WO2021179274A1

WO2021179274A1 - ErbB RECEPTOR INHIBITORS AS ANTI-TUMOR AGENTS

Info

Publication number: WO2021179274A1
Application number: PCT/CN2020/079097
Authority: WO
Inventors: Ding Zhou; Ziqiang CHENG; Zheng Wang
Original assignee: Suzhou Zanrong Pharma Ltd.
Priority date: 2020-03-13
Filing date: 2020-03-13
Publication date: 2021-09-16
Also published as: CA3175102A1; AU2020435503A1

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 HER1) , ErbB2 (HER2) , ErbB3 (HER3) , and ErbB4 (HER4) (Reviewed in Riese and Stern, Bioessays (1998) 20: 41-48; Olayioye et ah, EMBO Journal (2000) 19: 3159-3167; and Schlessinger, Cell (2002) 110: 669-672) . The structures of all the four family members are nearly the same, made up of an extracellular region or ectodomain or ligand binding region, a single transmembrane-spanning region, and an intracellular cytoplasmic tyrosine kinase domain.

It has been demonstrated that HER2 plays a role in development of cancer. HER2 overexpression occurs in 20-25%of breast cancer (BC) patients (Leyland-Jones B, J Clin Oncol. 2009, 5278-86) . About 1.7 million new BC incidences are diagnosed every year (Cardoso F, et al. Breast 2018, 131-138) and 80%of BC are invasive, which require chemotherapy, radiation or target therapy besides surgery (Dai X., et al. Am J Cancer Res, 2015, 2929-2943) . Brain metastases are a frequent occurrence in metastatic breast cancer patients. Overall survival for breast cancer brain metastases (BCBM) patients ranges from 2-25.3 months (Leone J.P. Exp. Hematol. Oncol. 2015, 4, 33) . Surgery, whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) are the three main treatment options for BCBM. Surgery is used for solitary or up to three brain metastases. SRS can be used in patients with four or fewer intracranial lesions. WBRT is used to manage multiple brain metastases, but can lead to significant neuro-cognitive decline (Venur V.A. et al. Int. J. Mol. Sci. 2016, 1543) .

Compared to other types of breast cancer, HER2 positive tumors have a higher incidence of brain metastases, up to 50%of HER2positive breast cancer patients develop intracranial metastases (Leyland-Jones B, J Clin Oncol. 2009, 5278-86) . The high prevalence of BCBM in HER2 positive patients is ascribed to inherent tropism of HER2 positive breast cancer cells to the brain, prolonged survival of patients treated with anti-HER2 therapy and limited intracranial activity of anti-HER2 therapy (Venur V.A. et al. Int. J. Mol. Sci. 2016, 17, 1543) .

Several anti-HER2 agents have been developed for clinical use, but none of them is central nervous system (CNS) penetrable. The blood-brain barrier (BBB) is essential to protect the CNS from potentially harmful agents in the peripheral circulation; however, it also prevents potential therapeutics from reaching the site of action. It is estimated that 98%of all small molecules and 100%large molecules, such as antibodies and antibody drug conjugate do not cross the BBB (Pardridge W.M. NeuroRx, 2005, 2, 3-14) , which presents great challenges to CNS drug discovery. Efflux transport is a major determinant of drug disposition to the CNS. Several ATP-dependent efflux pumps from the ABC superfamily (P-gp and BCRP) have been localized at the luminal side of human brain capillary endothelial cells (Giacomini K.M. et. al. Nature Reviews Drug Discovery, 2010, 9, 215-236) and Pgp and BCRP have been shown to play an important role in limiting entry of various drugs into the CNS (Enokizono, J. et al. Drug Metabolism and Disposition, 2008, 36, 995-1002. Zhou, L. et al. Drug Metabolism and Disposition, 2009, 37, 946-955) .

Trastuzumab, like other monoclonal antibodies, does not cross blood-brain barrier (BBB) with brain to blood ratio (K _p) <0.01 (Kabraji S. et al. Clinical Cancer Research. 2018, 3351) . T-DM1, an antibody drug conjugate (ADC) , does not cross BBB either with K _p<0.01 (Askoxylakis V., et al. JNCI J Natl Cancer Inst, 2015, 763-763) . Approved tyrosine kinase inhibitors (TKIs) lapatinib, neratinib and afatinib are strong Pgp substrates, and have poor brain penetration with K _p of 0.04, 0.079 and<0.08, respectively (Tanaka, Y. et al, Scientific Reports, 2018, 343; Zhang, Shirong, et al, Acta Pharmacologica Sinica, 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 K _p at 0.02-0.05 (Dinkel V, et al. Cancer Research, 2012, 72) . In addition, the evaluation of resected brain metastases has revealed that the BBB was 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) :

or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof, wherein:

G is C (R ₅) or N;

A is CH or N;

B is CH or N;

D is CH of N;

X ₁, X ₂, X ₃, X ₄, X ₅, X ₆, and X ₇ are each independently CH or N;

E is O, NH, or S;

L is selected from the group consisting of O, C (=O) , S, SO, SO ₂and N (R ₆) ;

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 ₈) , 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;

R ₂ 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 (R ₁₀) (R ₁₁) ;

R ₆ is hydrogen or alkyl; or when L is N (R ₆) , R ₂ and R ₆ 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 (R ₁₀) (R ₁₁) ;

R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, halogen, cyano, amino, hydroxyl, nitro, alkyl, alkenyl, alkynyl, alkyl-OH, haloalkyl and alkoxyl;

R ₅ is selected from the group consisting of hydrogen, halogen and cyano;

R ₇ and R ₈ 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

R ₇ and R ₈ 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, O, S, SO, SO ₂ and NR ₁₂, 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;

R ₉ is selected from the group consisting of alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, acyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, wherein said alkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocyclyl are optionally substituted by one or more groups independently selected from the group consisting of halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, alkoxyl, acyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl;

R ₁₀ and R ₁₁ are each independently selected from the group consisting of hydrogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl, wherein said alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl are optionally substituted with one or more groups independently selected from alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl; or

R ₁₀ and R ₁₁ 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, O, S, SO, SO ₂ and NR ₁₂, 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;

R ₁₂ is selected from the group consisting of hydrogen, alkyl, alkyl-OH, haloalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl, wherein said alkyl, alkyl-OH, haloalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl are optionally substituted with one or more groups independently selected from halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl;

n is 0, 1 or 2;

n1 is 0, 1 or 2.

In some embodiments according to Formula (I) , at least one of X ₁, X ₆ and X ₇ is N.

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

G is C (R ₅) or N;

M is CH or N;

A is CH or N;

B is CH or N;

D is CH of N;

X ₁, X ₂, X ₃, X ₄, X ₅, X ₆, and X ₇ are each independently CH or N, with the proviso that when M is CH, at least one of X ₁, X ₆ and X ₇ is N;

E is O, NH, or S;

L is selected from the group consisting of O, C (=O) , S, SO, SO ₂ and N (R ₆) ;

R ₆ is hydrogen or alkyl; or

when L is N (R ₆) , R ₂ and R ₆ 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, haloalkyl, saturated and partially unsaturated cycloalkyl, and N (R ₁₀) (R ₁₁) ;

R ₅ is selected from the group consisting of hydrogen, halogen and cyano;

n is 0, 1 or 2;

n1 is 0, 1 or 2.

In some embodiments of the compounds according to Formula (II) , at least one of X ₁, X ₆ and X ₇ is N. In some embodiments, X ₇ is N, and at least one of X ₁ and X ₆ is N. In some embodiments, M is N, X ₇ is N, and at least one of X ₁ and X ₆ is N.

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

G is C (R ₅) 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 O, 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 Y ₁, Y ₂, 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 R ₁;

R ₆ is hydrogen or alkyl; or

R ₅ is selected from the group consisting of hydrogen, halogen and cyano;

n is 0, 1 or 2;

and n1 is 0, 1 or 2.

In another aspect, there is provided a pharmaceutical composition comprising: (i) a compound of any of Formula (I) , Formula (II) , and Formula (III) , or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof, and (ii) at least one pharmaceutically acceptable diluent, excipient or carrier.

In a further aspect, there is provided a method of treating type I receptor kinases-associated diseases or conditions in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any of Formula (I) , Formula (II) , and Formula (III) , or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof.

In a further aspect, there is provided a method of treating HER2-associated diseases or conditions in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any of Formula (I) , Formula (II) , or Formula (III) , or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof.

In a further aspect, there is provided a compound of any of Formula (I) , Formula (II) , or Formula (III) , or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof, for use in the treatment of type I receptor kinases-associated diseases or conditions, in particular HER2-associated diseases or conditions.

In a further aspect, there is provided use of a compound of any of Formula (I) , Formula (II) , or Formula (III) , or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof, in the manufacture of a medicament for the treatment of type I receptor kinases-associated diseases or conditions, in particular HER2-associated diseases or conditions.

In a further aspect, there is provided a compound of any of Formula (I) , Formula (II) , or Formula (III) , or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof for use in the treatment of type I receptor kinases-associated diseases or conditions, in particular HER2-associated diseases or conditions, wherein the compound is administered simultaneously, separately or sequentially with radiotherapy.

In a further aspect, there is provided a compound of any of Formula (I) , Formula (II) , or Formula (III) , a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof or a pharmaceutically acceptable salt thereof, administered simultaneously, separately or sequentially with one or more additional chemotherapeutic agents.

In a further aspect, there is provided a compound of any of Formula (I) , Formula (II) , or Formula (III) , or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof, administered simultaneously, separately or sequentially with one or more additional HER2 targeted antibodies.

In a further aspect, there is provided a kit for the treatment or prevention of type I receptor kinases-associated diseases or conditions, in particular HER2-associated diseases or conditions, said kit comprising a compound of any of Formula (I) , Formula (II) , or Formula (III) , or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof, a container, and optionally a package insert or label indicating a treatment. The kit may further comprise a second compound or formulation comprising a second pharmaceutical agent useful for treating said disease or disorder.

DETAILED DESCRIPTION OF THE DISCLOSURE

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that 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, 75 ^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, 5 ^th Edition, John Wiley&Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3 ^rd 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 “C _i-j” indicates a range of the carbon atoms numbers, wherein i and j are integers and the range of the carbon atoms numbers includes the endpoints (i.e. i and j) and each integer point in between, and wherein j is greater than i. For examples, C _1-6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms. In some embodiments, the term “C _1-12” indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3 or particularly 1 to 2 carbon atoms.

As used herein, the term “alkyl” , whether as part of another term or used independently, refers to a saturated linear or branched-chain hydrocarbon radical, which may be optionally substituted independently with one or more substituents described below. The term “C _i-j alkyl” refers to an alkyl having i to j carbon atoms. In some embodiments, alkyl groups contain 1 to 12 carbon atoms. In some embodiments, alkyl groups contain 1 to 11 carbon atoms. In some embodiments, alkyl groups contain 1 to 11 carbon atoms, 1 to 10 carbon atoms, 1 to 9 carbon atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl group include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl) , 2-propyl (isopropyl) , 1-butyl (n-butyl) , 2-methyl-1-propyl (i-butyl) , 2-butyl (s-butyl) , 2-methyl-2-propyl (t-butyl) , 1-pentyl (n-pentyl) , 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-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 “C _1-12 alkyl” include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl. Examples of “C _1-6 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-1-butyl, 2-methyl-1-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 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, 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 “C _i-j alkoxy” means that the alkyl moiety of the alkoxy group has i to j carbon atoms. In some embodiments, alkoxy groups contain 1 to 12 carbon atoms. In some embodiments, alkoxy groups contain 1 to 11 carbon atoms. In some embodiments, alkoxy groups contain 1 to 11 carbon atoms, 1 to 10 carbon atoms, 1 to 9 carbon atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of “C _1-12 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 (=O) 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 C _1-6 alkyl-carbonyl group, a C _2-6 alkenyl-carbonyl group (e.g., acryloyl) , a C _3-10 cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl) , a C _3-10cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl) , a C _6-14 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 C _1-6 alkoxy-carbonyl group, a C _6-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl) , a C _7-16aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl) , a carbamoyl group, a mono- or di-C _1-6 alkyl-carbamoyl group, a mono- or di-C _2-6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl) , a mono- or di-C _3-10 cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl) , a mono- or di-C _6-14 aryl-carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C _7-16 aralkyl-carbamoyl group, a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl) , a thiocarbamoyl group, and the like. As used herein, the term “acyloxy” refers to an acyl group attached to the parent molecule through an oxygen atom.

As used herein, the term “amino” or “amine” refers to moieties where a nitrogen atom is covalently bonded to at least one carbon or heteroatom. “Alkylamino” includes groups of compounds wherein nitrogen is bound to at least one alkyl group. Examples of alkylamino groups include benzylamino, methylamino, ethylamino, phenethylamino, etc. “Dialkylamino” includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino and diethylamino. “Arylamino” and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively. “Alkylarylamino” , “alkylaminoaryl” or “arylaminoalkyl” refers to an amino group which is bound to at least one alkyl group and at least one aryl group. “Alkaminoalkyl” refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group. “Acylamino” includes groups wherein nitrogen is bound to an acyl group. Examples of acylamino include, but are not limited to, alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.

As used herein, the term “amide” or “aminocarboxy” refers to compounds or moieties that contain a nitrogen atom that is bound to the carbon of a carbonyl or a thiocarbonyl group. The term includes “alkaminocarboxy” groups that include alkyl, alkenyl or alkynyl groups 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–N ₃ 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- (C _1-12 alkyl) carbamoyl” include, but are not limited to, methylaminocarbonyl and ethylaminocarbonyl. Examples of “N, N- (C _1-12 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, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, 1-cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.

In some embodiments, the cycloalkyl group may be saturated or partially unsaturated polycyclic (e.g., bicyclic and tricyclic) carbocyclic ring system, which can be arranged as a fused, spiro or bridged ring system. As used herein, the term “fused ring” refers to a ring system having two rings sharing two adjacent atoms, the term “spiro ring” refers to a ring systems having two rings connected through one single common atom, and the term “bridged ring” refers to a ring system with two rings sharing three or more atoms. Examples of fused carbocyclyl include, but are not limited to, naphthyl, benzopyrenyl, anthracenyl, 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-C _1-3 alkyl, such as, but not limited to, cyclopropylmethyl.

As used herein, the term “cyano” refers to –CN.

As used herein, the term “halo” or “halogen” refers to an atom selected from fluorine (or fluoro) , chlorine (or chloro) , bromine (or bromo) and iodine (or iodo) .

As used herein, the term “haloalkyl” refers to an alkyl group substituted with one or more halogen atoms.

As used herein, the term “haloalkoxy” or “haloalkoxyl” refers to an alkoxyl group substituted with one or more halogen atoms.

As used herein, the term “heteroalkyl” refers to an alkyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, 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, O, or S. The heteroalkenyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) , and may be optionally substituted independently with one or more substituents described herein.

As used herein, the term “heteroalkynyl” refers to an alkynyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, or S. The heteroalkynyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) , and may be optionally substituted independently with one or 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] -l, 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 may be 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-C _1-3alkyl 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-C _1-3alkyls 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 –NO ₂ 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 ⁱ) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R ⁱ moieties, then the group may optionally be substituted with up to two R ⁱ moieties and R ⁱ at each occurrence is selected independently from the definition of R ⁱ. 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) :

G is C (R ₅) or N;

A is CH or N;

B is CH or N;

D is CH of N;

E is O, NH, or S;

R ₆ is hydrogen or alkyl; or

R ₅ is selected from the group consisting of hydrogen, halogen and cyano;

n is 0, 1 or 2;

n1 is 0, 1 or 2.

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

G is C (R ₅) or N;

M is CH or N;

A is CH or N;

B is CH or N;

D is CH of N;

E is O, NH, or S;

R ₆ is hydrogen or alkyl; or

R ₅ is selected from the group consisting of hydrogen, halogen and cyano;

n is 0, 1 or 2;

n1 is 0, 1 or 2.

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

G is C (R ₅) 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 O, NH, or S;

Y is a bicyclic aryl formed by:

(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;

R ₆ is hydrogen or alkyl; or

R ₅ is selected from the group consisting of hydrogen, halogen and cyano;

n is 0, 1 or 2;

n1 is 0, 1 or 2.

The following description of embodiments applies to compounds of any of Formula (I) , Formula (II) , and Formula (III) , unless otherwise specifically indicated.

In some embodiments, each of X ₂, X ₃, X ₄, and X ₅ is CH.

In some embodiments, X ₁ is CH.

In some embodiments, X ₁ 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 X ₆ and X ₇ is CH, and the other is N.

In some embodiments, R ₁ is selected from hydrogen, N (R ₇) (R ₈) , O (R ₉) , or saturated or partially unsaturated hetercyclyl optionally substituted by acyl.

In some embodiments, R ₁ is N (R ₇) (R ₈) , and R ₇ and R ₈ 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, R ₁ is N (R ₇) (R ₈) , R ₇ is hydrogen, and R ₈ is saturated or partially unsaturated cycloalkyl substituted by alkyl.

In some embodiments, R ₁ is N (R ₇) (R ₈) , R ₇ is hydrogen, and R ₈ is 4, 4-dimethyl-4, 5-dihydrooxazol-2-yl.

In some embodiments, R ₁ is N (R ₇) (R ₈) , R ₇ is hydrogen, and R ₈ is acyl substituted by alkylamino or saturated and partially unsaturated heterocyclyl substituted by alkyl.

In some embodiments, R ₁ is N (R ₇) (R ₈) , R ₇ is hydrogen, and R ₈ is (dimethyamino) but-2-ene-carbonyl or (1-methyl-pyrrolidin-2-yl) -acryloyl.

In some embodiments, R ₁ is O (R ₉) , and R ₉ is selected from the group consisting of alkyl, acyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, wherein said alkyl, cycloalkyl, and heterocyclyl are optionally substituted by one or more groups independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, acyl, and alkoxyl.

In some embodiments, R ₁ is O (R ₉) , and R ₉ is selected from the group consisting of C _1-6alkyl, C _1-6 acyl, 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 (R ₉) , 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, R ₁ is partially unsaturated hetercyclyl optionally substituted by acyl. In some embodiments, R ₁ is partially unsaturated hetercyclyl substituted by acryloyl. In some embodiments, R ₁ is tetrahydropyridyl substituted by acryloyl.

In some embodiments, R ₁ is O (R ₉) , R ₉ is selected from the group consisting of C _1-6 alkyl, 3 to 6 membered saturated or partially unsaturated cycloalkyl, 3 to 6 membered saturated or partially unsaturated heterocyclyl, wherein said alkyl, cycloalkyl, and heterocyclyl are optionally substituted by one or more groups independently selected from halogen, alkyl, or alkoxyl, L is O, 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, saturated or partially unsaturated cycloalkyl, and N (R ₁₀) (R ₁₁) .

In certain embodiments, R ₁ is O (R ₉) , R ₉ is C _1-6 alkyl, L is O, and R ₂ 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, saturated or partially unsaturated cycloalkyl, and N (R ₁₀) (R ₁₁) .

In some embodiments, R ₂ is optionally substituted with one or more of groups selected from methyl, fluoro, cyclopropyl and dimethylamino. In certain embodiments, R ₂ is substituted with one or more methyl groups. In certain embodiments, R ₂ is substituted with one or more fluoro groups. In certain embodiments, R ₂ is substituted with one or more cyclopropyl groups. In certain embodiments, R ₂ is substituted with one or more dimethylamino groups. In certain embodiments, R ₂ is substituted with one or more methyl groups and one or more fluoro groups.

In some embodiments, L is N (R ₆) , and R ₂ and R ₆ 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, haloalkyl, saturated and partially unsaturated cycloalkyl, and N (R ₁₀) (R ₁₁) .

In some embodiments, L is N (R ₆) , and R ₂ 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, O 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 (R ₁₀) (R ₁₁) .

In some embodiments, the phrase “R ₂ 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 R ₆ 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 R ₂ and R ₆ 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 R ₂ and R ₆ together with the nitrogen atom to which they are attached.

In some embodiments, L is N (R ₆) , and R ₂ and R ₆ together with the nitrogen atom to which they are attached form:

each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, alkyl, and N (R ₁₀) (R ₁₁) , 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 R ₂ and R ₆ 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 O, 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, saturated or partially unsaturated cycloalkyl, and N (R ₁₀) (R ₁₁) .

In some embodiments, L is O, and R ₂ 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, saturated or partially unsaturated cycloalkyl, and N (R ₁₀) (R ₁₁) .

In some embodiments, L is O, and R ₂ 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 (R ₁₀) (R ₁₁) .

In some embodiments, L is N (R ₆) , R ₁ 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 (R ₇) (R ₈) , and O (R ₉) , and R ₂ 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, O 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 (R ₁₀) (R ₁₁) .

In certain embodiments, L is N (R ₆) , R ₁ is N (R ₇) (R ₈) , and R ₂ 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, O 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 (R ₁₀) (R ₁₁) . In certain embodiments, R ₇ is hydrogen, and R ₈ is saturated or partially unsaturated cycloalkyl substituted by alkyl. In certain embodiments, R ₇ is hydrogen, and R ₈ is 4, 4-dimethyl-4, 5-dihydrooxazol-2-yl.

In certain embodiments, L is N (R ₆) , R ₁ is O (R ₉) , R ₉ is selected from the group consisting of C _1-6 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 R ₂ 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, O 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 (R ₁₀) (R ₁₁) .

In certain embodiments, L is N (R ₆) , R ₁ is O (R ₉) , R ₉ is selected from methyl, ethyl, isopropyl, cyclopropyl, or tetrahydrofuranyl, each of which is optionally substituted by one or more fluoro, and R ₂ 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, O 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 (R ₁₀) (R ₁₁) .

In some embodiments, R ₃ is halogen.

In certain embodiments, R ₃ is chloro.

In some embodiments, R ₃ is C _1-6 alkyl.

In certain embodiments, R ₃ is methyl.

In some embodiments, R ₄ is hydrogen.

In a further aspect, the present disclosure provides a compound of Formula (IVa) , (IVb) , (IVc) , (IVd) , (IVe) , (IVf) , (IVg) , (IVh) , or (IVi) below:

or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof, wherein G, L, E, R ₁, R ₂, R ₃ and R ₄ have the meanings as defined in Formula (I) and various embodiments thereof.

In some embodiments of Formula (I) , (IVa) , (IVb) , (IVc) , (IVd) , (IVe) , (IVf) , (IVg) , (IVh) , (IVi) , L is selected from O or N (R ₆) ; R ₁ is O (R ₉) , N (R ₇) (R ₈) , or partially unsaturated heterocyclyl optionally substituted by acyl; R ₂ is selected from C _4-6 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 (R ₁₀) (R ₁₁) , orR ₂ 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, O 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 (R ₁₀) (R ₁₁) ; R ₃ is selected from halogen or alkyl; R ₄ and R ₅ are hydrogen; R ₇ and R ₈ 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, C _3-7 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 R ₁₀ and R ₁₁ 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) :

or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof, wherein G, L, E, R ₁, R ₂, R ₃ 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 O or N (R ₆) ; R ₁ is O (R ₉) , N (R ₇) (R ₈) , or partially unsaturated heterocyclyl optionally substituted by acyl; R ₂ is selected from C _4-6 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 (R ₁₀) (R ₁₁) ; orR ₂ and R ₆ together with the nitrogen atom to which they are attached form a4 to 9 membered saturated monocyclic, spirocyclic or fused heterocyclyl ring optionally containing one or more additional heteroatoms selected from N, O 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 (R ₁₀) (R ₁₁) ; R ₃ is selected from halogen or alkyl; R ₄ and R ₅ are hydrogen; R ₇ and R ₈ 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, C _3-7 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; andR ₁₀ and R ₁₁ are each independently an alkyl.

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

a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof, wherein L is selected from O or N (R ₆) ; R ₂ is selected from C _4-6 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 (R ₁₀) (R ₁₁) ; or R ₂ 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, O 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 (R ₁₀) (R ₁₁) ; wherein R ₁₀ and R ₁₁ 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-methylpiperidin-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) azetidin-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;

(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- (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- (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;

(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;

(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;

(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;

(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;

(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;

(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;

(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;

(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-amine;

(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-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-isopropoxypyrido [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-isopropoxypyrido [3, 4-d] pyrimidin-4-amine;

(R) -N- (4- ( [1, 2, 4] triazolo [1, 5-a] pyridin-7-yloxy) -3-methylphenyl) -6- (cyclopropylmethoxy) -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- (cyclopropylmethoxy) -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;

(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-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- (2, 2, 2-trifluoroethoxy) pyrido [3, 4-d] pyrimidin-4-amine;

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

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

N- (4- ( [1, 2, 4] triazolo [1, 5-a] pyridin-7-yloxy) -3-methylphenyl) -6-methoxy-5- (4-methylpiperazin-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-methylpiperidin-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-methylpiperidin-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-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 [3.2.0] 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-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-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-b] pyridazin-7-yloxy) -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-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-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-yloxy) -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;

(R) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxy-N- (3-methyl-4- (tetrazolo [1, 5-a] pyridin-7-yloxy) phenyl) pyrido [3, 4-d] pyrimidin-4-amine;

(S) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxy-N- (3-methyl-4- (tetrazolo [1, 5-a] pyridin-7-yloxy) phenyl) pyrido [3, 4-d] pyrimidin-4-amine;

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

(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;

(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;

(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;

(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;

(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;

(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;

(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-methylpiperidin-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-methylpiperidin-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- (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-d3) -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- (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;

(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;

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

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

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

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

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

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

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

(R) -5- ( (3, 3-difluoro-1- (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;

(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;

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

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

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

(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;

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

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

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

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

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

(S) -5- ( (3, 3-difluoro-1- (methyl-d3) piperidin-4-yl) oxy) -6-methoxy-N- (3-methyl-4- (pyrazolo [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;

(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-ethoxypyrido [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-ethoxypyrido [3, 4-d] pyrimidin-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- (methoxy-d3) pyrido [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- (methoxy-d3) pyrido [3, 4-d] pyrimidin-4-amine;

(R) -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;

(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;

(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-methoxyquinazolin-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-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;

(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- (methoxy-d3) quinazolin-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- (methoxy-d3) quinazolin-4-amine;

(R) -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-methoxyquinazolin-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-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;

(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;

(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;

(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;

(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;

(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;

(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;

(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;

(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-ethoxypyrido [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- (methoxy-d3) pyrido [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- (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-difluoro-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-difluoro-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-difluoro-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-difluoro-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-difluoro-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;

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

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

(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;

(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;

(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;

(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;

(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) quinoline-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) quinoline-3-carbonitrile;

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

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. For example, 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, 19 ^thed., 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 H ₂O. 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 ¹H, ²H, ³H, ¹¹C, ¹²C, ¹³C, ¹⁴C, ¹⁴N, ¹⁵N, ¹⁶O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³²S, ³³S, ³⁴S, ³⁶S, ¹⁷F, ¹⁹F, ³⁵Cl, ³⁷Cl, ⁷⁹Br, ⁸¹Br, ¹²⁷I and ¹³¹I. In some embodiments, hydrogen includes protium, deuterium and tritium. In some embodiments, carbon includes ¹²C and ¹³C.

SYNTHESIS OF THE COMPOUNDS

Synthesis of the compounds provided herein, including pharmaceutically acceptable salts thereof, are illustrated in the synthetic schemes in the examples. The compounds provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, and thus these schemes are illustrative only and are not meant to limit other possible methods that can be used to prepare the compounds provided herein. Additionally, the steps in the Schemes are for better illustration and can be changed as appropriate. The embodiments of the compounds in examples were synthesized for the purposes of research and potentially submission to regulatory agencies.

The reactions for preparing compounds of the present disclosure can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants) , the intermediates, or products at the temperatures at which the reactions are carried out, e.g. temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one 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. ¹H or ¹³C) , infrared spectroscopy, spectrophotometry (e.g. UV-visible) , mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) , liquid chromatography-mass spectroscopy (LCMS) , or thin layer chromatography (TLC) . Compounds can be purified by one skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ( “Preparative LC-MS Purification: Improved Compound Specific Method Optimization” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6 (6) , 874-883, which is incorporated herein by reference in its entirety) , and normal phase silica chromatography.

The structures of the compounds in the examples are characterized by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS) . NMR chemical shift (δ) is given in the unit of 10 ^-6 (ppm) . ¹H-NMR spectra is recorded in CDCl ₃, CD ₃OD or DMSO-d ₆ 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 (THF) , N, N-dimethylformamide (DMF) , dichloromethane (DCM) , dichloroethane (DCE) , dioxane and 1, 1, 2, 2-tetrachloroethane were purchased from Aldrich in Sure seal bottles and used as received.

Unless otherwise specified, the reactions of the present disclosure were all done under a positive pressure of nitrogen or argon or with a drying tube in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.

For illustrative purposes, the following shows general synthetic route for preparing the compounds of the present disclosure as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

USE OF COMPOUNDS

The compounds of the present disclosure (as used herein, “a compound of the present disclosure” or “compounds of the present disclosure” refers to any compound of Formula (I) , Formula (II) and Formula (III) , as well as the various more specific embodiments thereof as described herein, as well as solvates, hydrates, stereoisomers, or pharmaceutically salts or esters thereof) show inhibitory activity against type I receptor tyrosine kinase, in particular HER2.

As used herein, the term “inhibitory activity against type I receptor tyrosine kinase” refers to a decrease in the activity of type I receptor tyrosine kinase as a direct or indirect response to the presence of a compound of the present disclosure, or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof, relative to the activity of type I receptor tyrosine kinase in the absence of compounds of the present disclosure. Such a decrease in activity may be due to the direct interaction of the compound of the present disclosure with type I receptor tyrosine kinase, or due to the interaction of the compound of the present disclosure, with one or more other factors that in turn affect activity of type I receptor tyrosine kinase. For example, the compounds of the present disclosure may decrease activity of type I receptor tyrosine kinase by directly binding to the type I receptor tyrosine kinase, by causing (directly or indirectly) another factor to decrease type I receptor tyrosine kinase activity, or by (directly or indirectly) decreasing the amount of type I receptor tyrosine kinase present in the cell or organism.

In some embodiments, the compounds of the present disclosure are selective inhibitors for HER2 over other type I receptor tyrosine kinases, such as wild type EGFR (wt-EGFR) .

As used herein, the term “selective inhibitor of HER2” or “selectively inhibitsHER2” means that a provided compound inhibits HER2 in at least one assay described herein (e.g., biochemical or cellular) over other type I receptor tyrosine kinases, such as wt-EGFR. In some embodiments, the term “selective inhibitor of HER2 over EGFR” or “selectively inhibitsHER2 over EGFR” means that a provided compound has the IC ₅₀ for wt-EGFR at least 10 fold higher, at least 20 fold higher, at least 30 fold higher, at least 40 fold higher, at least 50 fold higher, at least 60 fold higher, at least 70 fold higher, at least 80 fold higher, at least 90 fold higher, at least 100 fold higher, at least 200 fold higher, at least 300 fold higher, at least 400 fold higher, at least 500 fold higher, at least 600 fold higher, at least 700 fold higher, at least 800 fold higher, at least 900 fold higher, at least 1000 fold higher, at least 2000 fold higher than the IC ₅₀ for HER2, as determined by assays described herein.

Accordingly, there is provided compounds of the present disclosure which are highly potent HER2 inhibitors and are highly selective for HER2 relative to EGFR. Such compounds would allow treatment of cancers which can be treated by inhibiting HER2, for example cancers which express or overexpress HER2, in a relatively selective manner, 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 K _p 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 inhibition IC ₅₀ of greater than about 2μM, greater than about 3μM, greater than about 4μM, greater than about 5μM, greater than about 6μM, greater than about 7μM, greater than about 8μM, greater than about 9μM, greater than about 10μM. 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.

In some embodiments, there is provided a compound of the present disclosure for use in the manufacture of a medicament for the treatment of type I receptor tyrosine kinase-associated diseases or conditions.

In some embodiments, there is provided a compound of the present disclosure for use in the manufacture of a medicament for the treatment of HER2-associated diseases or conditions.

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, PLURONICS ^TM or polyethylene glycol (PEG) .

The composition may also comprise one or more stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament) . The active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, 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 (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.

In another aspect, there is also provided veterinary compositions comprising a compound of the present disclosure together with a veterinary carrier. Veterinary carriers 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 5α-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 ^TM] 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 integrinανβ3 function and angiostatin) , or inhibitors of angiopoietins and their receptors (Tie-1 and Tie-2) , inhibitors of PLGF, inhibitors of delta- like ligand (DLL-4) ;

(vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in PCT Publication Nos. WO 99/02166, WO 0/40529, WO 00/41669, WO 01/92224, WO 02/04434, and WO 02/08213;

(vii) antisense therapies (for example, those which are directed to the targets listed above such as ISIS 2503, and anti-ras antisense) ;

(viii) gene therapy approaches, including for example GVAX ^TM, approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAI or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy;

(ix) interferon;

(x) immunotherapy approaches, including, but not limited to, ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor; approaches to decrease T-cell anergy or regulatory T-cell function; approaches that enhance T-cell responses to tumours, such as blocking antibodies to CTLA4 (for example ipilimumab and tremelimumab) , B7H1, PD-1 (for example BMS-936558 or AMP-514) , PD-L1 (for example MEDI4736) and agonist antibodies to CD137; approaches using transfected immune cells such as cytokine-transfected dendritic cells; approaches using cytokine-transfected tumour cell lines, approaches using antibodies to tumour associated antigens, and antibodies that deplete target cell types (e.g., unconjugated anti-CD20 antibodies such as Rituximab, radiolabeled anti-CD20 antibodies Bexxar and Zevalin, and anti-CD54 antibody Campath) ; approaches using anti-idiotypic antibodies; approaches that enhance Natural Killer cell function; and approaches that utilize antibody-toxin conjugates (e.g. anti-CD33 antibody Mylotarg) ; immunotoxins such as moxetumumabpasudotox; agonists of toll-like receptor 7 or toll-like receptor 9;

(xi) efficacy enhancers, such as leucovorin.

Accordingly, there is provided pharmaceutical composition comprising a compound of the present disclosure, and at least one additional anti-tumor agent.

In some embodiment, the additional anti-tumour agent is selected from the group consisting of TKIs (such as lapatinib, neratinib and afatinib) , anti-HER2 agents (for example, monoclonal antibodies such as Trastuzumab, ADCs such as T-DM1) and combination thereof. In some embodiments, the additional anti-tumour agent includes capecitabine, anti-HER2 antibodies, and T-DM1. In some embodiments, there is one additional 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. In some embodiments, the warm-blooded animal is a human.

In this context, the term “therapeutically effective amount” refers to an amount of a compound of the present disclosure which is effective to provide “therapy” in a subject, or to “treat” a type I receptor tyrosine kinase-associated disease or disorder in a subject. In the case of cancer, the therapeutically effective amount may cause any of the changes observable or measurable in a subject as described in the definition of “therapy” , “treatment” and “prophylaxis” above. For example, the effective amount can reduce the number of cancer or tumour cells; reduce the overall tumour size; inhibit or stop tumour cell infiltration into peripheral organs including, for example, the soft tissue and bone; inhibit and stop tumour metastasis; inhibit and stop tumour growth; relieve to some extent one or more of the symptoms associated with the cancer; reduce morbidity and mortality; improve quality of life; or a combination of such effects. An effective amount may be an amount sufficient to 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 WO98/45479 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; WO91/05264 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; WO91/05264; 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
Boc ₂O	di-tert-butyl dicarbonate
CH ₂Cl ₂	dichloromethane
Cs ₂CO ₃	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
Et ₃N	triethylamine
EtOAc	ethyl acetate
HCHO	formaldehyde
HCOOH	formic acid
H ₂SO ₄	Sulfuric acid
hr (s)	hour (s)
IPA	isopropyl alcohol
K ₂CO ₃	potassium carbonate

KOtBu or tBuOK	potassium tert-butoxide
LDA	lithium diisopropylamide
LiAlH ₄	lithium aluminium hydride
MeCN	acetonitrile
MeI	methyl iodide
MeOH	methanol
NaBH (OAc) ₃	sodium triacetoxyborohydride
NaH	sodium hydride
NaHCO ₃	sodium bicarbonate
NaOH	sodium hydroxide
Na ₂SO ₄	sodium sulfate
NH ₄Cl	ammonium chloride
NH ₄OH	ammonium hydroxide
Pd ₂ (dba) ₃	tris (dibenzylideneacetone) dipalladium (0)
Pd (OAc) ₂	palladium (II) acetate
PE	petroleum ether
POCl ₃	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-methylpiperidin-4-yl) oxy) -6-methoxypyrido [3, 4-d] pyrimidin-4-amine

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

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℃. The mixture was stirred at 25℃ 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 Na ₂SO ₄, 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

To a solution of 5-bromo-3-fluoro-2-methoxypyridine (9 g, 43.7 mmol) in THF (100 mL) was added LDA (28.4 mL, 56.81 mmol, 2.0 M in THF) drop-wise at -78℃ under N ₂ atmosphere and the mixture was stirred at -78℃ for 1 hr. Then the mixture was degassed and purged with CO ₂. The mixture was stirred at -78℃ 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 Na ₂SO ₄, 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

To a solution of 5-bromo-3-fluoro-2-methoxyisonicotinic acid (8.9 g, 36 mmol) and K ₂CO ₃ (9.96 g, 72 mmol) in DMF (100 mL) was added MeI (10.2 g, 72 mmol) . The mixture was stirred at 25℃ 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 Na ₂SO ₄, 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

To a solution of methyl 5-bromo-3-fluoro-2-methoxyisonicotinate (3 g, 11.4 mmol) in dioxane (100 mL) was added diphenylmethanimine (3.1g, 17.1mmol) , Pd ₂ (dba) ₃ (522mg, 0.57 mmol) , Xantphos (660 mg, 1.14 mmol) and Cs ₂CO ₃ (7.43 g, 22.8 mmol) . The mixture was stirred at 100℃ 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

To a solution of methyl 5- ( (diphenylmethylene) amino) -3-fluoro-2-methoxyisonicotinate (5 g, 13.7 mmol) in THF/H ₂O (120 mL/12 mL) was added diluted hydrochloric acid (30 mL, 1M) . The mixture was stirred at 25℃ 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 Na ₂SO ₄, 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

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℃ for 12 hrs. The mixture was diluted with water (50 mL) , extracted with EtOAc (100 mL x2) . The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated to 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-ol

A solution of 5-fluoro-6-methoxypyrido [3, 4-d] pyrimidin-4-ol (800 mg, 4.1 mmol) , (R) -3, 3-difluoro-1-methylpiperidin-4-ol (1.23 g, 8.2 mmol) and potassium tert-butoxide (918 mg, 8.2 mmol) in dimethyl sulfoxide (5 mL) was stirred at 160℃ for 2 hrs. The mixture was diluted with water (20 mL) , adjusted pH=8 with diluted hydrochloric acid (1M) , and extracted with DCM/MeOH (5: 1, 50 mLx2) . The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄, 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] pyrimidine

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-ol (300 mg, 0.92 mmol) at 85℃. The mixture was stirred at 85℃ 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 Na ₂SO ₄, 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

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℃ 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. ¹H NMR (400 MHz, CDCl ₃) δ 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-methylpiperidin-4-yl) oxy) -6-methoxypyrido [3, 4-d] pyrimidin-4-amine

Step 1: 4-chloro-6-hydrazinylpyrimidine

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℃ for 1 hr. After addition, the mixture was stirred at 50℃ 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

The solution of 4-chloro-6-hydrazinylpyrimidine (18.2 g, 126.4 mmol) in trimethoxymethane (100 mL) was stirred at 90℃ overnight. The mixture was concentrated to dryness and the residue was diluted with saturated aq. NaHCO ₃ (100 mL) , extracted with EtOAc (100 mL x2) . The combined organic phases were washed with brine, dried over Na ₂SO ₄, 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

To a solution of 2-chloro-4-nitrophenol (2 g, 13 mmol) in MeCN (30 mL) was added K ₂CO ₃ (4.5 g, 32.6 mmol) at 0℃ 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℃ 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

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) , NH ₄Cl (190 mg, 3.8 mmol) and water (1 mL) . The reaction was stirred at 85℃ for 1 hr. The mixture was cooled and filtered, the filtrate was concentrated and diluted with saturated aq. NaHCO ₃ (10 mL) , extracted with DCM (10 mL x2) . The combined organic layers were washed with brine, dried over Na ₂SO ₄, 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:

A solution of 4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-chloroaniline (100 mg, 0.38 mmol) and (R) -4-chloro-5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxypyrido [3, 4-d] pyrimidin e (131 mg, 0.38 mmol) in IPA (3 mL) was stirred at 65℃ 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 Na ₂SO ₄ 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. ¹H-NMR (400 MHz, DMSO-d ₆) δ 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) azetidin-1-yl) -6-methoxypyrido [3, 4-d] pyrimidin-4-amine

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

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℃ 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

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℃ and the mixture was stirred at 85℃ for 3 hrs. The mixture was concentrated to dryness and the residue was neutralized with ice-cooled saturated aq. NaHCO ₃ solution. The mixture was extracted with EtOAc (5 mL x2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated to dryness to give desired product (100 mg, 87%yield) . MS (ESI) m/z: 294 (M+H) ⁺.

Step 3:

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℃ 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. ¹H-NMR (400 MHz, DMSO-d ₆) δ 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.

Example 2

White solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.92 (s, 1H) , 9.66 (d, J=1.0 Hz, 1H) , 8.70 (s, 1H) , 8.58 (s, 1H) , 8.54 (s, 1H) , 7.82 (d, J=2.0 Hz, 1H) , 7.73 (d, J=8.8 Hz, 1H) , 7.23 (d, J=8.7 Hz, 1H) , 7.19 (s, 1H) , 5.10-4.92 (m, 1H) , 4.09 (s, 3H) , 3.14 (s, 1H) , 2.82 (m, 1H) , 2.47-2.35 (m, 1H) , 2.20 (m, 8H) , 2.01-1.86 (m, 1H) .

Example 3

White solid. ¹H NMR (400 MHz, CDCl ₃) δ 9.96 (s, 1H) , 9.20 (d, J=1.2 Hz, 1H) , 8.70 (s, 1H) , 8.60 (s, 1H) , 8.33 (s, 1H) , 7.87 (s, 1H) , 7.79 (d, J=8.6 Hz, 1H) , 7.11 (d, J=8.8 Hz, 1H) , 6.89 (d, J=1.2 Hz, 1H) , 4.93-4.80 (m, 1H) , 4.65-4.51 (m, 2H) , 3.21 (s, 1H) , 2.98 (s, 1H) , 2.42-2.30 (m, 5H) , 2.26 (s, 3H) , 2.23-2.13 (m, 2H) , 1.50 (t, J=6.8 Hz, 3H) .

Example 5

White solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.89 (s, 1H) , 9.66 (d, J=1.1 Hz, 1H) , 8.86 (s, 1H) , 8.75 (s, 1H) , 8.66 (s, 1H) , 8.59 (s, 1H) , 7.81 (d, J=2.3 Hz, 1H) , 7.72 (dd, J=8.8, 2.4 Hz, 1H) , 7.25 (d, J=8.7 Hz, 1H) , 7.19 (d, J=1.1 Hz, 1H) , 5.53–5.26 (m, 1H) , 3.24 (s, 1H) , 2.85 (d, J=11.4 Hz, 1H) , 2.57 (d, J=11.8 Hz, 1H) , 2.36 (dd, J=24.5, 10.3 Hz, 2H) , 2.30 (s, 3H) , 2.20 (s, 3H) , 1.98 (d, J=8.9 Hz, 1H) .

Example 9

White solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.92 (s, 1H) , 9.66 (d, J=1.0 Hz, 1H) , 8.70 (s, 1H) , 8.58 (s, 1H) , 8.53 (s, 1H) , 7.81 (s, 1H) , 7.73 (d, J=8.9 Hz, 1H) , 7.23 (d, J=8.7 Hz, 1H) , 7.18 (d, J=0.9 Hz, 1H) , 5.08–4.91 (m, 1H) , 3.13 (d, J=7.3 Hz, 1H) , 2.82 (d, J=12.0 Hz, 1H) , 2.48–2.37 (m, 1H) , 2.20 (m, 8H) , 1.94 (dd, J=21.9, 9.8 Hz, 1H) .

Example 11

White solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 10.08 (s, 1H) , 9.66 (d, J=1.1 Hz, 1H) , 8.67 (s, 1H) , 8.58 (s, 1H) , 8.53 (s, 1H) , 7.89 (s, 1H) , 7.79 (d, J=8.3 Hz, 1H) , 7.25 (d, J=8.7 Hz, 1H) , 7.18 (s, 1H) , 4.67 (m, 1H) , 4.07 (s, 3H) , 2.83 (m, 2H) , 2.13-2.26 (m, 10H) , 1.84 (m, 2H) .

Example 17

(R) -N- (4- ( [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

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

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℃ under N ₂ atmosphere and the mixture was stirred at 0℃ 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℃ 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 Na ₂SO ₄, 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) ⁺.

Step 2: (E) -N-hydroxy-N'- [4- (2-methyl-4-nitrophenoxy) pyridin-2-yl] methanimidamide

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℃ for 2 hrs. Hydroxylamine hydrochloride (170 mg, 2.47 mmol) was added and the resulting mixture was stirred at 50℃ 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

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℃ and the reaction mixture was stirred at 25℃ 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:

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. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.95 (s, 1H) , 8.94 (d, J=7.5 Hz, 1H) , 8.71 (s, 1H) , 8.55 (s, 1H) , 8.39 (s, 1H) , 7.88 (d, J=2.2 Hz, 1H) , 7.79 (dd, J=8.7, 2.4 Hz, 1H) , 7.26 (d, J=8.7 Hz, 1H) , 7.03 (dd, J=7.5, 2.6 Hz, 1H) , 6.83 (d, J=2.5 Hz, 1H) , 5.00 (ddd, J=17.0, 11.1, 5.5 Hz, 1H) , 4.10 (s, 3H) , 3.15 (s, 1H) , 2.83 (d, J=11.5 Hz, 1H) , 2.47-2.37 (m, 1H) , 2.20 (m, 8H) , 1.95 (dt, J=11.4, 7.9 Hz, 1H) . MS (ESI) m/z: 549 (M+H) ⁺.

Example 19

(R) -N- (4- ( [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

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

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℃ 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) ⁺.

Step 2: (4R) -3, 3-difluoro-1- (methyl-d3) -4- ( (tetrahydro-2H-pyran-2-yl) oxy) piperidine

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℃ and the mixture was stirred at 70℃ 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℃. The mixture was filtered and the filter cake was washed with EtOAc (5 mL x3) . The filtrate was washed with brine, dried over Na ₂SO ₄, 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) ⁺.

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

To a solution of (4R) -4- ( {4-chloro-6-methoxypyrido [3, 4-d] pyrimidin-5-yl} oxy) -3, 3-difluoro-1- (D ₃) 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℃ for 2 hrs. The mixture was basified with saturated aq. NaHCO ₃ solution and extracted with chloroform/IPA (5 mL x3, 3/1, v/v) . The combined organic layers were washed with brine, dried over Na ₂SO ₄, 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:

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. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.96 (s, 1H) , 8.93 (d, J=7.4 Hz, 1H) , 8.71 (s, 1H) , 8.55 (s, 1H) , 8.39 (s, 1H) , 7.89 (d, J=2.2 Hz, 1H) , 7.79 (dd, J=8.8, 2.4 Hz, 1H) , 7.26 (d, J=8.7 Hz, 1H) , 7.04 (dd, J=7.5, 2.6 Hz, 1H) , 6.83 (d, J=2.5 Hz, 1H) , 5.00 (m, 1H) , 4.10 (s, 3H) , 3.20-3.07 (m, 1H) , 2.82 (m, 1H) , 2.40 (M, 1H) , 2.26-2.08 (m, 5H) , 2.05-1.86 (m, 1H) . MS (ESI) m/z: 552 (M+H) ⁺.

Example 21

(R) -N- (4- ( [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

Step 1: tert-butyl

(R) -3, 3-difluoro-4- ( (4-hydroxy-6-methoxypyrido [3, 4-d] pyrimidin-5-yl) oxy) piperidine-1-carboxylate

A mixture of 5-fluoro-6-methoxypyrido [3, 4-d] pyrimidin-4-ol (400 mg, 2.05 mmol) , tert-butyl (R) -3, 3-difluoro-4-hydroxypiperidine-1-carboxylate (486 mg, 2.0 mmol) and t-BuOK (453 mg, 4.1 mmol) in DMSO (10 mL) was stirred at 160℃ 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-d] pyrimidin-4-ol

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℃ for 18 hrs. The mixture was concentrated to dryness and the residue was basified with saturated aq. NaHCO ₃ solution and extracted with DCM (5 mL x3) . The combined organic layers were washed with brine, dried over Na ₂SO ₄, 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-d] pyrimidin-4-ol

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℃ 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 Na ₂SO ₄, 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:

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. ¹H-NMR (400 MHz, DMSO-d ₆) δ 10.00 (s, 1H) , 8.98 (d, J=7.5 Hz, 1H) , 8.75 (d, J=3.6 Hz, 1H) , 8.59 (s, 1H) , 8.44 (s, 1H) , 7.95 (s, 1H) , 7.79 (t, J=15.9 Hz, 1H) , 7.31 (d, J=8.7 Hz, 1H) , 7.09 (dd, J=7.5, 2.6 Hz, 1H) , 6.88 (d, J=2.5 Hz, 1H) , 5.14-4.88 (m, 1H) , 4.15 (s, 3H) , 3.21-3.10 (m, 1H) , 2.87 (dd, J=12.9, 6.7 Hz, 2H) , 2.71-2.61 (m, 1H) , 2.43 (t, J=11.4 Hz, 1H) , 2.26 (s, 4H) , 1.92 (dd, J=21.7, 9.7 Hz, 1H) , 1.00 (d, J=6.5 Hz, 6H) . MS (ESI) m/z: 577 (M+H) ⁺.

Example 23

(R) -N- (4- ( [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

Step 1:

(R) -5- ( (1-cyclopropyl-3, 3-difluoropiperidin-4-yl) oxy) -6-methoxypyrido [3, 4-d] pyrimidin-4-ol

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 NaBH ₃CN (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 Na ₂SO ₄, 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:

The crude product was prepared in a similar fashion to Example 1, which was purified by prep-TLC (DCM: MeOH=15: 1) to give desired product as white solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.90 (s, 1H) , 8.92 (d, J=7.5 Hz, 1H) , 8.69 (s, 1H) , 8.53 (s, 1H) , 8.38 (s, 1H) , 7.89 (d, J=2.4 Hz, 1H) , 7.73 (dd, J=8.8, 2.5 Hz, 1H) , 7.24 (d, J=8.7 Hz, 1H) , 7.02 (dd, J=7.5, 2.6 Hz, 1H) , 6.81 (d, J=2.5 Hz, 1H) , 5.00 (ddd, J=21.0, 11.1, 5.5 Hz, 1H) , 4.09 (s, 3H) , 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-methylpiperidin-4-yl) oxy) -6- (difluoromethoxy) pyrido [3, 4-d] pyrimidin-4-amine

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

To a solution of methyl 5-bromo-3-fluoro-2-methoxyisonicotinate (2 g, 7.5 mmol) in CH ₃CN (40 mL) was added TMSCl (2.9 mL, 22.7 mmol) and NaI (3.4 g, 22.7 mmol) and the mixture was stirred at 85℃ for 2 hrs. The reaction mixture was concentrated under reduced pressure to give crude product, which was purified by chromatography on silica gel (DCM: MeOH=20: 1) to give desired product (1.8 g, 95%yield) . MS (ESI) m/z: 250 (M+H) ⁺.

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

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 Na ₂SO ₄ (252 mg, 1.7 mmol) and the mixture was stirred at 70℃ 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:

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 desired product as white solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.85 (s, 1H) , 8.93 (d, J=7.5 Hz, 1H) , 8.75 (s, 1H) , 8.66 (s, 1H) , 8.39 (s, 1H) , 8.15 (s, 1H) , 7.96-7.53 (m, 3H) , 7.27 (d, J=8.7 Hz, 1H) , 7.04 (dd, J=7.5, 2.6 Hz, 1H) , 6.83 (d, J=2.5 Hz, 1H) , 4.90 (ddd, J=20.2, 11.2, 5.5 Hz, 1H) , 3.17 (d, J=5.3 Hz, 1H) , 2.87 (d, J=11.7 Hz, 1H) , 2.41 (dd, J=29.3, 12.3 Hz, 1H) , 2.23 (m, 7H) , 2.15 (d, J=12.1 Hz, 1H) , 2.10-1.96 (m, 1H) . MS (ESI) m/z: 585 (M+H) ⁺.

Example 18

White solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.94 (s, 1H) , 8.93 (d, J=7.5 Hz, 1H) , 8.69 (s, 1H) , 8.54 (s, 1H) , 8.38 (s, 1H) , 7.87 (d, J=2.2 Hz, 1H) , 7.78 (dd, J=8.7, 2.3 Hz, 1H) , 7.25 (d, J=8.7 Hz, 1H) , 7.02 (dd, J=7.5, 2.6 Hz, 1H) , 6.82 (d, J=2.5 Hz, 1H) , 5.11-4.90 (m, 1H) , 4.09 (s, 3H) , 3.20-3.06 (m, 1H) , 2.88-2.76 (m, 1H) , 2.47-2.35 (m, 1H) , 2.25-2.14 (m, 8H) , 2.00-1.88 (m, 1H) .

Example 25

White solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.99 (s, 1H) , 8.98 (d, J=7.5 Hz, 1H) , 8.75 (s, 1H) , 8.59 (s, 1H) , 8.44 (s, 1H) , 7.94 (t, J=6.4 Hz, 1H) , 7.82 (ddd, J=9.1, 7.2, 2.8 Hz, 1H) , 7.31 (d, J=8.7 Hz, 1H) , 7.08 (dd, J=7.5, 2.6 Hz, 1H) , 6.88 (d, J=2.5 Hz, 1H) , 5.18-4.94 (m, 1H) , 3.20 (dt, J=10.9, 4.9 Hz, 1H) , 2.87 (d, J=11.4 Hz, 1H) , 2.49 (dd, J=29.8, 12.2 Hz, 1H) , 2.25 (m, 8H) , 2.06-1.93 (m, 1H) .

Example 29

White solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.95 (s, 1H) , 8.93 (d, J=7.5 Hz, 1H) , 8.69 (s, 1H) , 8.54 (s, 1H) , 8.39 (s, 1H) , 7.89 (d, J=2.2 Hz, 1H) , 7.80 (d, J=8.7 Hz, 1H) , 7.26 (d, J=8.7 Hz, 1H) , 7.04 (dd, J=7.5, 2.6 Hz, 1H) , 6.82 (d, J=2.5 Hz, 1H) , 5.48–5.37 (m, 1H) , 4.91 (dd, J=21.4, 10.8 Hz, 1H) , 3.15 (s, 1H) , 2.87 (d, J=11.2 Hz, 1H) , 2.44–2.32 (m, 1H) , 2.23 (d, J=14.4 Hz, 8H) , 2.00 (d, J=8.2 Hz, 1H) , 1.45 (d, J=6.2 Hz, 3H) , 1.41 (d, J=6.1 Hz, 3H) .

Example 31

White solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.97 (s, 1H) , 8.93 (d, J=7.5 Hz, 1H) , 8.66 (s, 1H) , 8.54 (s, 1H) , 8.39 (s, 1H) , 7.89 (d, J=2.3 Hz, 1H) , 7.80 (dd, J=8.8, 2.5 Hz, 1H) , 7.26 (d, J=8.7 Hz, 1H) , 7.03 (dd, J=7.5, 2.6 Hz, 1H) , 6.82 (d, J=2.5 Hz, 1H) , 5.08-4.97 (m, 1H) , 4.38 (dd, J=10.9, 7.2 Hz, 1H) , 4.28 (dd, J=10.9, 7.5 Hz, 1H) , 3.18 (s, 1H) , 2.88 (d, J =10.9 Hz, 1H) , 2.42-2.31 (m, 2H) , 2.25 (s, 3H) , 2.21 (s, 4H) , 2.08-2.00 (m, 1H) , 1.35 (m, J=12.6, 7.9, 5.0 Hz, 1H) , 0.64-0.58 (m, 2H) , 0.48-0.39 (m, 2H) .

Example 33

White solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.96 (s, 1H) , 8.99 (d, J=7.5 Hz, 1H) , 8.79 (s, 1H) , 8.62 (s, 1H) , 8.44 (s, 1H) , 7.93 (s, 1H) , 7.84 (d, J=8.4 Hz, 1H) , 7.31 (d, J=8.7 Hz, 1H) , 7.09 (dd, J=7.4, 2.4 Hz, 1H) , 6.88 (d, J=2.3 Hz, 1H) , 4.95-4.75 (m, 1H) , 4.55 (d, J= 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. ¹H-NMR (400 MHz, CD ₃OD) δ 8.63 (d, J=7.5 Hz, 1H) , 8.52 (s, 1H) , 8.42 (s, 1H) , 8.18 (s, 1H) , 7.76 (d, J=2.4 Hz, 2H) , 7.10-7.05 (m, 1H) , 6.96 (dd, J=7.5, 2.6 Hz, 1H) , 6.71 (d, J=2.4 Hz, 1H) , 5.01 (q, J=8.7 Hz, 2H) , 4.85 (m, 1H) , 3.16–3.06 (m, 1H) , 2.89 (d, J=12.1 Hz, 1H) , 2.37-2.22 (m, 5H) , 2.14 (m, 4H) , 2.05 (dd, J=12.4, 3.5 Hz, 1H) .

Example 39

white solid. ¹H-NMR (400 MHz, CD ₃OD) δ 8.74 (d, J=7.5 Hz, 1H) , 8.62 (s, 1H) , 8.47 (s, 1H) , 8.28 (s, 1H) , 7.91 (d, J=2.3 Hz, 1H) , 7.86 (dd, J=8.6, 2.5 Hz, 1H) , 7.21 (d, J=8.7 Hz, 1H) , 7.07 (dd, J=7.5, 2.6 Hz, 1H) , 6.79 (d, J=2.4 Hz, 1H) , 4.82 (s, 1H) , 4.14 (s, 3H) , 3.12 (d, J=12.1 Hz, 2H) , 2.57-2.42 (m, 5H) , 2.24 (m, 5H) , 2.05-1.94 (m, 2H) .

Example 40

¹H-NMR (400 MHz, DMSO-d ₆) δ 13.48 (s, 1H) , 8.94 (d, J=7.5 Hz, 1H) , 8.82 (s, 1H) , 8.53 (s, 1H) , 8.39 (s, 1H) , 8.02 (d, J=2.3 Hz, 1H) , 7.88 (dd, J=8.7, 2.5 Hz, 1H) , 7.29 (d, J=8.7 Hz, 1H) , 7.05 (dd, J=7.5, 2.6 Hz, 1H) , 6.82 (d, J=2.5 Hz, 1H) , 4.09 (s, 3H) , 4.01 (d, J=9.7 Hz, 2H) , 3.81 (t, J=11.0 Hz, 2H) , 3.70 (dd, J=11.6, 8.8 Hz, 2H) , 2.99 (d, J=11.1 Hz, 2H) , 2.23 (s, 3H) .

Example 41

White solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 13.59 (s, 1H) , 8.94 (d, J=7.5 Hz, 1H) , 8.80 (s, 1H) , 8.52 (s, 1H) , 8.39 (s, 1H) , 8.02-7.95 (m, 2H) , 7.32-7.26 (m, 1H) , 7.04 (dd, J=7.5, 2.6 Hz, 1H) , 6.83 (d, J=2.3 Hz, 1H) , 4.07 (s, 3H) , 3.70 (m, 2H) , 2.99-3.01 (d, J=11.8 Hz, 2H) , 2.92-2.95 (d, J=11.8 Hz, 2H) , 2.34 (d, J=12.2 Hz, 5H) , 2.23 (s, 3H) .

Example 42

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

Step 1: 5-bromo-3-fluoro-2-methoxypyridine-4-carboxamide

To a solution of 5-bromo-3-fluoro-2-methoxypyridine-4-carboxylic acid (4 g, 16.0 mmol) in DCM(40 mL) was added oxalyl chloride (2.7 mL, 32.0 mmol) and DMF (62 mg, 0.80 mmol) at 0℃ and the mixture was stirred at 25℃ 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℃ 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

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 ℃ and the reaction mixture was stirred at 25℃ 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

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℃ under N ₂ atmosphere and the mixture was stirred at 0℃ 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℃ 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 Na ₂SO ₄, filtered and concentrated to give crude product. The residue was purified by chromatography on silica gel (PE: EtOAc=10: 1) to give desired product (200 mg, 36%yield) as yellow solid. MS (ESI) m/z: 430 (M+H) ⁺.

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

To a solution of cis-tert-butyl 4- ( (5-bromo-4-cyano-2-methoxypyridin-3-yl) oxy) -3-fluoropiperidine-1-carboxylate (200 mg, 0.46 mmol) in DCM (2 mL) was added TFA (1 mL) and the mixture was stirred at 25℃ for 18 hrs. The mixture was concentrated to dryness and the residue was basified with saturated aq. NaHCO ₃ solution and extracted with DCM (5 mL x3) . The combined organic layers were washed with brine, dried over Na ₂SO ₄, 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-carbonitrile

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℃ 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 Na ₂SO ₄, 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

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 BocNH ₂ (68 mg, 0.58 mmol) , Pd ₂ (dba) ₃ (13 mg, 0.015 mmol) , XantPhos (17 mg, 0.030 mmol) and Cs ₂CO ₃ (189 mg,0.58 mmol) . The mixture was degassed under N ₂ atmosphere and stirred under N ₂ atmosphere at 100℃ 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

To a solution of tert-butyl

(4-cyano-5- ( (cis-3-fluoro-1-methylpiperidin-4-yl) oxy) -6-methoxypyridin-3-yl) carbamate (100 mg, 0.26 mmol) in DCM (2 mL) was added diluted TFA (1 mL) and the mixture was stirred at 25℃ for 16 hrs. The mixture was basified with saturated aq. NaHCO ₃ solution to pH=7 and extracted with EtOAc (30 mL x2) . The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄, 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

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℃ 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:

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℃ for 16 hrs. The mixture was basified with saturated aq. NaHCO ₃ solution to pH=7 and extracted with DCM (10 mL x2) . The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄, 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. ¹H-NMR (400 MHz, DMSO-d ₆) δ 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

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. ¹H-NMR (400 MHz, DMSO-d ₆) δ 10.12 (s, 1H) , 8.94 (d, J=7.5 Hz, 1H) , 8.71 (s, 1H) , 8.56 (s, 1H) , 8.39 (s, 1H) , 7.98–7.81 (m, 2H) , 7.25 (d, J=8.7 Hz, 1H) , 7.04 (dd, J=7.5, 2.6 Hz, 1H) , 6.81 (d, J=2.3 Hz, 1H) , 5.55 (d, J=9.0 Hz, 1H) , 4.10 (s, 3H) , 3.23 (d, J=11.6 Hz, 2H) , 2.87–2.70 (m, 2H) , 2.30 (s, 3H) , 2.22 (s, 3H) . MS (ESI) m/z: 549 (M+H) ⁺.

(S) -N- (4- ( [1, 2, 4] triazolo [1, 5-a] pyridin-7-yloxy) -3-methylphenyl) -5- ( (4, 4-difluoro-1-met hylpyrrolidin-3-yl) oxy) -6-methoxypyrido [3, 4-d] pyrimidin-4-amine as white solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 10.12 (s, 1H) , 8.94 (d, J=7.5 Hz, 1H) , 8.71 (s, 1H) , 8.56 (s, 1H) , 8.36 (d, J=20.8 Hz, 1H) , 7.97-7.79 (m, 2H) , 7.25 (d, J=8.8 Hz, 1H) , 7.04 (dd, J=7.5, 2.6 Hz, 1H) , 6.82 (t, J=5.1 Hz, 1H) , 5.55 (d, J=9.4 Hz, 1H) , 4.10 (s, 3H) , 3.32-3.17 (m, 2H) , 2.90-2.69 (m, 2H) , 2.32 (d, J=13.0 Hz, 3H) , 2.22 (s, 3H) . MS (ESI) m/z: 549 (M+H) ⁺.

SFC condition: Column: ChiralPak AD, 250×21.2 mm I.D., 5μm; Mobile phase: A for CO ₂ and B for Methanol (0.1%NH ₄OH) ; Gradient: B 20%; Flow rate: 50 mL/min; Column temperature: 35℃.

Example 50

(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

Example 51

(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

(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 as yellow solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.00 (d, J=7.5 Hz, 1H) , 8.83 (s, 1H) , 8.54 (s, 1H) , 8.45 (s, 1H) , 7.95 (d, J=6.6 Hz, 2H) , 7.34 (d, J=9.3 Hz, 1H) , 7.11 (dd, J=7.5, 2.6 Hz, 1H) , 6.89 (d, J=2.4 Hz, 1H) , 5.23–5.43 (d, J=56.2 Hz, 1H) , 4.50–4.73 (m, 2H) , 4.24 (s, 3H) , 3.59–3.97 (m, 4H) , 2.91–3.15 (m, 2H) , 2.72 (s, 3H) , 2.29 (s, 3H) . MS (ESI) m/z: 542 (M+H) ⁺.

(R) -N- (4- ( [1, 2, 4] 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 as yellow solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.00 (d, J=7.5 Hz, 1H) , 8.83 (s, 1H) , 8.54 (s, 1H) , 8.45 (s, 1H) , 7.95 (d, J=6.5 Hz, 2H) , 7.34 (d, J=9.3 Hz, 1H) , 7.11 (dd, J=7.5, 2.6 Hz, 1H) , 6.87-6.89 (d, J=2.4 Hz, 1H) , 5.21-5.40 (d, J=55.7 Hz, 1H) , 4.63-4.69 (m, 2H) , 4.22 (s, 3H) , 3.74-3.98 (m, 4H) , 2.92-3.14 (m, 2H) , 2.71 (s, 3H) , 2.29 (s, 3H) . MS (ESI) m/z: 542 (M+H) ⁺.

SFC condition: Column: ChiralPak AD, 250×21.2 mm I.D., 5μm; Mobile phase: A for CO ₂ and B for Methanol (0.1%NH ₄OH) ; Gradient: B 30%; Flow rate: 50 mL/min; Column temperature: 35℃.

Example 43

White solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.96 (s, 1H) , 8.94 (d, J=7.4 Hz, 1H) , 8.68 (s, 1H) , 8.53 (s, 1H) , 8.39 (s, 1H) , 7.91 (s, 1H) , 7.82 (d, J=8.6 Hz, 1H) , 7.26 (d, J=8.6 Hz, 1H) , 7.04 (m, 1H) , 6.83 (d, J=2.3 Hz, 1H) , 4.93 (m, 1H) , 4.58 (m, 1H) , 4.08 (s, 3H) , 3.12 (m, 1H) , 2.76 (m, 1H) , 2.22 (s, 7H) , 2.13-1.99 (m, 2H) , 1.97-1.85 (m, 1H) .

Example 46

Yellow solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 8.92 (d, J=6.8 Hz, 1H) , 8.77 (s, 1H) , 8.51 (s, 1H) , 8.37 (s, 1H) , 8.18 (s, 1H) , 7.99 (s, 2H) , 7.25 (s, 1H) , 7.04 (s, 1H) , 6.79 (s, 1H) , 4.07 (s, 3H) , 3.86 (s, 2H) , 3.29-3.15 (m, 2H) , 2.94 (m, 1H) , 2.23 (m, 11H) .

Example 47

Light yellow solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 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. ¹H-NMR (400 MHz, DMSO-d ₆) δ 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

Step 1: 3-chloro-5-methoxypyridazine

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℃. 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

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℃ 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

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. NaHCO ₃ 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

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℃ 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

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℃ 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

To a solution of imidazo [1, 2-b] pyridazin-7-ol (100 mg, 0.74 mmol) in DMF (5 mL) was added K ₂CO ₃ (204 mg, 1.48 mmol) and 1-fluoro-2-methyl-4-nitrobenzene (115 mg, 0.74 mmol) and the mixture was stirred at 100℃ for 2 hrs. The mixture was diluted with EtOAc (10 mL) , washed with saturated aq. NH ₄Cl (5 mL x3) and brine, dried over Na ₂SO ₄, 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

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 NH ₄Cl (161 mg, 3.00 mmol) and the mixture was stirred at 80℃ 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:

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℃ 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. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.94 (s, 1H) , 8.71 (s, 1H) , 8.65 (d, J=2.7 Hz, 1H) , 8.55 (s, 1H) , 8.22 (s, 1H) , 7.88 (d, J=2.3 Hz, 1H) , 7.76 (dd, J=8.7, 2.5 Hz, 1H) , 7.66 (d, J=1.3 Hz, 1H) , 7.25 (m, 1H) , 7.13 (m, 1H) , 5.08–4.93 (m, 1H) , 4.10 (s, 3H) , 3.15 (m, 1H) , 2.82 (m, 1H) , 2.46–2.32 (m, 1H) , 2.26 (s, 3H) , 2.24 (s, 3H) , 2.20 (m, 2H) , 1.97 (m, 1H) . MS (ESI) m/z: 549 (M+H) ⁺.

Example 55

(R) -N- (4- ( [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

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

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 N ₂ atmosphere at 100℃ for 16 hrs. The mixture was diluted with EtOAc (10 mL) , washed with water and brine, dried over anhydrous Na ₂SO ₄, 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

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℃ 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

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℃ 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

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℃ 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:

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. ¹H-NMR (400 MHz, CD ₃OD) δ 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

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

To a solution of 2-aminopyridin-4-ol (500 mg, 4.5 mmol) in 1, 4-dioxane (10 mL) was added 2-chloroacetaldehyde (2.1 mL, 13.6 mmol) and the mixture was stirred at 100℃ 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

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℃ under N ₂ atmosphere and the mixture was stirred at 0℃ for 1 hr. Then 2-fluoro-1-methyl-4-nitrobenzene (115 mg, 0.7 mmol) was added and the reaction mixture was stirred at 25℃ 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 Na ₂SO ₄, 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:

The crude product was prepared in a similar fashion to Example 53, which was purified by prep-TLC (DCM: MeOH=15: 1) to give desired product as white solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.92 (s, 1H) , 8.70 (s, 1H) , 8.55 (d, J=7.3 Hz, 2H) , 8.18 (s, 1H) , 7.84 (s, 2H) , 7.75 (dd, J=8.6, 2.3 Hz, 1H) , 7.44 (s, 1H) , 7.18 (d, J=8.7 Hz, 1H) , 6.80 (dd, J=7.4, 2.4 Hz, 1H) , 6.57 (d, J=2.3 Hz, 1H) , 5.09-4.88 (m, 1H) , 4.09 (s, 3H) , 3.14 (s, 1H) , 2.82 (d, J=11.9 Hz, 1H) , 2.40 (dd, J=31.6, 19.3 Hz, 1H) , 2.21 (m, 8H) , 2.02-1.86 (m, 1H) . MS (ESI) m/z: 548 (M+H) ⁺.

Example 59

Yellow solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.91 (s, 1H) , 9.28 (d, J=1.2 Hz, 1H) , 8.70 (s, 1H) , 8.53 (s, 1H) , 7.97 (s, 1H) , 7.80 (s, 1H) , 7.71 (d, J=8.9 Hz, 1H) , 7.57 (d, J=1.4 Hz, 1H) , 7.17 (d, J=8.7 Hz, 1H) , 6.81 (s, 1H) , 5.01 (s, 1H) , 4.09 (s, 3H) , 3.15 (s, 1H) , 2.80 (s, 1H) , 2.43–2.32 (m, 1H) , 2.21 (t, J=12.0 Hz, 8H) , 1.94 (d, J=7.7 Hz, 1H) .

Example 67

White solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.95 (s, 1H) , 8.93 (d, J=7.5 Hz, 1H) , 8.71 (s, 1H) , 8.55 (s, 1H) , 8.39 (s, 1H) , 7.88 (d, J=2.3 Hz, 1H) , 7.82-7.72 (m, 1H) , 7.26 (d, J=8.7 Hz, 1H) , 7.03 (dd, J=7.5, 2.6 Hz, 1H) , 6.82 (d, J=2.5 Hz, 1H) , 5.11-4.93 (m, 1H) , 4.10 (s, 3H) , 3.17 (s, 1H) , 2.83 (s, 1H) , 2.35 (d, J=13.3 Hz, 1H) , 2.28-2.15 (m, 8H) , 1.99-1.90 (m, 1H) .

Example 77

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

Step 1: 1-amino-3-methoxypyridin-1-ium 2, 4-dinitrobenzen-1-olate

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

To a solution of 1-amino-3-methoxypyridin-1-ium 2, 4-dinitrobenzen-1-olate (5 g, 16.22 mmol) in DMF (50 mL) was added K ₂CO ₃ (3.14 g, 22.70 mmol) and methyl prop-2-ynoate (1.52 mL, 17.03 mmol) at 0℃. The resulting mixture was stirred at rt under N ₂ atmosphere overnight. The reaction mixture was diluted with EtOAc (50 mL) , washed with water and brine, dried over Na ₂SO ₄, filtered and concentrated to dryness. The residue was purified by flash chromatography (PE: EtOAc=5: 1) to afford the title compound (560 mg, 16%yield) as yellow solid. ¹H-NMR (400 MHz, CDCl ₃) δ 8.31 (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

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℃ 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 Na ₂SO ₄, 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:

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 yellow solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.83 (s, 1H) , 8.69 (s, 1H) , 8.51 (s, 1H) , 8.38–8.32 (m, 1H) , 7.96 (d, J=2.3 Hz, 1H) , 7.77 (dd, J=9.4, 5.9 Hz, 2H) , 7.65 (dd, J=8.7, 2.4 Hz, 1H) , 7.14 (dd, J=9.6, 2.1 Hz, 1H) , 7.02 (d, J=8.8 Hz, 1H) , 6.65 (d, J=1.9 Hz, 1H) , 5.08–4.96 (m, 1H) , 4.09 (s, 3H) , 3.32–3.28 (m, 1H) , 2.91 (s, 1H) , 2.47 (s, 1H) , 2.25 (d, J=44.2 Hz, 8H) , 1.96 (d, J=11.7 Hz, 1H) . MS (ESI) m/z: 548 (M+H) ⁺.

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

Step 1: pyrazolo [1, 5-a] pyrimidin-6-ol

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℃. After addition, the mixture was stirred at 65℃ 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 Na ₂SO ₄, 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:

The crude product was prepared in a similar fashion to Example 53, which was purified by purified by column chromatography on silica gel (eluted with DCM: MeOH=20: 1) to give desired product as yellow solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 9.86 (s, 1H) , 8.96 (dd, J=2.6, 0.9 Hz, 1H) , 8.68 (s, 1H) , 8.60 (d, J=2.6 Hz, 1H) , 8.50 (s, 1H) , 8.20 (d, J=2.4 Hz, 1H) , 7.79 (d, J=2.4 Hz, 1H) , 7.63 (dd, J=8.8, 2.5 Hz, 1H) , 7.07 (d, J=8.8 Hz, 1H) , 6.79 (dd, J =2.4, 0.9 Hz, 1H) , 5.06-4.89 (m, 1H) , 4.08 (s, 3H) , 3.17-3.06 (m, 1H) , 2.80 (d, J=11.1 Hz, 1H) , 2.47-2.37 (m, 1H) , 2.34 (d, J=9.6 Hz, 3H) , 2.24-2.11 (m, 5H) , 1.97-1.85 (m, 1H) . MS (ESI) m/z: 549 (M+H) ⁺.

Example 107

(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

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

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℃ 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 Na ₂SO ₄, 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

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℃ overnight. The reaction mixture was concentrated to dryness, diluted with water (20 mL) , adjusted pH value to 1-2 with 1M aq. HCl and extracted with IPA/DCM (20 mL x 3, 3/1, v/v) . The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄, filtered and 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-ol (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

The crude product was prepared in a similar fashion to Example 53, which was purified by column chromatography silica gel (DCM: MeOH=20: 1) and prep-TLC (PE: EtOAc=1: 3) to give desired product as white solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 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) ⁺.

Example 147

(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

Step 1:

methyl (E) -3-fluoro-2-methoxy-5- ( ( (methylamino) methylene) amino) isonicotinate

A solution of methyl 5-amino-3-fluoro-2-methoxyisonicotinate (260 mg, 1.30 mmol) in DMF-DMA (5 mL) was stirred at 70℃ 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

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℃. 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℃, AcOH (1 mL) was added, and the mixture was stirred for 2 hrs. The mixture was basified with aq. NaHCO ₃ and extracted with DCM (5 mL x 3) . The combined organic layers were washed with water and brine, dried over Na ₂SO ₄, 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:

The crude product was prepared in a similar fashion to Example 1, which was purified by prep-TLC (DCM: MeOH=15: 1) to give desired product as white solid. ¹H-NMR (400 MHz, DMSO-d ₆) δ 10.00 (s, 1H) , 9.71 (d, J=1.1 Hz, 1H) , 8.81 (s, 1H) , 8.56 (s, 1H) , 8.44 (s, 1H) , 7.43 (s, 1H) , 7.37-7.21 (m, 2H) , 6.98 (d, J=1.1 Hz, 1H) , 4.99 (m, 1H) , 4.11 (s, 3H) , 3.12 (s, 1H) , 2.80 (m, 1H) , 2.44-2.30 (m, 1H) , 2.17 (m, 8H) , 1.93 (m, 1H) . MS (ESI) m/z: 574 (M+H) ⁺.

Example 176

Biological Assays

Assay a) BT474 cellular assay (HER2 inhibition)

Inhibition of phosphor HER2 was determined by enzyme-linked immunosorbent assay (ELISA) in BT474 cells. BT474 cell line was purchased from ATCC (catalog number HTB-20) . Human Phospho-ErbB2 ELISA kit was purchased from R&D systems (catalog number DYC1768) .

Day 1:

When the cells reach 70-90%confluence, cells were trypsinized and re-suspended. 5000 cells per well were seeded to a 384-well plate. The plate was incubated at 37℃ with 5%CO ₂for 24 hours. ELISA plate was coated with 2μg/ml capture antibody, which was incubated at 4℃ overnight.

Day 2:

25nl compounds was dosed by Echo from source plate and the 384-well plate was incubated at 37℃ for 2 hours. 30μllysis buffer was added to each well and the 384-well plate was shaken softly at 4℃ for30 minutes. The ELISA plate was washed, blocked and incubated at room temperature for 1-2 hours. The blocked ELISA plate was washed and 20μl cell lysate was transferred from the 384-well plate to the ELISA plate, which was incubated overnight at 4℃.

Day3:

The ELISA plate was washed 3 times. 25μl/well detection antibody was added (diluted 1 by2000 in 1%BSA in PBS) . After 2 hours of incubation with detection antibody, the ELlSA plate was washed 3times, 25μl/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 IC ₅₀ 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 IC ₅₀ result of no more than 1000nM. Some have an IC ₅₀ result no more than 300nM, some no more than 200nM, or no more than 100nM, or even no more than 50nM.

Assay b) NCI H838 cellular assay (wt-EGFR inhibition)

Inhibition of phosphor wt-EGFR was determined by enzyme-linked immunosorbent assay (ELISA) in NCI H838 cells (ATCC, catalog number CRL-5844) . Human Phospho-EGFR DuoSet IC ELISA kit was purchased from R&D systems (catalog number DYC1095) .

Day 1:

When the cells reach 70-90%confluence, cells were trypsinized and re-suspended. 5000 cells per well were seeded to a 384-well plate. The plate was incubated at 37℃ with 5%CO ₂for 24 hours.

Day 2:

Cell culture medium was replaced with 40μL FBS-Free RPMI1640. After 2hours of starvation, the 384-well plate was dosed with 40 nL of compounds by Echo from source plate and the 384-well plate was incubated at 37℃ with 5%CO ₂ for 2 hours. After 2hours of incubation with compounds, EGF (final concentration at 100ng/ml) was added to the plate which was incubated at 37℃ with 5%CO ₂ for 5-10 minutes. Medium was discarded from the plate and30μl/well lysis buffer was added to the plate which was incubated at 4℃ for 10 minutes. The cell lysates can be stored at -80℃ in cell plates but must be thawed at room temperature for at least 30 minutes prior to use and continuing the assay. ELISA plate was coated by diluting capture antibody to 4μg/ml with PBS, and 25μl/well was dispensed to 384 well

ELISA Plate, which was incubated at 4℃ overnight.

Day 3:

After the plates were washed three times with 100μl/well of wash buffer, the plates were blocked by adding 75μl of Block Buffer to each well and incubated at room temperature for 3 hours. After the plates were washed three times with 100μl/well of wash buffer, 20μl 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 100μl/well of wash buffer, 25μl/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 μl/well TMB substrate was added to the ELISA plate which was incubated for about 10-15min, protected from light before addition of 25μl/well stop solution. Absorbance was read at 450 nm and 570 nm within 30 minutes.

Results of exemplary compounds of the present disclosure in assays a) and b) are shown in Table 2. From Table 2, it can be found that the compounds of the present disclosure not only have good inhibition of HER2, they are also very selective for HER2overwt-EGFR. For the other Example compounds for which the results are not shown, all have an IC ₅₀ against HER2 of no more than 1000 nM. Some of these compounds have an IC ₅₀ 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 ₅₀ against wt-EGFR of more than 0.5μM, more than 1μM, some more than 2μM, more than 3μM, more than 4μM, more than 6μM, more than 8μM, or even more than 10μM.

Table 2: HER2 and wt-EGFR inhibition data for exemplary compounds in assays a) -b)

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 ¹- (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 1μM. The multi-well insert plate was incubated at 37℃ 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 30μM. The final concentrations of test compounds and control compound were at 1μM. The multi-well insert plate was incubated at 37℃ 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℃. 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 K _p was determined using the equation:

Brain K _p=AUC0-7hr brain/AUC0-7hr plasma

Unbound brain to plasma ratio was determined using the equation:

Brain K _p, uu=K _p*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)

From Table 3, it is shown that Reference compound 1 is a strong hERG inhibitor with IC ₅₀<2μM. 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 K _pu, 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 K _pu, 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 K _pu, 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

A compound of Formula (I) :

or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof, wherein:

G is C (R ₅) or N;

A is CH or N;

B is CH or N;

D is CH of N;

X ₁, X ₂, X ₃, X ₄, X ₅, X ₆, and X ₇ are each independently CH or N;

E is O, NH, or S;

L is selected from the group consisting of O, C (=O) , S, SO, SO ₂ and N (R ₆) ;

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 ₈) , 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;

R ₂ 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 (R ₁₀) (R ₁₁) ;

R ₆ is hydrogen or alkyl; or

when L is N (R ₆) , R ₂ and R ₆ 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, haloalkyl, saturated and partially unsaturated cycloalkyl, and N (R ₁₀) (R ₁₁) ;

R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, 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;

R ₇ and R ₈ 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

R ₇ and R ₈ 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, O, S, SO, SO ₂ and NR ₁₂, 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;

R ₉ is selected from the group consisting of alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, acyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, wherein said alkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocyclyl are optionally substituted by one or more groups independently selected from the group consisting of halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, alkoxyl, acyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl;

R ₁₀ and R ₁₁ are each independently selected from the group consisting of hydrogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl, wherein said alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl are optionally substituted with one or more groups independently selected from alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl; or

R ₁₀ and R ₁₁ 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, O, S, SO, SO ₂ and NR ₁₂, 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;

R ₁₂ is selected from the group consisting of hydrogen, alkyl, alkyl-OH, haloalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl, wherein said alkyl, alkyl-OH, haloalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl are optionally substituted with one or more groups independently selected from halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl;

n is 0, 1 or 2;

n1 is 0, 1 or 2.
A compound of Formula (II) :

or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof, wherein:

G is C (R ₅) or N;

M is CH or N;

A is CH or N;

B is CH or N;

D is CH of N;

X ₁, X ₂, X ₃, X ₄, X ₅, X ₆, and X ₇ are each independently CH or N, with the proviso that when M is CH, at least one of X ₁, X ₆ and X ₇ is N;

E is O, NH, or S;

L is selected from the group consisting of O, C (=O) , S, SO, SO ₂ and N (R ₆) ;

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 ₈) , 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;

R ₂ 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 (R ₁₀) (R ₁₁) ;

R ₆ is hydrogen or alkyl; or

when L is N (R ₆) , R ₂ and R ₆ 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, haloalkyl, saturated and partially unsaturated cycloalkyl, and N (R ₁₀) (R ₁₁) ;

R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, halogen, cyano, amino, hydroxyl, nitro, alkyl, alkenyl, alkynyl, alkyl-OH, haloalkyl and alkoxyl;

R ₅ is selected from the group consisting of hydrogen, halogen and cyano;

R ₇ and R ₈ 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

R ₇ and R ₈ 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, O, S, SO, SO ₂ and NR ₁₂, 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;

R ₉ is selected from the group consisting of alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, acyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, wherein said alkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocyclyl are optionally substituted by one or more groups independently selected from the group consisting of halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, alkoxyl, acyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl;

R ₁₀ and R ₁₁ are each independently selected from the group consisting of hydrogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl, wherein said alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl are optionally substituted with one or more groups independently selected from alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl; or

R ₁₀ and R ₁₁ 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, O, S, SO, SO ₂ and NR ₁₂, 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;

R ₁₂ 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, alkenyl, alkyl-OH, haloalkyl, alkynyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl;

n is 0, 1 or 2;

n1 is 0, 1 or 2.
A compound of Formula (III) :

or a solvate, hydrate, stereoisomer, or a pharmaceutically salt or ester thereof, wherein:

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 ₈) , 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;

G is C (R ₅) 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 O, 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 Y ₁, Y ₂, 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 R ₁;

L is selected from the group consisting of O, C (=O) , S, SO, SO ₂ and N (R ₆) ;

R ₂ 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 (R ₁₀) (R ₁₁) ;

R ₆ is hydrogen or alkyl; or

when L is N (R ₆) , R ₂ and R ₆ 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, haloalkyl, saturated and partially unsaturated cycloalkyl, and N (R ₁₀) (R ₁₁) ;

R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, halogen, cyano, amino, hydroxyl, nitro, alkyl, alkenyl, alkynyl, alkyl-OH, haloalkyl and alkoxyl;

R ₅ is selected from the group consisting of hydrogen, halogen and cyano;

R ₇ and R ₈ 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

R ₇ and R ₈ 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, O, S, SO, SO ₂ and NR ₁₂, 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;

R ₉ is selected from the group consisting of alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, acyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, wherein said alkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocyclyl are optionally substituted by one or more groups independently selected from the group consisting of halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, alkoxyl, acyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro, haloalkyl, haloalkoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl;

R ₁₀ and R ₁₁ are each independently selected from the group consisting of hydrogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl, wherein said alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl are optionally substituted with one or more groups independently selected from alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl; or

R ₁₀ and R ₁₁ 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, O, S, SO, SO ₂ and NR ₁₂, 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;

R ₁₂ is selected from the group consisting of hydrogen, alkyl, alkyl-OH, haloalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl, wherein said alkyl, alkyl-OH, haloalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl are optionally substituted with one or more groups independently selected from halogen, alkyl, alkyl-OH, haloalkyl, alkenyl, alkynyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl;

n is 0, 1 or 2;

n1 is 0, 1 or 2.
The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester thereof as claimed in claim 1, wherein at least one of X ₁, X ₆ and X ₇ is N.
The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester thereof, as claimed in claim 2, wherein at least one of X ₁, X ₆ and X ₇ is N.
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 X ₁ and X ₆ is N.
The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester thereof, as claimed in claim 2, wherein X ₇ is N, and at least one of X ₁ and X ₆ is N.
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 X ₂, X ₃, X ₄, and X ₅ is CH.
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 X ₇ is CH; or

b) X ₆ is CH, and X ₇ is N.
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:

wherein G, L, E, R ₁, R ₂, R ₃ and R ₄ have the meanings as defined in claim 1.
The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester thereof, as claimed in claim 10, wherein:

L is selected from O or N (R ₆) ;

R ₁ is O (R ₉) , N (R ₇) (R ₈) , or partially unsaturated heterocyclyl optionally substituted by acyl;

R ₂ 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 (R ₁₀) (R ₁₁) , or;

R ₂ 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, O 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 (R ₁₀) (R ₁₁) ;

R ₃ is selected from halogen or alkyl;

R ₄ and R ₅ are hydrogen;

R ₇ and R ₈ 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, C _3-7 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

R ₁₀ and R ₁₁ are each independently an alkyl.
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:

wherein G, L, E, R ₁, R ₂, R ₃ and R ₄ have the meanings as defined in claim 2.
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 O or N (R ₆) ;

R ₁ is O (R ₉) , N (R ₇) (R ₈) , or partially unsaturated heterocyclyl optionally substituted by acyl;

R ₂ 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 (R ₁₀) (R ₁₁) ; or

R ₂ 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, O 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 (R ₁₀) (R ₁₁) ;

R ₃ is selected from halogen or alkyl;

R ₄ and R ₅ are hydrogen;

R ₇ and R ₈ 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, C _3-7 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

R ₁₀ and R ₁₁ are each independently an alkyl.
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:

wherein G, L, E, R ₁, R ₃ and R ₄ have the meanings as defined in claim 2, and wherein R ₂ 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 (R ₁₀) (R ₁₁) ; or when L is N (R ₆) , R ₂ 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, O 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 (R ₁₀) (R ₁₁) ; wherein R ₁₀ and R ₁₁ are each independently an alkyl.
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.
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 O.
The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester thereof, as claimed in any one of preceding claims, wherein R ₁ is selected from hydrogen, N (R ₇) (R ₈) , O (R ₉) , or saturated or partially unsaturated hetercyclyl optionally substituted by acyl.
The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester thereof, as claimed in any of claims 1-17, wherein R ₂ 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, O 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 (R ₁₀) (R ₁₁) .
The compound the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester thereof, as claimed in claim 18, wherein R ₂ and R ₆ together with the nitrogen atom to which they are attached form:

each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, alkyl, haloalkyl, saturated and partially unsaturated cycloalkyl, N (R ₁₀) (R ₁₁) , wherein p is 1, 2 or 3, and q is 1, 2 or 3.
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 O, 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 (R ₁₀) (R ₁₁) .
The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester thereof, as claimed in any of claims 1-17, wherein R ₂ is selected from C _4-6 saturated cycloalkyl or 5 to 6 membered saturated heterocyclyl, wherein said C _4-6saturated 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 (R ₁₀) (R ₁₁) .
The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester thereof, as claimed in any one of preceding claims, wherein R ₃ is selected from halogen or alkyl.
The compound or the solvate, hydrate, stereoisomer, or the pharmaceutically salt or ester thereof, as claimed in any one of preceding claims, wherein R ₄ is hydrogen.
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;

(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-methylpiperidin-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) azetidin-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;

(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- (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- (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;

(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;

(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;

(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;

(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;

(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;

(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;

(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;

(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-amine;

(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-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-isopropoxypyrido [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-isopropoxypyrido [3, 4-d] pyrimidin-4-amine;

(R) -N- (4- ( [1, 2, 4] triazolo [1, 5-a] pyridin-7-yloxy) -3-methylphenyl) -6- (cyclopropylmethoxy) -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- (cyclopropylmethoxy) -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;

(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-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- (2, 2, 2-trifluoroethoxy) pyrido [3, 4-d] pyrimidin-4-amine;

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

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

N- (4- ( [1, 2, 4] triazolo [1, 5-a] pyridin-7-yloxy) -3-methylphenyl) -6-methoxy-5- (4-methylpiperazin-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-methylpiperidin-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-methylpiperidin-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-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 [3.2.0] 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-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-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-b] pyridazin-7-yloxy) -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-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-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-yloxy) -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;

(R) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxy-N- (3-methyl-4- (tetrazolo [1, 5-a] pyridin-7-yloxy) phenyl) pyrido [3, 4-d] pyrimidin-4-amine;

(S) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxy-N- (3-methyl-4- (tetrazolo [1, 5-a] pyridin-7-yloxy) phenyl) pyrido [3, 4-d] pyrimidin-4-amine;

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

(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;

(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;

(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;

(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;

(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;

(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;

(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-methylpiperidin-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-methylpiperidin-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- (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-d3) -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- (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;

(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;

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

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

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

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

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

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

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

(R) -5- ( (3, 3-difluoro-1- (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;

(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;

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

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

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

(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;

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

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

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

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

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

(S) -5- ( (3, 3-difluoro-1- (methyl-d3) piperidin-4-yl) oxy) -6-methoxy-N- (3-methyl-4- (pyrazolo [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;

(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;

(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-ethoxypyrido [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-ethoxypyrido [3, 4-d] pyrimidin-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- (methoxy-d3) pyrido [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- (methoxy-d3) pyrido [3, 4-d] pyrimidin-4-amine;

(R) -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;

(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;

(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-methoxyquinazolin-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-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;

(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-ethoxypyrido [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-ethoxypyrido [3, 4-d] pyrimidin-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- (methoxy-d3) quinazolin-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- (methoxy-d3) quinazolin-4-amine;

(R) -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-methoxyquinazolin-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-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;

(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;

(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;

(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;

(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;

(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;

(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;

(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;

(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-ethoxypyrido [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-ethoxypyrido [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- (methoxy-d3) pyrido [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- (methoxy-d3) pyrido [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- (methoxy-d3) pyrido [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- (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-difluoro-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-difluoro-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-difluoro-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-difluoro-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-difluoro-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;

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

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

(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;

(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;

(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;

(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;

(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) quinoline-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) 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.
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.
The pharmaceutical composition of claim 25, which does not comprise an agent for facilitating BBB entry.
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 1 to 24.
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.
The method of claim 28, wherein the metastasis is in brain.
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.
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.
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.
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, wherein the compound is administered simultaneously, separately or sequentially with one or more chemotherapeutic agents.
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.