RELATED APPLICATION

[001] The application claims priority to, and the benefit of, U.S. Provisional Application No. 63/146,313, filed on February 5, 2021, the contents of which are incorporated herein by reference in their entirety.

SEQUENCE LISTING

[002] The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on February 5, 2021 is named “ASET-010_P01US_SeqList.txt” and is about 10.5 KB in size.

BACKGROUND

[003] The HER family receptor tyrosine kinases are mediators of cell growth, differentiation and survival. They include the four distinct members EGFR (epidermal growth factor receptor, also HER1), HER2, HER3 and HER4. Upon ligand binding the receptors form homo- and heterodimers and subsequent activation of the intrinsic tyrosine kinase activity leads to receptor auto-phosphorylation and the activation of downstream signaling molecules. De-regulation of EGFR by overexpression or mutation has been implicated in many types of human cancer including colorectal, pancreatic, gliomas, head and neck, and lung cancer, in particular non-small cell lung cancer (NSCLC).

[004] Tyrosine kinase inhibitors (TKIs) against EGFR have been developed over the past three decades and have become standard treatment in the clinic for subjects with advanced EGFR mutant NSCLC. First-generation EGFR TKIs, e.g. gefitinib and erlotinib, bind competitively and reversibly to the ATP -binding site of the EGFR tyrosine kinase domain and have resulted in a significant improvement in outcome for patients having NSCLC with activating EGFR mutations (L858R and Dell9). Yet, the emergence of resistance led to the second-generation irreversible EGFR TKIs that were broader spectrum and therefore expected to better inhibit EGFR-dependent tumor growth. However, these second-generation EGFR TKIs are also prone to acquired resistance (with the T790M mutation being the most prevalent cause) and thus did not have the expected clinical activity (presumably because of dose-limiting toxicity due to simultaneous inhibition of wild-type EGFR). The subsequent third-generation EGFR TKIs, e.g. osimertinib, rociletinib, olmutinib, naquotinib, nazartinib (see e.g. Cross et al., Cancer Discov. 2014; 4(9): 1046-61; Walter et al., Cancer Discov. 2013; 3(12):404-15; Wang et al., J. Hemat. and Oncol. 2016; 9:34), selectively and irreversibly target EGFR T790M and activating EGFR mutations and show promising efficacy in NSCLC resistant to the first- and second-generation EGFR TKIs as well as limited inhibitory effect on wild-type EGFR (e.g. a response rate of > 50 percent in subjects suffering from NSCLC exhibiting the EGFR-mutation T790M, who have developed resistance to gefitinib or erlotinib, see e.g. Janne et al., N Eng J Med 2015; 372: 1689-99; Sequist et al., N Eng J Med 2015; 372: 1700-9).

[005] Yet, as was the case with first and second-generation EGFR TKIs, mutations imparting resistance to third-generation EGFR TKIs are emerging (see e.g. Thress et al, Nat Med (2015) 21 :560-562; Yu et al, JAMA Oncol (2015) 1 :982-984). These include in particular the C797 mutations C797S and C797G at position 797 in exon 20 of EGFR, which impair covalent binding between the cysteine residue and third-generation EGFR TKIs (e.g., Ercan et al., Clin Can Res 2015 21(17)3913-3923; Minari et al, Transl. Lung Cancer Res, 29016; 5(6): 695-708).

Thus, there is a need for new treatments that can address the variable and reduced responsiveness of cancer subjects to current treatments. The present disclosure addresses this need.

SUMMARY

[006] In some aspects, the present disclosure provides a compound of formula I: or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:

X ¹ is -O-, -S-, or -NR ² -; each R ^a independently is -H or -Ci-4 alkyl; each R ^b independently is -H or -Ci-4 alkyl; each R ^c independently is -H or -Ci-4 alkyl; each R ^d independently is -H or -Ci-4 alkyl; R ¹ is -H or -Ci-4 alkyl;

R ² is -H or -Ci-4 alkyl;

R ³ is -H or -O-Ci-4 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and

Ar ¹ is Ce-io aryl optionally substituted with one or more halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH ₂ , -NH(CI-6 alkyl), -N(CI-C ₆ alkyl) ₂ , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) ₂ , -C(O)O(Ci-6 alkyl), or - NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH ₂ , - NH(CI-C ₆ alkyl), or -N(CI-C ₆ alkyl) ₂ .

[007] In some embodiments, the compound is not 2-[4-[4-(3-chloro-2-fluoroanilino)-7-methox- yquinazolin-6-yl]oxypiperidin-l-yl]-7V-methylacetamide or 2-(3-((4-((3-chloro-2-fluoro- phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)-N- methylacetamide.

[008] In some embodiments, the compound is not 2-[4-[4-(3-chloro-2-fluoroanilino)-7-methox- yquinazolin-6-yl]oxypiperidin-l-yl]-7V-methylacetamide.

[009] In some embodiments, the compound is not 2-(3-((4-((3-chloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin-l-yl)-N-methylacetamide.

[010] In some aspects, the present disclosure provides an isotopic derivative of a compound disclosed herein.

[011] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein and one or more pharmaceutically acceptable carriers or excipients. [012] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound disclosed herein.

[013] In some aspects, the present disclosure provides a compound disclosed herein for treating or preventing cancer in a subject.

[014] In some aspects, the present disclosure provides a use of a compound disclosed herein in the manufacture of a medicament for treating or preventing cancer in a subject.

[015] In some embodiments, the cancer is characterized by an EGFR mutation C797. [016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[017] Other features and advantages of the disclosure will be apparent from the following detailed description and claims.

DETAILED DESCRIPTION

Compounds of the Present Disclosure

[018] In some aspects, the present disclosure provides a compound of formula I: or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:

X ¹ is -O-, -S-, or -NR ² -; each R ^a independently is -H or -Ci-4 alkyl; each R ^b independently is -H or -Ci-4 alkyl; each R ^c independently is -H or -Ci-4 alkyl; each R ^d independently is -H or -Ci-4 alkyl;

R ¹ is -H or -Ci-4 alkyl;

R ² is -H or -Ci-4 alkyl;

R ³ is -H or -O-Ci-4 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and

Ar ¹ is Ce-io aryl optionally substituted with one or more halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH ₂ , -NH(CI-6 alkyl), -N(CI-C ₆ alkyl) ₂ , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) ₂ , -C(O)O(Ci-6 alkyl), or - NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH ₂ , - NH(CI-C ₆ alkyl), or -N(CI-C ₆ alkyl) ₂ .

[019] In some embodiments, the compound is not 2-[4-[4-(3-chloro-2-fluoroanilino)-7-methox- yquinazolin-6-yl]oxypiperidin-l-yl]-A-methylacetamide or 2-(3-((4-((3-chloro-2-fluoro- phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)-N- methylacetamide.

[020] In some embodiments, the compound is not 2-[4-[4-(3-chloro-2-fluoroanilino)-7-methox- yquinazolin-6-yl]oxypiperidin-l-yl]-A-methylacetamide or 2-(3-((4-((3-chloro-2-fluoro- phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l-yl)-N- methylacetamide or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[021] In some embodiments, the compound is not 2-[4-[4-(3-chloro-2-fluoroanilino)-7-methox- yquinazolin-6-yl]oxypiperidin-l-yl]-A-methylacetamide.

[022] In some embodiments, the compound is not 2-[4-[4-(3-chloro-2-fluoroanilino)-7-methox- yquinazolin-6-yl]oxypiperidin-l-yl]-A-methylacetamide, or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[023] In some embodiments, the compound is not 2-(3-((4-((3-chloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin-l-yl)-N-methylacetamide.

[024] In some embodiments, the compound is not 2-(3-((4-((3-chloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)azetidin-l-yl)-N-methylacetamide or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[025] In some embodiments, when X ¹ is -O-, R ³ is -OMe, R ¹ , R ^a , R ^b , R ^c , and R ^d are each -H, n and m are each 1 or are each 2, then Ar ¹ is not 3-chloro-2-fluorophenyl.

[026] In some embodiments, when X ¹ is -O-, R ³ is -OMe, R ¹ , R ^a , R ^b , R ^c , and R ^d are each -H, n and m are each 2, then Ar ¹ is not 3-chloro-2-fluorophenyl.

[027] In some embodiments, when X ¹ is -O-, R ³ is -OMe, R ¹ , R ^a , R ^b , R ^c , and R ^d are each -H, n and m are each 1, then Ar ¹ is not 3-chloro-2-fluorophenyl.

[028] In some aspects, the present disclosure provides a compound of formula I: or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:

X ¹ is -O-, -S-, or -NR ² -; each R ^a independently is -H or -Ci-4 alkyl; each R ^b independently is -H or -Ci-4 alkyl; each R ^c independently is -H or -Ci-4 alkyl; each R ^d independently is -H or -Ci-4 alkyl;

R ¹ is -H or -Ci-4 alkyl;

R ² is -H or -Ci-4 alkyl;

R ³ is -H or -O-Ci-4 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and

Ar ¹ is Ce-io aryl optionally substituted with one or more halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH ₂ , -NH(CI-6 alkyl), -N(CI-C ₆ alkyl) ₂ , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) ₂ , -C(O)O(Ci-6 alkyl), or - NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH ₂ , - NH(CI-C ₆ alkyl), or -N(CI-C ₆ alkyl) ₂ ; provided that the compound is not 2-[4-[4-(3-chloro-2-fluoroanilino)-7-methox- yquinazolin-6-yl]oxypiperidin-l-yl]-7V-methylacetamide or 2-(3-((4-((3-chloro-2- fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l- yl)-N-methylacetamide.

[029] In some aspects, the present disclosure provides a compound of formula I: (I) or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:

X ¹ is -O-, -S-, or -NR ² -; each R ^a independently is -H or -Ci-4 alkyl; each R ^b independently is -H or -Ci-4 alkyl; each R ^c independently is -H or -Ci-4 alkyl; each R ^d independently is -H or -Ci-4 alkyl;

R ¹ is -H or -Ci-4 alkyl;

R ² is -H or -Ci-4 alkyl;

R ³ is -H or -O-Ci-4 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and

Ar ¹ is Ce-io aryl optionally substituted with one or more halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH ₂ , -NH(CI-6 alkyl), -N(CI-C ₆ alkyl) ₂ , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) ₂ , -C(O)O(Ci-6 alkyl), or - NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH ₂ , - NH(CI-C ₆ alkyl), or -N(CI-C ₆ alkyl) ₂ ; provided that when X ¹ is -O-, R ³ is -OMe, R ¹ , R ^a , R ^b , R ^c , and R ^d are each H, n and m are each 2, then Ar ¹ is not 3-chloro-2-fluorophenyl, and when X ¹ is -O-, R ³ is -OMe, R ¹ , R ^a , R ^b , R ^c , and R ^d are each H, n and m are each 1, then Ar ¹ is not 3-chloro-2-fluorophenyl.

Variables X ¹ , R ¹ , R ² , and R ³

[030] In some embodiments, X ¹ is -O-, -S-, or -NR ² -.

[031] In some embodiments, X ¹ is -O-. In some embodiments, X ¹ is -S-.

[032] In some embodiments, X ¹ is -NR ² -.

[033] In some embodiments, X ¹ is -NH-. In some embodiments, X ¹ is -N(CI-4 alkyl)-.

[034] In some embodiments, X ¹ is -N(CH3)-.

[035] In some embodiments, R ¹ is -H or -Ci-4 alkyl.

[036] In some embodiments, R ¹ is -H. In some embodiments, R ¹ is -C1-4 alkyl.

[037] In some embodiments, R ¹ is methyl, ethyl, n-propyl, or n-butyl. [038] In some embodiments, R ¹ is methyl.

[039] In some embodiments, R ² is -H or -Ci-4 alkyl.

[040] In some embodiments, R ² is -H. In some embodiments, R ² is -C1-4 alkyl.

[041] In some embodiments, R ² is methyl, ethyl, n-propyl, or n-butyl.

[042] In some embodiments, R ² is methyl.

[043] In some embodiments, R ³ is -H or -O(Ci-6 alkyl).

[044] In some embodiments, R ³ is -H or -OMe.

[045] In some embodiments, R ³ is -H. In some embodiments, R ³ is -OMe.

Variables R ^a , R ^b , R ^c , R ^d , m, and n

[046] In some embodiments, at least one R ^a is -H or -Ci-4 alkyl.

[047] In some embodiments, at least one R ^a is -H. In some embodiments, at least one R ^a is -Ci-4 alkyl.

[048] In some embodiments, at least one R ^a is methyl, ethyl, n-propyl or n-butyl.

[049] In some embodiments, at least one R ^b is -H or -Ci-4 alkyl.

[050] In some embodiments, at least one R ^b is -H. In some embodiments, at least one R ^b is -Ci-4 alkyl.

[051] In some embodiments, at least one R ^b is methyl, ethyl, n-propyl or n-butyl.

[052] In some embodiments, at least one R ^c is -H or -Ci-4 alkyl.

[053] In some embodiments, at least one R ^c is -H. In some embodiments, at least one R ^c is -Ci-4 alkyl.

[054] In some embodiments, at least one R ^c is methyl, ethyl, n-propyl or n-butyl.

[055] In some embodiments, at least one R ^d is -H or -Ci-4 alkyl.

[056] In some embodiments, at least one R ^d is -H. In some embodiments, at least one R ^d is -Ci-4 alkyl.

[057] In some embodiments, at least one R ^d is methyl, ethyl, n-propyl or n-butyl.

[058] In some embodiments, m is 0, 1, or 2.

[059] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[060] In some embodiments, n is 1, 2, or 3.

[061] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. [062] In some embodiments, m is 1 and n is 1.

[063] In some embodiments, m is 2 and n is 2.

Variables Ar ¹

[064] In some embodiments, Ar ¹ is Ce-io aryl optionally substituted with one or more halogen, - CF3, C1-6 alkyl, C1-6 alkoxy, -NH2, -NH(CI-6 alkyl), -N(Ci-Ce alkyl)2, -C(O)O(Ci-6 alkyl), or - NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, - C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH2, -NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl)2.

[065] In some embodiments, Ar ¹ is phenyl optionally substituted with one or more halogen, - CF3, C1-6 alkyl, C1-6 alkoxy, -NH2, -NH(CI-6 alkyl), -N(Ci-Ce alkyl)2, -C(O)O(Ci-6 alkyl), or - NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, - C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH2, -NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl)2.

[066] In some embodiments, Ar ¹ is Ce-io aryl.

[067] In some embodiments, Ar ¹ is phenyl.

[068] In some embodiments, Ar ¹ is Ce-io aryl optionally substituted with one or more halogen, - CF3, or C1-6 alkyl.

[069] In some embodiments, Ar ¹ is phenyl optionally substituted with one or more halogen, - CF3, or C1-6 alkyl.

[070] In some embodiments, Ar ¹ is Ce-io aryl substituted with one or more halogen, -CF3, or Ci- 6 alkyl.

[071] In some embodiments, Ar ¹ is phenyl substituted with one or more halogen, -CF3, or C1-6 alkyl.

[072] In some embodiments, Ar ¹ is Ce-io aryl optionally substituted with one or more halogen.

[073] In some embodiments, Ar ¹ is phenyl optionally substituted with one or more halogen.

[074] In some embodiments, Ar ¹ is Ce-io aryl substituted with one or more halogen.

[075] In some embodiments, Ar ¹ is phenyl optionally substituted with F and Cl.

[076] In some embodiments, Ar ¹ is phenyl substituted with one or more halogen.

[077] In some embodiments, Ar ¹ is phenyl substituted with F and Cl. [078] In some embodiments,

Y^^ci [079] In some embodiments, Ar ¹ is not F

[080] In some embodiments, wherein:

R ⁴ is halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH2, -NH(CI-6 alkyl), -N(Ci-Ce alkyl)2, -

C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, -C(0)0(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, Ci-6 alkoxy, -NH2, -NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl)2;

R ⁵ is halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH2, -NH(CI-6 alkyl), -N(Ci-Ce alkyl)2, - C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH2, -NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl)2;

R ⁵ ’ is halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH2, -NH(CI-6 alkyl), -N(Ci-Ce alkyl)2, - C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH2, -NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl)2;

R ⁶ is halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH2, -NH(CI-6 alkyl), -N(Ci-Ce alkyl)2, - C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH2, -NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl)2; and

R ⁶ ’ is halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH2, -NH(CI-6 alkyl), -N(Ci-Ce alkyl)2, - C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH2, -NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl)2. [081] In some embodiments, R ⁴ is halogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, hydroxy C1-5 alkyl, Ci-6 alkoxy-Ci-6 alkyl, amino Ci-4 alkyl, Ci-6 alkylamino, Ci-6 alkoxycarbonyl, or Ci-6 alkoxyaminocarbonyl.

[082] In some embodiments, R ⁴ is -H.

[083] In some embodiments, R ⁴ is Ci-6 haloalkyl. In some embodiments, R ⁴ is -CF3.

[084] In some embodiments, R ⁴ is halogen. In some embodiments, R ⁴ is -F, -Cl, -Br, or -I.

[085] In some embodiments, R ⁴ is -F. In some embodiments, R ⁴ is -Cl.

[086] In some embodiments, R ⁵ is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy C1-5 alkyl, C1-6 alkoxy-Ci-6 alkyl, amino Ci-4 alkyl, C1-6 alkylamino, C1-6 alkoxycarbonyl, or C1-6 alkoxyaminocarbonyl.

[087] In some embodiments, R ⁵ is -H.

[088] In some embodiments, R ⁵ is C1-6 haloalkyl. In some embodiments, R ⁵ is -CF3.

[089] In some embodiments, R ⁵ is halogen. In some embodiments, R ⁵ is -F, -Cl, -Br, or -I.

[090] In some embodiments, R ⁵ is -F. In some embodiments, R ⁵ is -Cl.

[091] In some embodiments, R ⁵ is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy C1-5 alkyl, C1-6 alkoxy-Ci-6 alkyl, amino Ci-4 alkyl, C1-6 alkylamino, C1-6 alkoxycarbonyl, or C1-6 alkoxyaminocarbonyl.

[092] In some embodiments, R ⁵ is -H.

[093] In some embodiments, R ⁵ is C1-6 haloalkyl. In some embodiments, R ⁵ is -CF3.

[094] In some embodiments, R ⁵ is halogen. In some embodiments, R ⁵ is -F, -Cl, -Br, or -I.

[095] In some embodiments, R ⁵ is -F. In some embodiments, R ⁵ is -Cl.

[096] In some embodiments, R ⁶ is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy C1-5 alkyl, C1-6 alkoxy-Ci-6 alkyl, amino Ci-4 alkyl, C1-6 alkylamino, C1-6 alkoxycarbonyl, or C1-6 alkoxyaminocarbonyl.

[097] In some embodiments, R ⁶ is -H.

[098] In some embodiments, R ⁶ is C1-6 haloalkyl. In some embodiments, R ⁶ is -CF3.

[099] In some embodiments, R ⁶ is halogen. In some embodiments, R ⁶ is -F, -Cl, -Br, or -I. [0100] In some embodiments, R ⁶ is -F. In some embodiments, R ⁶ is -Cl.

[0101] In some embodiments, R ⁶ is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy C1-5 alkyl, C1-6 alkoxy-Ci-6 alkyl, amino Ci-4 alkyl, C1-6 alkylamino, C1-6 alkoxycarbonyl, or C1-6 alkoxyaminocarbonyl. [0102] In some embodiments, R ⁶ is -H.

[0103] In some embodiments, R ⁶ is Ci-6 haloalkyl. In some embodiments, R ⁶ is -CF3.

[0104] In some embodiments, R ⁶ is halogen. In some embodiments, R ⁶ is -F, -Cl, -Br, or -I.

[0105] In some embodiments, R ⁶ is -F. In some embodiments, R ⁶ is -Cl.

Exemplary Embodiments of the Compounds

[0106] In some embodiments, the compound is of any one of Formulae (la), (lb), (Ic), (Id), (le),

(If), (Ig), or (Ih):

or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the compound is of Formula (II): or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof. [0108] In some embodiments, the compound is of any one of Formulae (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), or (IIh):

or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the compound is of Formula (III) or (IV): or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0110] In some embodiments, the compound is of any one of Formulae (Illa), (Illb), (IIIc), (Hid), (IVa), (IVb), (IVc), or (IVd): wo 2022/170052

or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the compound is a compound described in Table I, or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0112] In some embodiments, the compound is a compound described in Table I or pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the compound is a compounds described in Table I.

[0114] In some embodiments, the compound is selected from Compound Nos. 2-10 and 12-15, or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0115] In some embodiments, the compound is selected from Compound Nos. 2-10 and 12-15, or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments, the compound is selected from Compound Nos. 2-10 and 12-15.

Table I

[0117] In some aspects, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds disclosed herein.

[0118] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table I and pharmaceutically acceptable salts thereof.

[0119] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table I.

[0120] It is understood that the isotopic derivative can be prepared using any of a variety of art- recognized techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0121] In some embodiments, the isotopic derivative is a deuterium labeled compound.

[0122] In some embodiments, the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.

[0123] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table I and pharmaceutically acceptable salts thereof.

[0124] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table I.

[0125] It is understood that the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.

[0126] In some embodiments, the deuterium labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium.

[0127] It is understood that the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a deuterium labeled reagent for a non-deuterium labeled reagent.

[0128] A compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the present disclosure. Further, substitution with deuterium (/.< ., ² H) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. [0129] For the avoidance of doubt it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

[0130] A suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, formic, citric methane sulphonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxy- ethyl)amine.

[0131] It will be understood that the compounds of the present disclosure and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds.

[0132] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

[0133] As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents.

[0134] As used herein, the term “chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn etal., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0135] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0136] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity.

[0137] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity.

[0138] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

[0139] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (- OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

[0140] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[0141] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-su- perimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0142] The compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centers (E- and Z- isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess inflammasome inhibitory activity. [0143] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.

[0144] It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulphate, bisulphate, sulphamate, nitrate, phosphate, citrate, methanesulphonate, trifluoroacetate, glutamate, glu- curonate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulphonate, and acetate (e.g., trifluoroacetate).

[0145] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0146] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0147] As used herein, the term “solvate” means 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 H2O.

[0148] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound. [0149] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0150] As used herein, the term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulphonamides, tetrazoles, sulphonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0151] It is also to be understood that certain compounds of the present disclosure may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a dihydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess inflammasome inhibitory activity.

[0152] It is also to be understood that certain compounds of the present disclosure may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof, which possess inflammasome inhibitory activity. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis.

[0153] Compounds of the present disclosure may exist in a number of different tautomeric forms and references to compounds of the present disclosure include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, ni- troso/oxime, thioketone/enethiol, and nitro/aci -nitro. keto enol enolate

[0154] Compounds of the present disclosure containing an amine function may also form N-ox- ides. A reference herein to a compound disclosed herein that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N- oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-oxides can be formed by treatment of the corresponding amine with an oxidising agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0155] The compounds of the present disclosure may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the sulphonylurea group in a compound of the any one of the Formulae disclosed herein.

[0156] Accordingly, the present disclosure includes those compounds of the present disclosure as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of the present disclosure that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the present disclosure may be a synthetically-produced compound or a metabolically-produced compound.

[0157] A suitable pharmaceutically acceptable prodrug of a compound of the present disclosure is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “ProDrugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0158] A suitable pharmaceutically acceptable prodrug of a compound of the present disclosure that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the present disclosure containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include Ci-Cio alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci-Cio alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(Ci-Ce alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkyla- minomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin- 1-ylmethyl and 4-(CI-C4 al- kyl)piperazin-l-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups. [0159] A suitable pharmaceutically acceptable prodrug of a compound of the present disclosure that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a Ci-4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or di ethylamine, a C1-C4 alkoxy-C2- C4 alkylamine such as 2 -methoxy ethylamine, a phenyl-Ci-C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof. [0160] A suitable pharmaceutically acceptable prodrug of a compound of the present disclosure that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with Ci-Cio alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin- 1-ylmethyl, and 4-(CI-C4 alkyl)piperazin-l-ylmethyl.

[0161] The in vivo effects of a compound of the present disclosure may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the present disclosure. As stated hereinbefore, the in vivo effects of a compound of the present disclosure may also be exerted by way of metabolism of a precursor compound (a prodrug).

Methods of Synthesis

[0162] In some aspects, the present disclosure provides a method of preparing a compound disclosed herein.

[0163] In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps as described herein.

[0164] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound described herein.

[0165] In some aspects, the present disclosure provides an intermediate being suitable for use in a method for preparing a compound described herein.

[0166] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.

[0167] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised.

[0168] It will be appreciated that during the synthesis of the compounds of the disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

[0169] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxy carbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxy carbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(tri- fluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0170] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0171] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0172] Once a compound of the present disclosure has been synthesized by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound of the present disclosure into another compound of the present disclosure; (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or (iv) forming a prodrug thereof.

[0173] The resultant compounds of the present disclosure can be isolated and purified using techniques well known in the art.

[0174] Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as tri chlorethylene, 1,2-di chloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methylisobutylketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N- methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulphoxides, such as dimethyl sulphoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the said solvents or mixtures with water. [0175] The reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used.

[0176] Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours.

[0177] Moreover, by utilizing the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0178] As will be understood by the person skilled in the art of organic synthesis, compounds of the present disclosure are readily accessible by various synthetic routes, some of which are exemplified in the accompanying examples. The skilled person will easily recognize which kind of reagents and reactions conditions are to be used and how they are to be applied and adapted in any particular instance - wherever necessary or useful - in order to obtain the compounds of the present disclosure. Furthermore, some of the compounds of the present disclosure can readily be synthesized by reacting other compounds of the present disclosure under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present disclosure, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person. Likewise, the skilled person will apply - whenever necessary or useful - synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well-known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons).

[0179] General routes for the preparation of a compound of the application are described in Schemes 1-4. In the schemes, R is a protecting group (e.g., benzyloxycarbonyl), Z is a protecting group (e.g., dimethoxybenzyl), and X is a leaving group (e.g., halogen). Scheme 1

Nucleophilic displacement Scheme 3

Nucleophilic displacement

Scheme 4 displacement

Nucleophilic displacement

Biological Assays

[0180] Compounds designed, selected and/or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.

Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

[0181] Various in vitro or in vivo biological assays are may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

Retroviral Production

[0182] In some embodiments, the biological assay is a retrovirus production assay. In some embodiments, the EGFR mutants are subcloned I and the retroviral expression vector is produced by transient transfection (e.g., of HEK 293T cells with a retroviral EGFR mutant expression vector). In some embodiments, the cells may be plated and incubated (e.g., overnight) and the retroviral plasmids may be mixed in serum (e.g., Optimem). In some embodiments, the mixture may be incubated (e.g., at room temperature for a period of time) and then added to serum comprising transfection reagent (e.g., Lipofectamine) and incubated for a period of time (e.g., 20 minutes). In some embodiments, the mixture may be added to the cells and the medium replaced with fresh culture medium and the retrovirus may be harvested.

[0183] In some embodiments, the biological assay is the generation of EGFR mutant stable cell lines. In some embodiments the cells (e.g., BaF3 cells) may be infected with a viral supernatant, centrifuged, and incubated for a period of time (e.g., overnight). In some embodiments, the cells may then be spun to pellet the cells and the supernatant removed. In some embodiment, the cells may be re-infected a fresh viral supernatant, centrifuges, and incubated for a period of time (e.g., overnight). In some embodiments, the cells may then be maintained in IL-3, followed by the cells being selected for retroviral infection. In some embodiments, the blasticidin resistant populations may be washed buffered saline prior to plating in media lacking IL-3 to select for IL-3 independent growth. [0184] In some embodiments, the biological assay is an assay for cell proliferation. In some embodiments the cell lines, (e.g., BaF3 cell lines) may be resuspended and dispensed in plates. In some embodiments, to determine the effect of drug on cell proliferation, the cells may be incubated in the presence of vehicle control or test drug at varying concentrations. In some embodiments, the inhibition of cell growth may be determined by luminescent quantification of intracellular ATP content (e.g., using Cell Titer Gio). In some embodiments, the comparison of cell number on different days (e.g., day 0 versus 72 hours post drug treatment) may be used to plot dose-response curves. In some embodiments, inhibition of proliferation, relative to vehicle-treated controls was expressed as a fraction of 1 and graphed using PRISM® software, as well as ECso values determined utilizing the same application

[0185] In some embodiments, a cell line (e.g., the A431 lung cancer cell line, which natively expresses WT-EGFR) may be used to assess WT-EGFR inhibition.

[0186] In some embodiments, a cell line (e.g., the BT474, which natively expresses WT-HER2) may be used to assess WT-HER2 inhibition.

[0187] In some embodiments, to perform the proliferation assays, cells may be plated in well plates and subjected to various doses of compound to generate a dose-response curve for each cell line to be assessed (e.g., by using a Cell Titer Gio cell proliferation kit). In some embodiments, doseresponse curves may be generated for each cell line and ICso values generated.

Pharmaceutical Compositions

[0188] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient.

[0189] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table I.

[0190] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. [0191] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0192] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/ suspending agent, buffer, and pH modifying agent, and a mixture thereof.

Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-P- cyclodextrin, methyl-P-cyclodextrin, randomly methylated-P-cyclodextrin, ethylated-P- cyclodextrin, triacetyl-P-cyclodextrin, peracetylated-P-cyclodextrin, carboxymethyl-P- cyclodextrin, hydroxy ethyl-P-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-P- cyclodextrin, glucosyl-P-cyclodextrin, sulphated P-cyclodextrin (S-P-CD), maltosyl-P- cyclodextrin, P-cyclodextrin sulphobutyl ether, branched-P-cyclodextrin, hydroxypropyl-y- cyclodextrin, randomly methylated-y-cyclodextrin, and trimethyl-y-cyclodextrin, and mixtures thereof.

[0193] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, di sodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0194] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hy- droxybenzoate, and sorbic acid, and mixtures thereof. [0195] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.

[0196] The aqueous vehicle may also contain a viscosity/ suspending agent. Suitable viscosity/sus- pending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid crosslinked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.

[0197] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid. These acidic and/or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0198] The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and 8-aminocaproic acid, and mixtures thereof.

[0199] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxy ethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

[0200] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0201] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0202] The compositions of the disclosure may 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) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0203] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents. [0204] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent an inflammasome related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.

[0205] The size of the dose for therapeutic or prophylactic purposes of a compound of the present disclosure will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

Methods of Use

[0206] Without wishing to be bound by theory, it is understood that compounds of the present disclosure could be highly selective inhibitors and specifically inhibit C797 (i.e. C797S/G) containing EGFR mutants. The compounds of the present disclosure could therefore be useful and effective in the therapeutic treatment in patients suffering from cancer comprising such mutation^), and specifically in patients who have acquired resistance to treatment with EGFR TKIs and show a reduced response or are not or no longer responding to therapies with EGFR TKIs.

[0207] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, comprising administering to the subject a pharmaceutically effective amount of at least one compound of the present disclosure.

[0208] In some aspects, the present disclosure provides a method of treating cancer in a subject, comprising administering to the subject a pharmaceutically effective amount of at least one compound of the present disclosure.

[0209] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, comprising administering to the subject at least one compound of the present disclosure.

[0210] In some aspects, the present disclosure provides a method of treating cancer in a subject, comprising administering to the subject at least one compound of the present disclosure.

[0211] In some aspects, the present disclosure provides at least one compound of the present disclosure for treating or preventing cancer in a subject.

[0212] In some aspects, the present disclosure provides at least one compound of the present disclosure for treating cancer in a subject. [0213] In some aspects, the present disclosure provides use of at least one compound of the present disclosure in the manufacture of a medicament for treating or preventing cancer in a subject.

[0214] In some aspects, the present disclosure provides use of at least one compound of the present disclosure in the manufacture of a medicament for treating cancer in a subject.

[0215] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure.

[0216] In some aspects, the present disclosure provides a method of treating cancer in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure.

[0217] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, comprising administering to the subject a compound of the present disclosure.

[0218] In some aspects, the present disclosure provides a method of treating cancer in a subject, comprising administering to the subject a compound of the present disclosure.

[0219] In some aspects, the present disclosure provides a compound of the present disclosure for treating or preventing cancer in a subject.

[0220] In some aspects, the present disclosure provides a compound of the present disclosure for treating cancer in a subject.

[0221] In some aspects, the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for treating or preventing cancer in a subject.

[0222] In some aspects, the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for treating cancer in a subject.

[0223] In some embodiments, the cancer is characterized by an EGFR mutation C797.

[0224] In some embodiments, an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.

[0225] In some aspects, the present disclosure provides a method of treating or preventing a cancer characterized by an EGFR mutation C797 in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of at least one compound of the present disclosure. [0226] In some aspects, the present disclosure provides a method of treating a cancer characterized by an EGFR mutation C797 in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of at least one compound of the present disclosure.

[0227] In some aspects, the present disclosure provides a method of treating or preventing a cancer characterized by an EGFR mutation C797 in a subject in need thereof, comprising administering to the subject at least one compound of the present disclosure.

[0228] In some aspects, the present disclosure provides a method of treating a cancer characterized by an EGFR mutation C797 in a subject in need thereof, comprising administering to the subject at least one compound of the present disclosure.

[0229] In some aspects, the present disclosure provides a method of treating or preventing a cancer characterized by an EGFR mutation C797 in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure.

[0230] In some aspects, the present disclosure provides a method of treating a cancer characterized by an EGFR mutation C797 in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure.

[0231] In some aspects, the present disclosure provides a method of treating or preventing a cancer characterized by an EGFR mutation C797 in a subject in need thereof, comprising administering to the subject a compound of the present disclosure.

[0232] In some aspects, the present disclosure provides a method of treating a cancer characterized by an EGFR mutation C797 in a subject in need thereof, comprising administering to the subject a compound of the present disclosure.

[0233] In some aspects, the present disclosure provides a method of treating or preventing a cancer in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of at least one compound of the present disclosure, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.

[0234] In some aspects, the present disclosure provides a method of treating a cancer in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of at least one compound of the present disclosure, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.

[0235] In some aspects, the present disclosure provides a method of treating or preventing a cancer in a subject in need thereof, comprising administering to the subject at least one compound of the present disclosure, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.

[0236] In some aspects, the present disclosure provides a method of treating a cancer in a subject in need thereof, comprising administering to the subject at least one compound of the present disclosure, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.

[0237] In some aspects, the present disclosure provides a method of treating or preventing a cancer in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.

[0238] In some aspects, the present disclosure provides a method of treating a cancer in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.

[0239] In some aspects, the present disclosure provides a method of treating or preventing a cancer in a subject in need thereof, comprising administering to the subject a compound of the present disclosure, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.

[0240] In some aspects, the present disclosure provides a method of treating a cancer in a subject in need thereof, comprising administering to the subject a compound of the present disclosure, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.

[0241] In some aspects, the present disclosure provides at least one compound of the present disclosure for use in treating or preventing a cancer characterized by an EGFR mutation C797 in a subject in need thereof.

[0242] In some aspects, the present disclosure provides at least one compound of the present disclosure for use in treating a cancer characterized by an EGFR mutation C797 in a subject in need thereof.

[0243] In some aspects, the present disclosure provides a compound of the present disclosure for use in treating or preventing a cancer characterized by an EGFR mutation C797 in a subject in need thereof. [0244] In some aspects, the present disclosure provides a compound of the present disclosure for use in treating a cancer characterized by an EGFR mutation C797 in a subject in need thereof.

[0245] In some aspects, the present disclosure provides at least one compound of the present disclosure for use in treating or preventing a cancer in a subject in need thereof, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.

[0246] In some aspects, the present disclosure provides at least one compound of the present disclosure for use in treating a cancer in a subject in need thereof, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.

[0247] In some aspects, the present disclosure provides a compound of the present disclosure for use in treating or preventing a cancer in a subject in need thereof, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.

[0248] In some aspects, the present disclosure provides a compound of the present disclosure for use in treating a cancer in a subject in need thereof, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.

[0249] In some aspects, the present disclosure provides use of at least one compound of the present disclosure in the manufacture of a medicament for treating or preventing a cancer characterized by an EGFR mutation C797 in a subject in need thereof.

[0250] In some aspects, the present disclosure provides use of at least one compound of the present disclosure in the manufacture of a medicament for treating a cancer characterized by an EGFR mutation C797 in a subject in need thereof.

[0251] In some aspects, the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for treating or preventing a cancer characterized by an EGFR mutation C797 in a subject in need thereof.

[0252] In some aspects, the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for treating a cancer characterized by an EGFR mutation C797 in a subject in need thereof.

[0253] In some aspects, the present disclosure provides use of at least one compound of the present disclosure for treating or preventing a cancer in a subject in need thereof, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject. [0254] In some aspects, the present disclosure provides use of at least one compound of the present disclosure for treating a cancer in a subject in need thereof, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.

[0255] In some aspects, the present disclosure provides use of a compound of the present disclosure for treating or preventing a cancer in a subject in need thereof, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.

[0256] In some aspects, the present disclosure provides use of a compound of the present disclosure for treating a cancer in a subject in need thereof, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.

[0257] In some aspects, the present disclosure provides a pharmaceutical composition comprising at least one compound of the present disclosure for treating or preventing cancer in a subject.

[0258] In some aspects, the present disclosure provides a pharmaceutical composition comprising at least one compound of the present disclosure for treating cancer in a subject.

[0259] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure for treating or preventing cancer in a subject.

[0260] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure for treating cancer in a subject.

[0261] In some aspects, the present disclosure provides a pharmaceutical kit comprising at least one compound of the present disclosure for treating or preventing cancer in a subject.

[0262] In some aspects, the present disclosure provides a pharmaceutical kit comprising at least one compound of the present disclosure for treating cancer in a subject.

[0263] In some aspects, the present disclosure provides a pharmaceutical kit comprising a compound of the present disclosure for treating or preventing cancer in a subject.

[0264] In some aspects, the present disclosure provides a pharmaceutical kit comprising a compound of the present disclosure for treating cancer in a subject.

[0265] In some aspects, the present disclosure provides a method of providing therapy recommendation for a subject having a cancer, the method comprising: (a) determining the presence or absence of an oncogenic mutation and/or an oncogenic variant in a biological sample from the subject; and (b) recommending the administration of at least one therapeutically effective amount of at least one compound of the present disclosure when the presence of the oncogenic mutation and/or the oncogenic variant is identified. [0266] In some aspects, the present disclosure provides a method of providing therapy recommendation for a subject having a cancer, the method comprising: (a) determining the presence or absence of an oncogenic mutation and/or an oncogenic variant in a biological sample from the subject; and (b) recommending the administration of a therapeutically effective amount of a compound of the present disclosure when the presence of the oncogenic mutation and/or the oncogenic variant is identified.

[0267] In some aspects, the present disclosure provides a method of providing therapy recommendation for a subject having a cancer, the method comprising: (a) determining the presence or absence of an oncogenic mutation and/or an oncogenic variant in a biological sample from the subject; and (b) recommending the administration of at least one compound of the present disclosure when the presence of the oncogenic mutation and/or the oncogenic variant is identified.

[0268] In some aspects, the present disclosure provides a method of providing therapy recommendation for a subject having a cancer, the method comprising: (a) determining the presence or absence of an oncogenic mutation and/or an oncogenic variant in a biological sample from the subject; and (b) recommending the administration of a compound of the present disclosure when the presence of the oncogenic mutation and/or the oncogenic variant is identified.

[0269] In some aspects, the present disclosure provides a method of treating a subject having a cancer, the method comprising: (a) determining the presence or absence of an oncogenic mutation and/or an oncogenic variant in a biological sample from the subject; and (b) administrating to the subject at least one therapeutically effective amount of at least one compound of the present disclosure when the presence of the oncogenic mutation and/or the oncogenic variant is identified.

[0270] In some aspects, the present disclosure provides a method of treating a subject having a cancer, the method comprising: (a) determining the presence or absence of an oncogenic mutation and/or an oncogenic variant in a biological sample from the subject; and (b) administrating to the subject a therapeutically effective amount of a compound of the present disclosure when the presence of the oncogenic mutation and/or the oncogenic variant is identified.

[0271] In some aspects, the present disclosure provides a method of treating a subject having a cancer, the method comprising: (a) determining the presence or absence of an oncogenic mutation and/or an oncogenic variant in a biological sample from the subject; and (b) administrating to the subject at least one compound of the present disclosure when the presence of the oncogenic mutation and/or the oncogenic variant is identified. [0272] In some aspects, the present disclosure provides a method of treating a subject having a cancer, the method comprising: (a) determining the presence or absence of an oncogenic mutation and/or an oncogenic variant in a biological sample from the subject; and (b) administrating to the subject a compound of the present disclosure when the presence of the oncogenic mutation and/or the oncogenic variant is identified.

[0273] In some aspects, the preceding methods can further comprise administering at least one therapeutically effective amount of at least a second anticancer therapy to the subject.

[0274] In some aspects, the preceding methods can further comprise administering a therapeutically effective amount of a second anticancer therapy to the subject.

[0275] In some aspects, the preceding methods can further comprise administering at least one second anticancer therapy to the subject.

[0276] In some aspects, the preceding methods can further comprise administering a second anticancer therapy to the subject.

[0277] In some aspects, the preceding uses can further comprise administering at least one therapeutically effective amount of at least a second anticancer therapy to the patient.

[0278] In some aspects, the preceding uses can further comprise administering a therapeutically effective amount of a second anticancer therapy to the patient.

[0279] In some aspects, the preceding uses can further comprise administering at least one second anticancer therapy to the patient.

[0280] In some aspects, the preceding uses can further comprise administering a second anticancer therapy to the patient.

[0281] In some embodiments, the second anticancer therapy is a surgical therapy, chemotherapy, radiation therapy, cryotherapy, hormonal therapy, toxin therapy, immunotherapy, or cytokine therapy.

[0282] In some aspects, the present disclosure provides a method of selecting a drug therapy for a patient having cancer comprising: (a) obtaining a sample of the cancer; (b) determining the presence or absence of an EGFR mutation C797 in the cancer; and (c) if the EGFR mutation C797 is present selecting and administering a therapeutically effective amount of a compound of the present disclosure to the subject. [0283] In some aspects, the present disclosure provides a method of selecting a drug therapy for a patient having cancer comprising: (a) obtaining a sample of the cancer; (b) determining the presence or absence of an EGFR mutation C797 in the cancer; and (c) if the EGFR mutation C797 is present selecting and administering a compound of the present disclosure to the subject.

Suitable Subjects and Diseases

[0284] In some embodiments, the subject is a mammal.

[0285] In some embodiments, the subject is a human.

[0286] In some embodiments, the subject has previously undergone at least one round of anticancer therapy. In some embodiments, the subject has previously undergone at least one round of anti-cancer therapy and has acquired resistance to treatment with the anti-cancer therapy. In some embodiments, the anti-cancer therapy can comprise the administration of EGFR TKIs.

[0287] In some embodiments, the subject is a non-human mammal.

[0288] In some embodiments, the subject has previously undergone at least one round of anticancer therapy.

[0289] In some embodiments, the subject has previously undergone one round of anti-cancer therapy.

[0290] In some embodiments, the subject has previously undergone two rounds of anti-cancer therapy.

[0291] In some embodiments, the subject has previously undergone three rounds of anti-cancer therapy.

[0292] In some embodiments, the subject is treated at least a second time.

[0293] In some embodiments, the subject is treated over a period of 1 week to 6 months.

[0294] In some embodiments, the subject has been shown to be resistant to selected first-generation inhibitors and/or selected second-generation inhibitors.

[0295] In some embodiments, the treatment results in one or more of: (a) inhibition of tumor growth; (b) reduction in tumor size; (c) reduction in the number of tumors, and (d) decreased tumor burden in the subject.

[0296] In some embodiments, the cancer is characterized by at least one oncogenic variant of at least one ErbB protein. In some embodiments, the at least one ErbB protein is EGFR. Accordingly, in some embodiments, the cancer is characterized by at least one oncogenic variant of EGFR. [0297] It is understood that a cancer that is characterized by at least one oncogenic variant of at least one ErbB protein is a cancer that is typically associated with the at least one oncogenic variant of the at least one ErbB protein, including, but not limited to, cancers whose primary oncogenic activity is thought to be driven by the at least one oncogenic variant in the at least one ErbB protein. It is understood that an oncogenic variant of an ErbB protein (e.g. EGFR) is an ErbB protein (e.g. EGFR) that comprises at least one oncogenic mutation.

[0298] As would be appreciated by the skilled artisan, an oncogenic mutation can include, but is not limited to, a mutation that results in the substitution of one amino acid for another at a specific position within an ErbB protein (e.g. EGFR), an insertion of one or more amino acids between two positions within an ErbB protein (e.g. EGFR), a deletion of one more amino acids between two positions within an ErbB protein (e.g. EGFR).

[0299] As would be appreciated by the skilled artisan, in the context of a gene, an oncogenic mutation can include, but is not limited to, a missense mutation, a nonsynonymous mutation, an insertion of one or more nucleotides, a deletion of one or more nucleotides, an inversion and a deletion-insertion.

[0300] As would be appreciated by the skilled artisan, in the context of a protein (e.g. EGFR), an oncogenic mutation, but is not limited to, the substitution of one amino acid for another at a specific position within EGFR, an insertion of one or more amino acids between two positions within EGFR, a deletion of one more amino acids between two positions within EGFR, and a fusion of EGFR, or portion thereof, with another protein, or portion thereof.

[0301] A wild type EGFR sequence of the disclosure may comprise or consist of the amino acid sequence of:

1 mrpsgtagaa llallaalcp as raleekkv cqgtsnkltq Igtfedhfls Iqrmfnncev

61 vlgnleityv qrnydls flk tiqevagyvl ialntverip lenlqiirgn myyensyala

121 vlsnydankt glkelpmrnl qeilhgavrf snnpalcnve siqwrdivs s dflsnmsmdf

181 qnhlgs cqkc dps cpngs cw gageencqkl tkiicaqqcs grcrgkspsd cchnqcaagc

241 tgpresdclv crkfrdeatc kdtcpplmly npttyqmdvn pegkys fgat cvkkcprnyv

301 vtdhgs cvra cgadsyemee dgvrkckkce gpcrkvcngi gigefkdsls inatnikhfk

361 nctsisgdlh ilpvafrgds fthtppldpq eldilktvke itgflliqaw penrtdlhaf

421 enleiirgrt kqhgqfslav vslnitslgl rslkeisdgd viisgnknlc yantinwkkl

481 fgtsgqktki isnrgens ck atgqvchalc spegcwgpep rdcvscrnvs rgrecvdkck

541 llegeprefv enseciqchp eclpqamnit ctgrgpdnci qcahyidgph cvktcpagvm

601 genntlvwky adaghvchlc hpnctygctg pglegcptng pkipsiatgm vgalllllvv

661 algigl fmrr rhivrkrtlr rllqerelve pltpsgeapn qallrilket efkkikvlgs

721 gafgtvykgl wipegekvki pvaikelrea tspkankeil deayvmasvd nphvcrllgi

781 cltstvqlit qlmpfgclld yvrehkdnig sqyllnwcvq iakgmnyled rrlvhrdlaa

841 rnvlvktpqh vkitdfglak llgaeekeyh aeggkvpikw malesilhri ythqsdvwsy

901 gvtvwelmtf gs kpydgipa seis silekg erlpqppict idvymimvkc wmidads rpk

961 freliiefs k mardpqrylv iqgdermhlp sptdsnfyra Imdeedmddv vdadeylipq 1021 qgffs spsts rtplls slsa tsnnstvaci drnglqs cpi keds flqrys sdptgalted

1081 siddtflpvp eyinqsvpkr pagsvqnpvy hnqplnpaps rdphyqdphs tavgnpeyln

1141 tvqptcvnst fdspahwaqk gshqisldnp dyqqdffpke akpngi fkgs taenaeylrv

1201 apqs sefiga (SEQ ID NO: 1, corresponding to epidermal growth factor receptor [Homo sapiens] and Genbank Accession No. CAA25240).

[0302] In some embodiments, the ErbB protein has at least one deletion in Exon 19. Accordingly, in aspects wherein the ErbB protein is EGFR, the oncogenic variant of EGFR has at least one deletion in Exon 19 (EGFR-A19).

[0303] In some embodiments wherein the ErbB protein is EGFR, the oncogenic variant of EGFR can have an oncogenic mutation which is a substitution of the Cysteine residue at position 797 for another amino acid. That is, in some embodiments, the oncogenic variant of EGFR has an amino acid substitution of the Cysteine residue at position 797, herein referred to as "EGFR-C797X," "C797 mutation" or "EGFR mutation C797."

[0304] In some embodiments, an amino acid substitution of the Cysteine residue at position 797 of EGFR can be a substitution of Serine for the Cysteine (C797S). Accordingly, the oncogenic variant of EGFR can be EGFR-C797S.

[0305] In some embodiments, an amino acid substitution of the Cysteine residue at position 797 of EGFR can be a substitution of Glycine for the Cysteine (C797G). Accordingly, the oncogenic variant of EGFR can be EGFR-C797S.

[0306] In some embodiments wherein the ErbB protein is EGFR, the oncogenic variant of EGFR can have a first and an at least second oncogenic mutations, wherein the first oncogenic mutation is a substitution of the Cysteine residue at position 797 for another amino acid, and wherein the at least second oncogenic mutation is a deletion of one more amino acids, wherein the deletion is in Exon 19. Accordingly, the oncogenic variant of EGFR can be EGFR-C797X-A19.

[0307] In some embodiments, the subject is a subject who has been shown to have developed an oncogenic variant of EGFR as the result of a previous anti-cancer treatment.

[0308] In some embodiments, the subject is a subject who has an oncogenic variant of at least one ErbB protein. In some embodiments, the subject is a subject who has an oncogenic variant of EGFR.

[0309] In some embodiments, the cancer is a carcinoma, a lymphoma, a blastoma, a sarcoma, a leukemia, a brain cancer, a breast cancer, a blood cancer, a bone cancer, a lung cancer, a skin cancer, a liver cancer, an ovarian cancer, a bladder cancer, a renal cancer, a kidney cancer, a gastric cancer, a thyroid cancer, a pancreatic cancer, an esophageal cancer, a prostate cancer, a cervical cancer, a uterine cancer, a stomach cancer, a soft tissue cancer, a laryngeal cancer, a small intestine cancer, a testicular cancer, an anal cancer, a vulvar cancer, a joint cancer, an oral cancer, a pharynx cancer, a renal pelvis cancer, intrahepatic bile duct cancer, bronchus cancer or a colorectal cancer. [0310] In some embodiments, the cancer is metastatic, recurrent, or multi-drug resistant.

[0311] In some embodiments, the cancer comprises malignant primary cancer tumors.

[0312] In some embodiments, the cancer comprises metastatic secondary cancer tumors.

[0313] In some embodiments, the cancer is non-small cell lung cancer (NSCLC), glioblastoma, breast, head or neck, colon, gastric, pancreatic, bladder cancer.

[0314] In some embodiments, the cancer is NSCLC.

[0315] In some embodiments, the NSCLC is an metastatic NSCLC tumor in the brain.

[0316] In some embodiments, the NSCLC is in the brain.

[0317] In some embodiments, the cancer is resistant to treatment with EGFR TKIs.

[0318] In some embodiments, EGFR TKIs can include, but are not limited to, gefitinib, erlotinib, osimertinib, rociletinib, olmutinib, naquotinib, nazartinib an any other EGFR TKI known in the art.

[0319] The compound of the present disclosure to be administered contains asymmetric centers and thus - without designation of the stereochemistry - it is to be understood to include all the optical isomers (e.g., diastereomers, enantiomers, etc) in pure or substantially pure form, as well as mixtures thereof (e.g. a racemic mixture, or an enantiomerically enriched mixture). It is well known in the art how to prepare such optically active forms (e.g. by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, by chromatographic separation using a chiral stationary phase, and other methods).

The compounds can be isotopically-labeled compounds, for example, compounds including various isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, or chlorine.

[0320] The compound of the present disclosure to be administered also includes any pharmaceutically acceptable salts and stereoisomers thereof, see e.g. Berge et al, "Pharmaceutical Salts," J. Pharm. Sci, 1977:66: 1-19. It may exist in solid, i.e. crystalline or noncrystalline form (optionally as solvates) or liquid form. In the solid state, it may exist in, or as a mixture thereof. In crystalline solvates, solvent molecules are incorporated into the crystalline lattice during crystallization. The formation of solvates may include non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or aqueous solvents such as water (also called “hydrates”). It is common knowledge that crystalline forms (and solvates thereof) may exhibit polymorphism, i.e. exist in different crystalline structures known as "polymorphs”, that have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties, and may display different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. Such different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, during preparation of the compound of the present disclosure.

[0321] Administration of compound of Formula I may be in form of a pharmaceutical composition.

[0322] It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3 ^rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N. Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N. Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18 ^th edition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure.

[0323] It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0324] The term "pharmaceutical composition" is intended to encompass a composition comprising the specified pharmaceutically active compound(s) in the specified amounts in combination with one or more pharmaceutically acceptable carriers and/or excipients for the administration route of choice. The amount of pharmaceutically active compound in each case should be in amounts which are sufficient to achieve the dosage ranges given below. Thus, the disclosure further provides a pharmaceutical composition comprising a therapeutically-effective amount of a compound of the present disclosure or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and/or excipients. The excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).

[0325] The term "therapeutically-effective amount" as used herein refers to the amount of a compound of the present disclosure that results in a beneficial effect for at least a statistically significant fraction of patients, such as an improvement of symptoms, a cure, a reduction in disease load, reduction in tumor mass or cell numbers, extension of life, improvement in quality of life, or other effect generally recognized as positive by medical doctors familiar with treating the particular type of disease or condition.

[0326] Pharmaceutical compositions of a compound of the present disclosure may be in unit dose form containing a predetermined amount of a compound of the present disclosure per unit dose. Such a unit may contain a therapeutically effective dose of a compound of the present disclosure or salt thereof or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of a compound of the present disclosure or salt thereof.

[0327] In some embodiments the cancer to be treated comprising an EGFR mutation C797 is metastatic, recurrent, or multi-drug resistant. In other embodiments the cancer to be treated comprising an EGFR mutation C797 comprises malignant primary cancer tumors and/or metastatic secondary cancer tumors.

[0328] The compound of the present disclosure may be administered by any acceptable means in solid or liquid form, including (1) oral administration, for example, drenches (aqueous or nonaqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8) nasally; (9) pulmonary; or (10) intrathecally. [0329] The phrase "pharmaceutically-acceptable carrier" as used herein means a pharmaceuti- cally-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical compositions.

[0330] Such compositions may contain further components conventional in pharmaceutical preparations, e.g. wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants, pH modifiers, bulking agents, and further active agents. Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0331] Such compositions may be prepared by any method known in the art, for example, by bringing into association the active ingredient with one or more carriers and/or excipients. Different compositions and examples of carriers and/or excipients are well known to the skilled person and are described in detail in, e.g., Remington: The Science and Practice of Pharmacy. Pharmaceutical Press, 2013; Rowe, Sheskey, Quinn: Handbook of Pharmaceutical Excipients. Pharmaceutical Press, 2009. Excipients that may be used in the preparation of the pharmaceutical compositions may include one or more of buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide a composition suitable for an administration of choice.

[0332] As indicated above, the compounds of the present disclosure may be in solid or liquid form and administered by various routes in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.

[0333] In solid dosage forms of the present disclosure for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), a compound is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and nonionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets, and other solid dosage forms of the pharmaceutical compositions of the present disclosure, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0334] Liquid dosage forms for oral administration of the compounds of the present disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. An oral composition can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0335] In form of suspensions, a compound may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. [0336] Dosage forms for rectal or vaginal administration of a compound of the present disclosure include a suppository, which may be prepared by mixing one or more compounds of the present disclosure with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. Other suitable forms include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0337] Dosage forms for the topical or transdermal administration of a compound of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically- acceptable carrier, and with any preservatives, buffers, or propellants which may be required. Such ointments, pastes, creams and gels may contain, in addition to a compound of the present disclosure, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0338] Dosage forms such as powders and sprays for administration of a compound of the present disclosure, may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0339] Dosage forms such as transdermal patches for administration of a compound of the present disclosure may include absorption enhancers or retarders to increase or decrease the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel. Other dosage forms contemplated include ophthalmic formulations, eye ointments, powders, solutions and the like. It is understood that all contemplated compositions must be stable under the conditions of manufacture and storage, and preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0340] The dosage levels of a compound of the present disclosure in the pharmaceutical compositions of the present disclosure may be adjusted in order to obtain an amount of a compound of the present disclosure which is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being deleterious to the subject. The dosage of choice will depend upon a variety of factors including the nature of the particular compound of the present disclosure used, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound used, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts. A medical practitioner having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.

[0341] Typically, a suitable daily dose of a compound of the present disclosure will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this present disclosure for a subject, when used for the indicated analgesic effects, will range from about 0.1 to 100 mg/kg per kilogram of body weight of recipient (subject, mammal) per day.

[0342] The effective dose of a compound of the present disclosure may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout a specified period (per day or per week or per month), optionally, in unit dosage forms. Preferred dosing also depends on factors as indicated above, e.g. on the administration, and can be readily arrived at by one skilled in medicine or the pharmacy art.

[0343] The compounds of the present disclosure may be used in a combination treatment with at least a second anticancer therapy, such as a surgical therapy, chemotherapy, radiation therapy, cryotherapy, hormonal therapy, toxin therapy, immunotherapy, or cytokine therapy. The term "treatment" is intended to encompass prophylaxis, therapy and cure.

[0344] The compound of the present disclosure and further therapeutically active agent may be administered separately (which implies that they are formulated separately) or together (which implies that they are formulated together). Hence, the administration of compound of the present disclosure may be prior to, concurrent to, or subsequent to the administration of the other active agent of the combination. [0345] The method of treatment enabled by the present disclosure comprises administration of therapeutically effective amount of the compound of the present disclosure, optionally in combination with the administration of a further therapeutically active agent, to a subject in need thereof. [0346] In the uses and method of treatment enabled by the present disclosure the compound of the present disclosure is administered intermittent or in a daily dosage such that the plasma level of the active substance preferably lies between 10 and 5000 nM for at least 12 hours of the dosing interval. The compound of the present disclosure may be administered to the subject in a daily dose of 0.01-4 mg/kg of body weight (bw). For oral treatment the compounds of formula (I) may be administered daily in a total dose of about 0.1 mg to about 1000 mg, optionally divided into multiple doses, e.g. 1 to 3 doses to be administered through the day. In some embodiments, the oral daily dose is administered only once. Especially for higher doses periods of treatment should alternate with periods of recovery, without administering the compound of the present disclosure. For instance, treatment could follow a "7 day on - 7 day off, a " 14 day on - 14 day off, a "21 day on 7 day off or a continuous dosing schedule. "On-off time periods can be chosen shorter, especially if higher doses are administered, or individually adapted to the needs of the subject. The skilled person will know it may be necessary to deviate from the amounts specified, depending on the body weight or method of administration, the individual response to the medication, the nature of the formulation used and the time or interval over which it is administered. Thus, in some cases, it may be sufficient to use less than the minimum quantity specified above, while in other cases the upper limit specified will have to be exceeded. When large amounts are administered it may be advisable to spread them over the day in a number of single doses.

[0347] Dosages and treatment schedules for the optionally included further therapeutically active agent are known in the art and may be applied analogously for the present disclosure. The dosage of the therapeutically active agent(s) in a combination may be reduced, e.g. may vary in the range of 1/1 to 1/20 of the dosages described in the prior art.

Definitions

[0348] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below. [0349] Without wishing to be limited by this statement, it is understood that, while various options for variables are described herein, the disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options.

[0350] It is to be understood that a compound of the present disclosure may be depicted in a neutral form, a cationic form (e.g., carrying one or more positive charges), or an anionic form (e.g., carrying one or more negative charges), all of which are intended to be included in the scope of the present disclosure. For example, when a compound of the present disclosure is depicted in an anionic form, such depiction also refers to the various neutral forms, cationic forms, and anionic forms of the compound. For another example, when a compound the present disclosure is depicted in an anionic form, such depiction also refers to various salts (e.g., sodium salt) of the anionic form of the compound. In some embodiments, the amine of a compound of the present disclosure is protonated.

[0351] The term "compound of the present disclosure” refers to any of the compound of formula I to IV including all their forms, such as polymorphs, hydrates, solvates or pharmaceutically acceptable salt.

[0352] It is understood that “independently of each other” means that when a group is occurring more than one time in any compound, its definition on each occurrence is independent from any other occurrence. It is further understood that a dashed line (or a wave being transverse to a bond) depicts the site of attachment of a residue (i.e. a partial formula).

[0353] The term "halogen" or "hal" as used herein may be fluoro, chloro, bromo or iodo preferably fluoro, chloro.

[0354] The term "alkyl" as used herein refers to a fully saturated branched or unbranched hydrocarbon moiety. The term "Ci-6 alkyl" and "Ci-4alkyl" refer to a fully saturated branched or unbranched hydrocarbon moiety having 1, 2, 3, 4, 5 or 6 carbon atoms and 1, 2, 3 or 4 carbon atoms, respectively. Representative examples of Ci-4alkyl include, but are not limited to, methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl.

[0355] As used herein, the term “aryl” includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. Conveniently, an aryl is phenyl, the term “aryl” includes multicyclic aryl, e.g., tricyclic, bicyclic, e.g., naphthalene,

[0356] As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =0), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0357] 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.

[0358] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

[0359] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O'.

[0360] As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkyl- carbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphon- amido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

[0361] As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and/or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.

[0362] The term "biological sample" as used herein refers to any biological material isolated from a subject. In non-limiting examples, a biological sample can comprise blood, plasma, serum, urine, breast milk, cerebrospinal fluid, mucus, gastric juice, peritoneal fluid, pleural fluid, saliva, sebum, semen, sweat, tears, vaginal secretion, vomit, endolymph, perilymph or any combination thereof. In non-limiting examples, a biological sample can comprise a tissue sample, wherein the tissue sample comprises cancerous tissue, non-cancerous tissue or a combination thereof.

[0363] As would be appreciated by the skilled artisan, anti-cancer therapy can include, but is not limited to, a surgical therapy, chemotherapy, radiation therapy, cryotherapy, hormonal therapy, toxin therapy, immunotherapy, cytokine therapy or any combination thereof.

[0364] In some embodiments, chemotherapy may include administration of a further therapeutically active agent such as for example:

Tyrosine kinase inhibitors: Erlotinib hydrochloride (e.g. Tarceva® by Genentech/Roche), Linifanib (or ABT 869, by Genentech), sunitinib malate (e.g. Sutent® by Pfizer), bosutinib (or SKI-606, described in US 6,780,996), dasatinib (e.g. Sprycel® by Bristol-Myers Squibb), armala (e.g. pazopanib, e.g. Votrient® by GlaxoSmithKline), imatinib and imatinib mesylate (e.g. Gil- vec® and Gleevec® by Novartis); ascular Endothelial Growth Factor (VEGF) receptor inhibitors: Bevacizumab, or Avastin® (by Genentech/Roche), axitinib, (or AG013736, described in WO 01/002369), Brivanib Alaninate (or BMS-582664), motesanib (or AMG-706, described in PCT WO 02/066470), pasireotide (e.g. SOM230, described in WO 02/010192), sorafenib (e.g. Nexavar®);

HER2 receptor inhibitors: Trastuzumab (e.g. Herceptin® by Genentech/Roche), neratinib (or HKI-272, described WO 05/028443), lapatinib or lapatinib ditosylate (e.g. Tykerb® by GlaxoSmithKline); CD20 antibodies: Rituximab (e.g. Riuxan® and Mab Thera® by Genentech/Roche), tositumomab (e.g. Bexxar® by GlaxoSmithKline), ofatumumab (e.g. Arzerra® by GlaxoSmithKline);

Bcr/Abl kinase inhibitors: nilotinib hydrochloride (e.g. Tasigna® by Novartis); DNA Synthesis inhibitors: Capecitabine (e.g. Xeloda® by Roche), gemcitabine hydrochloride (e.g. Gemzar® by Eli Lilly and Company), nelarabine (or Arranon® and Atriance® by GlaxoSmithKline); Antineoplastic agents: oxaliplatin (e.g. Eloxatin® ay Sanofi-Aventis described in US 4,169,846 );

Epidermal growth factor receptor (EGFR) inhibitors: Gefitinib (or Iressa®), Afatinib (or Tovok® by Boehringer Ingelheim), cetuximab (e.g. Erbitux® by Bristol-Myers Squibb), pani- tumumab (e.g. Vectibix® by Amgen);

HER dimerization inhibitors: Pertuzumab (e.g. Omnitarg®, by Genentech); Human Granulocyte colony-stimulating factor (G-CSF) modulators: Filgrastim (e.g. Neupogen® by Amgen);

Immunomodulators: Afutuzumab (by Roche), pegfilgrastim (e.g. Neulasta® by Amgen), lenalidomide (e.g. CC-5013, e.g. Revlimid®), thalidomide (e.g. Thalomid®);

CD40 inhibitors: Dacetuzumab (e.g. SGN-40 or huS2C6, by Seattle Genetics, Inc); Pro- apoptotic receptor agonists (PARAs): Dulanermin (e.g. AMG-951, by Amgen/Genentech);

Hedgehog antagonists: Vismodegib (or GDC-0449, described in WO 06/028958);

PI3K inhibitors: Pictilisib (or GDC-0941 described in WO 09/036082 and WO 09/055730 ), Dactolisib (or BEZ 235 or NVP-BEZ 235, described in WO 06/122806);

Phospholipase A2 inhibitors: Anagrelide (e.g. Agrylin®);

BCL-2 inhibitors: Navitoclax (or ABT-263, described in WO 09/155386);

Mitogen-activated protein kinase (MEK) inhibitors: XL-518 (Cas No. 1029872-29-4, by ACC Corp.); Aromatase inhibitors: Exemestane (e.g. Aromasin® by Pfizer), letrozole (e.g. Femara® by Novartis), anastrozole (e.g. Arimidex®);

Topoisomerase I inhibitors: Irinotecan (e.g. Camptosar® by Pfizer), topotecan hydrochloride (e.g. Hycamtin® by GlaxoSmithKline);

Topoisomerase II inhibitors: etoposide (e.g. VP-16 and Etoposide phosphate, e.g. Toposar®, VePesid® and Etopophos®), teniposide (e.g. VM-26, e.g. Vumon®); mTOR inhibitors: Temsirolimus (e.g. Torisel® by Pfizer), ridaforolimus (formally known as deferolimus, (or AP23573 and MK8669, described in WO 03/064383), everolimus (e.g. Afini- tor® by Novartis);

Osteoclastic bone resorption inhibitors: zoledronic acid (or Zometa® by Novartis);

CD33 Antibody Drug Conjugates: Gemtuzumab ozogamicin (e.g. Mylotarg® by Pfizer/Wyeth);

CD22 Antibody Drug Conjugates: Inotuzumab ozogamicin (also referred to as CMC-544 and WAY-207294, by Hangzhou Sage Chemical Co., Ltd.);

CD20 Antibody Drug Conjugates: Ibritumomab tiuxetan (e.g. Zevalin®); Somatostain analogs: octreotide (e.g. octreotide acetate, e.g. Sandostatin® and Sandostatin LAR®);

Synthetic Interleukin- 11 (IL-11): oprelvekin (e.g. Neumega® by Pfizer/Wyeth); Synthetic erythropoietin: Darbepoetin alfa (e.g. Aranesp® by Amgen);

Receptor Activator for Nuclear Factor kappa B (RANK) inhibitors: Denosumab (e.g. Pro- lia® by Amgen);

Thrombopoietin mimetic peptibodies: Romiplostim (e.g. Nplate® by Amgen;

Cell growth stimulators: Palifermin (e.g. Kepivance® by Amgen);

Anti-Insulin-like Growth Factor-1 receptor (IGF-1R) antibodies: Figitumumab (e.g. CP- 751,871, by ACC Corp), robatumumab (CAS No. 934235-44-6);

Anti-CSl antibodies: Elotuzumab (HuLuc63, CAS No. 915296-00-3);

CD52 antibodies: Alemtuzumab (e.g. Campath®);

CTLA-4 inhibitors: Tremelimumab (IgG2 monoclonal antibody by Pfizer, formerly known as ticilimumab, CP-675,206), ipilimumab (CTLA-4 antibody, e.g. MDX-010, CAS No. 477202- 00-9);

Histone deacetylase inhibitors (HDI): Voninostat (e.g. Zolinza® by Merck); Alkylating agents: Temozolomide (e.g. Temodar® and Temodal® by Schering- Plough/Merck), dactinomycin (e.g. actinomycin-D and e.g. Cosmegen®), melphalan (e.g. L-PAM, L-sarcolysin, and phenylalanine mustard, e.g. Alkeran®), altretamine (e.g. hexamethylmelamine (HMM), e.g. Hexalen®), carmustine (e.g. BiCNU®), bendamustine (e.g. Treanda®), busulfan (e.g. Busulfex® and Myleran®), carboplatin (e.g. Paraplatin®), lomustine (e.g. CCNU, e.g. CeeNU®), cisplatin (e.g. CDDP, e.g. Platinol® and Platinol®-AQ), chlorambucil (e.g. Leukeran®), cyclophosphamide (e.g. Cytoxan® and Neosar®), dacarbazine (e.g. DTIC, DIC and imidazole carboxamide, e.g. DTIC-Dome®), altretamine (e.g. hexamethylmelamine (HMM) e.g. Hexalen®), ifosfamide (e.g. Ifex®), procarbazine (e.g. Matulane®), mechlorethamine (e.g. nitrogen mustard, mustine and mechloroethamine hydrochloride, e.g. Mustargen®), streptozocin (e.g. Zanosar®), thiotepa (e.g. thiophosphoamide, TESPA and TSP A, e.g. Thioplex®;

Biologic response modifiers: bacillus calmette-guerin (e.g. theraCys® and TICE® BCG), denileukin diftitox (e.g. Ontak®);

Anti-tumor antibiotics: doxorubicin (e.g. Adriamycin® and Rubex®), bleomycin (e.g. le- noxane®), daunorubicin (e.g. dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, e.g. Cerubidine®), daunorubicin liposomal (daunorubicin citrate liposome, e.g. DaunoX- ome®), mitoxantrone (e.g. DHAD, e.g. Novantrone®), epirubicin (e.g. Ellence™), idarubicin (e.g. Idamycin®, Idamycin PFS®), mitomycin C (e.g. Mutamycin®);

Anti-microtubule agents: Estramustine (e.g. Emcyl®);

Cathepsin K inhibitors: Odanacatib (or MK-0822, by Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, described in WO 03/075836);

Epothilone B analogs: Ixabepilone (e.g. Lxempra® by Bristol-Myers Squibb);

Heat Shock Protein (HSP) inhibitors: Tanespimycin (17-allylamino-17-demethoxygel- danamycin, e.g. KOS-953 and 17-AAG, by SIGMA, described in US 4,261,989);

TpoR agonists: Eltrombopag (e.g. Promacta® and Revolade® by GlaxoSmithKline);

Anti-mitotic agents: Docetaxel (e.g. Taxotere® by Sanofi -Aventis);

Adrenal steroid inhibitors: aminoglutethimide (e.g. Cytadren®);

Anti-androgens: Nilutamide (e.g. Nilandron® and Anandron®), bicalutamide (sold under tradename Casodex®), flutamide (e.g. Fulexin™);

Androgens: Fluoxymesterone (e.g. halotestin®); Proteasome inhibitors: Bortezomib (e.g. Velcade®); CDK1 inhibitors: Alvocidib (e.g. flovopirdol or HMR-1275, described in US 5,621,002);

Gonadotropin-releasing hormone (GnRH) receptor agonists: Leuprolide or leuprolide acetate (e.g. Viadure® by Bayer AG, Eligard® by Sanofi -Aventis and Lupron® by Abbott Lab);

Taxane anti-neoplastic agents: Cabazitaxel, larotaxel;

5HTla receptor agonists: Xaliproden (or SR57746, described in US 5,266,573);

HPC vaccines: Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck;

Iron Chelating agents: Deferasinox (e.g. Exjade® by Novartis);

Anti-metabolites: Claribine (2-chlorodeoxyadenosine, e.g. leustatin®), 5 -fluorouracil (e.g. Adrucil®), 6-thioguanine (e.g. Purinethol®), pemetrexed (e.g. Alimta®), cytarabine (e.g. arabino- sylcytosine (Ara-C), e.g. Cytosar-U®), cytarabine liposomal (e.g. Liposomal Ara-C, e.g. Depo- Cyt™), decitabine (e.g. Dacogen®), hydroxyurea (e.g. Hydrea®, Droxia™ and Mylocel™), fludarabine (e.g. Fludara®), floxuridine (e.g. FUDR®), cladribine (e.g. 2-chlorodeoxyadenosine (2-CdA) e.g. Leustatin™), methotrexate (e.g. amethopterin, methotrexate sodium (MTX), e.g. Rheumatrex® and Trexall™), pentostatin (e.g. Nipent®);

Bisphosphonates: Pamidronate (e.g. Aredia®), zoledronic acid (e.g. Zometa®);

Demethylating agents: 5-azacitidine (e.g. Vidaza®), decitabine (e.g. Dacogen®);

Plant Alkaloids: Paclitaxel protein-bound (e.g. Abraxane®), vinblastine (e.g. vinblastine sulfate, vincaleukoblastine and VLB, e.g. Alkaban-AQ® and Velban®), vincristine (e.g. vincristine sulfate, LCR, and VCR, e.g. Oncovin® and Vincasar Pfs®), vinorelbine (e.g. Navelbine®), paclitaxel (e.g. Taxol and Onxal™);

Retinoids: Alitretinoin (e.g. Panretin®), tretinoin (all-trans retinoic acid, e.g. ATRA, e.g. Vesanoid®), Isotretinoin (13-cis-retinoic acid, e.g. Accutane®, Amnesteem®, Claravis®, Claims®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), bexarotene (e.g. Targre- tin®);

Glucocorticosteroids: Hydrocortisone (e.g. cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and e.g. Ala-Cort®, Hydrocortisone Phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort®), dexamethasone, prednisolone (e.g. Delta-Cortel®, Orapred®, Pediapred® and Prelone®), prednisone (e.g. Deltasone®, Liquid Red®, Meticorten® and Orasone®), methylprednisolone (e.g. 6-Methylprednisolone, Methylprednisolone Acetate, Methylprednisolone Sodium Succinate, e.g. Duralone®, Medralone®, Medrol®, M-Prednisol® and Solu-Medrol®); Cytokines: interleukin-2 (e.g. aldesleukin and IL-2, e.g. Proleukin®), interleukin- 11 (e.g. oprevelkin, e.g. Neumega®), alpha interferon alfa (e.g. IFN-alpha, e.g. Intron® A, and Roferon- A®);

Lutinizing hormone releasing hormone (LHRH) agonists: Goserelin (e.g. Zoladex®); Progesterones: megestrol (e.g. megestrol acetate, e.g. Megace®);

Miscellaneous cytotoxic agents: Arsenic trioxide (e.g. Trisenox®), asparaginase (e.g. L- asparaginase, Erwinia L-asparaginase, e.g. Elspar® and Kidrolase®);

Anti-nausea drugs: NK-1 receptor antagonists: Casopitant (e.g. Rezonic® and Zunrisa® by GlaxoSmithKline); or

Cytoprotective agents: Amifostine (e.g. Ethyol®), leucovorin (e.g. calcium leucovorin, cit- rovorum factor and folinic acid).

[0365] In some embodiments, combinations may include combinations with a therapeutically active agent such as osimertinib, afatinib, neratinib, poziotinib, TAK-788, or dacomitinib.

[0366] In some embodiments, combinations may include combinations with osimertinib, afatinib, neratinib, poziotinib, TAK-788, or dacomitinib.

[0367] As used herein, "acquiring resistance” or “acquired resistance" refers to a condition wherein a cancer that was sensitive to the inhibitory effects of at least one anti-cancer treatment becomes non-responsive or less-responsive over time to the effects of that at least one anti-cancer treatment. In a non-limiting example, the cancer may be a cancer characterized by an oncogenic variant of EGFR, wherein the cancer was previous sensitive to the inhibitory effects of at least one EGFR TKI, but has become non-responsive or less-responsive over time to the effects of the at least one EGFR-TKI. Without wishing to be bound by any one theory, it is believed that acquired resistance to EGFR-TKIs in EGFR-mutant cancers occurs due to one or more additional mutations to EGFR or non-EGFR genetic alterations in bypass signaling that develops after the onset of an EGFR-TKI treatment regimen. For example, non-limiting exemplary acquired resistance EGFR- mutants in NSCLCs include, but are not limited to, EGFR T790M substitutions, in particular C797 substitutions, i.e. C797S and C797G substitutions. In contrast, an intrinsic (or primary) resistance refers to a condition wherein a cancer with a EGFR mutation is not responsive to the inhibitory effects of initial EGFR-TKI treatment. A diagnosis of TKI resistance may be accomplished by way of monitoring tumor progression during treatment with the respective TKI(s) by e.g. comparing tumor status with time, such as by means of radiography, for example, X-ray, CT scan, and other known monitoring methods, by palpitation of the cancer or by monitoring tumor biomarker levels, indicating tumor growth, new tumors or metastasis or tumor growth, or else by testing for the occurrence of an EGFR mutation C797.

[0368] As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the subject is a human.

[0369] As used herein, the term “subject in need thereof’ refers to a subject having a disease or having an increased risk of developing the disease. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy.

[0370] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model.

[0371] It is to be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevant disease, condition, or disorder, or used to identify suitable candidates for such purposes. [0372] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0373] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

[0374] In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.

[0375] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.

Exemplary Embodiments

[0376] Embodiment 1. A compound of formula I: or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:

X ¹ is -O-, -S-, or -NR ² -; each R ^a independently is -H or -Ci-4 alkyl; each R ^b independently is -H or -Ci-4 alkyl; each R ^c independently is -H or -Ci-4 alkyl; each R ^d independently is -H or -Ci-4 alkyl;

R ¹ is -H or -Ci-4 alkyl;

R ² is -H or -Ci-4 alkyl;

R ³ is -H or -O-Ci-4 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and

Ar ¹ is Ce-io aryl optionally substituted with one or more halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH ₂ , -NH(CI-6 alkyl), -N(CI-C ₆ alkyl) ₂ , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) ₂ , -C(O)O(Ci-6 alkyl), or - NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH ₂ , - NH(CI-C ₆ alkyl), or -N(CI-C ₆ alkyl) ₂ .

[0377] Embodiment 2. The compound of embodiment 1, wherein the compound is not 2-[4-[4- (3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiper idin-l-yl]-7V-methylacetamide or 2-(3-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazoli n-6-yl)oxy)azetidin-l-yl)-N- methylacetamide.

[0378] Embodiment 3. The compound of any one of the preceding embodiments, wherein when X ¹ is O, R ³ is -OMe, R ¹ , R ^a , R ^b , R ^c , and R ^d are each -H, n and m are each 2, then Ar ¹ is not 3- chloro-2-fluorophenyl, and when X ¹ is O, R ³ is -OMe, R ¹ , R ^a , R ^b , R ^c , and R ^d are each -H, n and m are each 1, then Ar ¹ is not 3-chloro-2-fluorophenyl.

[0379] Embodiment 4. The compound of any one of the preceding embodiments, wherein:

X ¹ is -O-, -S-, or -NR ² -; each R ^a independently is -H or -Ci-4 alkyl; each R ^b independently is -H or -Ci-4 alkyl; each R ^c independently is -H or -Ci-4 alkyl; each R ^d independently is -H or -Ci-4 alkyl; R ¹ is -H or -Ci-4 alkyl;

R ² is -H or -Ci-4 alkyl;

R ³ is -H or -O-Ci-4 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and

Ar ¹ is Ce-io aryl optionally substituted with one or more halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH ₂ , -NH(CI-6 alkyl), -N(CI-C ₆ alkyl) ₂ , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) ₂ , -C(O)O(Ci-6 alkyl), or - NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH ₂ , - NH(CI-C ₆ alkyl), or -N(CI-C ₆ alkyl) ₂ ; provided that the compound is not 2-[4-[4-(3-chloro-2-fluoroanilino)-7-methox- yquinazolin-6-yl]oxypiperidin-l-yl]-A-methylacetamide or 2-(3-((4-((3-chloro-2- fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-l- yl)-N-methylacetamide.

[0380] Embodiment 5. The compound of any one of the preceding embodiments, wherein:

X ¹ is -O-, -S-, or -NR ² -; each R ^a independently is -H or -Ci-4 alkyl; each R ^b independently is -H or -Ci-4 alkyl; each R ^c independently is -H or -Ci-4 alkyl; each R ^d independently is -H or -Ci-4 alkyl;

R ¹ is -H or -C1-4 alkyl;

R ² is -H or -C1-4 alkyl;

R ³ is -H or -O-C1-4 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and

Ar ¹ is Ce-io aryl optionally substituted with one or more halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH ₂ , -NH(CI-6 alkyl), -N(CI-C ₆ alkyl) ₂ , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) ₂ , -C(O)O(Ci-6 alkyl), or - NHC(O)O(CI-6 alkyl) is optionally substitued with one or more hydroxy, C1-6 alkoxy, -NH ₂ , - NH(CI-C ₆ alkyl), or -N(CI-C ₆ alkyl) ₂ ; provided that when X ¹ is O, R ³ is -OMe, R ¹ , R ^a , R ^b , R ^c , and R ^d are each H, n and m are each 2, then Ar ¹ is not 3-chloro-2-fluorophenyl, and when X ¹ is O, R ³ is -OMe, R ¹ , R ^a , R ^b , R ^c , and R ^d are each H, n and m are each 1, then Ar ¹ is not 3-chloro-2-fluorophenyl.

[0381] Embodiment 6. The compound of any one of the preceding embodiments, wherein X ¹ is -O-.

[0382] Embodiment 7. The compound of any one of the preceding embodiments, wherein X ¹ is -S-.

[0383] Embodiment 8. The compound of any one of the preceding embodiments, wherein X ¹ is -NR ² -.

[0384] Embodiment 9. The compound of any one of the preceding embodiments, wherein X ¹ is -NH-.

[0385] Embodiment 10. The compound of any one of the preceding embodiments, wherein X ¹ is -N(CH ₃ )-.

[0386] Embodiment 11. The compound of any one of the preceding embodiments, wherein R ¹ is -H.

[0387] Embodiment 12. The compound of any one of the preceding embodiments, wherein R ³ is -H.

[0388] Embodiment 13. The compound of any one of the preceding embodiments, wherein R ³ is -OMe.

[0389] Embodiment 14. The compound of any one of the preceding embodiments, wherein at least one R ^a is -H.

[0390] Embodiment 15. The compound of any one of the preceding embodiments, wherein at least one R ^a is -Ci-4 alkyl.

[0391] Embodiment 16. The compound of any one of the preceding embodiments, wherein at least one R ^b is -H.

[0392] Embodiment 17. The compound of any one of the preceding embodiments, wherein at least one R ^b is -Ci-4 alkyl.

[0393] Embodiment 18. The compound of any one of the preceding embodiments, wherein at least one R ^c is -H. [0394] Embodiment 19. The compound of any one of the preceding embodiments, wherein at least one R ^c is -Ci-4 alkyl.

[0395] Embodiment 20. The compound of any one of the preceding embodiments, wherein at least one R ^d is -H.

[0396] Embodiment 21. The compound of any one of the preceding embodiments, wherein at least one R ^d is -Ci-4 alkyl.

[0397] Embodiment 22. The compound of any one of the preceding embodiments, wherein m is

1.

[0398] Embodiment 23. The compound of any one of the preceding embodiments, wherein m is

2.

[0399] Embodiment 24. The compound of any one of the preceding embodiments, wherein n is

1.

[0400] Embodiment 25. The compound of any one of the preceding embodiments, wherein n is 2.

[0401] Embodiment 26. The compound of any one of the preceding embodiments, wherein m is

1 and n is 1.

[0402] Embodiment 27. The compound of any one of the preceding embodiments, wherein m is

2 and n is 2.

[0403] Embodiment 28. The compound of any one of the preceding embodiments, wherein Ar ¹ is Ce-io aryl optionally substituted with one or more halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH2, -NH(CI- ₆ alkyl), -N(CI-C ₆ alkyl) ₂ , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the Ci- 6 alkyl, Ci-6 alkoxy, -NH(CI-C ₆ alkyl), -N(CI-C ₆ alkyl) ₂ , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl) is optionally substituted with one or more hydroxy, C1-6 alkoxy, -NH ₂ , -NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl) ₂ .

[0404] Embodiment 29. The compound of any one of the preceding embodiments, wherein Ar ¹ is phenyl optionally substituted with one or more halogen, -CF3, C1-6 alkyl, C1-6 alkoxy, -NH ₂ , - NH(CI-6 alkyl), -N(Ci-Ce alkyl) ₂ , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl), wherein the C1-6 alkyl, C1-6 alkoxy, -NH(CI-C ₆ alkyl), -N(CI-C ₆ alkyl) ₂ , -C(O)O(Ci-6 alkyl), or -NHC(O)O(CI-6 alkyl) is optionally substituted with one or more hydroxy, C1-6 alkoxy, -NH ₂ , -NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl) ₂ . [0405] Embodiment 30. The compound of any one of the preceding embodiments, wherein Ar ¹ is Ce-io aryl optionally substituted with one or more halogen, -CF3, or C1-6 alkyl.

[0406] Embodiment 31. The compound of any one of the preceding embodiments, wherein Ar ¹ is phenyl optionally substituted with one or more halogen, -CF3, or C1-6 alkyl.

[0407] Embodiment 32. The compound of any one of the preceding embodiments, wherein Ar ¹ is Ce-io aryl optionally substituted with one or more halogen.

[0408] Embodiment 33. The compound of any one of the preceding embodiments, wherein Ar ¹ is phenyl optionally substituted with one or more halogen.

[0409] Embodiment 34. The compound of any one of the preceding embodiments, wherein Ar ¹

[0410] Embodiment 35. The compound of any one of the preceding embodiments, being of any one of Formulae (la), (lb), (Ic), (Id), (le), (If), (Ig), or (Ih): or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0411] Embodiment 36. The compound of any one of the preceding embodiments, being of Formula (II): or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0412] Embodiment 37. The compound of any one of the preceding embodiments, being of any one of Formulae (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), or (Ilh):

or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0413] Embodiment 38. The compound of any one of the preceding embodiments, being of Formula (III) or Formula (IV): or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0414] Embodiment 39. The compound of any one of the preceding embodiments, being of any one of Formulae (Illa), (Illb), (IIIc), (Hid), (IVa), (IVb), (IVc), or (IVd):

or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0415] Embodiment 40. The compound of any one of the preceding embodiments, wherein the compound is selected from a compound described in Table I, or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0416] Embodiment 41. The compound of any one of the preceding embodiments, wherein the compound is selected from Compound Nos. 2-15, or a stereoisomer, polymorph, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0417] Embodiment 42. An isotopic derivative of the compound of any one of the preceding embodiments.

[0418] Embodiment 43. The isotopic derivative, being an isotopic derivative of a compound described in Table I, or a pharmaceutically acceptable salt thereof.

[0419] Embodiment 44. A pharmaceutical composition comprising the compound of any one of the preceding embodiments and one or more pharmaceutically acceptable carriers or excipients. [0420] Embodiment 45. A method of treating or preventing cancer in a subject, comprising administering to the subject the compound of any one of the preceding embodiments.

[0421] Embodiment 46. A compound of any one of the preceding embodiments for treating or preventing cancer in a subject.

[0422] Embodiment 47. Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for treating or preventing cancer in a subject.

[0423] Embodiment 48. Use of the compound of any one of the preceding embodiments for treating or preventing cancer in a subject.

[0424] Embodiment 49. The method, compound, or use of any one of embodiments 45-48, wherein the cancer is characterized by an EGFR mutation C797.

[0425] Embodiment 50. The method, compound, or use of embodiment 49, wherein an EGFR mutation C797 is detected in the subject or in a sample obtained from the subject.

[0426] Embodiment 51. The method, compound, or use of any one of embodiments 45-50, wherein the subject is a human.

[0427] Embodiment 52. The method, compound, or use of any one of embodiments 45-51, wherein the subject has previously undergone at least one round of anti-cancer therapy.

[0428] Embodiment 53. The method, compound, or use of any one of embodiments 45-52, wherein the subject has previously undergone at least one round of anti-cancer therapy and has acquired resistance to treatment with the anti-cancer therapy.

[0429] Embodiment 54. The method, compound, or use of any one of embodiments 45-53, wherein the cancer is a carcinoma, a lymphoma, a blastoma, a sarcoma, a leukemia, a brain cancer, a breast cancer, a blood cancer, a bone cancer, a lung cancer, a skin cancer, a liver cancer, an ovarian cancer, a bladder cancer, a renal cancer, a kidney cancer, a gastric cancer, a thyroid cancer, a pancreatic cancer, an esophageal cancer, a prostate cancer, a cervical cancer, a uterine cancer, a stomach cancer, a soft tissue cancer, a laryngeal cancer, a small intestine cancer, a testicular cancer, an anal cancer, a vulvar cancer, a joint cancer, an oral cancer, a pharynx cancer, a renal pelvis cancer, intrahepatic bile duct cancer, bronchus cancer or a colorectal cancer.

[0430] Embodiment 55. The method, compound, or use of any one of embodiments 45-54, wherein the cancer is metastatic, recurrent, or multi-drug resistant. [0431] Embodiment 56. The method, compound, or use of any one of embodiments 45-55, wherein the cancer is non-small cell lung cancer (NSCLC), glioblastoma, breast, head or neck, colon, gastric, pancreatic, bladder cancer.

[0432] Embodiment 57. The method, compound, or use of embodiment 56, wherein the cancer is NSCLC.

[0433] Embodiment 58. The method, compound, or use of embodiment 57, wherein the NSCLC is in the brain.

[0434] Embodiment 59. The method, compound, or use of any one of embodiments 45-58, wherein the cancer is a cancer that is resistant to treatment with EGFR TKIs.

EXAMPLES

[0435] For exemplary purpose, salts of the compounds of Formula (I) are synthesized and tested in the examples. It is understood that neutral compounds of Formula (I) may be similarly synthesized and tested using the exemplary procedures described in the examples. Further, it is understood that the salts (e.g., sodium salt) of the compounds of Formula (I) may be converted to the corresponding neutral compounds using routine techniques in the art (e.g., pH adjustment and, optionally, extraction (e.g., into an aqueous phase)).

[0436] Compounds of Formula (I) can be prepared using the methods detailed herein. Those skilled in the art may be able to envisage alternative synthetic routes, using a variety of starting materials and reagents to prepare the disclosed compounds of Formula (I) and to make further modifications. For exemplary purpose, salts of some of the compounds of Formula (I) are synthesized and tested in the examples. It is understood that neutral compounds of Formula (I) may be similarly synthesized and tested using the exemplary procedures described in the examples. Further, it is understood that the salts (e.g., hydrochloride salt) of the compounds of Formula (I) may be converted to the corresponding neutral compounds using routine techniques in the art (e.g., pH adjustment and, optionally, extraction (e.g., into an aqueous phase)).

[0437] Abbreviations: aq. Aqueous

ACN Acetonitrile

’H NMR Proton nuclear magnetic resonance spectroscopy

CDCh Deuterated chloroform

DCM Dichloromethane

DMF Dimethylformamide DMSO-de Hexadeuterodimethylsulfoxide

EtOAc Ethyl acetate eq- Equivalents h Hour(s)

HPLC high performance liquid chromatography

LC-MS Liquid chromatography-mass spectrometry mi ⁿ Minute(s) prep-HPLC preparative high performance liquid chromatography

EtsN Triethylamine

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin layer chromatography

^Y Yield

Example 1: Preparation of 2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazoli n-

6-yl)oxy)piperidin-l-yl)-N-methylacetamide (Compound 1)

Boc Boc

Preparation of tert-butyl 4-(tosyloxy)piperidine-l -carboxylate

[0438] To a solution of tert-butyl 4-hydroxypiperidine-l -carboxylate (10.0 g, 49.7 mmol, 1.00 eq) in di chloromethane (100 mL) was added tri ethylamine (15.3 g, 151 mmol, 21.0 mL, 3.04 eq) and 4-methylbenzene-l -sulfonyl chloride (10.5 g, 55.1 mmol, 1.11 eq) in portions. The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under vacuum to give a residue which was diluted with dichloromethane (300 mL) and water (50.0 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum to give a residue which was purified by column chromatography on silica gel eluted with petroleum ether/ethyl acetate = 1/0 to 10/1 to give tert-butyl 4-(tosyloxy)piperidine-l -carboxylate (7.50 g, 20.7 mmol, 41.6% yield, 98% purity) as a white solid. ^X H NMR (400 MHz, DMSO-tL) b = 7.81 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 4.68 (tt, J= 3.9, 7.9 Hz, 1H), 3.48 (ddd, J= 4.0, 6.5, 13.3 Hz, 2H), 3.19 - 3.10 (m, 2H), 2.42 (s, 3H), 1.75 - 1.66 (m, 2H), 1.54 - 1.42 (m, 2H), 1.38 - 1.36 (m, 9H).

Preparation of tert-butyl 4-((4-((3-chloro-2-jluorophenyl)amino)-7-methoxyquinazolin-6 - yl)oxy)piperidine-l -carboxylate

[0439] To a solution of 4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (300 mg, 938 pmol, 1.00 eq in dimethyl formamide (5.00 mL) was added cesium carbonate (915 mg, 2.81 mmol, 2.99 eq) and tert-butyl 4-(tosyloxy)piperidine-l -carboxylate (420 mg, 1.16 mmol, 1.23 eq in portions. The mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with ethyl acetate (50.0 mL) and water (50.0 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum to give a residue which was purified by column chromatography on silica gel eluted with petroleum ether/ethyl acetate = 2/1 to give tert-butyl 4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6 -yl)oxy)pi- peridine-1 -carboxylate (290 mg, 525 pmol, 56% yield, 91% purity) as a white solid. ¹ HNMR (400 MHz, CDCk) b = 8.70 - 8.64 (m, 1H), 8.45 - 8.35 (m, 1H), 7.39 (br s, 1H), 7.24 (s, 1H), 7.21 (s, 1H), 7.16 - 7.09 (m, 2H), 4.58 (tt, J= 3.5, 7.4 Hz, 1H), 3.98 (s, 3H), 3.82 - 3.73 (m, 2H), 3.30 (ddd, J= 3.7, 8.2, 13.4 Hz, 2H), 2.02 - 1.92 (m, 2H), 1.90 - 1.77 (m, 2H), 1.45 (s, 9H).

Preparation ofN-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy )quinazolin-4-amine [0440] To a solution of tert-butyl 4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin- 6-yl)oxy)piperidine -1 -carboxylate (290 mg, 525 pmol, 1.00 eq in dichloromethane (2.00 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.00 mL, 25.7 eq in portions. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under vacuum to give 7V-(3-chloro- 2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4- amine (580 mg, crude, trifluoroacetic acid) as a yellow oil. ’H NMR (400 MHz, DMSO-d6) d = 8.88 (s, 1H), 8.71 (br s, 2H), 8.14 (s, 1H), 7.95 (s, 1H), 7.70 - 7.64 (m, 1H), 7.58 - 7.52 (m, 1H), 7.40 - 7.36 (m, 1H), 4.83 (td, J = 3.6, 6.9 Hz, 1H), 4.03 (s, 3H), 3.29 (br s, 2H), 3.15 (br s, 2H), 2.27 - 2.15 (m, 2H), 2.02 - 1.92 (m, 2H).

Preparation of Compound 1

[0441] To a solution of 7V-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy) quinazolin- 4-amine (560 mg, 1.08 mmol, 1.00 eq, trifluoroacetic acid) (crude) in dimethyl formamide (5.00 mL) was added tri ethylamine (548 mg, 5.42 mmol, 754 pL, 5.00 eq) and 2-chloro-7V-m ethylacetamide (140 mg, 1.30 mmol, 1.20 eq) in portions. The mixture was stirred at 25 °C for 16 h. The mixture was diluted with ethyl acetate (50.0 mL) and water (30.0 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum to give a residue which was purified by p/cp-HPLC (column: Xtimate Cl 8 150*25mm*5pm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 22%-52%, 10 min). The desired fraction was collected and lyophilized to give 2-(4-((4-((3 -chi oro-2- fluoro- phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-l-yl)-A -methylacetamide (46.3 mg, 96.8 pmol, 9% yield, 99% purity) as a white solid. ’H NMR (400 MHz, DMSO-tL) 6 = 9.57 (s, 1H), 8.37 (s, 1H), 7.82 (s, 1H), 7.74 (br d, J= 4.4 Hz, 1H), 7.51 (td, J= 6.8, 13.7 Hz, 2H), 7.29 (dt, J= 1.0, 8.1 Hz, 1H), 7.22 (s, 1H), 4.57 (td, J = 4.0, 8.1 Hz, 1H), 3.94 (s, 3H), 2.95 (s, 2H), 2.79 - 2.72 (m, 2H), 2.63 (d, J= 4.8 Hz, 3H), 2.43 - 2.35 (m, 2H), 2.10 - 2.02 (m, 2H), 1.86 - 1.75 (m, 2H).

Example 2: Preparation of 2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazoli n-

6-yl)amino)piperidin-l-yl)-N-methylacetamide (Compound 2)

Preparation of benzyl 4-((4-((3-chloro-2-jluorophenyl)amino)-7-methoxyquinazolin-6 - yl)amino)piperidine-l -carboxylate

[0442] To a solution of benzyl 4-oxopiperidine-l -carboxylate (373 mg, 1.60 mmol, 319 pL, 1.70 eq) and 7V ^/ -(3-chloro-2-fluorophenyl)-7-methoxyquinazoline-4,6-di amine (300 mg, 941 pmol,

I.00 eq) in trifluoroacetic acid (10.0 mL) was added sodium triacetoxy borohydride (299 mg, 1.41 mmol, 1.50 eq) at 15 °C, The mixture was stirred at 15 °C for 1.5 h. The reaction mixture was poured into water (60.0 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (3 x 40.0 mL). The combined organic phase was washed with saturated sodium bicarbonate (50.0 mL) and brine (40.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (ethyl ace- tate/methanol = 10/1) to afford benzyl 4-((4-((3-chloro-2-fluorophenyl)amino)-7-methox- yquinazolin-6-yl)amino)piperidine-l -carboxylate (450 mg, 839 pmol, 89% yield) as a yellow solid. ^X HNMR (400 MHz, DMSO-t/e) b = 9.48 (br s, 1H), 8.30 (s, 1H), 7.58 - 7.46 (m, 2H), 7.42 - 7.39 (m, 1H), 7.38 (s, 2H), 7.35 - 7.27 (m, 2H), 7.26 (s, 1H), 7.11 (s, 1H), 5.41 (br d, J= 8.4 Hz, 1H), 5.20 - 5.05 (m, 2H), 4.11 - 3.99 (m, 4H), 3.80 - 3.62 (m, 1H), 3.04 (br s, 2H), 2.03 (br d, J =

I I.0 Hz, 2H), 1.59 - 1.37 (m, 2H). Preparation of N ⁴ -(3-chloro-2-fliiorophenyl)-7-melhoxy-N ⁶ -(piperidin-4-yl)quinazoHne-4, 6-dia- mine

[0443] A mixture of benzyl 4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6 - yl)amino)piperidine-l -carboxylate (400 mg, 746 pmol, 1.00 eq) in trifluoroacetic acid (3.00 mL) was stirred at 70 °C for 2 h. The reaction mixture was concentrated to give 7VA(3-chloro-2-fluoro- phenyl)-7-methoxy-A ⁶ -(piperidin-4-yl)quinazoline-4,6-diamine (350 mg, 678 pmol, 90% yield, TFA) as a yellow oil. MS (ESI) m/z 469.2 [M+H], Preparation of Compound 2

[0444] To a solution of A ^/ -(3-chloro-2-fluorophenyl)-7-methoxy-A ⁱ⁵ -(piperidin-4-yl)quinazoline- 4,6-diamine (350 mg, 870 pmol, 1.00 eq) and 2-chloro-A-methyl-acetamide (140 mg, 1.31 mmol, 1.50 eq) in dimethyl formamide (4.00 mL) was added potassium carbonate (601 mg, 4.35 mmol, 5.00 eq) at 15 °C, the mixture was stirred at 50 °C for 1 h. The reaction mixture was filtered to give a filtrate. The filtrate was purified by /?re/?-HPLC(column: Xtimate C18 150*25 mm*5 pm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 29%-59%,10min) and prep- HPLC(column: Phenomenex Synergi C18 150*30 mm*4 pm; mobile phase: [water(0.225%FA)- ACN];B%: l%-30%,12min) to afford 2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methox- yquinazolin-6-yl)amino)piperidin-l-yl)-A-methylacetamide (173 mg, 366 pmol, 42% yield) as a yellow solid. ’H NMR (400 MHz, CDCh) 3 = 8.51 (s, 1H), 8.43 (s, 1H), 8.22 (dt, J= 1.9, 7.5 Hz, 1H), 8.15 - 8.11 (m, 1H), 7.27 (d, J= 12.2 Hz, 2H), 7.24 - 7.11 (m, 2H), 6.80 (s, 1H), 4.01 (s, 3H), 3.60 - 3.46 (m, 1H), 3.12 (s, 2H), 2.92 (br d, J= 12.0 Hz, 2H), 2.87 (d, J= 4.9 Hz, 3H), 2.56 - 2.41 (m, 2H), 2.18 (br d, J= 10.7 Hz, 2H), 1.78 - 1.56 (m, 2H).

Example 3: Preparation of 2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazoli n- 6-yl)thio)piperidin-l-yl)-N-methylacetamide (Compound 3)

Preparation of 3-chloro-N-(3,4-dimethoxybenzyl)-2-jluoroaniline

[0445] To a solution of 3-chloro-2-fluoroaniline (5.00 g, 34.3 mmol, 1.00 eq and 3,4-dimethox- ybenzaldehyde (5.71 g, 34.3 mmol, 1.00 eq) in toluene (100 mL) was added 4-methylbenzenesul- fonic acid (295 mg, 1.72 mmol, 0.05 eq . After addition, the solution was stirred at 110 °C for 12 h. The reaction solution was concentrated in vacuum to give the crude product (Z)-3-chloro-A- (3,4-dimethoxybenzylidene)-2-fluoroaniline (11 g, crude) as a yellow solid was used for the next step directly without purification. MS (ESI) m/z 294.1 [M+H],

[0446] To a solution of (Z)-3-chloro-7V-(3,4-dimethoxybenzylidene)-2-fluoroaniline (10.0 g, 34.0 mmol, 1.00 eq in methanol (100 mL) was added sodium borohydride (2.58 g, 68.1 mmol, 2.00 eq in portions at 15 °C. After addition, the solution was stirred at 15 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (100 mL) and extracted with ether acetate (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate = 10/1 to 3/1) to give 3 -chi oro-A-(3,4-di methoxybenzyl )-2-fluoroan- iline (8.00 g, 27.05 mmol, 79.45% yield) as a yellow solid. ’H NMR (400 MHz, CDCh) 3 6.95 - 6.84 (m, 4H), 6.71 (dt, J= 1.3, 7.4 Hz, 1H), 6.64 - 6.55 (m, 1H), 4.40 - 4.34 (m, 1H), 4.34 - 4.29 (m, 2H), 3.90 (d, J= 2.0 Hz, 6H).

Preparation of 7-methoxy-6-nitroquinazolin-4-ol

[0447] To methanol (50.0 mL) was added sodium (1.65 g, 71.7 mmol, 1.70 mL, 3.00 eq) in portions at 0 °C and stirred for 0.5 h. Then to the reaction mixture was added 7-fluoro-6-nitro- quinazolin-4-ol (5.00 g, 23.9 mmol, 1.00 eq) in portions at 0 °C. After addition, the mixture was stirred at 50 °C for 3 h. The reaction mixture was concentrated to give a residue, the residue was poured into hydrochloric acid (IM) and stirred for 10 min, filtered and the filter cake was concentrated in vacuum to give 7-methoxy-6-nitroquinazolin-4-ol (5.00 g, 22.6 mmol, 94% yield) as a white solid. ’H NMR (400 MHz, DMSO ) 3 = 12.58 - 12.38 (m, 1H), 8.53 (s, 1H), 8.24 (s, 1H), 7.43 (s, 1H), 4.05 (s, 3H).

Preparation of 4-chloro-7-methoxy-6- nitroquinazoline

[0448] To a solution of 7-methoxy-6-nitro-quinazolin-4-ol (5.00 g, 22.6 mmol, 1.00 eq) in thionyl chloride (50.0 mL) was added dimethyl formamide (95.0 mg, 1.30 mmol, 100 pL, 5.75e' ² eq) at 25 °C, the mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated to give 4- chloro-7-methoxy-6-nitroquinazoline (5.00 g, 20.8 mmol, 92% yield) as a white solid. MS (ESI) m/z 240.1 [M+H],

Preparation of N-(3-chloro-2-fluorophenyl)-N- (3,4-dimethoxybenzyl)-7-methoxy-6-nitro- quinazolin-4-amine

[0449] A mixture of 4-chloro-7-methoxy-6-nitroquinazoline (2.00 g, 8.35 mmol, 1.00 eq) and 3- chloro-7V-(3,4- dimethoxybenzyl)-2-fluoroaniline (2.47 g, 8.35 mmol, 1.00 eq) in acetonitrile (10.0 mL) was stirred at 80 °C for 1 h. The reaction mixture was concentrated to give a residue. The residue was triturated with ethyl acetate (30.0 mL), filtered and concentrated in vacuum to give A- (3-chloro-2-fluorophenyl)-7V-(3,4-dimethoxybenzyl)-7-methoxy -6-nitroquinazolin-4-amine (3.30 g, 6.61 mmol, 79% yield) as a yellow solid. ’H NMR (400 MHz, DMSO-t/e) d = 9.03 (s, 1H), 7.76 - 7.69 (m, 1H), 7.66 - 7.59 (m, 2H), 7.54 (s, 1H), 7.45 - 7.38 (m, 1H), 6.93 (s, 1H), 6.84 (s, 2H), 5.45 (s, 2H), 3.70 (s, 3H), 3.64 (s, 3H), 3.17 (s, 3H).

Preparation of N ⁴ -(3-chloro-2-jluorophenyl)-N ⁴ -(3, 4-dimethoxybenzyl)-7-methoxyquinazoline- 4, 6-diamine

[0450] A mixture of A-(3-chloro-2-fluorophenyl)-A-(3,4-dimethoxybenzyl)-7-methox y-6-nitro- quinazolin-4-amine (3.00 g, 6.01 mmol, 1.00 eq), iron powder (1.01 g, 18.0 mmol, 3.00 eq) and ammonium chloride (1.61 g, 30.0 mmol, 5.00 eq) in methanol (10.0 mL) and water (5.00 mL) was stirred at 80 °C for 1 h. The reaction mixture was poured into methanol (50.0 mL) and stirred for 10 min, filtered and the filtrate was concentrated to give a residue. The residue was poured into water (80.0 mL) and the aqueous phase was extracted with ethyl acetate (3 x 40.0 mL). The combined organic phase was washed with brine (60.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give A ⁴ -(3-chloro-2-fluorophenyl)-A ⁴ -(3,4-dimethoxyben- zyl)-7-methoxyquinazoline-4, 6-diamine (2.30 g, 4.91 mmol, 81% yield) as a yellow solid. MS (ESI) m/z 469.2 [M+H],

Preparation of N-(3-chloro-2-fluorophenyl)-N-(3, 4-dimethoxybenzyl)-7-methoxy-6-thiocya- natoquinazolin-4-amine

[0451] A solution of 7V ⁴ -(3-chloro-2-fluorophenyl)-7V ⁴ -(3,4-dimethoxybenzyl)-7-methox- yquinazoline-4,6-diamine (1.50 g, 3.20 mmol, 1.00 eq in 30% sulfuric acid (30.0 mL) was stirred at 25 °C for 30 min. Then sodium nitrite (441 mg, 6.40 mmol, 2.00 eq) was added to the solution at 0 °C and stirred at 25 °C for another 30 min. The solution above was added dropwise to 150 mL aqueous solution of ferric trichloride (1.56 g, 9.60 mmol, 3.00 eq and potassium thiocyanate (3.11 g, 31.9 mmol, 10.0 eq and stirred at 25 °C for 12 h. The mixture was filtered. The filter cake was washed with water (20.0 mL) and dried in vacuum to give A-(3-chloro-2-fluorophenyl)-7V-(3,4- dimethoxybenzyl)-7-methoxy-6-thiocyanatoquinazolin-4-amine (2.00 g, crude) as a brown solid, which was used to next step without further purification.

Preparation of 4-( (3-chloro-2 fluorophenyl) ( 3, 4-dimethoxybenzyl)amino)-7-methoxyquinazoline- 6-thiol

[0452] To a mixture of A-(3-chloro-2-fluorophenyl)-7V-(3,4-dimethoxybenzyl)-7-metho xy-6-thio- cyanatoquinazolin-4-amine (2.00 g, 3.91 mmol, 1.00 eq in ethanol (5.00 mL) was added sodium borohydride (740 mg, 19.6 mmol, 5.00 eq . The mixture was stirred at 20 °C for 4 h. The mixture was quenched by methanol (10.0 mL) and concentrated to dryness to give 4-((3-chloro-2-fluoro- phenyl)(3,4-dimethoxybenzyl)amino)-7-methoxyquinazoline-6-th iol (2.00 g, crude) as a brown solid which was used to next step without further purification. Preparation of tert-butyl 4-((4-((3-chloro-2-fluorophenyl)(3,4-dimethoxybenzyl)amino)- 7-meth- oxyquinazolin-6-yl)thio)piperidine-l-carboxylate

[0453] A mixture of 4-((3-chloro-2-fluorophenyl)(3,4-dimethoxybenzyl)amino)-7-me thox- yquinazoline-6-thiol (700 mg, 1.44 mmol, 1.00 eq), tert-butyl 4-iodopiperidine-l -carboxylate (895 mg, 2.88 mmol, 2.00 eq) and potassium carbonate (1.99 g, 14.4 mmol, 10.0 eq) in ethyl alcohol (15.0 mL) was stirred at 50 °C for 12 h. The mixture was concentrated to dryness to give a residue. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate = 1/1 - 0/1) to give tert-butyl 4-((4-((3-chloro-2-fluorophenyl)(3,4-dimethoxybenzyl)amino)- 7-methox- yquinazolin-6-yl)thio)piperidine-l -carboxylate (400 mg, 598 pmol, 41% yield) as a yellow solid. ’H NMR (400MHz, CDCh) b = 8.73 (s, 1H), 7.26 - 7.20 (m, 1H), 7.19 (s, 1H), 7.13 (s, 1H), 7.07 (s, 1H), 6.98 - 6.92 (m, 2H), 6.89 - 6.84 (m, 1H), 6.79 (dd, J= 2.0, 8.4 Hz, 1H), 6.65 (d, J= 8.4 Hz, 1H), 5.25 (s, 2H), 3.91 (s, 3H), 3.75 (s, 5H), 3.71 (s, 3H), 2.89 (br t, J= 10.4 Hz, 2H), 2.82 - 2.73 (m, 1H), 1.66 - 1.58 (m, 2H), 1.40 (s, 9H), 1.27 (dtd, J= 4.2, 9.8, 13.5 Hz, 2H).

Preparation ofN-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-ylthi o)quinazolin-4-amine [0454] A solution of tert-butyl 4-((4-((3-chloro-2-fluorophenyl)(3,4-dimethoxybenzyl)amino)- 7- methoxyquinazolin-6-yl)thio)piperidine-l -carboxylate (400 mg, 612 pmol, 1.00 eq) in trifluoroacetic acid (4.00 mL) was stirred at 70 °C for 2 h. The mixture was concentrated to dryness to give 7V-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-ylthio )quinazolin-4-amine (335 mg, crude) as a yellow oil.

Preparation of Compound 3

[0455] To a mixture of A-(3-chloro-2-fluoro-phenyl)-7-methoxy-6-(4-piperidylsulfa- nyl)quinazolin-4-amine (335 mg, 799 pmol, 1.00 eq) and triethylamine (405 mg, 4.00 mmol, 557 pL, 5.00 eq) in dimethyl formamide (4.00 mL) was added 2-chloro-A-methylacetamide (129 mg, 1.20 mmol, 1.50 eq). The mixture was stirred at 25 °C for 12 h. The mixture was filtered to give filtrate. The filtrate was purified by prep-HPLC (column: Waters Xbridge 150*50 10 pm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 26%-56%,11.5 min) to give 2-(4-((4- ((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)th io)piperidin-l-yl)-A-methyla- cetamide (121 mg, 247 pmol, 31% yield) as a white solid. ^X H NMR (400MHz, DMSO- e) <5 = 9.85 (s, 1H), 8.43 (s, 1H), 8.32 (s, 1H), 7.68 (br d, J= 4.4 Hz, 1H), 7.59 - 7.48 (m, 2H), 7.35 - 7.26 (m, 1H), 7.23 (s, 1H), 3.99 (s, 3H), 3.60 - 3.48 (m, 1H), 2.90 (s, 2H), 2.76 (br d, J= 11.6 Hz, 2H), 2.61 (d, J= 4.6 Hz, 3H), 2.38 - 2.20 (m, 2H), 1.97 (br d, J= 10.8 Hz, 2H), 1.74 - 1.57 (m, 2H). Example 4: Preparation of 2-(4-((4-((3-chloro-2-fluorophenyl)amino) quinazolin-6- yl)amino)piperidin-l-yl)-N-methylacetamide (Compound 4)

Preparation of Compound 4

[0456] To a solution of 7V ⁴ -(3-chloro-2-fluorophenyl)-7V ⁶ -(piperidin-4-yl)quinazoline-4,6-diamine (150 mg, 367 umol, 1.00 eq, hydrochloric acid) in dimethyl formamide (2.00 mL) was added triethylamine (186 mg, 1.84 mmol, 256 pL, 5.00 eq), followed by dropwise addition of a solution of 2-chloro-7V-methylacetamide (29.6 mg, 276 pmol, 0.750 eq) in dimethyl formamide (0.200 mL) at 10 °C. The mixture was stirred at 10 °C for 2 h. Then 2-chloro-7V-methylacetamide (39.5 mg, 367 pmol, 1.00 eq) was added and the mixture was stirred at 25 °C for 2 h. The mixture was filtered to give a filtrate. The filtrate was purified by /c -HPLC (column: Waters Xbridge 150*25 5 um; mobile phase: [water(10 mM NH4HCCh)-ACN]; B%: 22%-52%,10 min) and lyophilized to give 2-(4-((4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)ami no)piperidin-l-yl)-7V-methyla- cetamide (48.61 mg, 106 pmol, 28% yield, 97% purity) as a yellow solid. ^X H NMR (400 MHz, DMSO-t/e) 3 = 9.39 (br s, 1H), 8.21 (s, 1H), 7.67 (br d, J= 4.4 Hz, 1H), 7.57 - 7.40 (m, 3H), 7.35 - 7.20 (m, 2H), 7.11 (s, 1H), 6.12 (br d, J= 7.7 Hz, 1H), 3.50 - 3.36 (m, 1H), 2.93 (s, 2H), 2.81 (br d, J= 11.5 Hz, 2H), 2.63 (d, J= 4.8 Hz, 3H), 2.32 - 2.21 (m, 2H), 2.00 (br d, J= 10.9 Hz, 2H), 1.60 - 1.45 (m, 2H).

Example 5: Preparation of 2-(3-((4-((3-chloro-2-fluorophenyl) amino)quinazolin-6- yl)thio)azetidin-l-yl)-N-methylacetamide (Compound 5)

Preparation of Compound 5

[0457] To a solution of 6-(azetidin-3-ylthio)-7V-(3-chloro-2-fluorophenyl)quinazolin -4-amine (200 mg, 503 pmol, 1.00 eq, HC1) in dimethylformamide (2.00 mL) was added cesium carbonate (656 mg, 2.01 mmol, 4.00 eq), 2-chloro-7V-methylacetamide (54.1 mg, 503 pmol, 1.00 eq) in portions. The mixture was stirred at 30 °C for 4 h. The mixture was filtered. The filtrate was purified by /c -HPLC (column: Waters Xbridge 150*25 mm* 5 um; mobile phase: [water(10 mM NH4HCO3)-ACN];B%: 20%-50%,10min) and lyophilized to give 2-(3-((4-((3-chloro-2-fluoro- phenyl)amino)quinazolin-6-yl)thio)azetidin-l-yl)-7V-methylac etamide (22.89 mg, 55.7 pmol, 11% yield, 97% purity) as a yellow solid. ^X H NMR (400 MHz, DMSO-tA) b = 10.13 - 9.93 (m, 1H), 8.41 (br s, 1H), 8.19 (s, 1H), 7.70 (s, 2H), 7.62 - 7.41 (m, 3H), 7.34 - 7.22 (m, 1H), 4.22 (quin, J = 6.5 Hz, 1H), 3.88 (t, J= 7.5 Hz, 2H), 3.20 (t, J= 7.0 Hz, 2H), 3.06 (s, 2H), 2.57 (br d, J= 4.6 Hz, 3H).

Example 6: Preparation of 2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazoli n-

6-yl)(methyl)amino)piperidin-l-yl)-N-methylacetamide (Compound 6)

Preparation of benzyl 4-((4-((3-chloro-2-jluorophenyl)(3,4-dimethoxybenzyl)amino)- 7-methox- yquinazolin-6-yl)amino)piperidine-l-carboxylate

[0458] To a solution of 7V ^v -(3-chloro-2-fluoro-phenyl)-7V ^v -[(3,4-dimethoxyphenyl)methyl]-7- methoxy-quinazoline-4,6-diamine (1.00 g, 2.13 mmol, 1.00 eq) in trifluoroacetic acid (8.00 mL) was added benzyl 4-oxopiperidine-l -carboxylate (1.24 g, 5.33 mmol, 1.06 mL, 2.50 eq) and sodium triacetoxy borohydride (903 mg, 4.27 mmol, 2.00 eq) at 15 °C, the mixture was stirred at 15 °C for 1.5 h. The reaction mixture was poured into water (80.0 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (3 x 50.0 mL). The combined organic phase was washed with saturated sodium bicarbonate (80.0 mL) and brine (60.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by reverse-phase HPLC (0.1% formic acid condition) to afford benzyl 4-((4-((3-chloro-2-fluoro- phenyl)(3,4-dimethoxybenzyl)amino)-7-methoxyquinazolin-6-yl) amino)piperidine-l -carboxylate (700 mg, 1.02 mmol, 47% yield) as a yellow solid. MS (ESI) m/z 686.3 [M+H],

Preparation of benzyl 4-((4-((3-chloro-2-fluorophenyl)(3,4-dimethoxybenzyl)amino)- 7-methox- yquinazolin-6-yl)(methyl)amino)piperidine-l-carboxylate

[0459] To a solution of benzyl 4-((4-((3-chloro-2-fluorophenyl)(3,4-dimethoxybenzyl)amino)- 7- methoxyquinazolin -6-yl)amino)piperidine-l -carboxylate (350 mg, 510 pmol, 1.00 eq) in trifluoroacetic acid (4.00 mL) was added formaldehyde (206 mg, 2.55 mmol, 189 pL, 37% purity, 5.00 eq) and triacetoxy borohydride (432 mg, 2.04 mmol, 4.00 eq) at 15 °C, the mixture was stirred at 15 °C for 1 h. The reaction mixture was poured into water (80.0 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (3 x 40.0 mL). The combined organic phase was washed with saturated sodium bicarbonate (60.0 mL) and brine (60.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give benzyl 4-((4-((3-chloro-2-fluoro- phenyl)(3,4-dimethoxybenzyl)amino)-7-methoxyquinazolin-6-yl) (methyl)amino)piperidine-l- carboxylate (350 mg, 499 pmol, 98% yield) as a yellow solid. MS (ESI) m/z 700.3 [M+H], Preparation of N ⁴ -( 3-chloro-2-fluorophenyl)~ 7-melhoxy-N ⁶ -melhyl-N ⁶ -(piperidin-4-yl)qiiinazo- line-4, 6-diamine

[0460] A mixture of benzyl 4-((4-((3-chloro-2-fluorophenyl)(3,4-dimethoxybenzyl)amino)- 7- methoxyquinazolin-6-yl)(methyl)amino)piperidine-l -carboxylate (290 mg, 414 pmol, 1.00 eq) in trifluoroacetic acid (2.00 mL) was stirred at 70 °C for 2 h. The reaction mixture was concentrated to give A ⁴ -(3-chloro-2-fluorophenyl)-7-methoxy-A ⁶ -methyl-A ⁶ -(piperidin-4-yl)quinazoline-4,6- diamine (200 mg, 377 pmol, 91% yield, trifluoroacetic acid) as a yellow oil. MS (ESI) m/z 416.1 [M+H],

Preparation of Compound 6

[0461] To a solution of A ⁴ -(3-chloro-2-fluoro-phenyl)-7-methoxy-A ⁶ -methyl-A ⁶ -(4-pi- peridyl)quinazoline-4, 6-diamine (200 mg, 480 pmol, 1.00 eq) and triethylamine (243 mg, 2.40 mmol, 334 pL, 5.00 eq) in dimethyl formamide (1.00 mL) was added 2-chloro-A-methyl-acetam- ide (77.0 mg, 721 pmol, 1.50 eq) at 0 °C, the mixture was stirred at 15 °C for 12 h. The reaction mixture was filtered to give a filtrate. The filtrate was purified by /c -HPLC (column: Waters Xbridge 150*25 5 um; mobile phase: [water(10mMNH4HCO3)-ACN];B%: 20%-50%,10 min) to afford 2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazoli n-6-yl)(methyl)amino)pi- peri din- l-yl)-7V-m ethylacetamide (81.0 mg, 166 pmol, 34% yield) as a yellow solid. ¹ HNMR (400 MHz, CDCh) 3 = 8.71 (s, 1H), 8.55 (dt, J= 2.8, 7.2 Hz, 1H), 7.41 (br s, 1H), 7.28 (d, J= 1.6 Hz, 2H), 7.21 - 7.17 (m, 1H), 7.16 - 7.13 (m, 2H), 4.04 (s, 3H), 3.43 (tt, J = 4.0, 11.4 Hz, 1H), 3.02 (s, 2H), 2.97 - 2.91 (m, 5H), 2.89 (d, J= 5.0 Hz, 3H), 2.29 - 2.16 (m, 2H), 1.93 - 1.75 (m, 4H).

Example 7: Preparation of 2-(3-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazoli n- 6-yl)(methyl)amino)azetidin-l-yl)-N-methylacetamide -N-methylacetamide (Compound 7)

Preparation of benzyl 3-((4-((3-chloro-2-jluorophenyl)(3,4-dimethoxybenzyl)amino)- 7-methox- yquinazolin-6-yl)amino)azetidine-l -carboxylate

[0462] To a mixture of 7V ⁴ -(3-chloro-2-fluorophenyl)-7V ⁴ -(3,4-dimethoxybenzyl)-7-methox- yquinazoline-4,6-diamine (700 mg, 1.49 mmol, 1.00 eq), benzyl 3 -oxoazetidine- 1 -carboxylate (367 mg, 1.79 mmol, 1.20 eq) in trifluoroacetic acid (5.00 mL) was added sodium triacetoxy bo- rohydride (380 mg, 1.79 mmol, 1.20 eq). The mixture was stirred at 25 °C for 1 h. The mixture was poured into water (30.0 mL) and extracted with ethyl acetate (3 x 20.0 mL). The combined organic phase was concentrated to dryness to give a residue. The residue was purified by reversed- phase HPLC (0.1% formic acid condition) to give benzyl 3-((4-((3-chloro-2-fluorophenyl)(3,4- dimethoxybenzyl)amino)-7-methoxyquinazolin-6-yl)amino)azetid ine-l-carboxylate (500 mg, 759 pmol, 51% yield) as a yellow solid. ^X H NMR (400MHz, CDC13) 8 = 8.65 (s, 1H), 7.32 - 7.23 (m, 5H), 7.19 (s, 1H), 7.21 - 7.18 (m, 1H), 7.11 (s, 1H), 7.06 (dt, J = 1.8, 7.2 Hz, 1H), 6.96 (d, J = 1.8 Hz, 1H), 6.89 - 6.83 (m, 1H), 6.83 - 6.78 (m, 2H), 6.64 (d, J = 8.4 Hz, 1H), 5.74 (s, 1H), 5.23 (s, 2H), 5.03 (s, 2H), 4.72 - 4.64 (m, 1H), 4.01 - 3.85 (m, 5H), 3.74 (s, 3H), 3.70 (s, 3H), 3.50 (br s, 3H). Preparation of benzyl 3-((4-((3-chloro-2-fluorophenyl)(3,4-dimethoxybenzyl)amino)- 7-methox- yquinazolin-6-yl)(methyl)amino)azetidine-l-carboxylate

[0463] To a mixture of 3-((4-((3-chloro-2-fluorophenyl)(3,4-dimethoxybenzyl)amino)- 7-methox- yquinazolin-6-yl) amino)azetidine-l -carboxylate (220 mg, 334 pmol, 1.00 eq) in trifluoroacetic acid (4.00 mL) was added formaldehyde (136 mg, 1.67 mmol, 5.00 eq) and triacetoxy borohydride (283 mg, 1.34 mmol, 4.00 eq). The mixture was stirred at 25 °C for 1 h. The mixture was poured into water (20.0 mL) and extracted with ethyl acetate (3 x 15.0 mL). The combined organic phase was washed with brine (20.0 mL) and concentrated in vacuum to give a residue. The residue was purified by reversed-phase HPLC (0.1% ammonia hydroxide) to give benzyl 3-((4-((3-chloro-2- fluorophenyl)(3,4-dimethoxybenzyl)amino)-7-methoxyquinazolin -6-yl)(methyl)amino)azetidine- 1 -carboxylate (165 mg, 245 pmol, 73% yield) as a yellow solid. ^T H NMR (400MHz, CDCk) b = 8.65 (s, 1H), 7.27 - 7.19 (m, 5H), 7.09 (s, 1H), 7.07 - 7.02 (m, 1H), 6.89 (d, J= 1.8 Hz, 1H), 6.87 - 6.80 (m, 2H), 6.73 (dd, J= 1.8, 8.4 Hz, 1H), 6.59 (d, J= 8.2 Hz, 1H), 6.23 (s, 1H), 5.18 (s, 2H), 4.95 (s, 2H), 3.84 (s, 3H), 3.78 - 3.67 (m, 5H), 3.64 (s, 3H), 3.63 - 3.55 (m, 2H), 3.52 - 3.44 (m, 1H), 2.39 (s, 3H).

Preparation of N ⁶ -(azelidin-3-yl)-N ⁴ -(3-chloro -2-fluorophenyl)-7-methoxy-N ⁶ -methylquinazo- line-4, 6-diamine

[0464] A mixture of 3-((4-((3-chloro-2-fluorophenyl)(3,4-dimethoxybenzyl)amino)- 7-methox- yquinazolin-6-yl) (methyl)amino)azetidine-l -carboxylate (160 mg, 238 pmol, 1.00 eq) in trifluoroacetic acid (5.00 mL) was stirred at 70 °C for 2 h. The mixture was concentrated to dryness to give A ⁶ -(azetidin-3-yl)-A ⁴ -(3 -chloro -2-fluorophenyl)-7-methoxy-A ⁶ -methylquinazoline-4,6- diamine (90.0 mg, 232 pmol, 97% yield) as a yellow solid which was used to next step without further purification.

Preparation of Compound 7

[0465] A mixture of A ⁶ -(azetidin-3-yl)-A ⁴ -(3-chloro-2-fluorophenyl)-7-methoxy-A ⁶ - methylquinazoline-4, 6-diamine (90.0 mg, 232 pmol, 1.00 eq), 2-chloro-A-methyl-acetamide (37.4 mg, 348 pmol, 1.50 eq) and triethylamine (117 mg, 1.16 mmol, 5.00 eq) in dimethyl formamide (2.00 mL) was stirred at 25 °C for 12 h. The mixture was filtered to give a filtrate. The filtrate was purified by /i/c -HPLC (column: Xtimate C18 150*25 mm*5 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 20%-50%,10 min) and (column: Phenomenex Gemini 150*25 mm*10 pm;mobile phase: [water(0.225%FA)-ACN];B%: l%-30%, 10 min) to give 2-(3- ((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-y l)(methyl)amino)azetidin-l-yl)- /'/-methylacetamide (15.5 mg, 33.8 pmol, 15% yield) as a white solid. ^X H NMR (400MHz, DMSO- tZ ₆ ) 3 = 9.68 (br s, 1H), 8.35 (s, 1H), 7.58 - 7.46 (m, 4H), 7.32 - 7.25 (m, 1H), 7.18 (s, 1H), 4.12 - 4.02 (m, 1H), 3.97 (s, 3H), 3.75 (br t, J= 6.8 Hz, 2H), 3.03 (s, 2H), 2.95 (t, J= 7.0 Hz, 2H), 2.71 (s, 3H), 2.58 (d, J= 4.8 Hz, 3H).

Example 8: Preparation of 2-(3-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazoli n- 6-yl)thio)azetidin-l-yl)-N-methylacetamide (Compound 8)

Preparation of tert-butyl 3-((4-((3-chloro-2-fluorophenyl)(3,4-dimethoxybenzyl)amino)- 7-meth- oxyquinazolin-6-yl)thio)azetidine-l-carboxylate

[0466] A mixture of 4-((3-chloro-2-fluorophenyl)(3,4-dimethoxybenzyl)amino)-7-me thox- yquinazoline-6-thiol (700 mg, 1.44 mmol, 1.00 eq), tert-butyl 3 -iodoazetidine- 1 -carboxylate (815 mg, 2.88 mmol, 2.00 eq) and potassium carbonate (1.99 g, 14.4 mmol, 10.0 eq) in ethyl alcohol (15.0 mL) was stirred at 50 °C for 12 h. The mixture was concentrated to dryness to give a residue. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate = 1/1 - 0/1) to give tert-butyl 3-((4-((3-chloro-2-fluorophenyl)(3,4-dimethoxybenzyl)amino)- 7-methox- yquinazolin-6-yl)thio)azetidine-l -carboxylate (500 mg, 779 pmol, 54% yield) as a yellow solid. ’H NMR (400MHz, CDCh) 3 = 8.73 (s, 1H), 7.26 (ddd, J= 1.6, 6.6, 8.2 Hz, 1H), 7.12 (s, 1H), 6.99 - 6.93 (m, 2H), 6.87 - 6.77 (m, 2H), 6.67 - 6.63 (m, 2H), 5.25 (s, 2H), 4.08 (t, J= 8.4 Hz, 2H), 3.91 (s, 3H), 3.75 (s, 3H), 3.71 (s, 3H), 3.58 (br dd, J= 5.2, 9.0 Hz, 2H), 3.21 (tt, J= 5.2, 7.8 Hz, 1H), 1.38 (s, 9H). Preparation of 6-(azetidin-3-ylthio)-N-( 3-chloro-2-jluorophenyl)-7-methoxyquinazolin-4-amine [0467] A solution of tert-butyl 3-((4-((3-chloro-2-fluorophenyl)(3,4-dimethoxybenzyl)amino)- 7- methoxyquinazolin -6-yl)thio)azetidine-l -carboxylate (200 mg, 312 pmol, 1.00 eq) in trifluoroacetic acid (4.00 mL) was stirred at 60 °C for 2 h. The mixture was concentrated to dryness to give 6-(azetidin-3-ylthio)-7V-(3-chloro-2-fluorophenyl)-7-methoxy quinazolin-4-amine (335 mg, crude) as a yellow oil. MS (ESI) m/z 391.2[M+H] ⁺ .

Preparation of 2-(3-((4-(( 3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl) thio)azet- idin-l-yl)-N-methylacetamide

[0468] To a mixture of 6-(azetidin-3-ylthio)-7V-(3-chloro-2-fluorophenyl)-7-methoxy quinazolin- 4-amine (130 mg, 333 pmol, 1.00 eq) and triethylamine (168 mg, 1.66 mmol, 5.00 eq) in dimethyl formamide (2.00 mL) was added 2-chloro-A-methylacetamide (53.6 mg, 499 pmol, 1.50 eq). The mixture was stirred at 25 °C for 12 h. The mixture was filtered to give filtrate. The filtrate was purified by /i/c -HPLC (column: Xtimate C18 150*25 mm*5 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 26%-56%,10min) and (column: Phenomenex Synergi Cl 8 150*30 mm*4 pm;mobile phase: [water(0.225%FA)-ACN];B%: 5%-35%, 10 min) to give 2-(3- ((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-y l)thio)azetidin-l-yl)-A-methyla- cetamide (41.1 mg, 89.1 pmol, 27% yield) as a white solid. ^X HNMR (400MHz, CDCk) 3 = 8.70 (s, 1H), 8.30 - 8.23 (m, 2H), 7.69 (s, 1H), 7.38 (s, 1H), 7.27 - 7.16 (m, 2H), 7.01 (br s, 1H), 4.31 - 4.21 (m, 1H), 4.19 - 4.13 (m, 2H), 4.06 (s, 3H), 3.56 (t, J = 7.4 Hz, 2H), 3.42 (s, 2H), 2.84 (d, J= 4.8 Hz, 3H).

Example 9: Preparation of 2-(3-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazoli n- 6-yl)amino)azetidin-l-yl)-N-methylacetamide (Compound 9)

Preparation of benzyl 3-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6 - yl)amino)azetidine-l-carboxylate

[0469] To a mixture of 7\^-(3-chloro-2-fluorophenyl)-7-methoxyquinazoline-4,6-diami ne (500 mg, 1.57 mmol, 1.00 eq) and benzyl 3 -oxoazetidine- 1 -carboxylate (400 mg, 1.95 mmol, 1.24 eq) in trifluoroacetic acid (5.00 mL) was added sodium borohydride acetate (400 mg, 1.89 mmol, 1.20 eq) at 15 °C. The mixture was stirred at 15 °C for 2 h. The mixture was poured into water (20.0 mL) and extracted with ethyl acetate (2 x 20.0 mL). The combined organic phase was washed with saturated sodium bicarbonate solution (30.0 mL), brine (20.0 mL) and concentrated to give a residue. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate = 1/1

0/1) to afford benzyl 3-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6 - yl)amino)azetidine-l -carboxylate (500 mg, 984 pmol, 63% yield) as a yellow solid. ^T H NMR (400MHz, DMSO-tA) b = 8.36 (br s, 1H), 7.58 (br t, J= 7.0 Hz, 1H), 7.53 (br t, J= 6.8 Hz, 1H), 7.45 - 7.31 (m, 7H), 7.18 (s, 1H), 7.05 (s, 1H), 6.44 (br d, J= 4.6 Hz, 1H), 5.12 (s, 2H), 4.47 (br s, 3H), 4.06 - 4.00 (m, 5H).

Preparation of N ⁶ -(azetidin-3-yl)-N ⁴ -(3-chloro-2-fluorophenyl)-7-methoxyquinazoline-4, 6-dia- mine

[0470] A solution of benzyl 3-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6 - yl)amino)azetidine-l -carboxylate (300 mg, 590 pmol, 1.00 eq) in trifluoroacetic acid (4.00 mL) was stirred at 70 °C for 2 h. The mixture was concentrated to dryness to give / ’-(azeti din-3 -yl)- A ⁴ -(3-chloro-2-fluorophenyl)-7-methoxyquinazoline-4,6-di amine (300 mg, crude) as a yellow oil which was used to next step without further purification. MS (ESI) m/z 374.0 [M+H] ⁺ Preparation of 2-(3-((4-(( 3-chloro-2-fluorophenyl) amino)- 7-methoxyquinazolin-6-yl)amino)azet- idin-l-yl)-N-methylacetamide

[0471] The mixture of 7V ⁶ -(azetidin-3-yl)-7V ⁴ -(3-chloro-2-fluorophenyl)-7-methoxyquinazoline- 4,6-diamine (100 mg, 267 pmol, 1.00 eq), 2-chloro-A-methylacetamide (57.5 mg, 535 pmol, 2.00 eq) and potassium carbonate (148 mg, 1.07 mmol, 4.00 eq) in dimethyl formamide (2.00 mL) was stirred at 60 °C for 1 h. The mixture was filtered to give a filtrate. The filtrate was purified by prep- HPLC (column: Waters Xbridge 150*25 5 um; mobile phase: [water(10mM NH4HCO3)- ACN];B%: 28%-45%,10 min) to give 2-(3-((4-((3-chloro-2-fluorophenyl)amino)-7-methox- yquinazolin-6-yl)amino)azetidin-l-yl)-A-m ethyl acetamide (7.14 mg, 16.1 pmol, 6% yield) as a white solid. ’H NMR (400MHz, CDCh) 3 = 8.66 (s, 1H), 8.63 - 8.56 (m, 1H), 7.28 - 7.24 (m, 1H), 7.23 - 7.11 (m, 3H), 7.06 - 6.90 (m, 1H), 6.42 (s, 1H), 5.03 (br d, J= 6.4 Hz, 1H), 4.36 - 4.22 (m, 1H), 4.06 (s, 3H), 3.99 (br t, J= 7.0 Hz, 2H), 3.27 (s, 2H), 3.22 (br t, J= 6.4 Hz, 2H), 2.89 (d, J= 5.0 Hz, 3H).

Example 10: Preparation of 2-(4-((4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)(me - thyl)amino)piperidin-l-yl)-N-methylacetamide (Compound 10)

Preparation of Compound 10

[0472] To a solution of 7V ⁴ -(3-chloro-2-fluorophenyl)-7V ⁶ -methyl-7V ⁶ -(piperidin-4-yl)quinazoline- 4,6-diamine (170 mg, 441 pmol, 1.00 eq and cesium carbonate (431 mg, 1.32 mmol, 3.00 eq) in dimethyl formamide (3.00 mL) was added 2-chloro-Wmethylacetamide (56.9 mg, 529 pmol, 1.20 eq in one portion. The mixture was stirred at 25 °C for 1 h. The mixture was filtered and the filtrate was purified by /c -HPLC (column: Waters Xbridge 150*25 5pm; mobile phase: [wa- ter(10mM NH4HCO3)-ACN]; B%: 28%-58%,10 min) and lyophilized to give 2-(4-((4-((3-chloro- 2-fluorophenyl)amino)quinazolin-6-yl)(methyl)amino)piperidin -l-yl)-7V-methylacetamide (64.15 mg, 136 pmol, 31% yield, 97% purity) as a yellow solid. ^X HNMR (400 MHz, DMSO-tA) 3 = 9.60 (br s, 1 H), 8.27 (s, 1 H), 7.74 (br d, J= 4.4 Hz, 1 H), 7.68 - 7.57 (m, 2 H), 7.51 (dt, J= 14.0, 7.0 Hz, 2 H), 7.39 (d, J= 2.3 Hz, 1 H), 7.33 - 7.26 (m, 1 H), 3.94 - 3.80 (m, 1 H), 2.93 (s, 2 H), 2.91 (s, 3 H), 2.87 (br s, 2 H), 2.64 (d, J= 4.8 Hz, 3 H), 2.29 (br t, J= 10.9 Hz, 2 H), 1.92 (qd, J= 12.0, 3.4 Hz, 2 H), 1.63 (br d, J= 10.3 Hz, 2 H).

Example 11: Preparation of 2-(3-((4-((3-chloro-2-fluorophenyl)amino)-7-methox- yquinazolin-6-yl)oxy)azetidin-l-yl)-N- methylacetamide (Compound 11)

Preparation of tert-butyl 3-((4-(( 3-chlor o-2 -fluorophenyl) amino)-7-methoxyquinazolin-6- yl) oxy) azetidine- 1 -carboxylate

[0473] To a solution of 4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (500 mg, 1.49 mmol, 1.00 eq) in dimethyl formamide (50.0 mL) was added cesium carbonate (1.50 g, 4.62 mmol, 3.10 eq) and tert-butyl 3 -(tosyloxy)azetidine-l -carboxylate (800 mg, 2.44 mmol, 1.64 eq). The mixture was stirred at 80 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 1/1) to give tert-butyl 3-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6 - yl)oxy)azetidine-l -carboxylate (420 mg, 831.31 pmol, 55.79% yield, 94% purity) as a yellow oil. ^X H NMR (400 MHz, CDCk) b = 8.71 (s, 1H), 8.41 (dt, J= 3.5, 6.8 Hz, 1H), 7.44 (br s, 1H), 7.32 (s, 1H), 7.19 - 7.14 (m, 2H), 6.85 (s, 1H), 5.08 (tt, J= 4.3, 6.4 Hz, 1H), 4.40 (dd, J= 6.5, 10.1 Hz, 2H), 4.17 (dd, J= 4.3, 10.1 Hz, 2H), 4.06 - 4.01 (m, 3H).

Preparation of 6-(azetidin-3-yloxy)-N-(3-chloro-2-fluorophenyl)-7-methoxyqu inazolin-4-amine [0474] To a solution of tert-butyl 3-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin- 6-yl)oxy)azetidine- 1-carboxylate (200 mg, 396 pmol, 1.00 eq) in di chloromethane (10.0 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 34.1 eq). The mixture was stirred at 15 °C for 2 h. The mixture was concentrated under reduced pressure to give 6-(azeti din-3 -yloxy)-7V-(3- chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine (280 mg, crude, trifluoroacetic acid salt) as a yellow oil which was used directly in the next step. MS (ESI) m/z 374.9 [M+H] ⁺ .

Preparation of Compound 11

[0475] To a solution of 6-(azetidin-3-yloxy)-7V-(3-chloro-2-fluorophenyl)-7-methoxyq uinazolin- 4-amine (280 mg, 573 pmol, 1.00 eq, trifluoroacetic acid salt) (crude) in dimethyl formamide (5.00 mL) was added triethylamine (290 mg, 2.87 mmol, 400 pL, 5.02 eq) and 2-bromo-A-methyl-acet- amide (100 mg, 658 pmol, 1.15 eq). The mixture was stirred at 25 °C for 16 h. The mixture was filtered to give a solution which was purified by /c -HPLC (column: Phenomenex Synergi Max- RP 150*50 mm*10 pm; mobile phase: [water(0.225% FA)-ACN];B%: 0%-30%,10 min). The desired fraction was collected and lyophilized to give 2-(3-((4-((3-chloro-2-fluorophenyl)amino)-7- m ethoxy quinazolin-6-yl)oxy)azeti din- l-yl)-A-m ethylacetamide (44.94 mg, 99.8 pmol, 17% yield, 99% purity, formate) as a white solid. ^X H NMR (400 MHz, DMSO-tA) b = 9.65 (s, 1H), 8.39 (s, 1H), 8.14 (s, 1H), 7.78 - 7.66 (m, 1H), 7.55 - 7.47 (m, 3H), 7.34 - 7.23 (m, 2H), 5.02 - 4.94 (m, 1H), 4.09 (br d, J= 5.4 Hz, 2H), 3.96 (s, 3H), 3.38 (br d, J= 2.2 Hz, 2H), 3.30 - 3.21 (m, 2H), 2.61 (d, J = 4.6 Hz, 3H).

Example 12: Preparation of 2-(3-((4-((3-chloro-2-fluorophenyl)amino)quinazolin-6- yl)amino)azetidin-l-yl)-N-methylacetamide (Compound 12)

Preparation of tert-butyl 3-((3-(methoxycarbonyl)-4-nitrophenyl)amino)azetidine-l-carb oxylate [0476] To a solution of methyl 5-fluoro-2-nitrobenzoate (1.00 g, 5.02 mmol, 1.00 eq in dimethylsulfoxide (10.0 mL) was added MA-diisopropylethylamine (1.95 g, 15.1 mmol, 2.62 mL, 3.00 eq) and tert-butyl 3 -aminoazetidine- 1 -carboxylate (952 mg, 5.53 mmol, 1.10 eq in portions. The mixture was stirred at 90 °C for 16 h. The reaction mixture was added dropwise to water (80 mL) and extracted with ethyl acetate (80.0 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum to give tert-butyl 3- ((3 -(methoxycarbonyl)-4-nitrophenyl)amino)azetidine-l -carboxylate (1.90 g, crude) as a yellow solid. ’H NMR (400 MHz, DMSO-tL) 3 = 7.98 (d, J= 8.9 Hz, 2H), 6.70 - 6.60 (m, 2H), 4.38 - 4.29 (m, 1H), 4.23 (br t, J= 13 Hz, 2H), 3.82 (s, 3H), 3.69 (dd, J= 4.7, 8.6 Hz, 2H), 1.38 (s, 9H). Preparation of tert-butyl 3-((4-amino-3-(methoxycarbonyl)phenyl)amino)azetidine-l-carb oxylate [0477] To a solution of tert-butyl 3 -((3 -(m ethoxycarbonyl)-4-nitrophenyl)amino)azeti dine- 1 -carboxylate (1.90 g, 5.41 mmol, 1.00 eq (crude) in ethyl alcohol (40.0 mL) and water (10.0 mL) was added iron powder (2.11 g, 37.9 mmol, 7.00 eq) and saturated ammonium chloride (2.60 g, 48.7 mmol, 9.00 eq in portions. The mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under vacuum to remove ethyl alcohol to give a residue which was diluted with water (300 mL) and ethyl acetate (200 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum to give tert-butyl 3- ((4-amino-3-(m ethoxy carbonyl)phenyl)amino)azeti dine- 1 -carboxylate (1.7 g, crude) as a yellow solid which was used directly in the next step. ’H NMR (400 MHz, DMSO-tL) 3 = 6.81 (d, J= 1.9 Hz, 1H), 6.71 - 6.63 (m, 2H), 6.00 (br s, 2H), 5.59 (br d, J= 6.9 Hz, 1H), 4.10 (br d, J= 6.5 Hz, 2H), 3.76 (s, 3H), 3.61 - 3.51 (m, 2H), 3.33 - 3.32 (m, 1H), 1.38 (s, 9H).

Preparation of tert-butyl 3-((4-hydroxyquinazolin-6-yl) amino)azetidine-l -carboxylate

[0478] To a solution of tert-butyl 3-((4-amino-3-(methoxycarbonyl)phenyl)amino)azetidine-l- carboxylate (1.70 g, 4.71 mmol, 1.00 eq) in ethyl alcohol (20.0 mL) was added formamidine acetate (588 mg, 5.65 mmol, 1.20 eq) in portions. The mixture was stirred at 80 °C for 3 h. The reaction mixture was concentrated under vacuum to remove ethyl alcohol to give a residue. The residue was triturated with water (50.0 mL) for 1 h. After filtration, the filter cake was dried in vacuum to give tert-butyl 3-((4-hydroxyquinazolin-6-yl) amino)azetidine-l -carboxylate (1.40 g, 4.12 mmol, 87% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-tL) 3 = 7.82 - 7.75 (m, 1H), 7.46 (d, J= 8.8 Hz, 1H), 7.09 (dd, J = 2.6, 8.8 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 6.80 (br d, J = 4.0 Hz, 1H), 5.75 (s, 1H), 4.22 (br s, 3H), 3.66 (br d, J= 3.6 Hz, 2H), 1.38 (s, 9H).

Preparation of tert-butyl 3-((4-chloroquinazolin-6-yl)amino)azetidine-l-carboxylate

[0479] To a solution of tert-butyl 3 -((4-hydroxyquinazolin-6-yl)amino)azetidine-l -carboxylate (535 mg, 1.57 mmol, 1.00 eq in toluene (15.0 mL) was added A,A-diisopropylethylamine (406 mg, 3.15 mmol, 548 pL, 2.00 eq and phosphoryl trichloride (289 mg, 1.89 mmol, 175 pL, 1.20 eq . The mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with water (50.0 mL) and ethyl acetate (80.0 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum to give a residue which was purified by column chromatography on silica gel eluted with petroleum ether/ethyl acetate = 1/1 to 0/1 to give tert-butyl 3 -((4-chloroquinazolin-6-yl)amino)azetidine-l -carboxylate (230 mg, 577 pmol, 37% yield, 84% purity) as a yellow solid. ^T H NMR (400 MHz, CDCh) <5 = 8.83 (s, 1H), 7.89 (d, J= 9.0 Hz, 1H), 7.35 - 7.28 (m, 1H), 6.90 - 6.86 (m, 1H), 4.68 (br d, J= 4.4 Hz, 1H), 4.47 - 4.41 (m, 2H), 3.84 (dd, J= 4.1, 9.0 Hz, 2H), 1.47 (s, 9H).

Preparation of tert-butyl 3-((4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)amino) azet- idine-1 -carboxylate

[0480] To a solution of tert-butyl 3 -((4-chloroquinazolin-6-yl)amino)azetidine-l -carboxylate (230 mg, 577 pmol, 1.00 eq in propan-2-ol (8.00 mL) was added dropwise 3-chloro-2-fluoroaniline (126 mg, 866 pmol, 1.50 eq). The mixture was stirred at 90 °C for 1 h. The reaction mixture was concentrated in vacuum to give a residue which was triturated with ethyl acetate (20.0 mL) and filtered. The filter cake was dried in vacuum to give tert-butyl 3-((4-((3-chloro-2-fluoro- phenyl)amino)quinazolin-6-yl)amino)azetidine-l -carboxylate (300 mg, crude) as a yellow solid. ’H NMR (400 MHz, DMSO-tL) b = 11.78 (br s, 1H), 8.73 - 8.70 (m, 1H), 7.80 (br d, J= 9.7 Hz, 1H), 7.67 - 7.62 (m, 1H), 7.58 - 7.51 (m, 4H), 7.41 - 7.34 (m, 1H), 4.39 (br s, 3H), 3.72 (br d, J = 4.0 Hz, 2H), 1.46 - 1.28 (m, 9H).

Preparation of N ⁶ -(azetidin-3-yl)-N ⁴ -( 3-chloro-2-fluorophenyl)quinazoline-4, 6-diamine

[0481] To a solution of tert-butyl 3-((4-((3-chloro-2-fluorophenyl)amino)quinazolin-6- yl)amino)azetidine-l -carboxylate (280 mg, 631 pmol, 1.00 eq in methanol (8.00 mL) was dropwise hydrochloric acid/ethyl acetate (4 M, 2.00 mL, 13.0 eq in portions. The mixture was stirred at 25 °C for 5 h. The reaction mixture was concentrated under vacuum to give / ’-(azeti din-3 -yl)- 7\^-(3-chloro-2-fluorophenyl)quinazoline-4, 6-diamine (300 mg, crude, hydrochloric acid) as a yellow solid. ’H NMR (400 MHz, DMSO-tL) b = 12.13 (br s, 1H), 9.51 - 9.18 (m, 2H), 8.78 - 8.63 (m, 1H), 7.83 (d, J= 9.2 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.67 - 7.61 (m, 1H), 7.58 - 7.51 (m, 2H), 7.39 - 7.33 (m, 1H), 4.65 - 4.45 (m, 3H), 3.96 - 3.88 (m, 2H).

Preparation of Compound 12

[0482] To a solution of M-(azetidin-3-yl)-A ^f7 -(3-chloro-2-fluorophenyl)quinazoline-4, 6-diamine (300 mg, 873 pmol, 1.00 eq (hydrochloric acid, crude) in dimethyl formamide (5.00 mL) was added triethylamine (266 mg, 2.63 mmol, 366 pL, 3.01 eq), followed 2-chloro-A-methylacetamide (113 mg, 1.05 mmol, 1.20 eq) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (3 x 50.0 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum to give a residue which was purified by prep- HPLC (column: Xtimate C18 150*25 mm*5 pm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 18%-48%, 10 min). The desired fraction was collected and concentrated to remove acetonitrile. The residual aqueous solution was lyophilized to give 2-(3-((4-((3 -chi oro-2 - fluorophenyl)amino)quinazolin-6-yl) amino)azeti din- l-yl)-A-m ethyl acetamide (54.8 mg, 129 umol, 14.8% yield, 98.0% purity) as a yellow solid. ^X H NMR (400 MHz, DMSO-tL) 3 = 9.48 (br s, 1H), 8.24 (s, 1H), 7.61 - 7.43 (m, 4H), 7.27 (br t, J= 8.3 Hz, 2H), 7.03 (s, 1H), 6.69 (br d, J = 6.9 Hz, 1H), 4.18 - 4.10 (m, 1H), 3.87 (br t, J= 6.6 Hz, 2H), 3.07 (s, 2H), 2.99 (t, J= 6.8 Hz, 2H), 2.60 (d, = 4.6 Hz, 3H).

Example 13: Preparation of 2-(3-((4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)(me - thyl)amino)azetidin-l-yl)-N- methylacetamide (Compound 13)

Preparation of Compound 13

[0483] To a mixture of A ⁶ -(azetidin-3-yl)-A ⁴ -(3-chloro-2-fluorophenyl)-A ⁶ -methylquinazoline- 4,6-diamine (370 mg, 938 pmol, 1.00 eq, HC1), cesium carbonate (1.22 g, 3.75 mmol, 4.00 eq) in dimethylformamide (3.00 mL) was added 2-chloro-A-methylacetamide (101 mg, 938 pmol, 1.00 eq) in one portion. The mixture was stirred at 30 °C for 1 h. The mixture was filtered and the filtrate was purified by /c -HPLC (column: Waters Xbridge 150*25 5pm; mobile phase: [wa- ter(10 mM NH4HCO3)-ACN];B%: 17%-47%,10 min) and lyophilized to give 2-(3-((4-((3-chloro- 2-fluorophenyl)amino)quinazolin-6-yl)(methyl)amino)azetidin- l-yl)-A-methylacetamide (20.1 mg, 45.9 pmol, 5% yield, 98% purity) as a yellow solid. ^X H NMR (400 MHz, DMSO-tA) 3 = 9.66 (br s, 1H), 8.30 (br s, 1H), 7.68 - 7.57 (m, 2H), 7.55 - 7.43 (m, 3H), 7.37 (d, J= 2.6 Hz, 1H), 7.33 - 7.24 (m, 1H), 4.34 (quin, J= 6.5 Hz, 1H), 3.82 (t, J= 7.2 Hz, 2H), 3.17 (t, J= 13 Hz, 2H), 3.08 (s, 2H), 3.00 (s, 3H), 2.60 (d, J= 4.6 Hz, 3H). Example 14: Preparation of 2-(3-((4-((3-chloro-2-fluorophenyl)amino)quinazolin-6- yl)oxy)azetidin-l-yl)-N-methylacetamide (Compound 14)

Preparation of 4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl acetate

[0484] A mixture of 4-chloroquinazolin-6-yl acetate (1.00 g, 4.49 mmol, 1.00 eq), 3-chloro-2- fluoroaniline (654 mg, 4.49 mmol, 1.00 eq) in acetonitrile (10.0 mL) was stirred at 25 °C for 1 h under nitrogen. The reaction mixture was concentrated under reduced pressure to give 4-((3- chloro-2-fluorophenyl)amino)quinazolin-6-yl acetate (1.49 g, crude) as a yellow solid. MS (ESI) m/z 332.1 [M+H] ⁺ .

Preparation of 4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-ol

[0485] A mixture of 4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl acetate (1.49 g, 4.49 mmol, 1.00 eq) in ammonium hydroxide (4.49 mmol, 20.0 mL, 1.00 eq) and methanol (20.0 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-ol (1.10 g, 3.80 mmol, 85% yield) as a brown solid. ^X H NMR (400MHz, DMSO ) 3 = 9.66 (br s, 1H), 8.34 (br s, 1H), 7.88 (s, 1H), 7.72 - 7.60 (m, 2H), 7.58 - 7.36 (m, 3H), 7.33 - 7.17 (m, 1H).

Preparation of tert-butyl 3-( ( 4-( 3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)oxy)azetidine- l- carboxylate

[0486] To a solution of 4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-ol (1.00 g, 3.45 mmol, 1.00 eq) in dimethyl formamide (4.00 mL) was added tert-butyl 3 -(tosyloxy)azeti dine- 1 -carboxylate (2.03 g, 6.21 mmol, 1.80 eq) and potassium carbonate (2.25 g, 6.91 mmol, 2.00 eq) at 25 °C, the mixture was stirred at 80 °C for 12 h. The reaction mixture was poured into water (40.0 mL) and the aqueous phase was extracted with ethyl acetate (3 x 60.0 mL). The combined organic phase was washed with brine (40.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate = 5/1 to 0/1) to afford tert-butyl 3-((4-((3-chloro-2-fluoro- phenyl)amino)quinazolin-6-yl)oxy)azetidine-l -carboxylate (900 mg, 2.02 mmol, 58% yield) as a yellow oil. MS (ESI) m/z 445.4 [M+H],

Preparation of 6-(azetidin-3-yloxy)-N-( 3-chloro-2-fluoro-phenyl)quinazolin-4-amine

[0487] To a solution of tert-butyl 3-((4-((3-chloro-2-fluorophenyl)amino)quinazolin-6- yl)oxy)azetidine-l- carboxylate (400 mg, 899 pmol, 1.00 eq) in dichloromethane (5.00 mL) was added trifluoroacetic acid (2.05 g, 18.0 mmol, 1.33 mL, 20.0 eq) at 25 °C, the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated to give a residue, the residue was poured into methanol and concentrated in vacuum to give 6-(azetidin-3-yloxy)-7V-(3-chloro-2-fluoro-phe- nyl)quinazolin-4-amine (400 mg, 871 pmol, 96% yield, trifluoroacetic acid) as a yellow solid. MS (ESI) m/z 344.9 [M+H], Preparation of Compound 14

[0488] To a solution of 6-(azetidin-3-yloxy)-7V-(3-chloro-2-fluoro-phenyl)quinazolin -4-amine (300 mg, 870 pmol, 1.00 eq) in dimethyl formamide (3.00 mL) was added 2-chloro-A-methyl- acetamide (187 mg, 1.74 mmol, 2.00 eq) and potassium carbonate (481 mg, 3.48 mmol, 4.00 eq) at 25 °C, the mixture was stirred at 60 °C for 1 h. The reaction mixture was filtered to give a filtrate, the filtrate was purified by /i/c -HPLC (column: Phenomenex Synergi Max-RP 150*50 mm* 10 pm; mobile phase: [water(0.225%FA)-ACN];B%: 1 %-31%, 11 min) to afford 2-(3-((4-((3- chloro-2-fluorophenyl)amino)quinazolin-6-yl)oxy)azetidin- 1 -yl )-ct/-m ethyl acetami de (15.5 mg, 37.2 pmol, 4.2% yield) as a white solid. ’H NMR (400 MHz, MeOD) d = 8.42 (s, 1H), 7.88 - 7.75 (m, 1H), 7.66 - 7.50 (m, 3H), 7.50 - 7.40 (m, 1H), 7.27 (dt, J= 1.2, 8.0 Hz, 1H), 5.21 - 5.10 (m, 1H), 4.27 (br t, J= 7.4 Hz, 2H), 3.71 (br d, J= 4.4 Hz, 2H), 3.54 (br s, 2H), 2.78 (s, 3H).

Example 15: Preparation of 2-(4-((4-((3-chloro-2-fluorophenyl)amino)quinazolin-6- yl)oxy)piperidin-l-yl)-N-methylacetamide (Compound 15)

Preparation of tert-butyl 4-((4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)oxy)pi peridine- 1-carboxylate

[0489] A mixture of 4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-ol (500 mg, 1.73 mmol, 1.00 eq), tert-butyl 4-(tosyloxy)piperidine-l -carboxylate (920 mg, 2.59 mmol, 1.50 eq) in dimethyl formamide (8.00 mL) was added potassium carbonate (477 mg, 3.45 mmol, 2.00 eq), then the mixture was stirred at 80 °C for 12 h under nitrogen. The reaction mixture was diluted with water (40.0 mL) and extracted with ethyl acetate (3 x 40.0 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCb, Petroleum ether/Ethyl acetate = 1/0 to 2/1) to give tert-butyl 4-((4-((3 -chi oro-2-fluorophenyl)amino)quinazolin-6-yl)oxy)piperi dine- 1 -carboxylate (416 mg, 880 pmol, 51% yield) as a brown solid. ^X H NMR (400MHz, DMSO-tA) 3 = 9.74 (s, 1H), 8.42 (s, 1H), 7.91 (d, J= 2.4 Hz, 1H), 7.77 (d, J= 9.0 Hz, 1H), 7.60 - 7.49 (m, 3H), 7.35

- 7.27 (m, 1H), 4.77 (td, J= 3.9, 7.5 Hz, 1H), 3.77 - 3.64 (m, 2H), 2.90 (s, 1H), 2.74 (s, 1H), 2.08

- 2.00 (m, 2H), 1.74 - 1.56 (m, 2H), 1.42 (s, 9H).

Preparation of N-( 3-chloro-2-fluorophenyl)-6-(piperidin-4-yloxy)quinazolin-4-a mine

[0490] A mixture of tert-butyl 4-((4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)oxy)pi per- idine-1 -carboxylate (416 mg, 880 pmol, 1.00 eq in dichloromethane (10.0 mL) was added trifluoroacetic acid (4.62 g, 40.5 mmol, 3.00 mL, 46.1 eq , then the mixture was stirred at 25 °C for 1 h under nitrogen. The reaction mixture was concentrated under reduced pressure to give N-(3- chloro-2-fluorophenyl)-6-(piperidin-4-yloxy)quinazolin-4-ami ne (600 mg, crude, TFA) as a white solid. ’H NMR (400MHz, DMSO ) 3 = 8.89 (s, 1H), 8.69 (br s, 2H), 8.17 (d, J= 2.3 Hz, 1H), 7.87 - 7.82 (m, 1H), 7.71 - 7.66 (m, 1H), 7.56 (br t, J= 6.7 Hz, 1H), 7.40 (t, J= 7.7 Hz, 1H), 4.94

- 4.82 (m, 1H), 3.31 (br d, J = 4.0 Hz, 2H), 3.20 - 3.10 (m, 2H), 2.25 - 2.16 (m, 2H), 2.00 - 1.94 (m, 2H)

Preparation of Compound 15

[0491] A mixture of A-(3-chloro-2-fluorophenyl)-6-(piperidin-4-yloxy)quinazolin- 4-amine (300 mg, 616 pmol, 1.00 eq, TFA), 2-chloro-A-methylacetamide (133 mg, 1.23 mmol, 2.00 eq in dimethyl formamide(3.50 mL) was added potassium carbonate (341 mg, 2.46 mmol, 4.00 eq , and the mixture was stirred at 60 °C for 1 h. The reaction mixture was filtered and the filtrate was purified by /c -HPLC [column: Waters Xbridge 150*25 5 pm; mobile phase: [water(10mM NH4HCO3)-ACN];B%: 20%-50%,10 min] and lyophilized to give 2-(4-((4-((3 -chloro- 2-fluoro- phenyl)amino)quinazolin-6-yl)oxy)piperidin-l-yl)-N-methylace tamide (100.03 mg, 225 pmol , 31 % yield, 99% purity) as a gray solid. ’H NMR (400MHz, DMSO-tA) 3 = 9.74 (br s, 1H), 8.39 (s, 1H), 7.86 (d, J= 2.2 Hz, 1H), 7.77 - 7.69 (m, 2H), 7.57 - 7.47 (m, 3H), 7.33 - 7.27 (m, 1H), 4.67 - 4.58 (m, 1H), 2.94 (s, 2H), 2.76 - 2.70 (m, 2H), 2.63 (d, J = 4.8 Hz, 3H), 2.41 (br t, J= 8.9 Hz, 2H), 2.06 (br d, J= 10.6 Hz, 2H), 1.86 - 1.73 (m, 2H).

Example 16: Biological Activity of the Compounds

Retroviral Production

[0492] EGFR mutants were subcloned into pMXs-IRES-Blasticidin (RTV-016, Cell Biolabs, San Diego, C A). Retroviral expression vector retrovirus was produced by transient transfection of HEK 293T cells with the retroviral EGFR mutant expression vector pMXs-IRES-Blasticidin (RTV-016, Cell Biolabs), pCMV-Gag-Pol vector and pCMV-VSV-G-Envelope vector. HEK 293T/17 cells were plated in 100 mm collagen coated plate (354450, Coming Life Sciences, Tewksbury, MA) (4x105 per plate) and incubated overnight. The next day, retroviral plasmids (3 mg of EGFR mutant, 1.0 mg of pCMV-Gag-Pol and 0.5 mg pCMV-VSV-G) were mixed in 500 mL of Optimem (31985, Life Technologies). The mixture was incubated at room temperature for 5 minutes and then added to Optimem containing transfection reagent Lipofectamine (11668, Invitrogen) and incubated for 20 minutes. The mixture was then added dropwise to HEK 293T cells. The next day the medium was replaced with fresh culture medium and the retrovirus was harvested at 24 hours and 48 hours.

Generation of EGFR mutant stable cell lines

[0493] BaF3 cells (1.5E5 cells) were infected with 1 mL of viral supernatant supplemented with 8 mg/mL polybrene by centrifuging for 30 minutes at 1000 rpm. Cells were placed in a 37 °C incubator overnight. Cells were then spun for 5 minutes to pellet the cells. Supernatant was removed and cells re-infected a fresh 1 mL of viral supernatant supplemented with 8 mg/mL polybrene by centrifuging for 30 minutes at 1000 rpm. Cells were placed in 37 °C incubator overnight. Cells were then maintained in RPMI containing 10% Heat Inactivated FBS, 2% L-glutamine containing 10 ng/mL IL-3. After 48 hours cells were selected for retroviral infection in 10 mg/mL Blasticidin for one week. Blasticidin resistant populations were washed twice in phosphate buffered saline before plating in media lacking IL-3 to select for IL-3 independent growth.

Assay for cell proliferation

[0494] BaF3 cell lines were resuspended at 1.3E5 c/mL in RPMI containing 10% Heat Inactivated FBS, 2% L-glutamine and 1% Pen/Strep and dispensed in triplicate (17.5E4 c/well) into 96 well plates. To determine the effect of drug on cell proliferation, cells were incubated for 3 days in the presence of vehicle control or test drug at varying concentrations. Inhibition of cell growth was determined by luminescent quantification of intracellular ATP content using Cell Titer Gio (Promega), according to the protocol provided by the manufacturer. Comparison of cell number on day 0 versus 72 hours post drug treatment was used to plot dose-response curves. The number of viable cells was determined and normalized to vehicle-treated controls. Inhibition of proliferation, relative to vehicle-treated controls was expressed as a fraction of 1 and graphed using PRISM® software (Graphpad Software, San Diego, CA). ECso values were determined with the same application

[0495] The A431 lung cancer cell line, which natively expresses WT-EGFR, was used to assess WT-EGFR inhibition. BT474, which natively expresses WT-HER2, was used to assess WT-HER2 inhibition. To perform the proliferation assays, cells were plated in 96-well plates and subjected to various doses of compound to generate a dose-response curve for each cell line. Proliferation was assessed using the Cell Titer Gio cell proliferation kit (Promegea # G7573). Cell Titer Gio reagent was thawed and allowed to equilibrate at room temperature for 30 minutes. Plated and dosed cells were also allowed to equilibrate at room temperature for 30 minutes. Cell Titer Gio was added to plated cells at 15 pL per well, the plate was shaken for 20 minutes at room temperature, and luminescence was measured using Victor X3 Multimode plate reader (Perkin Elmer). Cell Titer Gio readings were taken following 72 hours (T72) after addition of compound. Doseresponse curves were generated for each cell line and ICso values were generated.

[0496] Table A assigns each compound an ICso code: A, B, C, D, or E. According to the code, A represents an ICso value <5 nM; B represents an ICso value >5 nM and <25 nM; C represents an ICso value >25 nM and <100 nM; D represents an IC50 value >100 nM and <200 nM; and E represents an IC50 value >200 nm. Table A also assigns each compound a code for selectivity for EGFR exon-19 del +C797S/EGFR wt: + indicates selectivity >lx and <25x; ++ indicates selectivity >25x and <50x; +++ indicates selectivity >50x and <75x; ++++ indicates selectivity >75x and

<100x; and +++++ indicates selectivity >100x.

Table A. IC50 values

EQUIVALENTS

[0497] The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference.

[0498] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.