of 3,5-dichloropyridazine (9 g, 60.4 mmol) in MeOH (60 mL) was added

NaOMe (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 EtOAc (50 mL x3). The combined organic layers were

washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE: EtOAc=

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

0

N, NBoc N'N' H

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 N 2

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: MeOH = 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 0

H 2N 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: MeOH = 10: 1) to give desired product (200

mg, 60% yield) as brown oil. MS (ESI) m/z: 126 (M+H)*.

Step 4:7-methoxyimidazo[1,2-b]pyridazine

N' N N' /

To a solution of 5-methoxypyridazin-3-amine (200 mg, 1.60 mmol) in 1,4-dioxane (5 mL) 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: MeOH = 20: 1) to give desired product (300 mg, 94% yield) as pink oil. MS (ESI) m/z: 150 (M+H)*.

Step 5:imidazo[1,2-b]pyridazin-7-ol HO

NI

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: MeOH = 20: 1 to 10: 1) to give desired product (100 mg, 37% yield) as pink oil. MS

(ESI) m/z: 136 (M+H)*.

Step 6:7-(2-methyl-4-nitrophenoxy)imidazo[1,2-b]pyridazine O

0 2N N

To a solution of imidazo[1,2-b]pyridazin-7-ol (100 mg, 0.74 mmol) in DMF (5 mL) was

added K 2 CO3 (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 EtOAc

(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: EtOAc = 3: 1) to give desired product (80 mg, 40% yield) as yellow oil. MS (ESI) m/z:

271 (M+H)*.

Step 7:4-(imidazo[1,2-b]pyridazin-7-yloxy)-3-methylaniline ON

H 2N N

To a solution of 7-(2-methyl-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 NH4Cl (161 mg,

3.00 mmol) and the mixture was stirred at 80 °C for 1 hr. The mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel (DCM: MeOH = 30: 1) to give desired product (50 mg, 62% yield) as yellow solid.

MS (ESI) m/z: 241 (M+H)*.

Step 8: (R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-b]pyridazin-7-yloxy) -3-methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F FF 0 N

"0 HN N

N

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: MeOH = 15: 1) to give desired product (25 mg, 22% yield) as yellow solid.

'H-NMR (400 MHz, DMSO-d) 69.94 (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-([1,2,4]triazolo[4,3-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1 methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

H2N N

P t NBr con. HCI O NH2 O O ... k PhB(OH) ,NaOBu-t I 'I 2 H2 cat. TosOH ~ Ni BINAPPd(OAc) 2,toi

Py.HC HO N 02N F ONN Fe H2 02N, ~H2NJ:: FK2CO3, DMF F

o l F SNN F NN N) "0 HN x

IPA N

Step1:1-(diphenylmethylene)-2-(3-methoxyphenyl)hydrazine

H NON'N

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), NaOBu-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 EtOAc (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: EtOAc = 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-hydrazinyl-4-methoxypyridine H O0 N'NH 2

A solution of 2-[2-(diphenylmethylidene)hydrazin-1-yl]-4-methoxypyridine (2.70 g, 8.90

mmol) in concentrated aq.HCl (27 mL) was stirred at 60 °C overnight. The mixture was concentrated to dryness and the residue was alkalified by adding saturated aq. NaHCO 3 solution to pH = 8. The mixture was extracted with EtOAc (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-[1,2,4]triazolo[4,3-a]pyridine

70- N, N N-/

To a solution of 2-hydrazinyl-4-methoxypyridine (500 mg, 3.59 mmol) in trimethoxymethane (5 mL) was added TsOH (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: MeOH = 10: 1) to give desired product (100 mg, 18% yield) as yellow solid. MS (ESI) m/z: 150 (M+H)*.

Step 4: [1,2,4]triazolo[4,3-a]pyridin-7-ol HO N

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: MeOH = 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-([1,2,4]triazolo[4,3-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-meth ylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

F 0 Na F N

N0 HN N

N

The crude product was prepared in a similar fashion to Example 53, which was purified by

Prep-TLC (DCM: MeOH = 20: 1) to give desired product as white solid.H-NMR (400 MHz,

CD 30D) 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[1,2-a]pyridin-7-yloxy)-3 -methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine 0 2N F

HO r___ Pd/C, H 2

HO NH2 dioxane NaH,DMF 2N EtOH

F Na F

'O CI F O N ON N OHN

H 2 N5 PA N O

Step 1: imidazo[1,2-a]pyridin-7-ol

HO N

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.

The mixture was concentrated to dryness. The residue was purified by chromatography on

silica gel (DCM: MeOH= 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-methyl-4-nitrophenoxy)imidazo[1,2-a]pyridine 5 '10 _r

2N O

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 for1 hr. Then 2-fluoro-1-methyl-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 EtOAc (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: EtOAc= 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-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-a]pyridin-7-yloxy)-3 -methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F o Na F > 0 HNO

N_N

prep-TLC (DCM: MeOH = 15: 1) to give desired product as white solid. 'H-NMR(400 MHz,

DMSO-d) 69.92 (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)*.

The following compounds were prepared according to the above described methods using different starting materials.

Ex# Structure Name MS

m/z

N F - N (S)-5-((3,3-difluoro-1-methylpiperidin- m/z:

OHN N'N 4-yl)oxy)-N-(4-(imidazo[1,2-b]pyridazi 549

0 ,' N n-7-yloxy)-3-methylphenyl)-6-methoxy (M+H) N N pyrido[3,4-d]pyrimidin-4-amine

+ N FF O N, (S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin- m/z: N 56 HNN- / 7-yloxy)-3-methylphenyl)-5-((3,3-diflu 549 56 0 HN

O1N oro-1-methylpiperidin-4-yl)oxy)-6-meth (M+H) N N oxypyrido[3,4-d]pyrimidin-4-amine

+ NN m/z: N FF (S)-5-((3,3-difluoro-1-methylpiperidin- 4-yl)oxy)-N-(4-(imidazo[1,2-a]pyridin- 548 58 0 HN N

N 7-yloxy)-3-methylphenyl)-6-methoxypy (M+H) N / N_ rido[3,4-d]pyrimidin-4-amine + FFN 0N (R)-5-((3,3-difluoro-1-methylpiperidin- 549 ''O HN N N 4-yl)oxy)-N-(4-(imidazo[1,2-c]pyrimidi 0 N n-7-yloxy)-3-methylphenyl)-6-methoxy N ~N) pyrido[3,4-d]pyrimidin-4-amine

N FF (S)-5-((3,3-difluoro-1-methylpiperidin- 549 0 HN N N 4-yl)oxy)-N-(4-(imidazo[1,2-c]pyrimidi (M+H) 60 0 N n-7-yloxy)-3-methylphenyl)-6-methoxy N pyrido[3,4-d]pyrimidin-4-amine N N7

WO 2021/179274 PCT1CN20201079097

61 "0 HN N N-N n-7-yloxy)-3-methylphenyl)-5-((3,3-difi MH ~~ N uoro-lI-methylpiperidin-4-yl)oxy)-6-met(MH N N- hoxypyridoll3,4-d]pyrimidin-4-amine

N F 0 5:N (S)-N-(4-(II1,2,4]triazololll,5-b]pyridazi 550 62 0i-i ~ NN N n-7-yloxy)-3-methylphenyl)-5-((3,3-difi ~~N uoro-1I-methylpiperidin-4-yl)oxy)-6-met(MH N N- hoxypyridoll3,4-d]pyrimidin-4-amine

N F 0 - N, (R)-5 -((3,3 -difluoro-1I-methylpiperi din- 551 63 '0 HN N- ' 4-yl)oxy)-6-methoxy-N-(3-methyl-4-(te (MH 630HN trazol o[ 1, 5-c] pyri mi din-7-yl oxy)phenyl MH N N )pyrido[3,4-d]pyrimidin-4-amine

N F 0 rx N (S)-5 -((3,3 -difluoro-1I-methyl piperi din- 551 64z, 0 HN ' 4-yl)oxy)-6-methoxy-N-(3-methyl-4-(te (MH 640 N trazolo[1,5-c]pyrimidin-7-yloxy)phenyl MH N N- )pyrido[3,4-d]pyrimidin-4-amine

F N, (R)-5 -((3,3 -difluoro-1I-methylpiperi din- 50 NN 65' HN -. N-j 4-yl)oxy)-6-methoxy-N-(3-methyl-4-(te 65 0 NN trazolo[1,5-a]pyridin-7-yloxy)phenyl)py (M±H) N / rido[3,4-d]pyrimidin-4-amine

F N, (S)-5 -((3,3 -difluoro-1I-methyl piperi din- 50 NN 66 0- N HN. N~ 4-yl)oxy)-6-methoxy-N-(3-methyl-4-(te (MH 660 HN trazolo[1,5-a]pyridin-7-yloxy)phenyl)py MH N N rido[3,4-d]pyrimidin-4-amine

N F N: (R)-N-(4-([1,2,4]triazolo[ 1, 5-a]pyridin- 549 67 '0,H, , 6 -yloxy) -3 -methyl phenyl) -5 -((3,3 -di flu 670 N oro-1I-methylpiperidin-4-yl)oxy)-6-meth MH

N ~- oxypyrido[3,4-d]pyrimidin-4-amine _____ N

WO 2021/179274 PCT1CN20201079097

N F 0 - NN (S)-N-(4-([1,2,4]tri azolo [1, 5-]prdi-549 68 0HN N> 6-yloxy)-3-methylphenyl)-5-((3,3-diflu 68 0 HN oro-1I-methylpiperidin-4-yl)oxy)-6-meth MH N ~- oxypyrido[3,4-d]pyrimidin-4-amine N N F 0 Na F T N -N (R)-N-(4-([1,2,4]tri azolo [1, 5-a] pyri din- 569 69 ' HNN 6-yloxy)-3-chlorophenyl)-5-((3,3-difluo 69 0 HNa" ro-1I-methylpiperidin-4-yl)oxy)-6-metho (M±H) Nx xypyrido[3,4-d]pyrimidin-4-amine N N

N F 0 \ (S)-N-(4-([1,2,4]triazolo[ 1,5-a]pyridin- 569 700 NN 6-yloxy)-3 -chlorophenyl)-5-((3,3 -difluo 70 0- HN ro-1I-methylpiperidin-4-yl)oxy)-6-metho MH

N '_ NI xypyrido[3,4-d]pyrimidin-4-amine

F NN (R)-N-(4-([1,2,4]tri azol o [1, 5-a] pyridin- 56 71 ~ N ~ N 6-yloxy)-3-methylphenyl)-5-((3,3-diflu 710HN N oro-1I-methylpiperidin-4-yl)oxy)-6-etho (M±H) N- xypyrido[3,4-d]pyrimidin-4-amine N N F0 -~NN (S)-N-(4-([1,2,4]triazolo[ 1, 563pri n Na F N-ap563in 72 0 H '~ N 6-yloxy)-3-methylphenyl)-5-((3,3-diflu 720H~ oro-1I-methylpiperidin-4-yl)oxy)-6-etho MH

N - N_N xypyrido[3,4-d]pyrimidin-4-amine

F 0~ NN (R)-N-(4-([1,2,4]triazolo[ 1,5-a]pyridin \> 6 -yl oxy) -3-m ethyl phenyl) -5 -((3,3 -di flu 52 73 "0 HN ~N oro-1I-methylpiperidin-4-yl)oxy)-6-(met (M+H) 030 hoxy-d3)pyrido[3,4-d]pyrimidin-4-amin+ 0N e

N F 0~ NN (S)-N-(4-([1,2,4]tri azolo [1,5-a] pyri din \> 6 -yl oxy) -3-m ethyl phenyl) -5 -((3,3 -di flu 52 74 0 HN ~N oro-1I-methylpiperidin-4-yl)oxy)-6-(met (M+H) D 3C0 N hoxy-d3)pyrido[3,4-d]pyrimidin-4-amin+ N e

N3C F 0 N (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin DC > 6-yloxy)-3-methylphenyl)-5-((3,3-diflu 552 0 HN oro-1-(methyl-d3)piperidin-4-yl)oxy)-6- (M+H) ON methoxypyrido[3,4-d]pyrimidin-4-amin

+ N N e

N3C F 0 (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin DF6-yloxy)-3-methylphenyl)-5-((3,3-diflu 552 76 O HN N oro-1-(methyl-d3)piperidin-4-yl)oxy)-6- (M+H) O N methoxypyrido[3,4-d]pyrimidin-4-amin

+ N N e

Example 59

Yellow solid. IH-NMR (400 MHz, DMSO-d) 69.91 (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-NMR (400 MHz, DMSO-d) 69.95 (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

5-a]pyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine

- 0 HN2. /O NO'NH NO2 > O~ /F O N0 '_ HBr/H 20 HO _ 0 N-N NOAN K2C03 DMF O H~r/H2O HO K 2CO 3, DMF DCM NH 20 2N

F NN F 0 CI

0 ~N 4C FN ~ 0 ~N N, N F FN ~ -f5 N-N N ____)__ N 0 2N IPA/H 20 H 2N O IPA N O

N

Step1:1-amino-3-methoxypyridin-1-ium2,4-dinitrobenzen-1-olate N0 2 0 K 00 N NH 2 02 N

A suspension of 3-methoxypyridine (2.77 mL, 27.49 mmol) and

O-(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-methoxypyrazolo[1,5-a]pyridine-3-carboxylate o0 /

0

To a solution of1-amino-3-methoxypyridin-1-ium 2,4-dinitrobenzen-1-olate (5 g, 16.22

mmol) in DMF (50 mL) was added K2 CO3 (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 EtOAc (50 mL), washed with water and

flash chromatography (PE: EtOAc = 5: 1) to afford the title compound (560 mg, 16% yield)

as yellow solid. IH-NNMR (400 Mz, CDCl 3) 68.31 (s, 1H), 8.10 (d, J = 1.8 Hz, 1H),

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

HO - N

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 EtOAc (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: MeOH = 10: 1) to afford the title compound (160 mg, 43% yield) as

yellow solid. MS (ESI) m/z: 135 (M+H)*.

Steps 4-6:

5-a]pyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine

F N OF N

"0 HN6

prep-TLC (DCM: MeOH = 20: 1) to give desired product as yellow solid. IH-NMR (400

MVUlz, DMSO-d) 69.83 (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, J=

11.7 Hz, 1H). MS (ESI) m/z: 548 (M+H)*.

Ex# Structure Name MS

m/z F F NN (S)-5-((3,3-difluoro-1-methylpiperidin- 548

78 0 HN 4-yl)oxy)-6-methoxy-N-(3-methyl-4-(p (MH 7 N yrazolo[1,5-a]pyridin-6-yloxy)phenyl)p (M±H) N N yrido[3,4-d]pyrimidin-4-amine

F 0 N F N'N (R)-N-(3-chloro-4-(pyrazolo[1,5-a]pyri 568

79 0 HN C din-6-yloxy)phenyl)-5-((3,3-difluoro-1- (M+H) N NN methylpiperidin-4-yl)oxy)-6-methoxypy

N / N rido[3,4-d]pyrimidin-4-amine

F 0 _ N FF (S)-N-(3-chloro-4-(pyrazolo[1,5-a]pyrid 568

0 HN N in-6-yloxy)phenyl)-5-((3,3-difluoro-1-m ethylpiperidin-4-yl)oxy)-6-methoxypyri (M+H)

N /N do[3,4-d]pyrimidin-4-amine

N FF O N'N (R)-5-((3,3-difluoro-1-methylpiperidin- 562

81 "0 HN 4-yl)oxy)-6-ethoxy-N-(3-methyl-4-(pyr (M+H) O N azolo[1,5-a]pyridin-6-yloxy)phenyl)pyri N / N do[3,4-d]pyrimidin-4-amine

F N FF N'N (S)-5-((3,3-difluoro-1-methylpiperidin- 562 4-yl)oxy)-6-ethoxy-N-(3-methyl-4-(pyr

8 N azolo[1,5-a]pyridin-6-yloxy)phenyl)pyri N N. do[3,4-d]pyrimidin-4-amine

F F -N'N (R)-5-((3,3-difluoro-1-methylpiperidin- 551

83 '0 HN 4-yl)oxy)-6-(methoxy-d3)-N-(3-methyl- (M+H) D3C' N 4 -(pyrazolo[1,5-a]pyridin-6-yloxy)phen N / yl)pyrido[3,4-d]pyrimidin-4-amine N

F 0 N F N'N (S)-5-((3,3-difluoro-1-methylpiperidin- 551 840 HN 4-yl)oxy)-6-(methoxy-d3)-N-(3-methyl 84 (M+H) D 3C 0 N 4-(pyrazolo[1,5-a]pyridin-6-yloxy)phen N N yl)pyrido[3,4-d]pyrimidin-4-amine

D3C'N FF O N (R)-5-((3,3-difluoro-1-(methyl-d3)piper 551

' HN idin-4-yl)oxy)-6-methoxy-N-(3-methyl- (M+H) N 4-(pyrazolo[1,5-a]pyridin-6-yloxy)phen N - yl)pyrido[3,4-d]pyrimidin-4-amine

D3C'N F O N'N (S)-5-((3,3-difluoro-1-(methyl-d3)piperi 551

86 0 HN din-4-yl)oxy)-6-methoxy-N-(3-methyl-4 (M+H) 8 ,'N -(pyrazolo[1,5-a]pyridin-6-yloxy)pheny N - N l)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)pyrido[3,4-d]pyrimidin-4-amine

Br ~NN\ KO HO!t 'N\ N -x& 0 N Fe, NH 4CI FF NN MeOH, reflux K2 C0 3 ,DMF 0 2NN IPAIH-2O

F Na F

O CI F -- N F N

O x N N OHN N

H2 N N IPA, 650 C N

Step 1:pyrazolo[1,5-a]pyrimidin-6-ol HO '. NN

N

To a solution of 6-bromopyrazolo[1,5-a]pyrimidine (2 g, 0.01 mol) in MeOH (50 mL) was 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.HCl. The mixture was extracted with EtOAc (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)pyrido[3,4-d]pyrimidin-4-amine

NFF N

N'0 HN N

N 0-

purified by column chromatography on silica gel (eluted with DCM: MeOH = 20: 1) to give

desired product as yellow solid. 'H-NMR (400 MHz, DMSO-d) 69.86 (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

m/z

WO 2021/179274 PCT1CN20201079097

N F 0 (S)- 5-((3,3 -di fl uoro-1I-m ethyl pi peri di n- 549 88 OH ~ N ~ 4-yl)oxy)-6-methoxy-N-(3-methyl-4-(p 88 0 H N N yrazolo[ 1, 5-a]pyrimidin-6-yloxy)phenyl (M±H) NYx )pyrido[3,4-d]pyrimidin-4-amine

F0 Na F N (R)-N-(3-chloro-4-(pyrazolo[ 1,5-a]pyri 569 8 HNCr midin-6-yloxy)phenyl)-5-((3,3-difluoro 890HW N I1-methylpiperidin-4-yl)oxy)-6-methoxy (M±H) N x yrid[3,-d]pyrimidin-4-amine

N F 0 - (S)-N-(3-chloro-4-(pyrazolo[1,5-a]pyri 569 OHN midin-6-yloxy)phenyl)-5-((3,3-difluoro 90 0 N N 1-methylpiperidin-4-yl)oxy)-6-methoxy MH

N pyrido[3,4-d]pyrimidin-4-amine

N F ~NN (R)-5 -((3,3 -difluoro-1I-methylpiperi din- 56 "0 HN4-yl)oxy)-6-ethoxy-N-(3-methyl-4-(pyr 910H N azolo[ 1,5-a]pyrimidin-6-yloxy)phenyl)p (M±H)

N) ,yrd[,-d]pyrimidin-4-amine

N F ~NN (S)-5 -((3,3 -difluoro-1I-methyl piperi din- 56 4-yl)oxy)-6-ethoxy-N-(3-methyl-4-(pyr 92 0 N N azolo[ 1,5-a]pyrimidin-6-yloxy)phenyl)p (M±H)

N) ,yrd[,-d]pyrimidin-4-amine

F0 F -F N- N (R)-5-((3,3-difluoro-1I-methylpiperidin- 552 '0 HN -~4-yl)oxy)-6-(methoxy-d3)-N-(3-methyl

93~ 0 N 4-(pyrazolo[ 1,5-a]pyrimidin-6-yloxy)ph (M±H) N30C - enyl)pyrido[3,4-d]pyrimidin-4-amine

N F 0 (S)-5-((3,3-difluoro-1I-methylpiperidin- 552 4-yl)oxy)-6-(methoxy-d3)-N(M+H)yl 94 C N 4-(pyrazolo[ 1,5-a]pyrimidin-6-yloxy)ph MH _____k enyl)pyrido[3,4-d]pyrimidin-4-amine

D3C F 0 N F N (R)-5-((3,3-difluoro-1-(methyl-d3)piper 552 'O HN ~ N idin-4-yl)oxy)-6-methoxy-N-(3-methyl 9 N 4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)ph (M±H) N / N enyl)pyrido[3,4-d]pyrimidin-4-amine

D3C F O N (S)-5-((3,3-difluoro-1-(methyl-d3)piperi 552

96 OHN 0 HN N din-4-yl)oxy)-6-methoxy-N-(3-methyl-4 -(pyrazolo[1,5-a]pyrimidin-6-yloxy)phe (M±H)

N N nyl)pyrido[3,4-d]pyrimidin-4-amine

N F O N (R)-5-((3,3-difluoro-1-methylpiperidin- 548 97 'O H N N 4-yl)oxy)-6-methoxy-N-(3-methyl-4-(p (M+H) O7 0 HN yrazolo[1,5-a]pyrimidin-6-yloxy)phenyl )quinazolin-4-amine -N

F F 'N (S)-5-((3,3-difluoro-1-methylpiperidin- 548

98 OHN 0~ O N N 4-yl)oxy)-6-methoxy-N-(3-methyl-4-(p yrazolo[1,5-a]pyrimidin-6-yloxy)phenyl (M±H) N )quinazolin-4-amine

F N F N (R)-N-(3-chloro-4-(pyrazolo[1,5-a]pyri 568 '0 HN midin-6-yloxy)phenyl)-5-((3,3-difluoro SN 1-methylpiperidin-4-yl)oxy)-6-methoxy quinazolin-4-amine OI N F 0 N F N'N (S)-N-(3-chloro-4-(pyrazolo[1,5-a]pyri 568 SHNC midin-6-yloxy)phenyl)-5-((3,3-difluoro 0 HN 1-methylpiperidin-4-yl)oxy)-6-methoxy

quinazolin-4-amine N1(

N F NN (R)-5-((3,3-difluoro-1-methylpiperidin- 562 1010 HN -N 4-yl)oxy)-6-ethoxy-N-(3-methyl-4-(pyr 101 0HNON azolo[1,5-a]pyrimidin-6-yloxy)phenyl)q (M±H) uinazolin-4-amine N

N F N'N (S)-5-((3,3-difluoro-1-methylpiperidin- 562 02OHN N 4-yl)oxy)-6-ethoxy-N-(3-methyl-4-(pyr

O N azolo[1,5-a]pyrimidin-6-yloxy)phenyl)q (M±H) uinazolin-4-amine Nj F F O N (R)-5-((3,3-difluoro-1-methylpiperidin- 551

103 D3 C 0 'O HN ~N N 4-yl)oxy)-6-(methoxy-d3)-N-(3-methyl 4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)ph (M±H)

N enyl)quinazolin-4-amine

N F O N'N (S)-5-((3,3-difluoro-1-methylpiperidin- 551

104 ,4OHN, N N 4-yl)oxy)-6-(methoxy-d3)-N-(3-methyl 4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)ph (M±H)

I N enyl)quinazolin-4-amine

D3CN F O N (R)-5-((3,3-difluoro-1-(methyl-d3)piper 551

105 O0 HN N idin-4-yl)oxy)-6-methoxy-N-(3-methyl O0 0 N 4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)ph enyl)quinazolin-4-amine N

D3CN FF0O N (S)-5-((3,3-difluoro-1-(methyl-d3)piperi 551 6OHN N din-4-yl)oxy)-6-methoxy-N-(3-methyl-4 106 N -(pyrazolo[1,5-a]pyrimidin-6-yloxy)phe(M+H) ON (przl[,-+yiii--lx~h nyl)quinazolin-4-amine NJ

Example 107

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-m

ethylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine

F Br H O, -O Br NN KOH HO N N _____N ___ N _ _ _ _ ( -N N-N AcOH, 80C, N MeOH,65C, N K 2CO 3,DMF, 1C 02N N N F N F

NI _ 1 ~Na F -0 - Fe O NN O NN OHN N N NHACI' H 2N 0 N N IPA, 65 C O IPA/H 20,N 850C N

Step1:5-bromo-3-fluoro-2-methoxypyridine Br N

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 EtOAc (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:[1,2,4]triazolo[1,5-a]pyrimidin-6-ol H N

To a solution of 6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine (0.9 g, 4.5 mmol) in MeOH (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 IM aq. HCl and extracted with IPA/DCM (20 mL x 3, 3/1, v/v). The combined

concentrated to dryness. The residue was purified by column chromatography silica gel

(DCM: MeOH = 30: 1) to give [1,2,4]triazolo[1,5-a]pyrimidin-6-o (330 mg, 53% yield) as

yellow solid. MS (ESI) m/z: 136 (M+H)*.

Steps

3-5:(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro

1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine F

N F N

column chromatography silica gel (DCM: MeOH = 20: 1) and prep-TLC (PE: EtOAc= 1: 3)

to give desired product as white solid. H-NMR (400 MUz, DMSO-d) 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

m/z

F (S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi N>Fdin-6-yloxy)-3-methylphenyl)-5-((3,3- 550 108 0 HN N difluoro-1-methylpiperidin-4-yl)oxy)- (M+H) N 6-methoxypyrido[3,4-d]pyrimidin-4-a +

N mine

F 0 _N (R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi N F din-6-yloxy)-3-methylphenyl)-5-((3,3- 570 109 0 HN CI N N difluoro-1-methylpiperidin-4-yl)oxy)- (M+H) )N 6-methoxypyrido[3,4-d]pyrimidin-4-a +

N mine

F 0 N (S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi N F din-6-yloxy)-3-methylphenyl)-5-((3,3- 570 110 0 HN N difluoro-l-methylpiperidin-4-yl)oxy)- (M+H) O N 6-methoxypyrido[3,4-d]pyrimidin-4-a

+ N mine

F (R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi N F din-6-yloxy)-3-methylphenyl)-5-((3,3- 564 111 HN N difluoro-1-methylpiperidin-4-yl)oxy)- (M+H) O N 6-ethoxypyrido[3,4-d]pyrimidin-4-ami

+ N ne

F N (S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi N F Ndin-6-yloxy)-3-methylphenyl)-5-((3,3- 564 112 0 HN N N difluoro-1-methylpiperidin-4-yl)oxy)- (M+H) N 6-ethoxypyrido[3,4-d]pyrimidin-4-ami

+ Nx N ne

F 0 N (R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi N> Fdin-6-yloxy)-3-methylphenyl)-5-((3,3- 553 113 0 HN N difluoro-1-methylpiperidin-4-yl)oxy)- (M+H) 0 D3 C N 6-(methoxy-d3)pyrido[3,4-d]pyrimidin

+ N -4-amine

F -0 NN (S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi N F din-6-yloxy)-3-methylphenyl)-5-((3,3 114 0 HN N difluoro-1-methylpiperidin-4-yl)oxy)- (M+H) D3 C N 6-(methoxy-d3)pyrido[3,4-d]pyrimidin +

N -4-amine

D3C F (R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi N F O > din-6-yloxy)-3-methylphenyl)-5-((3,3- 553 115 "0 HN N N difluoro-1-(methyl-d3)piperidin-4-yl)o (M+H)

IN xy)-6-methoxypyrido[3,4-d]pyrimidin- +

N 4-amine

NC F 0 (S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi D3'N F> din-6-yloxy)-3-methylphenyl)-5-((3,3- 553

116 0 HN N N difluoro-1-(methyl-d3)piperidin-4-yl)o (M+H)

N xy)-6-methoxypyrido[3,4-d]pyrimidin- +

N 4-amine

WO 2021/179274 PCT1CN20201079097

N F 0 -~NN (R)-N- (4 -([ 1,2,4 ]tri azolo[ 1,5-a yim 54

117 '0 HNa N N din-6-yloxy)-3-methylphenyl)-5-((3,3- MH -~ - Ndifluoro-1I-methylpiperidin-4-yl)oxy) x) 6-methoxyquinazolin-4-amine

N F 0 NN (S)-N- (4 -([1,2,4 ]tri azol o [1,5-a yim 549

118 0 HNa N N din-6-yl oxy)-3 -methyl phenyl)-5 -((3,3 - (M+H) N difluoro-1I-methylpiperidin-4-yl)oxy) I) N 6-methoxyquinazolin-4-amine

N F 0 NNN (R)-N- (4 -([1,2,4 ]tri azolo [1,5-a yim 569

119 ' HN C N N din-6-yloxy)-3-chlorophenyl)-5-((3,3 190H N difluoro-1I-methylpiperidin-4-yl)oxy)- MH I) N 6-methoxyquinazolin-4-amine

F (S)-N-(4-([1,2,4]triazolo[ ,5-a]pyrimi 120 HN N>N -- din-6-yloxy)-3-chlorophenyl)-5-((3,3 120 0H N Cdifluoro-1I-methylpiperidin-4-yl)oxy)- MH

0) 6-methoxyquinazolin-4-amine

F - (R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi

121 '0 HN -~ N N din-6-yloxy)-3-methylphenyl)-5-((3,3- (M+H)

0 -- ~ difluoro-1I-methylpiperidin-4-yl)oxy) N N 6-ethoxyquinazolin-4-amine

F 0~ NN (S)-N-(4-([1,2,4]triazolo[ 1,5-a]pyrimi N~ tF> din-6-yloxy)-3-methylphenyl)-5-((3,3- 564 122 0 HN N N difluoro-1I-methylpiperidin-4-yl)oxy)- (M+H) SN6-ethoxypyrido[3,4-d]pyrimidin-4-ami+ N ne

N F 0~ N N (R)-N-(4-([1,2,4]triazolo[ 1, 5-a]pyrimi 552 123 '0 HN -x N N din-6-yloxy)-3-methylphenyl)-5-((3,3- (M+H) D3 N difluoro-1I-methylpiperidin-4-yl)oxy) D3- l N~ 6-(methoxy-d3)quinazolin-4-amine +

N F 0 N'N (S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi 552 024NO HNN N din-6-yloxy)-3-methylphenyl)-5-((3,3 D 3C'O N difluoro-1-methylpiperidin-4-yl)oxy)

D Nd 6-(methoxy-d3)quinazolin-4-amine

D3C N FF O N'N (R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi 552

125 '0 HN N N din-6-yloxy)-3-methylphenyl)-5-((3,3- (M+H) o difluoro-1-(methyl-d3)piperidin-4-yl)o

ON xy)-6-methoxyquinazolin-4-amine

D3C N FF O N'N (S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimi 552

126 0 HN N N din-6-yloxy)-3-methylphenyl)-5-((3,3- (M+H) o difluoro-1-(methyl-d3)piperidin-4-yl)o

ON xy)-6-methoxyquinazolin-4-amine

N FF O N (R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin 549

127 0 HN N -6-yloxy)-3-methylphenyl)-5-((3,3-difl (M+H) O N uoro-1-methylpiperidin-4-yl)oxy)-6-m N /- N ethoxypyrido[3,4-d]pyrimidin-4-amine

N FF N (S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin 549 1O HN N -6-yloxy)-3-methylphenyl)-5-((3,3-difl 128 (M+H) O 0 N uoro-1-methylpiperidin-4-yl)oxy)-6-m N N ethoxypyrido[3,4-d]pyrimidin-4-amine

N F FO N (R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin 569

129 O HN CI N -6-yloxy)-3-chlorophenyl)-5-((3,3-difl 12 0 sN uoro-1-methylpiperidin-4-yl)oxy)-6-m (M±H) N - N' ethoxypyrido[3,4-d]pyrimidin-4-amine

N F 0 - N-\N (S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin 569

130 HN N' -6-yloxy)-3-chlorophenyl)-5-((3,3-difl O3 0 N uoro-1-methylpiperidin-4-yl)oxy)-6-m (M±H) N - N' ethoxypyrido[3,4-d]pyrimidin-4-amine

F 0 N F N N (R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin 564 N 131 '0 HN N -6-yloxy)-3-methylphenyl)-5-((3,3-difl O N uoro-1-methylpiperidin-4-yl)oxy)-6-et N N-N N- hoxypyrido[3,4-d]pyrimidin-4-amine

F 0 N F N N (S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin 564 1 N 1O HN N -6-yloxy)-3-methylphenyl)-5-((3,3-dif1

N uoro-1-methylpiperidin-4-yl)oxy)-6-et (M±H) O3 N - hoxypyrido[3,4-d]pyrimidin-4-amine

F 0 (R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin N -6-yloxy)-3-methylphenyl)-5-((3,3-difl 552 133 0 HN uoro-1-methylpiperidin-4-yl)oxy)-6-( (M+H) D 3 C' N methoxy-d3)pyrido[3,4-d]pyrimidin-4-

+ N amine

F (S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin N -6-yloxy)-3-methylphenyl)-5-((3,3-difl 552 134 0 HN uoro-1-methylpiperidin-4-yl)oxy)-6-( (M+H) D 3 C' N methoxy-d3)pyrido[3,4-d]pyrimidin-4-

+ N amine

D 3C,. F (R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin Na F N-\ N -6-yloxy)-3-methylphenyl)-5-((3,3-dil 552 135 O HN uoro-1-(methyl-d3)piperidin-4-yl)oxy) (M+H) N -6-methoxypyrido[3,4-d]pyrimidin-4-a +

N N mine

D 3C, F (S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin N F N -6-yloxy)-3-methylphenyl)-5-((3,3-dil 552 136 0 HN uoro-l-(methyl-d3)piperidin-4-yl)oxy) (M+H) N -6-methoxypyrido[3,4-d]pyrimidin-4-a +

N N mine

F (R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimi N F O N din-6-yloxy)-3-methylphenyl)-5-((3,3- 550 137 0 HN N N difluoro-1-methylpiperidin-4-yl)oxy)- (M+H) 0 ''N 6-methoxypyrido[3,4-d]pyrimidin-4-a +

N mine

F (S)-N-(4-([1,2,4]triazolo[4,3-a]pyrimi N din-6-yloxy)-3-methylphenyl)-5-((3,3- 550 138 0 HN N N difluoro-1-methylpiperidin-4-yl)oxy)- (M+H) 0 N 6-methoxypyrido[3,4-d]pyrimidin-4-a

+ N mine

F (R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimi F NN din-6-yloxy)-3-chlorophenyl)-5-((3,3- 570 139 '0 HN CI N N difluoro-1-methylpiperidin-4-yl)oxy)- (M+H) N 6-methoxypyrido[3,4-d]pyrimidin-4-a

+ N mine

F (S)-N-(4-([1,2,4]triazolo[4,3-a]pyrimi N F ON din-6-yloxy)-3-chlorophenyl)-5-((3,3- 570 140 0 HN CIN N difluoro-1-methylpiperidin-4-yl)oxy)- (M+H) N 6-methoxypyrido[3,4-d]pyrimidin-4-a

+ N mine

F (R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimi N F O N din-6-yloxy)-3-methylphenyl)-5-((3,3- 564 141 0 HN N N difluoro-1-methylpiperidin-4-yl)oxy)- (M+H) SN 6-ethoxypyrido[3,4-d]pyrimidin-4-ami

+ N 60 N ne F 0 N F - O N (S)-N-(4-([1,2,4]triazolo[4,3-a]pyridin 564 O HN N NN -6-yloxy)-3-methylphenyl)-5-((3,3-difl N uoro-1-methylpiperidin-4-yl)oxy)-6-et (M±H) O N Nd hoxypyrido[3,4-d]pyrimidin-4-amine

F (R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimi Na F O N din-6-yloxy)-3-methylphenyl)-5-((3,3- 553 143 0 HN N N difluoro-1-methylpiperidin-4-yl)oxy)- (M+H) ~0 D 3 C' N0N 6-(methoxy-d3)pyrido[3,4-d]pyrimidin +

N -4-amine F (S)-N-(4-([1,2,4]triazolo[4,3-a]pyrimi N tF O N din-6-yloxy)-3-methylphenyl)-5-((3,3- 553 144 0 HN N N difluoro-1-methylpiperidin-4-yl)oxy)- (M+H) D3 C' N 6-(methoxy-d3)pyrido[3,4-d]pyrimidin +

Ny N -4-amine

D3C F O (R)-N-(4-([1,2,4]triazolo[4,3-a]pyrimi Na F N-\ 553 N din-6-yloxy)-3-methylphenyl)-5-((3,3- 145 0 HN N N difluoro-1-methylpiperidin-4-yl)oxy)- (M+H)

0N 6-(methoxy-d3)pyrido[3,4-d]pyrimidin

+ N N -4-amine

D3C F O (S)-N-(4-([1,2,4]triazolo[4,3-a]pyrimi Na F N--\\N din-6-yloxy)-3-methylphenyl)-5-((3,3- 553 146 0 HN N N difluoro-1-methylpiperidin-4-yl)oxy)- (M+H)

0N 6-(methoxy-d3)pyrido[3,4-d]pyrimidin

+ N N -4-amine

Example 147 (R)-4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)amino)-5-((3,3-difluo ro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile F F F NNX< F F 0 F O F OH FO OH O H DMFDMA ,O 1. n-BuLi, MeCN, THF CN t OH 0 -O N

NH 2 N ~ THFN N'N 2.HOAc N~ t-BuOK,DMSO i H NN

F F Na F 0 N N'- ZF - r-1

POC CI H 2N N "0 HN N CN PA OCN

N N

Step 1:

methyl (E)-3-fluoro-2-methoxy-5-(((methylamino)methylene)amino)isonicotinate

F 0

N ' N N H

A solution of methyl 5-amino-3-fluoro-2-methoxyisonicotinate (260 mg, 1.30 mmol) in

DMF-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 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 NCN

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: MeOH = 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)-4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)amino)-5-((3,3-difluo ro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile F

"O HN O O CN 0NO N

prep-TLC (DCM: MeOH= 15: 1) to give desired product as white solid. IH-NMR (400 MHz,

DMSO-d) 610.00 (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)*.

Ex# Structure Name MS

m/z

F 0 (S)-4-((4-([1,2,4]triazolo[1,5-c]pyrimidi N F O/> n-7-yloxy)-3-methylphenyl)amino)-5-(( 574 148 0 HN 3,3-difluoro-1-methylpiperidin-4-yl)oxy (M+H) O CN )-6-methoxy-1,7-naphthyridine-3-carbo

+ N N nitrile F (R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin N F 7-yloxy)-3-methylphenyl)amino)-5-((3, 573 149 0 HN 3-difluoro-1-methylpiperidin-4-yl)oxy)- (M+H) O CN 6-methoxy-1,7-naphthyridine-3-carboni

+ N N trile F (S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin N F 7-yloxy)-3-methylphenyl)amino)-5-((3, 573 150 0 HN 3-difluoro-1-methylpiperidin-4-yl)oxy)- (M+H) CN 6-methoxy-1,7-naphthyridine-3-carboni

+ N trile F (R)-4-((4-([1,2,4]triazolo[1,5-b]pyridazi F O > n-7-yloxy)-3-methylphenyl)amino)-5-(( 574 151 0 HN NN 3,3-difluoro-1-methylpiperidin-4-yl)oxy (M+H) CN )-6-methoxy-1,7-naphthyridine-3-carbo +

N nitrile F (S)-4-((4-([1,2,4]triazolo[1,5-b]pyridazi N F/O n-7-yloxy)-3-methylphenyl)amino)-5-(( 574 152 O HN NNN 3,3-difluoro-1-methylpiperidin-4-yl)oxy (M+H) O CN NJ )-6-methoxy-1,7-naphthyridine-3-carbo +

N nitrile

F 0 (R)-5-((3,3-difluoro-1-methylpiperidin N F O'N 4-yl)oxy)-6-methoxy-4-((3-methyl-4-(te 575 153 0 HNN N trazolo[1,5-c]pyrimidin-7-yloxy)phenyl (M+H)

CN )amino)-1,7-naphthyridine-3-carbonitril

+ N e

FF (S)-5-((3,3-difluoro-1-methylpiperidin N F ON. N 4-yl)oxy)-6-methoxy-4-((3-methyl-4-(te 5 154 0 HN trazolo[1,5-c]pyrimidin-7-yloxy)phenyl (M+H) )amino)-1,7-naphthyridine-3-carbonitril

+ N N e Fo N F O N (R)-5-((3,3-difluoro-1-methylpiperidin- 574 10 HN N " 4-yl)oxy)-6-methoxy-4-((3-methyl-4-(te 5O CN trazolo[1,5-a]pyridin-7-yloxy)phenyl)a N N_ mino)-1,7-naphthyridine-3-carbonitrile

N FF (S)-5-((3,3-difluoro-1-methylpiperidin- 574 O-H NrN 4-yl)oxy)-6-methoxy-4-((3-methyl-4-(te 156 0 HN(M+H) O CN trazolo[1,5-a]pyridin-7-yloxy)phenyl)a N N .mino)-1,7-naphthyridine-3-carbonitrile NT

F 0 N N (R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin N F O 6-yloxy)-3-methylphenyl)amino)-5-((3, 5 157 0 HN 3-difluoro-1-methylpiperidin-4-yl)oxy)- (M+H) O CN 6-methoxy-1,7-naphthyridine-3-carboni +

N N trile

F 0 NN (S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin N F6-yloxy)-3-methylphenyl)amino)-5-((3, 5 158 0 HN 3-difluoro-1-methylpiperidin-4-yl)oxy)- (M+H) O CN 6-methoxy-1,7-naphthyridine-3-carboni +

NNT trile

F 0 N (R)-4-((4-([1,2,4]triazolo[1,5-a]pyrimidi Na F O n-6-yloxy)-3-methylphenyl)amino)-5-(( 574 159 0 HN N N 3,3-difluoro-1-methylpiperidin-4-yl)oxy (M+H) )-6-methoxy-1,7-naphthyridine-3-carbo +

N nitrile

F 0 N (S)-4-((4-([1,2,4]triazolo[1,5-a]pyrimidi N F O n-6-yloxy)-3-methylphenyl)amino)-5-(( 574 160 0 HN N 3,3-difluoro-1-methylpiperidin-4-yl)oxy (M+H) )N-6-methoxy-1,7-naphthyridine-3-carbo

+ N nitrile

F (R)-4-((4-([1,2,4]triazolo[4,3-a]pyridin N 6-yloxy)-3-methylphenyl)amino)-5-((3, 573 161 0 HN 3-difluoro-1-methylpiperidin-4-yl)oxy)- (M+H) O CN 6-methoxy-1,7-naphthyridine-3-carboni

+ N N trile

F (S)-4-((4-([1,2,4]triazolo[4,3-a]pyridin

N F O N 6-yloxy)-3-methylphenyl)amino)-5-((3, 573 162 0 HN 3-difluoro-1-methylpiperidin-4-yl)oxy)- (M+H) 0 CN 6-methoxy-1,7-naphthyridine-3-carboni

+ N N trile

F (R)-4-((4-([1,2,4]triazolo[4,3-a]pyrimidi N n-6-yloxy)-3-methylphenyl)amino)-5-(( 574 163 0 HN N N 3,3-difluoro-1-methylpiperidin-4-yl)oxy (M+H) O CN )-6-methoxy-1,7-naphthyridine-3-carbo

+ N N nitrile

F (S)-4-((4-([1,2,4]triazolo[4,3-a]pyrimidi Na F N -\ N n-6-yloxy)-3-methylphenyl)amino)-5-(( 574 164 0 HN N N 3,3-difluoro-1-methylpiperidin-4-yl)oxy (M+H) OJCN )-6-methoxy-1,7-naphthyridine-3-carbo +

N nitrile

F (R)-5-((3,3-difluoro-1-methylpiperidin NFN 4-yl)oxy)-6-methoxy-4-((3-methyl-4-(p 573 165 O HN yrazolo[1,5-a]pyrimidin-6-yloxy)phenyl (M+H) O CN )amino)-1,7-naphthyridine-3-carbonitril +

N N e

F 0 N (S)-5-((3,3-difluoro-1-methylpiperidin

N F 4-yl)oxy)-6-methoxy-4-((3-methyl-4-(p 573 166 O HN N yrazolo[1,5-a]pyrimidin-6-yloxy)phenyl (M+H) O 1- CN )amino)-1,7-naphthyridine-3-carbonitril +

N N e

F , (R)-5-((3,3-difluoro-1-methylpiperidin- 572

167 'O HN 4-yl)oxy)-6-methoxy-4-((3-methyl-4-(p (M+H) O CN yrazolo[1,5-a]pyridin-6-yloxy)phenyl)a N N- - mino)-1,7-naphthyridine-3-carbonitrile

F F N'N (S)-5-((3,3-difluoro-1-methylpiperidin- 572

168 0 HN 4-yl)oxy)-6-methoxy-4-((3-methyl-4-(p (M+H) 0 CN yrazolo[1,5-a]pyridin-6-yloxy)phenyl)a N N_ mino)-1,7-naphthyridine-3-carbonitrile

FO N'N (R)-4-((4-([1,2,4]triazolo[1,5-a]pyrimidi 573 2> 169 ' HN N N n-6-yloxy)-3-methylphenyl)amino)-5-(( (M+H) O CN 3,3-difluoro-1-methylpiperidin-4-yl)oxy

N )-6-methoxyquinoline-3-carbonitrile

NF O NN (S)-4-((4-([1,2,4]triazolo[1,5-a]pyrimidi573 N F ,5-apy573d 170 0 HN -~ N N n-6-yloxy)-3-methylphenyl)amino)-5-(( (M+H) O CN 3,3-difluoro-1-methylpiperidin-4-yl)oxy

N )-6-methoxyquinoline-3-carbonitrile F 0 N F O - N (R)-4-((4-([1,2,4]triazolo[4,3-a]pyrimidi 573 1'0 HN N NN n-6-yloxy)-3-methylphenyl)amino)-5-(( 171 0 NN(M+H) 0 CN 3,3-difluoro-1-methylpiperidin-4-yl)oxy +

N )-6-methoxyquinoline-3-carbonitrile F N F O N- (S)-4-((4-([1,2,4]triazolo[4,3-a]pyrimidi 573 10 HN N N N n-6-yloxy)-3-methylphenyl)amino)-5-(( 172 0 NN N(M+H) 0 CN 3,3-difluoro-1-methylpiperidin-4-yl)oxy

N )-6-methoxyquinoline-3-carbonitrile

N F 0 -N'N (R)-5-((3,3-difluoro-1-methylpiperidin- 572

173 ''O HCN N 4-yl)oxy)-6-methoxy-4-((3-methyl-4-(p (M+H) 0 CN yrazolo[1,5-a]pyrimidin-6-yloxy)phenyl

N )amino)quinoline-3-carbonitrile

F N F O N'N (S)-5-((3,3-difluoro-1-methylpiperidin- 572 OHCN N 4-yl)oxy)-6-methoxy-4-((3-methyl-4-(p 174 0HNN(M+H) 0 * .0] CN yrazolo[1,5-a]pyrimidin-6-yloxy)phenyl

N )amino)quinoline-3-carbonitrile

N N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7 S> -yloxy)-3-methylphenyl)amino)-5-(3-(di 594 175 N N N methylamino)azetidin-1-yl)pyrido[3,4-d (M+H) NNJ N]pyrimidin-6-yl)-4-(dimethylamino)but-

+ N 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

numberDYC1768).

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%

CO 2for 24 hours. ELISA plate was coated with 2pg/ml capture antibody, which was

incubated at 4°C overnight.

Day 2:

25nl compounds was dosed by Echo from source plate and the 384-well plate was

incubated at 37 °C for 2 hours.30pllysis buffer was added to each well and the 384-well plate

was shaken softly at 40 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[l

cell lysate was transferred from the 384-well plate to the ELISA plate, which was incubated

overnight at 40 C.

Day3:

The ELISA plate was washed 3 times.25pl/well detection antibody was added (diluted 1

by2000 in 1% BSA in PBS). After 2 hours of incubation with detection antibody, the ELSA

plate was washed 3times, 25pl/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 IC5o 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 ICo result

of no more than 1000nM. Some have an IC5o 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) inNCIH838 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 pL FBS-Free RPMI1640. After2hoursof

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% C02 for 2 hours. After2hoursof

incubation with compounds, EGF (final concentration at 100ng/ml) was added to the plate

which was incubated at 37 °C with 5% C02 for 5-10 minutes. Medium was discarded from

the plate and30 1/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. ELISAplatewas

coated by diluting capture antibody to 4 pg/ml with PBS, and 25 1/well was dispensed to

384 well UltraCruz@ ELISA Plate, which was incubated at 4 °C overnight.

Day 3:

After the plates were washed three times with 100 1/well of wash buffer, the plates

were blocked by adding 75 1 of Block Buffer to each well and incubated at room

temperature for 3 hours. After the plates were washed three times with 100 1/well of wash

buffer, 20 d 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 100 1/well of

wash buffer, 25 1/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

1/well TMB substrate was added to the ELISA plate which was incubated for about

10-15min, protected from light before addition of 25 1/well stop solution. Absorbancewas

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 IC5 0

against HER2 of no more than 1000 nM. Some of these compounds have an ICo 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 IC 5 o against wt-EGFR of more than 0.5 [M, more than 1 M, some more

than 2[M, more than 3 M, more than 4 M, more than 6[M, more than 8[M, or even more

than 10 pM.

Table 2: HER2 and wt-EGFR inhibition data for exemplary compounds in assays a)-b) Example BT474 ICso(nM) H838 IC5 0 (pM) 1 20 >10 2 8.4 >10 3 12 >10 5 109 >10

WO 2021/179274 PCT1CN20201079097

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

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-N 4 -(5-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-N-(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-methylphenyl)-N6-(4,4-dimethyl-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 1 M. 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 30 M. The final concentrations of test compounds and control compound

were at 1 M. The multi-well insert plate was incubated at 37 °C for 2 hours. Efflux ratio

(-inhibitor/+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

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 BCRPER hERG (IC50) Mouse Kpu,u

Ref. compd. 1 0.57 1.1 < 2pM Not determined

Ref. compd. 2 >18.6 1.4 > 10 pM Too low to calculate Too low to Ref. compd. 3 23.8 2.1 > 10 p.M calculate

1 0.82 0.61 > 10 pM 0.23

3 1.06 0.69 > 10 pM N/A

17 0.42 0.43 > 10 pM 0.13

18 0.55 0.47 > 10 pM 0.12

48 1.3 N/A N/A N/A

53 1.45 N/A > 10 pM N/A

57 1.62 N/A >5 pM N/A

77 2.1 N/A > 10 pM N/A

87 1.22 N/A > 10 pM N/A

107 1.48 N/A > 10 pM N/A

From Table 3, it is shown that Reference compound 1 is a strong hERG inhibitor with

IC 5o<2 pM. 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 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.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I):

(R 4 ) n1 E X1 D A

R2', L HN X4 X5 X 7 N

\, G

N 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;

X1, X2, X3, X4, X5, X 6, 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, S02 and N(R); Ri is selected from the group consisting of hydrogen, halogen, cyano, nitro, amino,

heterocyclyl, aryl, N(R)(R), and O(R 9), wherein said cycloalkyl and heterocyclyl are

alkynyl, alkyl-OH and haloalkyl;

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

10 membered heterocyclyl ring is optionally substituted with one or more groups

and N(Rio)(Rii);

halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkyl-OH, haloalkyl and

alkoxyl;

R 5 is selected from the group consisting of hydrogen, halogen and cyano;

by alkyl, aryl, and heteroaryl; or

additional heteroatoms selected from N, 0, S, SO, SO 2 and NR 2 , wherein said heterocyclyl

partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl;

heteroarylalkyl, and heterocyclylalkyl;

saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl; or

heteroarylalkyl, and heterocyclylalkyl;

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; nI is 0, 1 or 2.

2. A compound of Formula (II):

R 4 ) n1 X2 E XN A R3

R21L HN X5 XD X7

R1 ),)n M N G (II

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;

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 X1, X6 and X7 is N;

E is 0, NH, or S;

L is selected from the group consisting of 0, C(=0), S, SO, SO 2 and N(R);

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;

R6 is hydrogen or alkyl; or

10 membered heterocyclyl ring is optionally substituted with one or more groups

and N(Rio)(Rii);

alkoxyl;

R 5 is selected from the group consisting of hydrogen, halogen and cyano;

by alkyl, aryl, and heteroaryl; or

heteroarylalkyl, and heterocyclylalkyl;

saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl; or

from halogen, alkyl, alkenyl, alkyl-OH, haloalkyl, alkynyl, saturated and partially

n is 0, 1 or 2;

nI is 0, 1 or 2.

3. A compound of Formula (III):

x 1.1, 2 R3 X2 E R2, :- X5 L HN X4

R, n

N (III)

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;

X 2 , X 3, X 4 , X 5, are each independently CH or N;

E is 0, NH, or S;

Y is a bicyclic aryl formed by:

(d) Y1 fused with Y2, wherein Y1 is a 6-membered heteroaryl, and Y2 is a

6-membered aryl or heteroaryl, or

(e) Y3 fused with Y4, wherein Y3 is a 5-membered aryl or heteroaryl, and Y4 is a

5-membered aryl or heteroaryl, or

(f) Y5 fused with Y6, wherein Y5 is a 5-membered aryl or heteroaryl, and Y6 is a

6-membered aryl or heteroaryl, wherein Y5 is connected to E;

wherein each of Yi, Y2 , Y 3 , Y 4 , Y 5, and Y 6 is optionally substituted by one or more of

groups each independently having the same definition as Ri;

L is selected from the group consisting of 0, C(=0), S, SO, S02 and N(R); R2 is selected from the group consisting of alkyl, saturated or partially unsaturated

R6 is hydrogen or alkyl; or

10 membered heterocyclyl ring is optionally substituted with one or more groups

and N(Rio)(Rii);

alkoxyl;

R5 is selected from the group consisting of hydrogen, halogen and cyano;

by alkyl, aryl, and heteroaryl; or

additional heteroatoms selected from N, 0, S, SO, S02 and NR2 , wherein said heterocyclyl

heteroarylalkyl, and heterocyclylalkyl;

saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl; or

heteroarylalkyl, and heterocyclylalkyl;

n is 0, 1 or 2;

nI is 0, 1 or 2.

4. The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

thereof as claimed in claim 1, wherein at least one of Xi, X6 and X7 is N.

5. The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

thereof, as claimed in claim 2, wherein at least one of X1, X6 and X 7 is N.

6. The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

thereof, as claimed in claim 2, wherein M is N, X 7 is N, and at least one of Xi and X6 is

N.

7. The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

thereof, as claimed in claim 2, wherein X7 is N, and at least one of Xi and X6 is N.

8. The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

thereof, as claimed in any of claims 1-3, wherein each of X2 , X 3 , X4 , and X5 is CH.

9. The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

thereof, as claimed in any of claim 1 and claim 2, wherein:

a) X 6 is N, and X7 is CH; or

b) X 6 is CH, and X7 is N.

10. The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

thereof, as claimed in claim 1, wherein the compound having a formula selected from the

group consisting of:

R3 E L HN

R1

N (Formula IVa)

R4

R2 L H N N

N, - G

N (Formula IVb)

E R3.~ R2 L HNE

N (Formula IVc)

R4

R2 L HN R,1

N (Formula IVd)

R4

R2 L H E N

R1

N (Formula IVe)

E NN R2 L HNN N'

N (Formula IVf)

R4

R2 L HN

N (Formula IVg)

R4 E N L HN R1G

N (Formula IVh)

R4

E NY N' N RsR3 -Nz NJ L HN

N (Formula IVi) wherein G, L, E, RI, R2, R3 and R 4 have the meanings as defined in claim 1.

11. The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

thereof, as claimed in claim 10, wherein:

L is selected from 0 or N(R6);

Ri is O(R9), N(R)(Rs), or partially unsaturated heterocyclyl optionally substituted

by acyl;

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, and N(Rio)(Rii), or;

R2 and R 6 together with the nitrogen atom to which they are attached form a4 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

unsaturated cycloalkyl, and N(Rio)(Rii);

R3 is selected from halogen or alkyl;

R4 and R5 are hydrogen;

R7 and Rs 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 R1 are each independently an alkyl.

12. The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

thereof, as claimed in claim 2, the compound having a formula selected from the group

consisting of:

E N-N R3 2 L HN N R1

N (Formula Va)

R4 E N-N R3 F12L HN N N

N (Formula Vb)

E N

L HN R1

N (Formula Vc)

R'4 E N R2 L H E NN R1G

N (Formula Vd)

E RR4 N

R2 L HN R1G

N (Formula Ve)

E R14 R2 L HN N

RR4

N (Formula V)

R1

E N

L HN R1G

N RR4 (Formula Vg)

E N-N

L2 R3 --- N LHN"

N (Formula Vh) wherein G, L, E, RI, R2, R3 and R 4 have the meanings as defined in claim 2.

13. The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

thereof, as claimed in any of claims 2, 5-7, and 12, wherein

L is selected from 0 or N(R6); Ri is O(R9), N(R)(Rs), or partially unsaturated heterocyclyl optionally substituted by

acyl;

R2 is selected from C4-6 saturated cycloalkyl or 5 to 6 membered saturated heterocyclyl,

wherein said C 4 -6 saturated cycloalkyl and 5 to 6 membered saturated heterocyclyl are

consisting of halogen, alkyl, and N(Rio)(Rii); or

heteroatoms selected from N, 0 and S, wherein said 4 to 9 membered saturated

unsaturated cycloalkyl, and N(Rio)(Rii);

R3 is selected from halogen or alkyl;

R4 and R5 are hydrogen;

R7 and Rs 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

alkoxyl; and

Rio and Ru are each independently an alkyl.

14. The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

consisting of:

R4 E N L ~ N N> L HN R1

N (Formula VIa)

R4 E N R3 N R2 L HN N R1 H

N (Formula VIb)

R4 F N\

R2 L HN N N R1G

N (Formula VIc)

R4 E tN-N

R2, RL R H3 ~E N R 1G

N (Formula VId)

wherein G, L, E, Ri, R3 and R4 have the meanings as defined in claim 2, and wherein R2

is selected from C 4 .6 saturated cycloalkyl or 5 to 6 membered saturated heterocyclyl,

wherein said C 4 -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, and N(Rio)(Rii); or when L is N(R6), 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);

wherein Rio and R1 are each independently an alkyl.

15. The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

thereof, as claimed in any one of preceding claims, wherein G is N.

16. The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

thereof, as claimed in any one of preceding claims, wherein E is 0.

17. The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

thereof, as claimed in any one of preceding claims, wherein R1 is selected from hydrogen,

N(R)(R), O(R9), or saturated or partially unsaturated hetercyclyl optionally substituted

by acyl.

18. The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

thereof, as claimed in any of claims 1-17, wherein 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

haloalkyl, saturated and partially unsaturated cycloalkyl, and N(Rio)(Rii).

19. The compound the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

thereof, as claimed in claim 18, wherein R2 and R6 together with the nitrogen atom to which they are attached form: 0 N

N N N N

N NN 0

N N N N N

N N N ' N

N N 0

, or N N

the group consisting of halogen, alkyl, haloalkyl, saturated and partially unsaturated

cycloalkyl, N(Rio)(Rii), wherein p is 1, 2 or 3, and q is 1, 2 or 3.

20. The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

thereof, as claimed in any one of claims 1-17, wherein L is 0, and R 2 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, and

N(Rio)(Rii).

21. The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

thereof, as claimed in any of claims 1-17, wherein R2 is selected from C 4 .6 saturated

cycloalkyl or 5 to 6 membered saturated heterocyclyl, wherein said C4.6saturated

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, and N(Rio)(Rii).

22. The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

thereof, as claimed in any one of preceding claims, wherein R3 is selected from halogen

or alkyl.

23. The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester

thereof, as claimed in any one of preceding claims, wherein R4 is hydrogen.

24. A compound or a solvate, hydrate, stereoisomer, or a pharmaceutically acceptable salt or

ester thereof, wherein the compound is selected from the group consisting of

(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-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-yloxy)-3-methylphenyl)-5-((3,3-difluoro

-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

-1-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;

-1-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine;

(R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-chlorophenyl)-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-yloxy)-3-chlorophenyl)-5-((3,3-difluoro

1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;

N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-6-methoxy-5-((1-m

ethylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine;

N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-(3-(dimethylamin

o)azetidin-1-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

-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-methylphenyl)-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-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1

methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

-isopropylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

isopropylpiperidin-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-methylphenyl)-5-((1-cyclopropyl

-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-methylphenyl)-5-((1-cyclopropyl

3,3-difluoropiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;

methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;

-(methyl-d3)piperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;

(methyl-d3)piperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;

-methylpiperidin-4-yl)oxy)-6-isopropoxypyrido[3,4-d]pyrimidin-4-amine;

methylpiperidin-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-methylphenyl)-6-(cyclopropylme

thoxy)-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-methylphenyl)-6-(cyclopropylmet

hoxy)-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-methylphenyl)-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-methylphenyl)-6-cyclopropoxy-5

-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine;

-methylpiperidin-4-yl)oxy)-6-(2,2,2-trifluoroethoxy)pyrido[3,4-d]pyrimidin-4-amine;

methylpiperidin-4-yl)oxy)-6-(2,2,2-trifluoroethoxy)pyrido[3,4-d]pyrimidin-4-amine;

-methylpiperidin-4-yl)oxy)-6-(difluoromethoxy)pyrido[3,4-d]pyrimidin-4-amine;

methylpiperidin-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-methylphenyl)-6-methoxy-5-((1-meth

ylpiperidin-4-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine;

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-methoxy-5-morphol

inopyrido[3,4-d]pyrimidin-4-amine;

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-methoxy-5-(4-meth

ylpiperazin-1-yl)pyrido[3,4-d]pyrimidin-4-amine;

cis-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-((3-fluoro-1-met

hylpiperidin-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-methylphenyl)-5-((3-fluoro-1-m

ethylpiperidin-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-methylphenyl)-5-((4,4-difluoro-1

-methylpyrrolidin-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-methylphenyl)-5-((4,4-difluoro-1

methylpyrrolidin-3-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(3-(dimethylamino)

pyrrolidin-1-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(4-(dimethylamino)

-3,3-difluoropyrrolidin-1-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-methoxy-5-(5-meth

yl-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-methylphenyl)-6-methoxy-5-(2-meth

yl-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-methylphenyl)-5-(7-fluoro-5-met

hyl-2,5-diazaspiro[3.4]octan-2-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(7-fluoro-5-met

hyl-2,5-diazaspiro[3.4]octan-2-yl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(7,7-difluoro-5-met

hyl-2,5-diazaspiro[3.4]octan-2-yl)-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-y

loxy)-3-methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-b]pyridazin-7-y

loxy)-3-methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(R)-N-(4-([1,2,4]triazolo[4,3-a]pyridin-7-yloxy)-3-methylphenyl)-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]pyridin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1

methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-a]pyridin-7-ylo

xy)-3-methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-a]pyridin-7-ylo

xy)-3-methylphenyl)-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

yloxy)-3-methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-N-(4-(imidazo[1,2-c]pyrimidin-7-y

loxy)-3-methylphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(R)-N-(4-([1,2,4]triazolo[1,5-b]pyridazin-7-yloxy)-3-methylphenyl)-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-b]pyridazin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro

-1-methylpiperidin-4-yl)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-(tetrazo

lo[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-(tetrazo

lo[1,5-c]pyrimidin-7-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;

lo[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-methylphenyl)-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-a]pyridin-6-yloxy)-3-methylphenyl)-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-a]pyridin-6-yloxy)-3-chlorophenyl)-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-a]pyridin-6-yloxy)-3-chlorophenyl)-5-((3,3-difluoro-1

methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;

methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;

-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;

methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;

-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(methyl-d3)piperidin-4-yl)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-(pyrazo

lo[1,5-a]pyridin-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-(pyrazo

lo[1,5-a]pyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;

(R)-N-(3-chloro-4-(pyrazolo[1,5-a]pyridin-6-yloxy)phenyl)-5-((3,3-difluoro-1-meth

ylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(S)-N-(3-chloro-4-(pyrazolo[1,5-a]pyridin-6-yloxy)phenyl)-5-((3,3-difluoro-1-meth

ylpiperidin-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]pyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;

(N)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-ethoxy-N-(3-methyl-4-(pyrazolo

[1,5-a]pyridin-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-(p

yrazolo[1,5-a]pyridin-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-(p

yrazolo[1,5-a]pyridin-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-methyl-4-(p

yrazolo[1,5-a]pyridin-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-methyl-4-(p

yrazolo[1,5-a]pyridin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;

lo[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)phenyl)-5-((3,3-difluoro-1-me

thylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(S)-N-(3-chloro-4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)-5-((3,3-difluoro-1-me

thylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

[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;

yrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)pyrido[3,4-d]pyrimidin-4-amine;

lo[1,5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine;

thylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine;

[1,5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine;

yrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)quinazolin-4-amine;

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)-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-a]pyrimidin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro

-1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

-1-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;

-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;

-1-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine;

(R)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-chlorophenyl)-5-((3,3-difluoro

-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine;

(S)-N-(4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-chlorophenyl)-5-((3,3-difluoro

1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine;

-1-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;

-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)quinazolin-4-amine;

-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-methylphenyl)-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]pyridin-6-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1

methylpiperidin-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-chlorophenyl)-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]pyridin-6-yloxy)-3-chlorophenyl)-5-((3,3-difluoro-1

methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;

methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;

-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;

methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;

-(methyl-d3)piperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

(methyl-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-methylphenyl)-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-methylphenyl)-5-((3,3-difluoro

-1-methylpiperidin-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-chlorophenyl)-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-chlorophenyl)-5-((3,3-difluoro

1-methylpiperidin-4-yl)oxy)-6-methoxypyrido[3,4-d]pyrimidin-4-amine;

-1-methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;

methylpiperidin-4-yl)oxy)-6-ethoxypyrido[3,4-d]pyrimidin-4-amine;

-1-methylpiperidin-4-yl)oxy)-6-(methoxy-d3)pyrido[3,4-d]pyrimidin-4-amine;

(R)-4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)amino)-5-((3,3

difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(S)-4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)amino)-5-((3,3

(R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5-((3,3-dif

luoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5-((3,3-dif

uoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(R)-4-((4-([1,2,4]triazolo[1,5-b]pyridazin-7-yloxy)-3-methylphenyl)amino)-5-((3,3

(S)-4-((4-([1,2,4]triazolo[1,5-b]pyridazin-7-yloxy)-3-methylphenyl)amino)-5-((3,3-d

ifluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-4-((3-methyl-4-(tetrazo

lo[1,5-c]pyrimidin-7-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile;

(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-4-((3-methyl-4-(tetrazo

lo[1,5-c]pyrimidin-7-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile;

lo[1,5-a]pyridin-7-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile;

(R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylphenyl)amino)-5-((3,3-dif

luoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylphenyl)amino)-5-((3,3-dif

uoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(R)-4-((4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)amino)-5-((3,3

(S)-4-((4-([1,2,4]triazolo[1,5-a]pyrimidin-6-yloxy)-3-methylphenyl)amino)-5-((3,3

(R)-4-((4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylphenyl)amino)-5-((3,3-dif

luoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(S)-4-((4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-3-methylphenyl)amino)-5-((3,3-difi

uoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-1,7-naphthyridine-3-carbonitrile;

(R)-4-((4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylphenyl)amino)-5-((3,3

(S)-4-((4-([1,2,4]triazolo[4,3-a]pyrimidin-6-yloxy)-3-methylphenyl)amino)-5-((3,3

(R)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-4-((3-methyl-4-(pyrazo

lo[1,5-a]pyrimidin-6-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile;

(S)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxy-4-((3-methyl-4-(pyrazo

lo[1,5-a]pyrimidin-6-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile;

lo[1,5-a]pyridin-6-yloxy)phenyl)amino)-1,7-naphthyridine-3-carbonitrile;

difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinoline-3-carbonitrile;

lo[1,5-a]pyrimidin-6-yloxy)phenyl)amino)quinoline-3-carbonitrile;

N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5-(3-(dimethyla

mino)azetidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)-4-(dimethylamino)but-2-enamide.

25. A pharmaceutical composition comprising a compound or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof, as claimed in any one of the

preceding claims, and at least one pharmaceutically acceptable excipient.

26. The pharmaceutical composition of claim 25, which does not comprise an agent for

facilitating BBB entry.

27. 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

or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof, as claimed

in any one of the claims I to 24.

28. The method of claim 27, wherein the HER2-associated diseases or conditions are cancer

such as breast cancer, gastric cancer, mCRC, NSCLC or metastasis thereof.

29. The method of claim 28, wherein the metastasis is in brain.

30. The method of claim 29, wherein the compound or the solvate, hydrate, stereoisomer, or

the pharmaceutically salt or ester thereof is capable of BBB entry in the absence of an

agent for facilitating BBB entry.

31. A compound or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester

thereof, as claimed in any one of the claims 1 to 24, for use in the treatment of

HER2-associated diseases or conditions.

32. Use of a compound or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof, as claimed in any one of the claims 1 to 24, in the manufacture of a medicament for the treatment of HER2-associated diseases or conditions.

33. A compound or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester

HER2-associated diseases or conditions, wherein the compound is administered

simultaneously, separately or sequentially with one or more chemotherapeutic agents.

34. The compound or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester

thereof, as claimed in claim 33, wherein the one or more chemotherapeutic agents

comprise capecitabine, T-DM1, radiotherapy and anti-HER2 antibody.