alkynyl quinazoline compounds

Abstract

The present disclosure relates to compounds of Formula (I') and pharmaceutically acceptable salts and stereoisomers thereof. The present disclosure also relates to methods of making these compounds, compositions comprising these compounds, and methods of using the same to prevent or treat abnormal cell growth in mammals, particularly humans.

Description

[0001] This application is a divisional application of patent application No. 202080072199.2, filed on August 14, 2020, entitled "Alkynequinazoline Compound". Related applications

[0002] This application claims priority and benefit to U.S. Application No. 63 / 065,028, filed August 13, 2020, and U.S. Application No. 62 / 887,392, filed August 15, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to novel compounds as receptor tyrosine kinase (RTK) inhibitors, specifically oncogenic mutants of the ErbB-receptor. This disclosure also relates to methods for preparing these compounds, compositions comprising these compounds, and methods for using them to prevent or treat abnormal cell growth in mammals, particularly humans. Background Technology

[0004] Mutations affecting the intracellular catalytic domain or extracellular ligand-binding domain of the ErbB receptor can produce oncogenic activity (the ErbB protein family consists of four members, including ErbB-1, also known as the epidermal growth factor receptor (EGFR), and Erb-2, also known as HER2 in humans). ErbB inhibitors are known treatments for a variety of cancers. However, not every patient responds satisfactorily to this treatment. Therefore, there has long been a need in the art for novel therapies that address the variable responsiveness of cancer patients to known therapies. This disclosure provides compositions and methods for the prevention or treatment of cancer in patients with these oncogenic mutations when no variable responsiveness is observed when treating patients with these ErbB mutants using existing standards of care. Summary of the Invention

[0005] In some respects, this disclosure provides a compound of formula (I'): Or its pharmaceutically acceptable salt or stereoisomer, wherein: W is CH or N; Z is arbitrarily defined by one or more R. Z Substituted 3- to 12-membered heterocyclic alkyl groups; Each R Z Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R Za replace; Each R Za Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl is optionally replaced by one or more R. T replace; Each R T Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R Ta replace; Each R TaIndependently, it is a halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; Ar 1 It is optionally controlled by one or more R A1 Replacement C6-C 10 Aryl; Each R A1 Independently, it is halogen, CN, -OH, -NH2, -OR A1a -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R A1a Replace; and Each R A1a Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R A1b Replace; and Each R A1b It can be halogen, CN, -OH or -NH2 independently.

[0006] In some aspects, this disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof, said compound having formula I, in W is CH or N, preferably CH; X 1 Is it -O-, -S-, or -NR? 3 -; R a R b Hydrogen is independent of each other. 1-4 Alkyl, or R a One of them is if X 1 It is NR 3 Then with X 1 -(CH2) forms a ring p , or R a One of them is with R 2 -(CH2) forms a ring p ; R c R d They are either hydrogen or C, independent of each other. 1-4 alkyl; R 1 It is H or F; R 2 Is it hydrogen or C? 1-4 Alkyl, or with R 3 Or with R a One of them forms a ring -(CH2). q ; R 3 Is it hydrogen or C? 1-4 Alkyl groups, preferably hydrogen or methyl, or those with R 2 -(CH2) forms a ring p -; m is 1, 2, or 3; n is 0, 1, or 2; p is 1 or 2; q is 0, 1, or 2; and Ar 1 It is a 6-membered aryl group that is either unsubstituted or substituted with one or more members selected from the group consisting of: halogens, -CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6heteroaryl, amino, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 Aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 alkoxyaminocarbonyl, aryl C 1-6 Alkyl or C6 aryl.

[0007] In some embodiments, when X 1 Yes -NR 3 -, R 2 It's not hydrogen.

[0008] In some embodiments, when X 1 Yes -NR 3 -, R 2 It is C 1-4 Alkyl, or with R 3 Or with R a One of them forms a ring -(CH2). q -

[0009] In some embodiments, X 1 Yes -NR 3 - and R 2 It's not hydrogen.

[0010] In some embodiments, X 1 Yes -NR 3 - and R 2 It is C 1-4 Alkyl, or with R 3 Or with R a One of them forms a ring -(CH2). q -

[0011] In some embodiments, X 1 It is NR 3 Or O and where R 3 It is methyl, ethyl, n-propyl, or n-butyl.

[0012] In some embodiments, R 1 It is hydrogen.

[0013] In some embodiments, R 2 It is methyl, ethyl, n-propyl or n-butyl, preferably methyl or R 2 Is with R 3 -(CH2)- or -(CH2)2, or R, form a ring. 2 Is with R a One of them forms a ring -(CH2)- or -(CH2)2.

[0014] In which R a One of them with R 3 In some embodiments of the ring formation, the formed ring is a 4-membered, 5-membered, or 6-membered ring, or a 5-membered or 6-membered ring, or a 5-membered ring.

[0015] In which R a One of them with R 3 In some embodiments where the ring is formed, the formed ring is a 3-membered, 4-membered, 5-membered, or 6-membered ring.

[0016] In which R 2 One of them with R 3 In some embodiments where the ring is formed, the formed ring is a 4-membered, 5-membered, or 6-membered ring, or a 5-membered, 6-membered ring.

[0017] In some embodiments, Ar 1 Having formula i or its pharmaceutically acceptable salt or stereoisomer, in R 4 It is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 heteroaryl, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 Aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 Alkoxyamino-carbonyl, aryl C 1-6 alkoxy or C6 aryl; R 5 R 5' R 6 R 6' They are hydrogen, -CF3 or halogens, and preferably F or Cl.

[0018] In some embodiments, R 1 It is hydrogen.

[0019] In some embodiments, R c and R d It is hydrogen. In some embodiments, Rb R c and R d It is hydrogen.

[0020] In some embodiments, R 2 Is it methyl or R? 2 Is with R 3 -(CH2)- or -(CH2)2- that form a ring, or R 2 Is with R a One of them forms a ring -(CH2)- or -(CH2)2-.

[0021] In some embodiments, Ar 1 Having formula ii-1, ii-2, ii-3 or ii-4 or their pharmaceutically acceptable salts or stereoisomers. in X 2 It is O, NH, or NMe; X 3 It is CH or N; o is 0 or 1; R 4 It is hydrogen or halogen, preferably F or Cl; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3, or halogen, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F.

[0022] In some embodiments, R 5 Is F and / or R 6 It is either F or Cl.

[0023] In some embodiments, R 1 It is hydrogen.

[0024] In some embodiments, R 2 Is it methyl or R? 2 Is with R 3 -(CH2)- or -(CH2)2- that form a ring, or R 2 Is with R a One of them forms a ring -(CH2)- or -(CH2)2-.

[0025] In some embodiments, R c and R d It is hydrogen. In some embodiments, R b R c and Rd It is hydrogen.

[0026] In some embodiments, Ar 1 Having formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7 or their pharmaceutically acceptable salts or stereoisomers, in X 3 It is CH or N; o is 0 or 1; R 4 It is hydrogen or halogen, preferably F or Cl; R 5 R 6 They are hydrogen, -CF3, or halogens, each independent of the other, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F.

[0027] In some embodiments, R 5 Is F and / or R 6 It is either F or Cl.

[0028] In some embodiments, R 1 It is hydrogen.

[0029] In some embodiments, R c and R d It is hydrogen. In some embodiments, R b R c and R d It is hydrogen.

[0030] In some embodiments, R 2 Is it methyl or R? 2 Is with R 3 -(CH2)- or -(CH2)2- that form a ring, or R 2 Is with R a One of them forms a ring -(CH2)- or -(CH2)2-.

[0031] In some embodiments, Ar 1 Having formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7 or their pharmaceutically acceptable salts or stereoisomers, in X 3 It is C or N, preferably N; o is 0 or 1; R4 It is hydrogen or halogen, preferably F or Cl; R 5 R 6 They are hydrogen, -CF3, or halogens, each independent of the other, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F.

[0032] In some embodiments, R 5 It is F and / or R. 6 It is either F or Cl.

[0033] In some embodiments, R 1 It is hydrogen.

[0034] In some embodiments, R c and R d It is hydrogen. In some embodiments, R b R c and R d It is hydrogen.

[0035] In some embodiments, R 2 Is it methyl or R? 2 Is with R 3 -(CH2)- or -(CH2)2- that form a ring, or R 2 Is with R a One of them forms a ring -(CH2)- or -(CH2)2-.

[0036] In some embodiments, Ar 1 Having formula iv-1, iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9 or their pharmaceutically acceptable salts or stereoisomers, in o is 0 or 1; R 4 It is hydrogen or halogen, preferably F or Cl; R 5 R 6 They are hydrogen, -CF3, or halogens, each independent of the other, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F.

[0037] In some embodiments, R 5 Is F and / or R 6 It is either F or Cl.

[0038] In some embodiments, R 1 It is hydrogen.

[0039] In some embodiments, R c and R d It is hydrogen. In some embodiments, R b R c and R d It is hydrogen.

[0040] In some embodiments, R 2 Is it methyl or R? 2 Is with R 3 -(CH2)- or -(CH2)2- that form a ring, or R 2 Is with R a One of them forms a ring-forming -(CH2)- or -(CH2)2-. In some embodiments, R 7 It is F.

[0041] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof having formula IIa or IIb. in X 1 Is it -O- or -NR? 3 -; R 1 It is H or F; R 2 Is it hydrogen or C? 1-4 Alkyl, preferably methyl, or with R 3 -(CH2) forms a ring q -; R 3 Is it hydrogen or C? 1-4 Alkyl groups, preferably hydrogen or methyl, or those with R 2 -(CH2) forms a ring p -; m is 1, 2, or 3; n is 0, 1, or 2; p is 1 or 2; q is 0, 1, or 2; r is 0 or 1; s is 1 or 2; and Ar 1 It is a 6-membered aryl group that is either unsubstituted or substituted with one or more members selected from the group consisting of: halogens, -CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 heteroaryl, amino, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 Aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 alkoxyaminocarbonyl, aryl C 1-6 Alkyl or C6 aryl.

[0042] In some embodiments, R 1 It is hydrogen.

[0043] In some embodiments, R 2 Is it methyl or R? 2 Is with R 3 -(CH2)- or -(CH2)2- form a ring.

[0044] In some embodiments, when X 1 Yes -NR 3 -, R 2 It's not hydrogen.

[0045] In some embodiments, when X 1 Yes -NR 3 -, R 2 It is C 1-4 Alkyl, or with R 3 Or with R a One of them forms a ring -(CH2). q -

[0046] In some embodiments, X 1 Yes -NR 3 - and R 2 It's not hydrogen.

[0047] In some embodiments, X 1 Yes -NR 3 - and R 2 It is C 1-4 Alkyl, or with R 3 Or with R a One of them forms a ring -(CH2). q -

[0048] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof having formula III. in R1 It is H or F; Ar 1 It is a 6-membered aryl group that is either unsubstituted or substituted with one or more members selected from the group consisting of: halogens, -CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 heteroaryl, amino, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 Aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 alkoxyaminocarbonyl or C6 aryl; and Z is selected from .

[0049] In some embodiments, R 1 It is hydrogen.

[0050] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof having formula IV. in R 1 It is H or F; R 4 It is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 heteroaryl, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 Aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 alkoxyamino-carbonyl or C6 aryl; R5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3, or halogen, preferably F or Cl; and Z is selected from .

[0051] In some embodiments, R 5 Is F and / or R 6 It is either F or Cl.

[0052] In some embodiments, R 1 It is hydrogen.

[0053] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof having the formula V-1, V-2, V-3, or V-4. in X 2 It is O, NH, or NMe; X 3 It is C or N; R 1 It is H or F; R 4 It is hydrogen or halogen, preferably F or Cl; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3, or halogen, preferably F or Cl; o is 0 or 1; R 7 It is hydrogen or halogen, preferably F; and Z is selected from .

[0054] In some embodiments, R 5 Is F and / or R 6 It is either F or Cl.

[0055] In some embodiments, R 1 It is hydrogen.

[0056] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof, said compound having the formula VI-1, VI-2, VI-3, or VI-4. in X2 It is O, NH, or NMe; X 3 It is C or N; R 1 It is H or F; o is 0 or 1; R 4 It is hydrogen or halogen, preferably F or Cl; R 5 R 6 They are hydrogen, -CF3, or halogens, each independent of the other, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F; and Z is selected from .

[0057] In some embodiments, R 5 Is F and / or R 6 It is either F or Cl.

[0058] In some embodiments, R 1 It is hydrogen.

[0059] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof having the formula VII-1, VII-2, VII-3 or VII-4, VII-5, VII-6, VII-7, VII-8 or VII-9. in R 1 It is H or F; o is 0 or 1; R 4 It is hydrogen or halogen, preferably F or Cl; R 5 R 6 They are hydrogen, -CF3, or halogens, each independent of the other, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F; Z is selected from .

[0060] In some embodiments, R 5 Is F and / or R 6 It is either F or Cl.

[0061] In some embodiments, R 1 It is hydrogen. In some embodiments, R 7 It is F.

[0062] In some aspects, this disclosure relates to a composition comprising a compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any of the embodiments described herein.

[0063] In some embodiments, the composition includes a pharmaceutically acceptable carrier.

[0064] In some embodiments, the composition includes a second therapeutic agent.

[0065] In some aspects, this disclosure relates to a method of inhibiting an oncogenic variant of the ErbB receptor (e.g., an oncogenic variant of EGFR), the method comprising administering a therapeutically effective amount of the compound described herein to a subject in need.

[0066] In some aspects, this disclosure relates to a method of inhibiting oncogenic variants of the ErbB receptor (e.g., oncogenic variants of EGFR), said method comprising administering the composition described herein to a subject in need.

[0067] In some aspects, this disclosure relates to a method for preventing or treating cancer, the method comprising administering a therapeutically effective amount of the compound described herein to a subject in need.

[0068] In some respects, this disclosure relates to a method for preventing or treating cancer, the method comprising administering the composition described herein to a subject in need.

[0069] In some respects, this disclosure relates to compounds described herein for inhibiting oncogenic variants of the ErbB receptor (e.g., oncogenic variants of EGFR).

[0070] In some respects, this disclosure relates to compounds described herein for the prevention or treatment of cancer.

[0071] In some respects, this disclosure relates to compositions described herein for inhibiting oncogenic variants of the ErbB receptor (e.g., oncogenic variants of EGFR).

[0072] In some respects, this disclosure relates to the compositions described herein for the prevention or treatment of cancer.

[0073] In some respects, this disclosure relates to the use of the compounds described herein for the manufacture of medicaments for inhibiting oncogenic variants of the ErbB receptor (e.g., oncogenic variants of EGFR).

[0074] In some respects, this disclosure relates to the use of the compounds described herein in the manufacture of medicaments for the prevention or treatment of cancer.

[0075] In some embodiments, the cancer is glioblastoma.

[0076] In some aspects, this disclosure relates to a method for preventing or treating glioblastoma, the method comprising administering to a subject in need a therapeutically effective amount of a compound described herein according to any of the embodiments.

[0077] In some respects, this disclosure relates to compounds described herein according to any embodiment of the examples, said compounds being used for the prevention or treatment of glioblastoma.

[0078] In some aspects, this disclosure relates to a method for preventing or treating glioblastoma, the method comprising administering to a subject in need a composition according to any of the embodiments described herein.

[0079] In some respects, this disclosure relates to compositions described herein according to any of the embodiments for the prevention or treatment of glioblastoma. Detailed Implementation

[0080] This disclosure relates to compounds as receptor tyrosine kinase (RTK) inhibitors, specifically oncogenic mutants of the ErbB-receptor. In some embodiments of the invention, oncogenic mutants of the ErbB-receptor are also allosteric mutants of the ErbB-receptor. In some embodiments, the allosteric mutant may include or consist of an ErbB-receptor variant having a mutation in a sequence outside the ATP-binding site. In some embodiments, the allosteric mutant may include or consist of an ErbB-receptor variant having a mutation in a sequence within one or more of the exon 19, exon 20, or the C1-C2 extracellular dimerization interface.

[0081] Mutations affecting the intracellular catalytic domain or extracellular ligand-binding domain of the ErbB receptor may produce oncogenic activity (the ErbB protein family consists of four members, including ErbB-1, also known as the epidermal growth factor receptor (EGFR), and Erb-2, also known as HER2 in humans). Extracellular mutants of the ErbB receptor in cancer, including EGFR-Viii (also EGFR-V3) and HER2-S310F, are constitutively activated in the absence of ligands, exhibiting persistent signaling resistant to downregulation and being both transformative and tumorigenic (Nishikawa, Ji et al., 1994, 2013; Francis, Zhang et al., 2014). Their expression is associated with metastasis and poor long-term overall survival.

[0082] In glioblastoma (also known as glioblastoma multiforme or GBM), EGFR-Viii is expressed in 20% of tumors (Sugawa, Ekstrand et al., 1990; Brennan, Verhaak et al., 2013). EGFR-Viii expression in GBM is often mutually exclusive with the expression of other RTK oncogenes, which are co-expressed with EGFR variants in only 7% of GBM tumors (Furnari, Cloughesy et al., 2015). These data suggest how EGFR-Viii exhibits a dominant and mutually exclusive expression pattern in GBM compared to other oncogenic drivers. EGFR-Viii is also expressed in approximately 30% of SCCHN tumors (Sok, Coppelli et al., 2006; Keller, Shroyer et al., 2010; Wheeler, Suzuki et al., 2010; Tinhofer, Klinghammer et al., 2011; Wheeler, Egloff et al., 2015) and 10% of squamous NSCLC (Ji, Zhao et al., 2006; Sasaki, Kawano et al., 2007), and is associated with resistance to current therapeutic agents, including the anti-EGFR antibody cetuximab (Sok, Coppelli et al., 2006; Tinhofer, Klinghammer et al., 2011). Normal tissues do not express this oncogenic receptor variant.

[0083] RNA sequencing data revealed that EGFR-Viii is just one of several EGFR aberration splicing variants expressed in GBM tumors. Two other variants result in truncation of exons 12-13 (EGFR-Vvi) and 14-15 (EGFR-Vii). Like EGFR-Viii, EGFR-Vii is both transforming and tumorigenic. In addition to splicing variants, GBM tumors also express a range of EGFR point mutations, including C620Y, A289V, and G598V, which are both transforming and tumorigenic.

[0084] HER2-S310F is the most common HER2 mutation expressed in human tumors, accounting for approximately 0.5% of all tumors. HER2-S310F expression is mutually exclusive with HER2 amplification. HER2-S310F is highly oncogenic, capable of converting BaF3 cells (mouse interleukin-3 (IL-3)-dependent progenitor B cell line) into IL-3-independent cells and promoting tumor growth in vivo.

[0085] Short insertions within exon 20 of EGFR and HER2 are expressed in lung adenocarcinoma tumors and other tumor groups. ErbB exon 20 insertion mutants are expressed in 4-5% of lung adenocarcinoma tumors. Examples include HER2-YVMA, EGFR-SVD, and EGFR-NPH. These ErbB exon 20 insertion mutants are highly oncogenic, converting BaF3 cells into IL-3-independent cells and promoting tumor growth in vivo.

[0086] ErbB inhibitors are known treatments for a variety of cancers. However, not every patient responds satisfactorily to this treatment. Therefore, there has long been a need in the art for novel therapies capable of addressing the variable responsiveness of cancer patients to known treatments. Because standards of care existed prior to the development of the compositions and methods disclosed herein, this invention overcomes some of the drawbacks of these standards of care.

[0087] Anomalous ErbB receptor activation While the mechanisms described herein apply to any form of cancer in which these EGFR variants of this disclosure are expressed, the prevalence of these variants in glioblastoma (GBM) is provided by way of example. Other cancers expressing the EGFR variants of this disclosure include, but are not limited to, solid carcinomas, epithelial carcinomas and / or cancers of epithelial origin, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma (GBM), head and neck cancer, lung cancer, and non-small cell lung cancer (NSCLC).

[0088] In GBM tumors, EGFR is frequently a target of genomic mutations and alternative splicing events leading to alterations in the extracellular dimer interface. Many tumors express more than one aberrant isoform. This disclosure provides the activation mechanisms of the most common variants, EGFR-Viii, EGFR-Vii, EGFR-Vvi, EGFR-G598V, and EGFR-A289V. Although each isoform / point mutant results from different extracellular domain alterations, they are all activated by a common mechanism involving covalent ligand-independent dimerization.

[0089] AMG-595 (Amgen) is an EGFR-Viii isotype-selective antibody that is inactive against wild-type EGFR or other splice-activated variants. Rindopepimut (Celldex) is a vaccine that selectively elicits an immune response against tumor cells expressing EGFR-Viii but not wild-type EGFR or other splice-activated isotypes. Other EGFR isotypes expressed in GBM tumors (EGFR-Vii and EGFR-Vvi) are constitutively active covalent receptors, and their expression may limit the breadth and duration of therapeutic benefit from ErbB inhibitors that are selective only against EGFR-Viii. Therefore, it may be useful to exclude patients whose tumors express EGFR-Vii, EGFR-Vvi, or EGFR extracellular domain point mutants from EGFR-Viii selective therapy.

[0090] Heterogeneous expression patterns of multiple extracellular domain variants of the ErbB receptor in tumors suggest that small-molecule inhibitors inhibiting all variants are preferred. The covalently activated EGFR isotype family responds very differently to small-molecule ErbB inhibitors compared to EGFR catalytic domain mutations observed in NSCLC. Importantly, type I inhibitors, including erlotinib, all induce the formation of covalently activated EGFR dimers and increase EGFR phosphorylation at subsaturated concentrations, an activity further enhanced when the ErbB inhibitor is washed away. This manifests as anomalous proliferative activation at subsaturated concentrations.

[0091] The discovery of anomalous proliferative activation at subsaturated concentrations of type I ErbB inhibitors further underscores the prevalence of a range of extracellular variants of HER2 in many cancers, including breast and bladder cancer. All variants exist as covalently activated receptors, and levels of the covalent dimer increase following treatment with type I inhibitors, including sapitinib and afatinib. Similar to covalently activated EGFR variants, subsaturated doses of type I inhibitors anomalously increase phosphorylation of HER2 variants, thereby increasing the proliferation of cells expressing them.

[0092] Compared to type I inhibitors, this disclosure demonstrates that non-type I (e.g., type II) inhibitors containing neratinib do not anomalously activate cells expressing ErbB extracellular domain variants. The finding that neratinib is a potent and selective preferred molecule for each member of the covalently activated EGFR family compared to wild-type EGFR is further supported.

[0093] In summary, this disclosure provides structure / function relationships for predicting how structural changes affecting receptor regions distal to the active site can confer significantly different responses to small molecule active site inhibitors. The discovery of anomalous activation of covalently activated ErbB receptor variants by type I inhibitors described herein has significant clinical implications. The data in this disclosure provide a mechanistic explanation for the failure of type I inhibitors in clinical studies in tumor types where covalently activated ErbB receptor expression is prevalent. This includes erlotinib and gefitinib in GBM tumors, erlotinib in SCCHN tumors, and saprotinib in breast tumors.

[0094] Glioblastoma Glioblastoma (GBM), or grade IV astrocytoma, is the most common form of brain cancer. Outcomes for this disease are devastating. The standard of care is surgery followed by radiation therapy and temozolomide; however, this produces a median overall survival (OS) of only 14.6 months, and very few patients survive to five years. Little progress has been made in extending survival in GBM patients over the past decade. While bevacizumab (evacizumab) has shown improved progression-free survival in relapsed settings, adding it to standard of care in first-line settings has not yielded an OS benefit.

[0095] EGFR is the most frequently altered oncogene in GBM. Besides EGFR gene amplification, many tumors express variants resulting from aberrant splicing or genomic mutations. The first recognized variant is EGFR-Viii, produced by truncation of exons 2–7, and expressed in approximately 20% of GBM tumors. EGFR-Viii is oncogenic. EGFR-Viii is constitutively activated in the absence of EGF ligands, exhibiting persistent signaling resistant to downregulation. Therefore, EGFR-Viii is both transformative and oncogenic. EGFR-Viii expression is associated with poorer long-term overall survival in GBM.

[0096] RNA sequencing data revealed that EGFR-Viii is just one of several aberrant EGFR splicing variants expressed in GBM tumors. Two other variants result in truncation of exons 12-13 (EGFR-Vvi) and 14-15 (EGFR-Vii). Like EGFR-Viii, EGFR-Vii is both transforming and oncogenic. In addition to splicing variants, GBM tumors also express a range of EGFR point mutations, including C620Y, A289V, and G598V, which are both transforming and oncogenic. The observation that many tumors express more than one receptor variant further complicates the EGFR alteration landscape in GBM.

[0097] Because the expression of multiple EGFR variants in GBM can lead to transformation and tumorigenic activity, and because EGFR is the most frequently altered oncogene present in GBM tumors, EGFR is a particularly attractive target for small molecule ErbB inhibitors. Following the success of small molecule EGFR therapies (erlotinib, gefitinib, and afatinib) targeting NSCLC tumors with activating mutations in EGFR, these drugs were tested in GBM. Despite extensive clinical studies of this group of ErbB inhibitors in GBM, involving >30 clinical trials and >1500 patients, no benefit was observed, even for tumors expressing EGFR-Viii. Surprisingly, some evidence suggests that erlotinib promotes disease progression. A phase 2 study evaluating erlotinib in combination with radiation and temozolomide showed median PFS (mPFS) and median OS (mOS) of 2.8 months and 8.6 months, respectively, compared to 6.9 months and 14.6 months, respectively, in patients receiving radiation and temozolomide alone. Another randomized phase II trial of erlotinib showed that patients receiving erlotinib, including those whose tumors expressed EGFR-Viii, had worse disease progression compared to patients receiving standard care. The clinical failure of ErbB inhibitors such as erlotinib in GBM tumors has cast doubt on the role of EGFR as a driver of GBM tumor growth and raised questions about why ErbB inhibitors, which are so effective in treating EGFR mutations in lung cancer, are so ineffective in treating EGFR variants in GBM.

[0098] A notable characteristic of EGFR variants expressed in GBM is their location within extracellular domains. This contrasts with activating EGFR mutations found in lung cancer, which typically reside in intracellular catalytic domains. EGFR consists of four extracellular domains (two ligand-binding domains and two cysteine-rich regions), one transmembrane domain, and one intracellular catalytic domain. Ligand binding promotes the dimerization of the extracellular cysteine-rich domains (CR1 and CR2), an event that confers dimerization of the intracellular domains and activation of receptor catalytic activity. Almost all EGFR splicing events and mutations in GBM affect the extracellular regions, particularly the two cysteine-rich regions (CR1 and CR2) that form the extracellular dimer interface. The CR regions contain >40 cysteine ​​residues, all of which form intramolecular disulfide bonds. In EGFR-Viii, truncation of exons 2–7 results in the partial loss of the sequence encoding the CR1 region. The result is the loss of a cysteine ​​residue from the Cys295-Cys307 pair, leaving Cys307 as a free, unpaired cysteine. For EGFR-Viii, this cysteine ​​can form an intermolecular disulfide bond with another EGFR monomer to drive covalent dimerization and constitutively activated receptors. The mutation from cysteine ​​307 to serine (C307S) prevents the formation of covalently dimerized EGFR-Viii and renders it inactive.

[0099] Although recent preclinical studies have shown that EGFR kinase inhibitors, such as erlotinib, are highly ineffective against EGFR-Viii, the mechanisms underlying this effect have not been proposed. Furthermore, the mechanisms responsible for activating other extracellular domain variants in GBM, including EGFR-Vii and EGFR-A289V, are also lacking. This disclosure provides mechanisms for receptor activation against four of the most common extracellular domain variants—GBM, EGFR-Viii, EGFR-Vii, EGFR-Vvi, EGFR-G598V, and EGFR-A289V—and their effects on ErbB inhibitor activity.

[0100] This disclosure shows that, like EGFR-Viii, another group of EGFR variants commonly found in GBM (EGFR-Vii, EGFR-Vvi, EGFR-G598V, and EGFR-A289V) exist as constitutively active covalent dimers and together form a family of EGFR isotypes activated through this common mechanism. Furthermore, this disclosure shows that the tendency of these variants to covalently dimerize is related to the conformation of the intracellular catalytic site, thereby conferring different activities to various small molecule inhibitors that bind to this distal site. Inhibitors that stabilize the active conformation of the kinase (type I inhibitors, including erlotinib) induce the formation of covalent dimers from all covalently activated EGFR isotypes. This is related to the tendency of type I inhibitors to increase EGFR phosphorylation at subsaturated concentrations and anomalously stimulate the proliferation of cells expressing covalently activated EGFR isotypes.

[0101] In the case of small molecule inhibitors (type II inhibitors, including lapatinib and neratinib) that stabilize the conformation of inactive kinases, neither enhanced dimerization nor anomalous EGFR activation was observed. Examples of type II inhibitors were identified as potent inhibitors of covalently activated EGFR isoforms compared to WT-EGFR and as selective for this family.

[0102] Similar to the mutations identified for EGFR, this disclosure identifies a set of splicing events and mutations affecting the CR domains of HER2 and HER4. This disclosure demonstrates that this set of splicing events and mutations affecting the CR domains of HER2 and HER4 exists as covalent dimers and is anomalously activated by agents with a type I binding mode. These data provide a mechanistic explanation for the failure of numerous clinical trials involving type I inhibitors, including >30 clinical trials of type I ErbB inhibitors in GBM. In summary, these data suggest that tumors expressing covalently activated EGFR isotypes should be excluded from treatment with type I ErbB inhibitors such as erlotinib due to their anomalous activation. These data further demonstrate the efficacy of optimizing type II ErbB inhibitors against the covalently activated ErbB family.

[0103] definition Unless otherwise stated, the following general definitions apply to all compounds of this disclosure in accordance with the specification.

[0104] As used herein, the term "compound of this disclosure" means a compound represented by any of the formulas described herein (e.g., formulas (I')-(IV') and (I) to (VII)) and any specific instance of the specific examples disclosed herein.

[0105] It will be understood that while the compounds disclosed herein may be presented in a particular configuration, such particular configuration should not be construed as limiting this disclosure to one or another isomer, tautomer, regio isomer, or stereoisomer, nor preclude mixtures of isomers, tautomers, regio isomers, or stereoisomers. In some embodiments, compounds presented herein in a particular configuration are intended to cover and refer to each of the available isomers, tautomers, regio isomers, and stereoisomers of the compound or any mixture thereof; and presentation is further intended to refer to a specific configuration of the compound.

[0106] Furthermore, it should be understood that although the compounds disclosed herein may be presented without specifying a configuration (e.g., without specifying a stereochemistry). Such presentation is intended to cover all available isomers, tautomers, regioisomers, and stereoisomers of the compounds. In some embodiments, compounds presented herein without specifying a configuration are intended to refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound or any mixture thereof.

[0107] As used herein, the term "isomerism" refers to compounds with the same molecular formula but different atomic bonding sequences or different atomic spatial arrangements. Isomers with different atomic spatial arrangements are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-overlapping mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomers with opposite chirality is called a "racemic mixture."

[0108] As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

[0109] As used herein, “chiral isomer” means a compound having at least one chiral center. Compounds having more than one chiral center may exist as individual diastereomers or as mixtures of diastereomers (referred to as “diastereomer mixtures”). In the presence of one chiral center, stereoisomers can be characterized by the absolute configuration (R or S) of said chiral center. Absolute configuration refers to the spatial arrangement of substituents connected to the chiral center. The substituents considered connected to the chiral center are in accordance with the order rules of Cahn, Ingold, and Prelog (…). Sequence Rule (Cahn et al., Applied Chemistry International Edition) Angew. Chem. Int. Edit. 1966, 5, 385; Errata 511; Cahn et al., Applied Chemistry 1966, 78, 413; Cahn and Ingold, Journal of Social Chemistry (J. Chem. Soc.) 1951 (London), 612; Cahn et al., Experiments ( Experientia ), 1956, 12, 81; Cahn, Journal of Chemistry Education ( J. Chem. Educ. 1964, 41, 116).

[0110] As used herein, the term “geometric isomer” refers to the presence of diastereomers attributable to rotational hindering around a double bond or cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished by the prefixes cis and trans, or Z and E, which, according to the Cahn-Ingold-Prelog rule, indicate that the groups are on the same or opposite sides of the double bond in the molecule.

[0111] It should be understood that "independent of each other" means that when a group appears more than once in any compound, its definition at each occurrence is independent of any other occurrence.

[0112] It should be further understood that the dashed lines (or wavy lines transverse to the bonds) depict the connection sites of the residues (i.e., the partial forms).

[0113] As used herein, the term "halogen" or "hal" can refer to fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine.

[0114] As used herein, “alkyl,” “C1, C2, C3, C4, C5, or C6 alkyl,” or “C1-C6 alkyl” is intended to include C1, C2, C3, C4, C5, or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5, or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl groups include portions having one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, or n-hexyl. In some embodiments, straight-chain or branched alkyl groups have six or fewer carbon atoms (e.g., C1-C6 for straight-chain and C3-C6 for branched groups), and in another embodiment, straight-chain or branched alkyl groups have four or fewer carbon atoms. In some embodiments, as used herein, the term “alkyl” refers to a fully saturated branched or unbranched hydrocarbon portion. Term "C" 1-4 "Alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety having one, two, three, or four carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.

[0115] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl group or an alkyl group having one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone replaced by a specified substituent. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid esters, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate esters, phosphonato, phosphinato, and amino groups (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino groups). Amino, acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylic acid ester, sulfate ester, alkyl thionyl, sulfonic acid (sulphonato), sulfamoyl (sulphamoyl), sulfonamide (sulphonamido), nitro, trifluoromethyl, cyano, azide, heterocyclic, alkyl aryl or aromatic or heteroaromatic moieties.

[0116] As used herein, the term "alkenyl" encompasses an unsaturated aliphatic group with a similar length and possible substitutions to the alkyl groups described above, but containing at least one double bond. For example, the term "alkenyl" encompasses straight-chain alkenyl groups (e.g., vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In some embodiments, the straight-chain or branched alkenyl groups have six or fewer carbon atoms in their backbone (e.g., C2-C6 for straight chains and C3-C6 for branched chains). The term "C2-C6" encompasses alkenyl groups containing two to six carbon atoms. The term "C3-C6" encompasses alkenyl groups containing three to six carbon atoms.

[0117] As used herein, the term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or an alkenyl having a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkylamino carbonyl, dialkylamino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonic acid, hypophosphonic acid, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amidinyl, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate ester, alkyl thionyl, sulfonic acid, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, heterocyclic, alkylaryl, or aromatic or heteroaromatic moieties.

[0118] As used herein, the term "alkynyl" encompasses an unsaturated aliphatic group with a similar length and possible substitutions to the alkyl groups described above, but containing at least one triple bond. For example, "alkynyl" encompasses straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentyynyl, hexynyl, heptyynyl, octyynyl, nonynyl, decanynyl) and branched alkynyl groups. In some embodiments, the straight-chain or branched alkynyl group has six or fewer carbon atoms in its main chain (e.g., C2-C6 for straight chains and C3-C6 for branched chains). The term "C2-C6" encompasses an alkynyl group containing two to six carbon atoms. The term "C3-C6" encompasses an alkynyl group containing three to six carbon atoms. As used herein, "C2-C6 alkenyl linker" or "C2-C6 alkenyl linker" is intended to encompass a C2, C3, C4, C5, or C6 chain (straight or branched) divalent unsaturated aliphatic hydrocarbon group. For example, C2-C6 imene-based connectors are designed to include C2, C3, C4, C5, and C6 imene-based connector groups.

[0119] As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl or an alkynyl having a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkylamino carbonyl, dialkylamino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonic acid, hypophosphonic acid, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate ester, alkyl thionyl, sulfonic acid, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl, or aromatic or heteroaromatic moieties.

[0120] Other optionally substituted portions (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) comprise both an unsubstituted portion and a portion having one or more of the specified substituents. For example, substituted heterocycloalkyl comprises those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0121] As used herein, the term "alkoxy (alkoxy or alkoxyl)" includes substituted and unsubstituted alkyl groups covalently linked to an oxygen atom. Examples of alkoxy groups (alkoxyl radicals) include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, and pentoxy.

[0122] As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) system of saturated or partially unsaturated hydrocarbons having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthyl, adamantyl, and hexahydroindenyl. It should be understood that for polycyclic (e.g., fused, bridged, or spirocyclic) systems, only one ring needs to be non-aromatic.

[0123] As used herein, the term "aryl" refers to an aromatic group comprising a "conjugated" or polycyclic system having one or more aromatic rings and containing no heteroatoms in the ring structure. The term aryl encompasses both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, etc. In some embodiments, the aryl group is phenyl.

[0124] As used herein, the term "heterocyclic alkyl" refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spirocyclic), or 11-14 membered tricyclic system (fused, bridged, or spirocyclic with one or more heteroatoms (such as O, N, S, P, or Se), for example, one or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, for example, one, two, three, four, five, or six heteroatoms, unless otherwise stated. Examples of heterocyclic alkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolyl, dioxyl, tetrahydrofuranyl, isoyindolyl, indololinyl, imidazoalkyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, ethylene oxide, aziridine, oxacyclobutane, thiophene, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiaranyl, 1,4-diazatyl, 1,4-oxatroyl, and 2-oxa-5-azabicyclo. [2.2.1]Heptyl, 2,5-diazabicyclo[2.2.1]Heptyl, 2-oxa-6-azaspiro[3.3]Heptyl, 2,6-diazaspiro[3.3]Heptyl, 1,4-dioxa-8-azaspiro[4.5]Decanyl, 1,4-dioxaspiro[4.5]Decanyl, 1-oxaspiro[4.5]Decanyl, 1-azaspiro[4.5]Decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl Hexane-1,5'-furan[3,4-b]pyridyl]-yl, 3'H-spiro[cyclohexane-1,1'-furan[3,4-c]pyridyl]-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hex-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-]pyrazolol[3,4-]pyrazolyl c] Pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 2-aza[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl-2-azaspiro[4.5]decyl, 2-oxazaspiro[3.4]octyl, 2-oxazaspiro[3.4]octyl-6-yl, etc. In the case of polycyclic heterocyclic alkyl groups, only one ring in the heterocyclic alkyl group needs to be non-aromatic.In some embodiments, the heterocyclic alkyl group is an oxetane, tetrahydrofuranyl, pyrrolyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexane, 2-azaspiro[3.3]heptane, or 2-oxa-5-azaspiro[3.4]octane, wherein the oxetane, tetrahydrofuranyl, pyrrolyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexane, 2-azaspiro[3.3]heptane, or 2-oxa-5-azaspiro[3.4]octane.

[0125] As used herein, the term "heteroaryl" is intended to encompass stable 5-, 6-, or 7-membered monocyclic aromatic heterocycles or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic aromatic heterocycles consisting of a carbon atom and one or more heteroatoms, for example, one or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or for example, one, two, three, four, five, or six heteroatoms, said heteroatoms being independently selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)). p (where p = 1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocycle is not greater than 1. In some embodiments, the term "heteroaryl" refers to a (complete) aromatic ring system having 3, 4, 5, or 6 ring atoms selected from C, N, O, or S, preferably C, N, or O, more preferably C, N, and preferably 6 ring atoms, wherein the number of N atoms is preferably 0, 1, 2, or 3, and the number of O and S atoms is 0, 1, or 2, respectively. Examples of "heteroaryl" include furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazinyl), pyridazinyl, pyridinyl, pyrimidinyl, pyrroleyl, thiazolyl, thiopheneyl, etc. Preferred examples of "heteroaryl" include pyridinyl.

[0126] In some embodiments, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is substituted at one or more cyclic positions (e.g., cyclic carbon or heteroatom, such as N) with such substituents as described above, said substituents being, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid ester, alkylcarbonyl, alkylaminocarbonyl, arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl The group may contain alkyl, aminocarbonyl, alkylthiocarbonyl, phosphate ester, phosphonic acid, hypophosphonic acid, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureyl), amido, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate ester, alkylthionyl, sulfonic acid, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl, or aromatic or heteroaromatic moiety. In some embodiments, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is substituted with a halogen (e.g., F or Cl).

[0127] As described herein, the term "substituted" means that any one or more hydrogen atoms on a specified atom are selectively substituted from an indicator group, provided that the substitution does not exceed the normal valence of the specified atom and the substitution forms a stable compound. When the substituent is an oxo or ketone group (i.e., =O), two hydrogen atoms on the atom are substituted. Ketone substituents are not present on aromatic moieties. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0128] The terms “nucleic acid” and “polynucleotide” are used interchangeably in this document to refer to single-stranded or double-stranded RNA, DNA, or a mixture of polymers. Polynucleotides may comprise genomic sequences, extragenomic sequences, and plasmid sequences suitable for expressing polypeptides, as well as smaller engineered gene segments.

[0129] "Isolated nucleic acids" are nucleic acids that are substantially separated from other genomic DNA sequences naturally accompanying their natural sequences, as well as proteins or complexes such as ribosomes and polymerases. The term encompasses nucleic acid sequences that have been removed from their natural environment and includes recombinant or cloned DNA isolates and chemically synthesized analogs or analogs biosynthesized from heterologous systems. Essentially pure nucleic acids comprise the isolated form of nucleic acids. This, of course, refers to the originally isolated nucleic acids and does not exclude genes or sequences subsequently added artificially to the isolated nucleic acids.

[0130] The term "peptide" is used in its conventional sense, that is, as a sequence of amino acids. A peptide is not limited to a specific length of product. Peptides, oligopeptides, and proteins are included within the definition of a peptide, and these terms are used interchangeably herein unless otherwise specified. This term does not refer to or exclude post-expression modifications of peptides, such as glycosylation, acetylation, phosphorylation, etc., as well as other modifications known in the art, both naturally occurring and non-natural. A peptide can be a complete protein or a subsequence of it.

[0131] "Isolated" polypeptides are polypeptides that have been identified, isolated, and / or recovered from components in their native environment. In a preferred embodiment, the isolated polypeptide will be purified (1) to achieve a polypeptide greater than 95% by weight, and most preferably greater than 99% by weight, as determined by the Lowry method, (2) to obtain at least 15 residues or an internal amino acid sequence at the N-terminus using a rotary cup sequencer, or (3) to be homogenized by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or preferably silver staining. The isolated polypeptide contains recombinant intracellular in situ polypeptides because at least one component of the polypeptide in its native environment will not be present. However, typically, the isolated polypeptide will be prepared by at least one purification step.

[0132] "Natural sequence" polynucleotides are polynucleotides that have the same nucleotide sequence as polynucleotides derived from nature. "Natural sequence" polypeptides are polypeptides that have the same amino acid sequence as polypeptides derived from nature (e.g., from any species) (e.g., EGFR). Such natural sequence polynucleotides and polypeptides can be isolated from nature or produced through recombinant or synthetic methods.

[0133] As used in this document, a polynucleotide “variant” is a polynucleotide that is typically different from the polynucleotide specifically disclosed herein in terms of one or more substitutions, deletions, additions, and / or insertions.

[0134] As used herein, a polypeptide “variant” is a polypeptide that is generally different from the polypeptide specifically disclosed herein in terms of one or more substitutions, deletions, additions and / or insertions or inversions. Such variants may be naturally occurring, non-natural, or synthetically produced.

[0135] The EGFR mutations (or variants) disclosed herein may include alterations in the amino acid sequence resulting in one or more substitutions, deletions, additions, and / or insertions or inversions that affect the function of the protein. Mutations can be detected, for example, by comparison or alignment of the nucleic acid or amino acid sequence with the wild-type sequence.

[0136] When comparing polynucleotide or polypeptide sequences, two sequences are said to be "identical" if the nucleotide or amino acid sequences are identical at maximum alignment, as described below. Comparisons between two sequences are typically performed by comparing sequences over a comparison window to identify and compare local regions of sequence similarity. As used herein, a "comparison window" refers to a segment of at least about 20, typically about 30 to about 75, about 40 to about 50 consecutive positions, where, after optimal alignment of the two sequences, the sequence can be compared to a reference sequence having the same number of consecutive positions.

[0137] Using default parameters, the Megalign program in the Lasergene Bioinformatics Software Suite (DNASTAR, Madison, Wisconsin) can be used to perform optimal alignment for comparison. This program embodies several alignment schemes described in the following references: Dayhoff, MO (1978) "A model of evolutionary change in proteins - Matrices for detecting distant relationships". Dayhoff, MO (ed.) *Atlas of Protein Sequence and Structure*, National Biomedical Research Foundation, Washington, D.C., Vol. 5, Supplement 3, pp. 345-358; Hein J. (1990) *Unified Approach to Alignment and Phylogenes*, pp. 626-645; *Enzymatic Methods* Methods in Enzymology Volume 183, Academic Press, Inc., San Diego, CA; Higgins, DG and Sharp, PM (1989). CABIOS5 :151-153; Myers, E. W., and Muller W. (1988) CABIOS 4 :11-17; Robinson, ED (1971) "Combinatorial Theory" Comb.Theor ) 11 :105; Santou, N. Nes, M. (1987) Molecular Biology Evolution ( Mol.Biol.Evol .) 4:406-425; Sneath, PHA and Sokal, RR (1973) Numerical Classification: Principles and Practice of Numerical Classification ( Numerical Taxonomy-the Principles and Practice of Numerical Taxonomy ), Freeman Press, San Franciscan Republic, California; Wilbur, WJ and Lipman, DJ (1983) Proceedings of the National Academy of Sciences (PNAS) Proc.Natl.Acad., Sci.USA)》 80 :726-730.

[0138] Alternatively, the best alignment of sequences for comparison can be performed using the following: Smith and Waterman (1981), *Advanced Applied Mathematics*. Add.APL.Math Local identity algorithm of 2:482; Needleman and Wunsch (1970) Journal of Molecular Biology J. Mol.Biol The identity comparison algorithm of 48:443 in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) was used; through Pearson and Lipman (1988). Proc.Natl.Acad.Sci.USA Similarity finding methods (see 85:2444) can be performed by computerized implementations of these algorithms (GAP, BESTFIT, BLAST, FASTA, and TFASTA from the Wisconsin Genetics Software Package at the Genetics Computer Group (GCG) at 575 Science Avenue, Madison, Wisconsin) or by inspection.

[0139] A preferred example of an algorithm suitable for determining percentage sequence identity and sequence similarity is the BLAST and BLAST 2.0 algorithms, described below, in Altschul et al., (1977) *Nucleic Acid Research*. Nucl.Acids Res .)》25:3389-3402 and Altschul et al., (1990) Journal of Molecular Biology ( J. Mol.Biol )》 215:403-410. BLAST and BLAST 2.0 can be used, for example, with the parameters described herein to determine the percentage sequence identity of polynucleotides and peptides of the present invention. Software for performing BLAST analyses is publicly available from the National Center for Biotechnology Information.

[0140] In an illustrative example, for a nucleotide sequence, the cumulative score can be calculated using parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatched residues; always <0). Word hit expansion in each direction is halted if: the cumulative alignment score decreases by an amount X from its maximum realized value; the cumulative score becomes zero or lower due to the accumulation of one or more negatively scored residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of alignment. The BLASTN program uses a word length (W) of 11 and an expected value (E) of 10, a BLOSUM62 score matrix (see Henikoff and Henikoff, (1989) Proceedings of the National Academy of Sciences 89:10915), an alignment (B) of 50, an expected value (E) of 10, M = 5, N = -4, and comparisons of both strands as default values.

[0141] For amino acid sequences, a scoring matrix can be used to calculate the cumulative score. The expansion of word hits in each direction is halted in the following cases: the cumulative alignment score decreases by an amount X from its maximum realized value; the cumulative score becomes zero or lower due to the accumulation of one or more negatively scored residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment.

[0142] In one approach, the "percentage of sequence identity" is determined by comparing two optimally aligned sequences across a comparison window of at least 20 positions. The portion of the polynucleotide or polypeptide sequence within the comparison window may include 20% or less, typically 5% to 15% or 10% to 12%, of additions or deletions (i.e., vacancies) compared to a reference sequence (excluding additions or deletions) to achieve optimal alignment. The percentage is calculated by: determining the number of positions in both sequences where the same nucleic acid base or amino acid residue appears, to arrive at the number of matching positions; dividing the number of matching positions by the total number of positions in the reference sequence (i.e., the window size); and multiplying the result by 100 to arrive at the percentage of sequence identity.

[0143] The wild-type EGFR sequence disclosed herein may include or consist of the following amino acid sequences: 1 mrpsgtagaa llallaalcp asraleekkv cqgtsnkltq lgtfedhfls lqrmfnncev 61 vlgnleityv qrnydlsflk tiqevagyvl ialntverip lenlqiirgn myyensyala 121 vlsnydankt glkelpmrnl qeilhgavrf snnpalcnve siqwrdivss dflsnmsmdf 181 qnhlgscqkc dpscpngscw gageencqkl tkiicaqqcs grcrgkspsd cchnqcaagc 241 tgpresdclv crkfrdeatc kdtcpplmly npttyqmdvn pegkysfgat cvkkcprnyv 301 vtdhgscvra cgadsyemee dgvrkckkce gpcrkvcngi gigefkdsls inatnikhfk 361 nctsisgdlh ilpvafrgds fthtppldpq eldilktvke itgflliqaw penrtdlhaf 421 enleiirgrt kqhgqfslav vslnitslgl rslkeisdgd viisgnknlc yantinwkkl 481 fgtsgqktki isnrgensck atgqvchalc spegcwgpep rdcvscrnvs rgrecvdkck 541 llegeprefv enseciqchp eclpqamnit ctgrgpdnci qcahyidgph cvktcpagvm 601 genntlvwky adaghvchlc hpnctygctg pglegcptng pkipsiatgm vgalllllvv 661 algiglfmrr 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 gskpydgipa seissilekg erlpqppict idvymimvkc wmidadsrpk 961 freliiefsk mardpqrylv iqgdermhlp sptdsnfyra lmdeedmddv vdadeylipq 1021 qgffsspsts rtpllsslsa tsnnstvaci drnglqscpi kedsflqryssdptgalted 1081 siddtflpvp eyinqsvpkr pagsvqnpvy hnqplnpaps rdphyqdphstavgnpeyln 1141 tvqptcvnst fdspahwaqk gshqisldnp dyqqdffpke akpngifkgstaenaeylrv 1201 apqssefiga (SEQ ID NO: 1, corresponding to epidermal growth factor receptor [Homo sapiens] and Genbank accession number CAA25240).

[0144] The wild-type HER2 receptor sequence disclosed herein may include or consist of the following amino acid sequences: 1 melaalcrwg lllallppga astqvctgtd mklrlpaspe thldmlrhly qgcqvvqgnl 61 eltylptnas lsflqdiqev qgyvliahnq vrqvplqrlr ivrgtqlfed nyalavldng 121 dplnnttpvt gaspgglrel qlrslteilk ggvliqrnpq lcyqdtilwk difhknnqla 181 ltlidtnrsr achpcspmck gsrcwgesse dcqsltrtvc aggcarckgp lptdccheqc 241 aagctgpkhs dclaclhfnh sgicelhcpa lvtyntdtfe smpnpegryt fgascvtacp 301 ynylstdvgs ctlvcplhnq evtaedgtqr cekcskpcar vcyglgmehl revravtsan 361 iqefagckki fgslaflpes fdgdpasnta plqpeqlqvf etleeitgyl yisawpdslp 421 dlsvfqnlqv irgrilhnga ysltlqglgi swlglrslre lgsglalihh nthlcfvhtv 481 pwdqlfrnph qallhtanrp edecvgegla chqlcarghc wgpgptqcvn csqflrgqec 541 veecrvlqgl preyvnarhc lpchpecqpq ngsvtcfgpe adqcvacahy kdppfcvarc 601 psgvkpdlsy mpiwkfpdee gacqpcpinc thscvdlddk gcpaeqrasp ltsiisavvg 661 illvvvlgvv fgilikrrqq kirkytmrrl lqetelvepl tpsgampnqa qmrilketel 721 rkvkvlgsga fgtvykgiwi pdgenvkipv aikvlrents pkankeilde ayvmagvgsp 781 yvsrllgicl tstvqlvtql mpygclldhv renrgrlgsq dllnwcmqia kgmsyledvr 841 lvhrdlaarn vlvkspnhvk itdfglarll dideteyhad ggkvpikwma lesilrrrft 901 hqsdvwsygv tvwelmtfga kpydgipare ipdllekger lpqppictid vymimvkcwm 961 idsecrprfr elvsefsrma rdpqrfvviq nedlgpaspl dstfyrslle dddmgdlvda 1021 eeylvpqqgf fcpdpapgag gmvhhrhrss strsgggdlt lglepseeeaprsplapseg 1081 agsdvfdgdl gmgaakglqs lpthdpsplq rysedptvpl psetdgyvapltcspqpeyv 1141 nqpdvrpqpp spregplpaa rpagatlerp ktlspgkngv vkdvfafggavenpeyltpq 1201 ggaapqphpp pafspafdnl yywdqdpper gappstfkgt ptaenpeylg ldvpv (SEQ ID NO: 2, corresponding to receptor tyrosine protein kinase erbB-2 isoform a precursor [Homo sapiens] and GenBank accession number NP_004439).

[0145] The wild-type HER2 receptor sequence disclosed herein may include or consist of the following amino acid sequences: 1 mklrlpaspe thldmlrhly qgcqvvqgnl eltylptnas lsflqdiqev qgyvliahnq 61 vrqvplqrlr ivrgtqlfed nyalavldng dplnnttpvt gaspgglrel qlrslteilk 121 ggvliqrnpq lcyqdtilwk difhknnqla ltlidtnrsr achpcspmck gsrcwgesse 181 dcqsltrtvc aggcarckgp lptdccheqc aagctgpkhs dclaclhfnh sgicelhcpa 241 lvtyntdtfe smpnpegryt fgascvtacp ynylstdvgs ctlvcplhnq evtaedgtqr 301 cekcskpcar vcyglgmehl revravtsan iqefagckki fgslaflpes fdgdpasnta 361 plqpeqlqvf etleeitgyl yisawpdslp dlsvfqnlqv irgrilhnga ysltlqglgi 421 swlglrslre lgsglalihh nthlcfvhtv pwdqlfrnph qallhtanrp edecvgegla 481 chqlcarghc wgpgptqcvn csqflrgqec veecrvlqgl preyvnarhc lpchpecqpq 541 ngsvtcfgpe adqcvacahy kdppfcvarc psgvkpdlsy mpiwkfpdee gacqpcpinc 601 thscvdlddk gcpaeqrasp ltsiisavvg illvvvlgvv fgilikrrqq kirkytmrrl 661 lqetelvepl tpsgampnqa qmrilketel rkvkvlgsga fgtvykgiwi pdgenvkipv 721 aikvlrents pkankeilde ayvmagvgsp yvsrllgicl tstvqlvtql mpygclldhv 781 renrgrlgsq dllnwcmqia kgmsyledvr lvhrdlaarn vlvkspnhvk itdfglarll 841 dideteyhad ggkvpikwma lesilrrrft hqsdvwsygv tvwelmtfga kpydgipare 901 ipdllekger lpqppictid vymimvkcwm idsecrprfr elvsefsrma rdpqrfvviq 961 nedlgpaspl dstfyrslle dddmgdlvda eeylvpqqgf fcpdpapgag gmvhhrhrss 1021 strsgggdlt lglepseeea prsplapseg agsdvfdgdl gmgaakglqslpthdpsplq 1081 rysedptvpl psetdgyvap ltcspqpeyv nqpdvrpqpp spregplpaarpagatlerp 1141 ktlspgkngv vkdvfafgga venpeyltpq ggaapqphpp pafspafdnlyywdqdpper 1201 gappstfkgt ptaenpeylg ldvpv (SEQ ID NO: 3, corresponding to receptor tyrosine protein kinase erbB-2 isotype b [Homo sapiens] and GenBank accession number NP_001005862).

[0146] The wild-type HER2 receptor sequence disclosed herein may include or consist of the following amino acid sequences: 1 mprgswkpqv ctgtdmklrl paspethldm lrhlyqgcqv vqgnleltyl ptnaslsflq 61 diqevqgyvl iahnqvrqvp lqrlrivrgt qlfednyala vldngdplnn ttpvtgaspg 121 glrelqlrsl teilkggvli qrnpqlcyqd tilwkdifhk nnqlaltlid tnrsrachpc 181 spmckgsrcw gessedcqsl trtvcaggca rckgplptdc cheqcaagct gpkhsdclac 241 lhfnhsgice lhcpalvtyn tdtfesmpnp egrytfgasc vtacpynyls tdvgsctlvc 301 plhnqevtae dgtqrcekcs kpcarvcygl gmehlrevra vtsaniqefa gckkifgsla 361 flpesfdgdp asntaplqpe qlqvfetlee itgylyisaw pdslpdlsvf qnlqvirgri 421 lhngaysltl qglgiswlgl rslrelgsgl alihhnthlc fvhtvpwdql frnphqallh 481 tanrpedecv geglachqlc arghcwgpgp tqcvncsqfl rgqecveecr vlqglpreyv 541 narhclpchp ecqpqngsvt cfgpeadqcv acahykdppf cvarcpsgvk pdlsympiwk 601 fpdeegacqp cpincthscv dlddkgcpae qraspltsii savvgillvv vlgvvfgili 661 krrqqkirky tmrrllqete lvepltpsga mpnqaqmril ketelrkvkv lgsgafgtvy 721 kgiwipdgen vkipvaikvl rentspkank eildeayvma gvgspyvsrl lgicltstvq 781 lvtqlmpygc lldhvrenrg rlgsqdllnw cmqiakgmsy ledvrlvhrd laarnvlvks 841 pnhvkitdfg larlldidet eyhadggkvp ikwmalesil rrrfthqsdv wsygvtvwel 901 mtfgakpydg ipareipdll ekgerlpqpp ictidvymim vkcwmidsec rprfrelvse 961 fsrmardpqr fvviqnedlg paspldstfy rslledddmg dlvdaeeylv pqqgffcpdp 1021 apgaggmvhh rhrssstrsg ggdltlglep seeeaprspl apsegagsdvfdgdlgmgaa 1081 kglqslpthd psplqrysed ptvplpsetd gyvapltcsp qpeyvnqpdvrpqppspreg 1141 plpaarpaga tlerpktlsp gkngvvkdvf afggavenpe yltpqggaapqphpppafsp 1201 afdnlyywdq dppergapps tfkgtptaen peylgldvpv (SEQ ID NO: 4, corresponding to receptor tyrosine protein kinase erbB-2 isotype c [Homo sapiens] and GenBank accession number NP_001276865).

[0147] The wild-type HER2 receptor sequence disclosed herein may include or consist of the following amino acid sequences: 1 melaalcrwg lllallppga astqvctgtd mklrlpaspe thldmlrhly qgcqvvqgnl 61 eltylptnas lsflqdiqev qgyvliahnq vrqvplqrlr ivrgtqlfed nyalavldng 121 dplnnttpvt gaspgglrel qlrslteilk ggvliqrnpq lcyqdtilwk difhknnqla 181 ltlidtnrsr achpcspmck gsrcwgesse dcqsltrtvc aggcarckgp lptdccheqc 241 aagctgpkhs dclaclhfnh sgicelhcpa lvtyntdtfe smpnpegryt fgascvtacp 301 ynylstdvgs ctlvcplhnq evtaedgtqr cekcskpcar vcyglgmehl revravtsan 361 iqefagckki fgslaflpes fdgdpasnta plqpeqlqvf etleeitgyl yisawpdslp 421 dlsvfqnlqv irgrilhnga ysltlqglgi swlglrslre lgsglalihh nthlcfvhtv 481 pwdqlfrnph qallhtanrp edecvgegla chqlcarghc wgpgptqcvn csqflrgqec 541 veecrvlqgl preyvnarhc lpchpecqpq ngsvtcfgpe adqcvacahy kdppfcvarc 601 psgvkpdlsy mpiwkfpdee gacqpcpinc thscvdlddk gcpaeqrasp ltsiisavvg 661 illvvvlgvv fgilikrrqq kirkytmrrl lqetelvepl tpsgampnqa qmrilketel 721 rkvkvlgsga fgtvykgiwi pdgenvkipv aikvlrents pkankeilde ayvmagvgsp 781 yvsrllgicl tstvqlvtql mpygclldhv renrgrlgsq dllnwcmqia kgmsyledvr 841 lvhrdlaarn vlvkspnhvk itdfglarll dideteyhad ggkvpikwma lesilrrrft 901 hqsdvwsygv tvwelmtfga kpydgipare ipdllekger lpqppictid vymimvkcwm 961 idsecrprfr elvsefsrma rdpqrfvviq nedlgpaspl dstfyrslle dddmgdlvda 1021 eeylvpqqgf fcpdpapgag gmvhhrhrss strnm (SEQ ID NO: 5, corresponding to receptor tyrosine protein kinase erbB-2 isotype d precursor [Homo sapiens] and GenBank accession number NP_001276866).

[0148] The wild-type HER2 receptor sequence disclosed herein may include or consist of the following amino acid sequences: 1 mklrlpaspe thldmlrhly qgcqvvqgnl eltylptnas lsflqdiqev qgyvliahnq 61 vrqvplqrlr ivrgtqlfed nyalavldng dplnnttpvt gaspgglrel qlrslteilk 121 ggvliqrnpq lcyqdtilwk difhknnqla ltlidtnrsr achpcspmck gsrcwgesse 181 dcqsltrtvc aggcarckgp lptdccheqc aagctgpkhs dclaclhfnh sgicelhcpa 241 lvtyntdtfe smpnpegryt fgascvtacp ynylstdvgs ctlvcplhnq evtaedgtqr 301 cekcskpcar vcyglgmehl revravtsan iqefagckki fgslaflpes fdgdpasnta 361 plqpeqlqvf etleeitgyl yisawpdslp dlsvfqnlqv irgrilhnga ysltlqglgi 421 swlglrslre lgsglalihh nthlcfvhtv pwdqlfrnph qallhtanrp edecvgegla 481 chqlcarghc wgpgptqcvn csqflrgqec veecrvlqgl preyvnarhc lpchpecqpq 541 ngsvtcfgpe adqcvacahy kdppfcvarc psgvkpdlsy mpiwkfpdee gacqpcpinc 601 ths (SEQ ID NO: 6, corresponding to receptor tyrosine protein kinase erbB-2 isotype e [Homo sapiens] and GenBank accession number NP_001276867).

[0149] Based on the definitions given throughout the application, those skilled in the art will know which combinations are comprehensively feasible and realistic; for example, combinations of groups that result in heteroatoms being directly connected to each other are generally not contemplated.

[0150] The compounds disclosed herein In some respects, this disclosure provides a compound of formula (I'): Or its pharmaceutically acceptable salt or stereoisomer, wherein: W is CH or N; Z is arbitrarily defined by one or more R.Z Substituted 3- to 12-membered heterocyclic alkyl groups; Each R Z Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R Za replace; Each R Za Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl is optionally replaced by one or more R. T replace; Each R T Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R Ta replace; Each R Ta Independently, it is a halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; Ar 1 It is optionally controlled by one or more R A1 Replacement C6-C 10 Aryl; Each R A1 Independently, it is halogen, CN, -OH, -NH2, -OR A1a -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R A1a Replace; and Each R A1a Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more RA1b Replace; and Each R A1b It can be halogen, CN, -OH or -NH2 independently.

[0151] In some respects, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH or N; Z is arbitrarily defined by one or more R. Z Substituted 3- to 12-membered heterocyclic alkyl groups; Each R Z Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- or 5- to 10-membered heteroaryl, is optionally surrounded by one or more R Za replace; Each R Za Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl is optionally replaced by one or more R. T replace; Each R T Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10aryl, 3- to 7-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 The aryl group, the 3- to 7-membered heterocyclic alkyl group, or the 5- to 10-membered heteroaryl group may optionally be separated by one or more R groups. Ta replace; Each R Ta Independently, it is a halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; Ar 1 It is optionally controlled by one or more R A1 Replacement C6-C 10 Aryl; Each R A1 Independently, it is halogen, CN, -OH, -NH2, -OR A1a -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally replaced by one or more R A1a Replace; and Each R A1a Independently, it is a halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted by one or more R A1b Replace; and Each R A1b It can be halogen, CN, -OH, or -NH2 independently; The condition is when Z is At that time, then Ar 1 It is a C6-C that is optionally substituted with one or more halogens. 10 Aryl.

[0152] In some respects, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH or N; Z is arbitrarily defined by one or more R. Z Substituted 3- to 12-membered heterocyclic alkyl groups; Each R Z Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- or 5- to 10-membered heteroaryl, is optionally surrounded by one or more R Za replace; Each R Za Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl is optionally replaced by one or more R. T replace; Each R T Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3 to 7-membered monocyclic heterocyclic alkyl or 5 to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10The aryl group, the 3- to 7-membered heterocyclic alkyl group, or the 5- to 10-membered heteroaryl group may optionally be separated by one or more R groups. Ta replace; Each R Ta Independently, it is a halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; Ar 1 It is optionally controlled by one or more R A1 Replacement C6-C 10 Aryl; Each R A1 Independently, it is halogen, CN, -OH, -NH2, -OR A1a -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally replaced by one or more R A1a Replace; and Each R A1a Independently, it is a halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted by one or more R A1b Replace; and Each R A1b It can be halogen, CN, -OH, or -NH2 independently; The condition is when Z is At that time, then Ar 1 It is a C6-C that is optionally substituted with one or more halogens. 10 Aryl.

[0153] In some embodiments, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is arbitrarily defined by one or more R. Z Substituted 3- to 12-membered heterocyclic alkyl groups; Each R Z Independently, it is a halogen, -O-(C1-C6 alkyl), C1-C6 alkyl, or a 3- to 10-membered heterocyclic alkyl; wherein the -O-(C1-C6 alkyl), the C1-C6 alkyl, or the 3- to 10-membered heterocyclic alkyl is optionally substituted by one or more halogens; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T replace; Each R T Independently, it is a halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2 or a 3 to 7-membered heterocyclic alkyl; wherein the -O-(C1-C6 alkyl), the -N(C1-C6 alkyl)2 or the 3 to 7-membered heterocyclic alkyl is optionally substituted by one or more -C(=O)OH; Ar 1 It is optionally controlled by one or more R A1 Replacement C6-C 10 Aryl; Each R A1 Independently or optionally by one or more R A1a Substituted halogens, -OR A1a or -O-(C1-C6 alkyl); and Each R A1a Independently, it is C6-C 10 aryl or 5- to 10-membered heteroaryl; wherein the C6-C 10 The aryl group or the 5- to 10-membered heteroaryl group may optionally be substituted with one or more halogens.

[0154] In some embodiments, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is arbitrarily defined by one or more R. Z Substituted 3- to 12-membered heterocyclic alkyl groups; Each R Z Independently, it is a halogen, -O-(C1-C6 alkyl), C1-C6 alkyl, or a 3- to 10-membered heterocyclic alkyl; wherein the -O-(C1-C6 alkyl), the C1-C6 alkyl, or the 3- to 10-membered heterocyclic alkyl is optionally substituted by one or more halogens; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T replace; Each R T Independently, it is a halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2 or a 3 to 7-membered monocyclic heterocyclic alkyl; wherein the -O-(C1-C6 alkyl), the -N(C1-C6 alkyl)2 or the 3 to 7-membered monocyclic heterocyclic alkyl is optionally substituted by one or more -C(=O)OH; Ar 1 It is optionally controlled by one or more R A1 Replacement C6-C 10 Aryl; Each R A1 Independently or optionally by one or more R A1a Substituted halogens, -OR A1a or -O-(C1-C6 alkyl); and Each R A1a Independently, it is C6-C 10 aryl or 5- to 10-membered heteroaryl; wherein the C6-C 10 The aryl group or the 5- to 10-membered heteroaryl group may optionally be substituted with one or more halogens.

[0155] In some embodiments, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is arbitrarily defined by one or more R. Z Substituted 3- to 12-membered heterocyclic alkyl groups; Each R Z It is independently a halogen, -O-(C1-C6 alkyl) or C1-C6 alkyl; wherein the -O-(C1-C6 alkyl) or the C1-C6 alkyl is optionally substituted with one or more halogens; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T replace; Each R T Independently, it is a halogen, -OH, -O-(C1-C6 alkyl) or a 3- to 7-membered heterocyclic alkyl; wherein the -O-(C1-C6 alkyl) or the 3- to 7-membered heterocyclic alkyl is optionally substituted by one or more -C(=O)OH; Ar 1 It is optionally controlled by one or more R A1 Replacement C6-C 10 Aryl; Each R A1 Independently or optionally by one or more R A1a Substituted halogens, -OR A1a or -O-(C1-C6 alkyl); and Each R A1a Independently, it is C6-C 10 aryl or 5- to 10-membered heteroaryl; wherein the C6-C 10 The aryl group or the 5- to 10-membered heteroaryl group may optionally be substituted with one or more halogens; The condition is when Z is At that time, then Ar 1 It is a C6-C that is optionally substituted with one or more halogens. 10 Aryl.

[0156] In some embodiments, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is arbitrarily defined by one or more R. Z Substituted 3- to 12-membered heterocyclic alkyl groups; Each R Z It is independently a halogen, -O-(C1-C6 alkyl) or C1-C6 alkyl; wherein the -O-(C1-C6 alkyl) or the C1-C6 alkyl is optionally substituted with one or more halogens; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T replace; Each R T Independently, it is a halogen, -OH, -O-(C1-C6 alkyl) or a 3- to 7-membered monocyclic heterocyclic alkyl; wherein the -O-(C1-C6 alkyl) or the 3- to 7-membered monocyclic heterocyclic alkyl is optionally substituted by one or more -C(=O)OH; Ar 1 It is optionally controlled by one or more R A1 Replacement C6-C 10 Aryl; Each R A1 Independently or optionally by one or more R A1a Substituted halogens, -OR A1a or -O-(C1-C6 alkyl); and Each R A1a Independently, it is C6-C 10 aryl or 5- to 10-membered heteroaryl; wherein the C6-C 10 The aryl group or the 5- to 10-membered heteroaryl group may optionally be substituted with one or more halogens; The condition is when Z is At that time, then Ar 1 It is a C6-C that is optionally substituted with one or more halogens. 10 Aryl.

[0157] In some embodiments, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is arbitrarily defined by one or more R. Z Substituted 3- to 12-membered heterocyclic alkyl groups; Each R Z It is independently a halogen, -O-(C1-C6 alkyl) or C1-C6 alkyl; wherein the -O-(C1-C6 alkyl) or the C1-C6 alkyl is optionally substituted with one or more halogens; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T replace; Each R T Independently, it is a halogen, -OH, -O-(C1-C6 alkyl) or a 3- to 7-membered heterocyclic alkyl; wherein the -O-(C1-C6 alkyl) or the 3- to 7-membered heterocyclic alkyl is optionally substituted by one or more -C(=O)OH; Ar 1 It is a C6-C that is optionally substituted with one or more halogens. 10 Aryl.

[0158] In some embodiments, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is arbitrarily defined by one or more R. Z Substituted 3- to 12-membered heterocyclic alkyl groups; Each R Z It is independently a halogen, -O-(C1-C6 alkyl) or C1-C6 alkyl; wherein the -O-(C1-C6 alkyl) or the C1-C6 alkyl is optionally substituted with one or more halogens; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T replace; Each R T Independently, it is a halogen, -OH, -O-(C1-C6 alkyl) or a 3- to 7-membered monocyclic heterocyclic alkyl; wherein the -O-(C1-C6 alkyl) or the 3- to 7-membered monocyclic heterocyclic alkyl is optionally substituted by one or more -C(=O)OH; Ar 1 It is a C6-C that is optionally substituted with one or more halogens. 10 Aryl.

[0159] In some embodiments, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is a 3- to 12-membered heterocyclic alkyl group optionally substituted with one or more C1-C6 alkyl groups; T is a C2-C6 alkenyl group optionally substituted with one or more 6-membered heterocyclic alkyl groups; and Ar 1 It is a C6 aryl group that is optionally substituted with one or more halogens.

[0160] In some embodiments, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is a 3- to 12-membered heterocyclic alkyl group optionally substituted with one or more C1-C6 alkyl groups; T is a C2-C6 alkenyl group optionally substituted with one or more 6-membered monocyclic heterocyclic alkyl groups; and Ar 1 It is a C6 aryl group that is optionally substituted with one or more halogens.

[0161] variable W In some embodiments, W is CH.

[0162] In some embodiments, W is N.

[0163] Variables Z, R Z and R Za In some embodiments, Z is optionally represented by one or more R Z Substituted 3- to 12-membered heterocyclic alkyl groups; and Each R ZIndependently, it is a halogen, -O-(C1-C6 alkyl), C1-C6 alkyl, or a 3- to 10-membered heterocyclic alkyl; wherein the -O-(C1-C6 alkyl), the C1-C6 alkyl, or the 3- to 10-membered heterocyclic alkyl is optionally substituted with one or more halogens.

[0164] In some embodiments, Z is a 3- to 12-membered heterocyclic alkyl group.

[0165] In some embodiments, Z is a subset of one or more R Z Substituted 3 to 12-membered heterocyclic alkyl groups.

[0166] In some embodiments, Z is an oxetane, tetrahydrofuranyl, pyrrolyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexane, 2-azaspiro[3.3]heptyl, 2-oxa-5-azaspiro[3.4]octyl, wherein the oxetane, tetrahydrofuranyl, pyrrolyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexane, 2-azaspiro[3.3]heptyl, or 2-oxa-5-azaspiro[3.4]octyl is optionally replaced by one or more R Z replace.

[0167] In some embodiments, Z is an oxetane, tetrahydrofuranyl, pyrrolyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexane, 2-azaspiro[3.3]heptyl, 2-oxa-5-azaspiro[3.4]octyl, wherein the oxetane, tetrahydrofuranyl, pyrrolyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexane, 2-azaspiro[3.3]hexane, or 2-oxa-5-azaspiro[3.4]octyl is optionally replaced by one or more R Z replace.

[0168] In some embodiments, Z is , , , , , , , , , , , , , , , , , , , , , , or .

[0169] In some embodiments, Z is , , , , , , , , , , , , , , , , , , , , , or .

[0170] In some embodiments, z is .

[0171] In some embodiments, z is .

[0172] In some embodiments, z is , , , , , , , , , , or .

[0173] In some embodiments, Z is or .

[0174] In some embodiments, z is , , , , or .

[0175] In some embodiments, z is , , , or .

[0176] In some embodiments, z is .

[0177] In some embodiments, Z is or .

[0178] In some embodiments, z is .

[0179] In some embodiments, z is .

[0180] In some embodiments, at least one R Z It is halogen.

[0181] In some embodiments, at least one R Z It is either F or Cl.

[0182] In some embodiments, at least one R Z It is F.

[0183] In some embodiments, at least one R Z It is Cl.

[0184] In some embodiments, at least one R Z It is F, and at least one R Z It is Cl.

[0185] In some embodiments, at least one R Z It is CN, -OH, or -NH2.

[0186] In some embodiments, at least one R Z It is -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R Za replace.

[0187] In some embodiments, at least one R Z It is optionally controlled by one or more R Za Substituted -O-(C1-C6 alkyl).

[0188] In some embodiments, at least one R Z It is -O-(C1-C6 alkyl).

[0189] In some embodiments, at least one R Z It is -OCH3.

[0190] In some embodiments, at least one R Z It is by one or more R Za Substituted -O-(C1-C6 alkyl).

[0191] In some embodiments, at least one R Z It is an -O-(C1-C6 alkyl) optionally substituted with one or more halogens (e.g., F or Cl).

[0192] In some embodiments, at least one R Z It is -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2, wherein the -NH(C1-C6 alkyl) or the -N(C1-C6 alkyl)2 is optionally separated by one or more R Za replace.

[0193] In some embodiments, at least one R Z It is optionally controlled by one or more R Za Substituted C1-C6 alkyl groups.

[0194] In some embodiments, at least one R Z It is a C1-C6 alkyl group.

[0195] In some embodiments, at least one R Z It is methyl, ethyl, or propyl (e.g., isopropyl).

[0196] In some embodiments, at least one R Z It is by one or more R Za Substituted C1-C6 alkyl groups.

[0197] In some embodiments, at least one R Z It is a C1-C6 alkyl group that is optionally substituted with one or more halogens (e.g., F or Cl).

[0198] In some embodiments, at least one R Z It is a C1-C6 alkyl group substituted with one or more F atoms.

[0199] In some embodiments, at least one R Z It's CF3.

[0200] In some embodiments, at least one R Z It is a C2-C6 alkenyl or C2-C6 ynyl, wherein the C2-C6 alkenyl or the C2-C6 ynyl is optionally surrounded by one or more R Za replace.

[0201] In some embodiments, at least one R Z It is C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; wherein the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R Za replace.

[0202] In some embodiments, at least one R Z It is optionally controlled by one or more R Za Replacement C3-C 10 Cycloalkyl.

[0203] In some embodiments, at least one R Z It is optionally controlled by one or more R Za Replacement C6-C 10 Aryl.

[0204] In some embodiments, at least one R Z It is optionally controlled by one or more R Za Substituted 3 to 10-membered heterocyclic alkyl groups.

[0205] In some embodiments, at least one R Z It is optionally controlled by one or more R Za Substituted 4-membered heterocyclic alkyl groups.

[0206] In some embodiments, at least one R Z It is a 4-membered heterocyclic alkyl group.

[0207] In some embodiments, at least one R Z It is an oxocyclic butyl group.

[0208] In some embodiments, at least one R Z It is optionally controlled by one or more R Za Replaced 5 to 10 heteroaryl groups.

[0209] In some embodiments, at least one R Za It is halogen.

[0210] In some embodiments, at least one R Za It is either F or Cl.

[0211] In some embodiments, at least one R Za It is F.

[0212] In some embodiments, at least one R Za It is Cl.

[0213] In some embodiments, at least one R Za It is CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3 to 10-membered heterocyclic alkyl or 5 to 10-membered heteroaryl.

[0214] Variables T, R T and R Ta In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the -O-(C1-C6 alkyl), the -NH-(C1-C6 alkyl), the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T replace; Each R T Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 7-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 The aryl group, the 3- to 7-membered heterocyclic alkyl group, or the 5- to 10-membered heteroaryl group may optionally be separated by one or more R groups. Ta Replace; and Each R Ta Independently, it is a halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C10 Aryl, 3 to 10-membered heterocyclic alkyl or 5 to 10-membered heteroaryl.

[0215] In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the -O-(C1-C6 alkyl), the -NH-(C1-C6 alkyl), the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T replace; Each R T Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3 to 7-membered monocyclic heterocyclic alkyl or 5 to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 7-membered monocyclic heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally separated by one or more R Ta Replace; and Each R Ta Independently, it is a halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3 to 10-membered heterocyclic alkyl or 5 to 10-membered heteroaryl.

[0216] In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T Replace; and Each R T Independently, it is a halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2 or a 3 to 7-membered heterocyclic alkyl; wherein the -O-(C1-C6 alkyl), the -N(C1-C6 alkyl)2 or the 3 to 7-membered heterocyclic alkyl is optionally substituted by one or more -C(=O)OH.

[0217] In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T Replace; and Each R T Independently, it is a halogen, -OH, -O-(C1-C6 alkyl), or a 3- to 7-membered heterocyclic alkyl; wherein the -O-(C1-C6 alkyl) or the 3- to 7-membered heterocyclic alkyl is optionally substituted with one or more -C(=O)OH.

[0218] In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T Replace; and Each R T Independently, it is a halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2 or a 3 to 7-membered monocyclic heterocyclic alkyl; wherein the -O-(C1-C6 alkyl), the -N(C1-C6 alkyl)2 or the 3 to 7-membered monocyclic heterocyclic alkyl is optionally substituted by one or more -C(=O)OH.

[0219] In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T Replace; and Each R T Independently, it is a halogen, -OH, -O-(C1-C6 alkyl), or a 3- to 7-membered heterocyclic alkyl; wherein the -O-(C1-C6 alkyl) or the 3- to 7-membered heterocyclic alkyl is optionally substituted with one or more -C(=O)OH.

[0220] In some embodiments, T is optionally represented by one or more R T Substituted -O-(C1-C6 alkyl).

[0221] In some embodiments, T is -O-(C1-C6 alkyl).

[0222] In some embodiments, T is -OCH3.

[0223] In some embodiments, T is optionally represented by one or more R TSubstituted -NH-(C1-C6 alkyl).

[0224] In some embodiments, T is -NH-(C1-C6 alkyl).

[0225] In some embodiments, T is -NHCH3.

[0226] In some embodiments, T is optionally represented by one or more R T Substituted -C1-C6 alkyl groups.

[0227] In some embodiments, T is a C1-C6 alkyl group.

[0228] In some embodiments, T is methyl or ethyl.

[0229] In some embodiments, T is a methyl group.

[0230] In some embodiments, T is ethyl.

[0231] In some embodiments, T is a signal generated by one or more Rs. T Substituted C1-C6 alkyl groups.

[0232] In some embodiments, T is a C1-C6 alkyl group substituted with one or more halogens (e.g., F or Cl).

[0233] In some embodiments, T is a methyl group substituted with one or more halogens (e.g., F or Cl).

[0234] In some embodiments, T is -CHFCl.

[0235] In some embodiments, T is a C1-C6 alkyl group substituted with one or more CN atoms.

[0236] In some embodiments, T is -CH2CN.

[0237] In some embodiments, T is optionally represented by one or more R T 取代的C2 -C6 alkenyl.

[0238] In some embodiments, T is a C2-C6 alkenyl group.

[0239] In some embodiments, T is vinyl (i.e., -CH=CH2).

[0240] In some embodiments, T is an propylene group (e.g., -C(CH3)=CH2 or –CH=CH-CH3).

[0241] In some embodiments, T is pentenyl (e.g., -CH=CH-C(CH3)2).

[0242] In some embodiments, T is a signal generated by one or more Rs. T 取代的C2 -C6 alkenyl.

[0243] In some embodiments, T is a C2-C6 alkenyl group substituted with one or more -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2 or 3 to 10-membered heterocyclic alkyl groups; wherein the 3 to 10-membered heterocyclic alkyl groups are optionally substituted with one or more -C(=O)OH groups.

[0244] In some embodiments, T is a C2-C6 alkenyl group substituted with one or more -OH groups.

[0245] In some embodiments, T is a C2-C6 alkenyl group substituted with one or more -O-(C1-C6 alkyl) groups.

[0246] In some embodiments, T is a C2-C6 alkenyl group substituted with one or more -OCH3 groups.

[0247] In some embodiments, T is a C2-C6 alkenyl group substituted with one or more -N(C1-C6 alkyl)2.

[0248] In some embodiments, T is a C2-C6 alkenyl group substituted with one or more -N(CH3)2.

[0249] In some embodiments, T is a C2-C6 alkenyl group substituted with one or more 3- to 10-membered heterocyclic alkyl groups.

[0250] In some embodiments, T is a C2-C6 alkenyl group substituted with one or more 3- to 10-membered heterocyclic alkyl groups; wherein the 3- to 10-membered heterocyclic alkyl groups are optionally substituted with one or more -C(=O)OH groups.

[0251] In some embodiments, T is a C2-C6 alkenyl group substituted with one or more 3- to 7-membered heterocyclic alkyl groups.

[0252] In some embodiments, T is a C2-C6 alkenyl group substituted with one or more 3- to 7-membered heterocyclic alkyl groups; wherein the 3- to 7-membered heterocyclic alkyl groups are optionally substituted with one or more -C(=O)OH groups.

[0253] In some embodiments, T is a C2-C6 alkenyl group substituted with one or more 3- to 7-membered heterocyclic alkyl groups.

[0254] In some embodiments, T is a C2-C6 alkenyl group substituted with one or more 3- to 7-membered monocyclic heterocyclic alkyl groups.

[0255] In some embodiments, T is a C2-C6 alkenyl group substituted with one or more 3- to 7-membered monocyclic heterocyclic alkyl groups; wherein the 3- to 7-membered monocyclic heterocyclic alkyl groups are optionally substituted with one or more -C(=O)OH groups.

[0256] In some embodiments, T is a C2-C6 alkenyl group substituted with one or more 3- to 7-membered monocyclic heterocyclic alkyl groups.

[0257] In some embodiments, T is a C2-C6 alkenyl group substituted with one or more 6-membered heterocyclic alkyl groups; wherein the 6-membered heterocyclic alkyl group is optionally substituted with one or more -C(=O)OH groups.

[0258] In some embodiments, T is a C2-C6 alkenyl group substituted with one or more 6-membered heterocyclic alkyl groups.

[0259] In some embodiments, T is a C2-C6 alkenyl group substituted with one or more 6-membered monocyclic heterocyclic alkyl groups; wherein the 6-membered monocyclic heterocyclic alkyl group is optionally substituted with one or more -C(=O)OH groups.

[0260] In some embodiments, T is a C2-C6 alkenyl group substituted with one or more 6-membered monocyclic heterocyclic alkyl groups.

[0261] In some embodiments, T is optionally represented by one or more R T Substituted C2-C6 ynyl group.

[0262] In some embodiments, T is a C2-C6 ynyl group.

[0263] In some embodiments, T is a propynyl group (e.g., -C≡C-CH3).

[0264] In some embodiments, T is a signal generated by one or more Rs. T Substituted C2-C6 ynyl group.

[0265] In some embodiments, T is a signal generated by one or more Rs. T Substituted propynyl group.

[0266] In some embodiments, T is -C≡C-CH2-R T .

[0267] In some embodiments, T is a C2-C6 alkynyl group substituted with one or more 3- to 10-membered heterocyclic alkyl groups.

[0268] In some embodiments, T is a propynyl group substituted with one or more 3- to 10-membered heterocyclic alkyl groups.

[0269] In some embodiments, T is a C2-C6 alkynyl group substituted with one or more 3- to 7-membered heterocyclic alkyl groups.

[0270] In some embodiments, T is a propynyl group substituted with one or more 3- to 7-membered heterocyclic alkyl groups.

[0271] In some embodiments, T is , , , , , , , , , , , , , , , , , or .

[0272] In some embodiments, T is , , , , , , , , , , , , , , , , or .

[0273] In some embodiments, T is .

[0274] In some embodiments, T is .

[0275] In some embodiments, T is or .

[0276] In some embodiments, T is , , , , , , , , , or .

[0277] In some embodiments, T is , , , , , , , , or .

[0278] In some embodiments, T is or .

[0279] In some embodiments, at least one R T It is a halogen (e.g., F or Cl).

[0280] In some embodiments, at least one R T It is F.

[0281] In some embodiments, at least one R T It is Cl.

[0282] In some embodiments, at least one R T It is CN, -OH, or -NH2.

[0283] In some embodiments, at least one R T It's CN.

[0284] In some embodiments, at least one R T It is -OH.

[0285] In some embodiments, at least one R T It is -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; wherein the O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), or the -N(C1-C6 alkyl)2 is optionally separated by one or more R Ta replace.

[0286] In some embodiments, at least one R T It is -O-(C1-C6 alkyl) or -N(C1-C6 alkyl)2; wherein the O-(C1-C6 alkyl)2 or the -N(C1-C6 alkyl)2 is optionally separated by one or more R Ta replace.

[0287] In some embodiments, at least one R T It is -O-(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0288] In some embodiments, at least one R TIt is -O-(C1-C6 alkyl).

[0289] In some embodiments, at least one R T It is -N(C1-C6 alkyl)2.

[0290] In some embodiments, at least one R T It is a C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 alkynyl is optionally surrounded by one or more R Ta replace.

[0291] In some embodiments, at least one R T It is C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; wherein the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R Ta replace.

[0292] In some embodiments, at least one R T It is optionally controlled by one or more R Ta Substituted 3 to 10-membered heterocyclic alkyl groups.

[0293] In some embodiments, at least one R T It is by one or more R Ta Substituted 3 to 10-membered heterocyclic alkyl groups.

[0294] In some embodiments, at least one R T It is a 3- to 10-membered heterocyclic alkyl group substituted with one or more C(=O)OH groups.

[0295] In some embodiments, at least one R T It is optionally controlled by one or more R Ta Substituted 3- to 7-membered heterocyclic alkyl groups.

[0296] In some embodiments, at least one R T It is a 3- to 7-membered heterocyclic alkyl group.

[0297] In some embodiments, at least one R T It is by one or more R Ta Substituted 3- to 7-membered heterocyclic alkyl groups.

[0298] In some embodiments, at least one R T It is a 3- to 7-membered heterocyclic alkyl group substituted with one or more C(=O)OH groups.

[0299] In some embodiments, at least one R T It is optionally controlled by one or more R Ta Substituted 6-membered heterocyclic alkyl groups.

[0300] In some embodiments, at least one R T It is a 6-membered heterocyclic alkyl group.

[0301] In some embodiments, at least one R T It is by one or more R Ta Substituted 6-membered heterocyclic alkyl groups.

[0302] In some embodiments, at least one R T It is a 6-membered heterocyclic alkyl group substituted with one or more C(=O)OH groups.

[0303] In some embodiments, at least one R T It is optionally controlled by one or more R Ta Substituted 3 to 7-membered monocyclic heterocyclic alkyl groups.

[0304] In some embodiments, at least one R T It is a 3- to 7-membered monocyclic heterocyclic alkyl group.

[0305] In some embodiments, at least one R T It is by one or more R Ta Substituted 3 to 7-membered monocyclic heterocyclic alkyl groups.

[0306] In some embodiments, at least one R T It is a 3- to 7-membered monocyclic heterocyclic alkyl group substituted with one or more C(=O)OH groups.

[0307] In some embodiments, at least one R T It is optionally controlled by one or more R Ta Substituted 6-membered monocyclic heterocyclic alkyl group.

[0308] In some embodiments, at least one R T It is a 6-membered monocyclic heterocyclic alkyl group.

[0309] In some embodiments, at least one R T It is by one or more R Ta Substituted 6-membered monocyclic heterocyclic alkyl group.

[0310] In some embodiments, at least one R T It is a 6-membered monocyclic heterocyclic alkyl group substituted with one or more C(=O)OH groups.

[0311] In some embodiments, at least one R Ta It is C(=O)OH.

[0312] In some embodiments, at least one R Ta It is a halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3 to 10-membered heterocyclic alkyl or 5 to 10-membered heteroaryl.

[0313] variable Ar 1 、R A1 、R A1a and R A1b In some embodiments, Ar 1 It is optionally controlled by one or more R A1 Replacement C6-C 10 Aryl; Each R A1 Independently, it is halogen, CN, -OH, -NH2, -OR A1a -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally replaced by one or more R A1a replace; Each R A1a Independently, it is a halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted by one or more R A1b Replace; and Each R A1b It can be halogen, CN, -OH or -NH2 independently.

[0314] In some embodiments, Ar 1 It is C6-C 10 Aryl.

[0315] In some embodiments, Ar 1It is by one or more R A1 Replacement C6-C 10 Aryl.

[0316] In some embodiments, Ar 1 It is by one or more R A1 Substituted phenyl groups.

[0317] In some embodiments, Ar 1 It is affected by one or more halogens, -OR A1a or -O-(C1-C6 alkyl)-substituted phenyl; wherein the -O-(C1-C6 alkyl) is optionally replaced by one or more R A1a Replace; and each R A1a Independently, it is C6-C 10 aryl or 5- to 10-membered heteroaryl; wherein the C6-C 10 The aryl group or the 5- to 10-membered heteroaryl group may optionally be substituted with one or more halogens.

[0318] In some embodiments, Ar 1 It is a phenyl group that has been substituted with one or more halogens.

[0319] In some embodiments, Ar 1 It is a phenyl group substituted with one or more F or Cl.

[0320] In some embodiments, Ar 1 It is a phenyl group substituted with one F and one Cl.

[0321] In some embodiments, Ar 1 It is a phenyl group optionally substituted with one or more halogens, wherein the phenyl group is further substituted with -O-(C6-C) halogens. 10 Aryl) or -O- (5 to 10 heteroaryl) substitution; wherein the -O- (C6-C 10 The aryl group or the -O- (5 to 10 heteroaryl group) may optionally be substituted with one or more halogens.

[0322] In some embodiments, Ar 1 It is a phenyl group optionally substituted with one or more halogens, wherein the phenyl group is further substituted with -O-phenyl or -O-pyridyl; wherein the -O-phenyl or the -O-pyridyl is optionally substituted with one or more halogens.

[0323] In some embodiments, Ar 1 It is a phenyl group optionally substituted with one or more halogens, wherein the phenyl group is further substituted with -O-phenyl; wherein the -O-phenyl group is optionally substituted with one or more halogens.

[0324] In some embodiments, Ar1 It is a phenyl group optionally substituted with one or more halogens, wherein the phenyl group is further substituted with -O-pyridyl; wherein the -O-pyridyl is optionally substituted with one or more halogens.

[0325] In some embodiments, Ar 1 yes , , , or .

[0326] In some embodiments, Ar 1 yes .

[0327] In some embodiments, Ar 1 yes .

[0328] In some embodiments, Ar 1 yes .

[0329] In some embodiments, Ar 1 yes .

[0330] In some embodiments, Ar 1 yes .

[0331] In some embodiments, Ar 1 yes , or .

[0332] In some embodiments, Ar 1 yes .

[0333] In some embodiments, Ar 1 yes .

[0334] In some embodiments, Ar 1 yes .

[0335] In some embodiments, Ar 1 yes or .

[0336] In some embodiments, Ar 1 yes .

[0337] In some embodiments, Ar 1 yes .

[0338] In some embodiments, Ar 1 yes .

[0339] In some embodiments, at least one R A1 It is a halogen (e.g., F or Cl).

[0340] In some embodiments, at least one R A1 It is F.

[0341] In some embodiments, at least one R A1 It is Cl.

[0342] In some embodiments, at least one R A1 It is F, and at least one R A1 It is Cl.

[0343] In some embodiments, at least one R A1 It is CN, -OH, or -NH2.

[0344] In some embodiments, at least one R A1 Yes - OR A1a .

[0345] In some embodiments, at least one R A1 It is -O-(C6-C) 10 aryl) or -O- (5 to 10-membered heteroaryl); wherein the -O- (C6-C 10 aryl) or -O- (5 to 10-membered heteroaryl) optionally constituting one or more R A1b replace.

[0346] In some embodiments, at least one R A1 It is -O-(C6-C) 10 aryl) or -O- (5 to 10-membered heteroaryl); wherein the -O- (C6-C 10 The aryl group or the -O- (5 to 10 heteroaryl group) may optionally be substituted with one or more halogens.

[0347] In some embodiments, at least one R A1 It is -O-phenyl or -O-pyridyl; wherein the -O-phenyl or the -O-pyridyl is optionally substituted with one or more halogens.

[0348] In some embodiments, at least one R A1 It is an -O-phenyl that is optionally substituted with one or more halogens.

[0349] In some embodiments, at least one R A1It is an -O-pyridyl group that is optionally substituted with one or more halogens.

[0350] In some embodiments, at least one R A1 It is -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally separated by one or more R A1a replace.

[0351] In some embodiments, at least one R A1 It is optionally controlled by one or more R A1a Substituted -O-(C1-C6 alkyl).

[0352] In some embodiments, at least one R A1 It is by one or more R A1a Substituted -O-(C1-C6 alkyl).

[0353] In some embodiments, at least one R A1 It is by one or more C6-C 10 Aryl or 5- to 10-membered heteroaryl-substituted -O-(C1-C6 alkyl), wherein the C6-C 10 The aryl group or the 5- to 10-membered heteroaryl group may optionally be substituted with one or more halogens.

[0354] In some embodiments, at least one R A1 It is -O-CH2-R A1a .

[0355] In some embodiments, at least one R A1 It is -O-CH2-(C6-C 10 aryl) or -O-CH2- (5 to 10-membered heteroaryl), wherein the -O-CH2- (C6-C 10 Aryl) or -O-CH2- (5 to 10 heteroaryl) may optionally be substituted with one or more halogens.

[0356] In some embodiments, at least one R A1 It is -O-CH2-phenyl or -O-CH2-pyridyl, wherein the -O-CH2-phenyl or the -O-CH2-pyridyl is optionally substituted with one or more halogens.

[0357] In some embodiments, at least one R A1 It is an -O-CH2-phenyl group optionally substituted with one or more halogens.

[0358] In some embodiments, at least one R A1 It is an -O-CH2-pyridyl group that is optionally substituted with one or more halogens.

[0359] In some embodiments, at least one R A1 It is C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; wherein the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R A1a replace.

[0360] In some embodiments, at least one R A1a It is a halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally separated by one or more R A1b replace.

[0361] In some embodiments, at least one R A1a It is C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; wherein the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R A1b replace.

[0362] In some embodiments, at least one R A1a It is C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; wherein the C3-C 10 cycloalkyl, the C6-C 10 The aryl group, the 3- to 10-membered heterocyclic alkyl group, or the 5- to 10-membered heteroaryl group may optionally be substituted with one or more halogens.

[0363] In some embodiments, at least one R A1a It is C6-C 10aryl or 5- to 10-membered heteroaryl; wherein the C6-C 10 The aryl group or the 5- to 10-membered heteroaryl group may optionally be substituted with one or more halogens.

[0364] In some embodiments, at least one R A1a It is phenyl or pyridyl; wherein the phenyl or pyridyl is optionally substituted with one or more halogens.

[0365] In some embodiments, at least one R A1a It is a phenyl group that is optionally substituted with one or more halogens.

[0366] In some embodiments, at least one R A1a It is a pyridinyl group that is optionally substituted with one or more halogens.

[0367] In some embodiments, at least one R A1b It is halogen.

[0368] In some embodiments, at least one R A1b It is F.

[0369] In some embodiments, at least one R A1b It is Cl.

[0370] In some embodiments, at least one R A1b It is F, and at least one R A1b It is Cl.

[0371] In some embodiments, at least one R A1b It is CN, -OH, or -NH2.

[0372] Exemplary embodiments of the compound In some embodiments, when Z is ,but T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, or C2-C6 ynyl is optionally replaced by one or more R T Substitution; and wherein the C2-C6 alkenyl group is replaced by one or more R T replace, Each R T Independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10aryl, 3- to 10-membered heterocyclic alkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, or the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R Ta Replace; and Each R Ta Independently, it is a halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3 to 10-membered heterocyclic alkyl or 5 to 10-membered heteroaryl.

[0373] In some embodiments, when Z is When, then T is not or .

[0374] In some embodiments, when Z is At that time, then Ar 1 It is a C6-C that is optionally substituted with one or more halogens. 10 Aryl.

[0375] In some embodiments, Z is not .

[0376] In some embodiments, Z is not , , or .

[0377] In some embodiments, T is not .

[0378] In some embodiments, the compound has formula (II'): (II'), Or its pharmaceutically acceptable salts or stereoisomers.

[0379] In some embodiments, the compound has formula (II'): (II'), Or its pharmaceutically acceptable salts or stereoisomers.

[0380] In some embodiments, the compound has formula (III') or (III'-a): (III') (III-a') Or its pharmaceutically acceptable salts or stereoisomers.

[0381] In some embodiments, the compound has the formula (IV') or (IV'-a): (IV') (IV-a') Or its pharmaceutically acceptable salts or stereoisomers.

[0382] In some aspects, this disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof, said compound having formula I, in W is CH or N, preferably CH; X 1 It is -O-, -S-, -NR 3 -; R a R b Hydrogen is independent of each other. 1-4 Alkyl, or R a One of them is if X 1 It is NR 3 Then with X 1 -(CH2) forms a ring p , or R a One of them is with R 2 -(CH2) forms a ring p ; R c R d They are either hydrogen or C, independent of each other. 1-4 alkyl; R 1 It is H or F; R 2 Is it hydrogen or C? 1-4 Alkyl, or with R 3 Or with R a One of them forms a ring -(CH2). q ; R 3 Is it hydrogen or C? 1-4 Alkyl groups, preferably hydrogen or methyl, or those with R 2 -(CH2) forms a ring p -; m is 1, 2, or 3; n is 0, 1, or 2; p is 1 or 2; q is 0, 1, or 2; and Ar 1 It is a 6-membered aryl group that is either unsubstituted or substituted with one or more members selected from the group consisting of: halogens, -CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 heteroaryl, amino, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 Aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 alkoxyaminocarbonyl, aryl C 1-6 Alkyl or C6 aryl.

[0383] In some embodiments of the compound of formula I, W is CH.

[0384] In some embodiments, when n is 0, R 2 Is with R 3 Or with R a One of them forms a ring -(CH2). q -

[0385] In some embodiments, when n is 0, R 2 Is with R 3 -(CH2) forms a ring q -

[0386] In some embodiments, n is 0, and R 2 Is with R 3 Or with R a One of them forms a ring -(CH2). q -

[0387] In some embodiments, n is 0, and R 2 Is with R 3 -(CH2) forms a ring q -

[0388] In some embodiments of the compound of formula I, X 1 Is it -O- or -NR? 3 -, more preferably -NR 3 -

[0389] In some embodiments of the compound of formula I, R b Always hydrogen, so that only R a It may not be hydrogen. For example, R b It can be hydrogen and R a It can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, or combined with R. 2 Forming a ring -(CH2)- or -(CH2)2-. Preferably, R b It can be hydrogen, and R a It can be methyl or with R 2 Forming rings -(CH2)- or -(CH2)2-. Furthermore, R a and R b Both can be hydrogen.

[0390] In some embodiments, X 1 One part of it is a single ring or a double ring.

[0391] In some embodiments of the compound of formula I, R c Always hydrogen, so that only R d It doesn't have to be hydrogen. For example, R c It can be hydrogen and R d It can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. Preferably, R c It can be hydrogen and R d It can be methyl. Furthermore, R c and R d Both can be hydrogen.

[0392] In some embodiments of the compound of formula I, R 1 It is hydrogen.

[0393] In some embodiments of the compound of formula I, R c and R d It is hydrogen. In some embodiments of the compound of formula I, R b R c and R d It is hydrogen. In some embodiments of the compound of formula I, R 1 R b R c and R d It is hydrogen.

[0394] In which R a One of them with R 3 In some embodiments of the compound of formula I that forms a ring, the formed ring is a 4-membered, 5-membered, or 6-membered ring, or a 5-membered or 6-membered ring, or a 5-membered ring.

[0395] In which R a One of them with R 3 In some embodiments of the compound of formula I that forms a ring, the formed ring is a 3-membered, 4-membered, 5-membered, or 6-membered ring.

[0396] In which R 2 One of them with R 3 In some embodiments of the compound of formula I that forms a ring, the formed ring is a 4-membered, 5-membered, or 6-membered ring, or a 5-membered, 6-membered ring, or a 6-membered ring.

[0397] In some embodiments of the compound of formula I, R 2 It is C 1-4 Alkyl, or with R 3 Or with R a -(CH2) forms a ring q -. For example, R 2 It can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, or R 2 Is with R 3 -(CH2)- or -(CH2)2, or R, form a ring. 2 Is with R a One of them forms a ring -(CH2)- or -(CH2)2-. Preferably, R 2 It can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl, or R 2 Is with R 3 -(CH2)- or -(CH2)2- that form a ring, or R 2 Is with R a One of them forms a ring -(CH2)- or -(CH2)2-. More preferably, R 2 It can be methyl.

[0398] In some embodiments of the compound of formula I, R 3 Is it hydrogen or methyl or R? 3 Is with R 2 -(CH2)- or -(CH2)2- form a ring.

[0399] In some embodiments of the compound of formula I, n is 0 and m is 1, 2 or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2 or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2 or 3; or n is 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1; or n is 1 or 2 and m is 1, 2 or 3; or n is 1 or 2 and m is 1 or 2; or n is 1 or 2 and m is 1 or 3; or n is 1 or 2 and m is 2 or 3.

[0400] In some embodiments of the compound of formula I, X 1 Can be combined with R 2 Directly bonded carbon atoms form heterocycles. For example, X 1 It can form 4-, 5-, 6-, or 7-membered heterocycles. In some embodiments of the compounds of formula I, X 1 It can form substituted or unsubstituted oxetane, thiaalkyl, azirnealkyl, pyrrolyl, tetrahydrofuranyl, tetrahydrothiaalkyl, dihydropyranyl, tetrahydropyranyl, piperidinyl, oxetane, thiophenyl, azirnealkyl, azirnebicyclo[2.2.1]heptane or azirnebicyclo[2.2.2]octane, preferably azirnealkyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, more preferably azirnealkyl, pyrrolyl or piperidinyl.

[0401] In some embodiments of the compound of formula I, Ar 1 Having formula i or its pharmaceutically acceptable salt or stereoisomer, in R 4 Hydrogen, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 heteroaryl, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 Aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 Alkoxyamino-carbonyl, aryl C 1-6 alkoxy or C6 aryl; R 5 R 5' R 6 R 6' They are hydrogen, -CF3 or halogens, and preferably F or Cl.

[0402] In some embodiments of the compound of formula I, where Ar 1 Having the formula i, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, hydroxy C1-5 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy-C6 aryl, C 1-4 Alkoxy-C 5-6 heteroaryl, amino C 1-4 Alkyl, C 1-4 Alkylamino, C 1-4 Aminoalkyl-C6 aryl, C 1-4 Aminoalkyl-C6 heteroaryl, C 1-4 alkoxycarbonyl, C 1-4 Alkoxyaminocarbonyl or C6 aryl.

[0403] In some embodiments of the compound of formula I, where Ar 1 Having the formula i, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy-C6 aryl, C 1-4 Alkoxy-C 5-6 Heteroaryl or C6 aryl.

[0404] In some embodiments of the compound of formula I, where Ar 1 Having the formula i, R 4Typically, these are hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-propoxy, n-butoxy, isobutoxy, n-pentoxy, isopentyloxy, n-hexyloxy, isohexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, methoxymethyl, methoxyethyl, methoxypropyl, methyl oxybutyl, methoxypentyl, methoxyhexyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, propoxyhexyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, butoxyhexyl, pentomethyl, pentoethyl, pentopropyl, pentobutyl, pentopentyl, pentohexyl, hexyl oxymethyl, hexoxyethyl, hexoxypropyl, hexoxybutyl, hexoxypentyl, hexoxyhexyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentooxycarbonyl, hexoxycarbonyl, methoxyaminocarbonyl, ethoxyaminocarbonyl, propoxyaminocarbonyl, butoxyaminocarbonyl , pentoxyaminocarbonyl, hexoxyaminocarbonyl, phenylmethoxy, phenylethoxy, phenylpropoxy, phenylbutoxy, phenylpentoxy, phenylhexyloxy, m-fluorophenylmethoxy, m-fluorophenylphenylethoxy, m-fluorophenylphenylpropoxy, m-fluorophenylphenylbutoxy, m-fluorophenylphenylpentoxy, m-fluorophenylphenylhexyloxy, pyridylmethoxy, pyridylethoxy, pyridylpropoxy, pyridylbutoxy, pyridylpentoxy, pyridylhexyloxy, phenyl, pyridyl or naphthyl.

[0405] In some embodiments of the compound of formula I, where Ar 1 Having the formula i, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen. Preferably, R 4 Hydrogen, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 heteroaryl, amino C 1-4 Alkyl, C1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 Aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 Alkoxyamino-carbonyl, aryl C 1-6 Alkyl or C6 aryl.

[0406] In some embodiments of the compound of formula I, where Ar 1 Having the formula i, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen. Preferably, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy-C6 aryl, C 1-4 Alkoxy-C 5-6 heteroaryl, amino C 1-4 Alkyl, C 1-4 Alkylamino, C 1-4 Aminoalkyl-C6 aryl, C 1-4 Aminoalkyl-C6 heteroaryl, C 1-4 alkoxycarbonyl, C 1-4 Alkoxyaminocarbonyl or C6 aryl.

[0407] In some embodiments of the compound of formula I, where Ar 1 Having formula i, Ar 1 This includes substituents that are not hydrogen, whether there are only one, two, or three. Therefore, R 4 R 5 R 5' R 6 or R 6' At least two of them can be hydrogen.

[0408] In some embodiments of the compound of formula I, where Ar 1 Having the formula i, R 1 It can be hydrogen and / or R 2 It can be methyl or R 2 Is with R 3 -(CH2)- or -(CH2)2- that form a ring, or R 2 Is with R aOne of them forms a ring -(CH2)- or -(CH2)2-.

[0409] In some embodiments of the compound of formula I, where Ar 1 Having the formula i, R c and R d It is hydrogen. In some embodiments of the compound of formula I, where Ar... 1 Having the formula i, R b R c and R d It is hydrogen.

[0410] In some embodiments of the compound of formula I, where Ar 1 It has the formula i, where R a One of them with R 3 The formed rings are 4-membered, 5-membered, or 6-membered rings, or 5-membered or 6-membered rings, or 5-membered rings.

[0411] In some embodiments of the compound of formula I, where Ar 1 It has the formula i, where R a One of them with R 3 The rings formed are 3-membered, 4-membered, 5-membered, or 6-membered rings.

[0412] In some embodiments of the compound of formula I, where Ar 1 It has the formula i, where R 2 One of them with R 3 The formed rings are 4-membered, 5-membered, or 6-membered rings.

[0413] In some embodiments of the compound of formula I, Ar 1 Having formula ii-1 or its pharmaceutically acceptable salt or stereoisomer in R 4 It is hydrogen, F, or Cl; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3 or halogen, preferably F or Cl.'

[0414] In some embodiments of the compound of formula I, Ar 1 Having formula ii-2, ii-3 or ii-4 or their pharmaceutically acceptable salts or stereoisomers. in X 2It is O, NH, or NMe; X 3 It is CH or N; o is 0 or 1; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3, or halogen, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F.

[0415] Those skilled in the art should understand that if X 3 Representing CH, then R 7 It can also typically combine with this carbon, making X 3 It can be CR 7 Preferably, the corresponding aryl or heteroaryl group is only affected by a single R. 7 Replacement. Furthermore, it can be understood that when X... 3 When it is N, R 7 It is usually not necessary to combine it with N.

[0416] In some embodiments of the compound of formula I, where Ar 1 Having formulas ii-1, ii-2, ii-3 or ii-4, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen.

[0417] In some embodiments of the compound of formula I, where Ar 1 If X has the formula ii-1, ii-2, ii-3 or ii-4, then X 3 If it is N, then R 7 Is it hydrogen and / or if X 3 If it is CH, then R 7 It is F.

[0418] In some embodiments of the compound of formula I, where Ar 1 It has the formula ii-1, ii-2, ii-3 or ii-4, where o is 1.

[0419] In some embodiments of the compound of formula I, where Ar 1 Having formulas ii-1, ii-2, ii-3 or ii-4, R 5 Is F and / or R 6 It is either F or Cl.

[0420] In some embodiments of the compound of formula I, where Ar 1Having formulas ii-1, ii-2, ii-3 or ii-4, R c and R d It is hydrogen. In some embodiments of the compound of formula I, where Ar... 1 Having formulas ii-1, ii-2, ii-3 or ii-4, R b R c and R d It is hydrogen.

[0421] In some embodiments of the compound of formula I, where Ar 1 It has the formula ii-1, ii-2, ii-3 or ii-4, where R a One of them with R 3 The formed rings are 4-membered, 5-membered, or 6-membered rings, or 5-membered or 6-membered rings, or 5-membered rings.

[0422] In some embodiments of the compound of formula I, where Ar 1 It has the formula ii-1, ii-2, ii-3 or ii-4, where R a One of them with R 3 The rings formed are 3-membered, 4-membered, 5-membered, or 6-membered rings.

[0423] In some embodiments of the compound of formula I, where Ar 1 It has the formula ii-1, ii-2, ii-3 or ii-4, where R 2 One of them with R 3 The formed rings are 4-membered, 5-membered, or 6-membered rings.

[0424] In some embodiments of the compound of formula I, where Ar 1 Having formulas ii-1, ii-2, ii-3 or ii-4, R 2 Is it methyl or R? 2 Is with R 3 -(CH2)- or -(CH2)2- that form a ring, or R 2 Is with R a One of them forms a ring -(CH2)- or -(CH2)2-.

[0425] In some embodiments, X 2 It is O that makes Ar 1 Having formula ii-1a or a pharmaceutically acceptable salt or stereoisomer thereof in R 4 It is hydrogen, F, or Cl; R 5 R5 '、R 6 R 6 'Independently hydrogen, -CF3 or halogen, preferably F or Cl.'

[0426] In some embodiments, X 2 It is O that makes Ar 1 Having formula ii-2a, ii-3a or ii-4a or a pharmaceutically acceptable salt or stereoisomer thereof in X 3 It is CH or N, preferably N; o is 0 or 1; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3, or halogen, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F.

[0427] In some embodiments of the compound of formula I, where Ar 1 Having the formula ii-1a, ii-2a, ii-3a or ii-4a, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen.

[0428] In some embodiments of the compound of formula I, where Ar 1 It has the formula ii-1a, ii-2a, ii-3a or ii-4a, where o is 1.

[0429] In some embodiments of the compound of formula I, where Ar 1 Having the formula ii-1a, ii-2a, ii-3a or ii-4a, R 5 Is F and / or R 6 It is either F or Cl.

[0430] In some embodiments of the compound of formula I, where Ar 1 Having the formula ii-1a, ii-2a, ii-3a or ii-4a, if X 3 If it is N, then R 7 Is it hydrogen and / or if X 3 If it is CH, then R 7 It is F.

[0431] In some embodiments of the compound of formula I, where Ar1 Having the formula ii-1a, ii-2a, ii-3a or ii-4a, R 2 Is it methyl or R? 2 Is with R 3 -(CH2)- or -(CH2)2- that form a ring, or R 2 Is with R a One of them forms a ring -(CH2)- or -(CH2)2-.

[0432] In some embodiments of the compound of formula I, where Ar 1 Having the formula ii-1a, ii-2a, ii-3a or ii-4a, R c and R d It is hydrogen. In some embodiments of the compound of formula I, where Ar... 1 Having the formula ii-1a, ii-2a, ii-3a or ii-4a, R b R c and R d It is hydrogen.

[0433] In some embodiments of the compound of formula I, where Ar 1 It has the formula ii-1a, ii-2a, ii-3a or ii-4a, where R a One of them with R 3 The formed rings are 4-membered, 5-membered, or 6-membered rings, or 5-membered or 6-membered rings, or 5-membered rings.

[0434] In some embodiments of the compound of formula I, where Ar 1 It has the formula ii-1a, ii-2a, ii-3a or ii-4a, where R a One of them with R 3 The rings formed are 3-membered, 4-membered, 5-membered, or 6-membered rings.

[0435] In some embodiments of the compound of formula I, where Ar 1 It has the formula ii-1a, ii-2a, ii-3a or ii-4a, where R 2 One of them with R 3 The formed rings are 4-membered, 5-membered, or 6-membered rings.

[0436] In some embodiments, X 3 It is N such that Ar 1 Having formula ii-1b or a pharmaceutically acceptable salt or stereoisomer thereof in R 4 It is hydrogen, F, or Cl; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3 or halogen, preferably F or Cl.'

[0437] In some embodiments, X 3 It is N such that Ar 1 Having the formula ii-2b, ii-3b, ii-4b, ii-5b or their pharmaceutically acceptable salts or stereoisomers, in X 2 It is O, NH or NMe, preferably O; o is 0 or 1; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3, or halogen, preferably F or Cl,' R 7 It is hydrogen or halogen, preferably F.

[0438] In some embodiments of the compound of formula I, where Ar 1 Having the formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen.

[0439] In some embodiments of the compound of formula I, where Ar 1 It has the formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, where o is 1.

[0440] In some of the compounds of formula I, where Ar 1 Having ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 5 Is F and / or R 6 It is either F or Cl.

[0441] In some of the compounds of formula I, where Ar 1 It is the formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 7 It is F.

[0442] In some of the compounds of formula I, where Ar 1Having the formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 2 Is it methyl or R? 2 Is with R 3 -(CH2)- or -(CH2)2- that form a ring, or R 2 Is with R a One of them forms a ring -(CH2)- or -(CH2)2-.

[0443] In some embodiments of the compound of formula I, where Ar 1 Having the formula ii-1b, ii-2b, ii-3b or ii-4b, R c and R d It is hydrogen. In some embodiments of the compound of formula I, where Ar... 1 Having the formula ii-1b, ii-2b, ii-3b or ii-4b, R b R c and R d It is hydrogen.

[0444] In some embodiments of the compound of formula I, where Ar 1 It has the formula ii-1b, ii-2b, ii-3b or ii-4b, where R a One of them with R 3 The formed rings are 4-membered, 5-membered, or 6-membered rings, or 5-membered or 6-membered rings, or 5-membered rings.

[0445] In some embodiments of the compound of formula I, where Ar 1 It has the formula ii-1b, ii-2b, ii-3b or ii-4b, where R a One of them with R 3 The rings formed are 3-membered, 4-membered, 5-membered, or 6-membered rings.

[0446] In some embodiments of the compound of formula I, where Ar 1 It has ii-1b, ii-2b, ii-3b or ii-4b, where R 2 One of them with R 3 The formed rings are 4-membered, 5-membered, or 6-membered rings.

[0447] In some embodiments, X 2 It is O, and X 3 It is N such that Ar 1 Having formula ii-1c or a pharmaceutically acceptable salt or stereoisomer thereof in R4 It is hydrogen, F, or Cl; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3 or halogen, preferably F or Cl.'

[0448] In some embodiments, X 2 It is O, and X 3 It is N such that Ar 1 Having the formula ii-2c, ii-3c, ii-4c, ii-5c, or their pharmaceutically acceptable salts or stereoisomers, in o is 0 or 1; R 4 It is hydrogen, F, or Cl; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3, or halogen, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F.

[0449] In some embodiments of the compound of formula I, where Ar 1 Having the formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen.

[0450] In some embodiments of the compound of formula I, where Ar 1 It has the formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, where o is 1.

[0451] In some embodiments of the compound of formula I, where Ar 1 Having the formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 5 Is F and / or R 6 It is either F or Cl.

[0452] In some embodiments of the compound of formula I, where Ar 1 Having the formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 7 It is F.

[0453] In some embodiments of the compound of formula I, where Ar 1 Having ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 2 Is it methyl or R? 2 Is with R 3 -(CH2)- or -(CH2)2- that form a ring, or R 2 Is with R a One of them forms a ring -(CH2)- or -(CH2)2-.

[0454] In some embodiments of the compound of formula I, where Ar 1 Having formulas ii-1c, ii-2c, ii-3c or ii-4c, R c and R d It is hydrogen. In some embodiments of the compound of formula I, where Ar... 1 Having formulas ii-1c, ii-2c, ii-3c or ii-4c, R b R c and R d It is hydrogen.

[0455] In some embodiments of the compound of formula I, where Ar 1 It has the formula ii-1c, ii-2c, ii-3c or ii-4c, where R a One of them with R 3 The formed rings are 4-membered, 5-membered, or 6-membered rings, or 5-membered or 6-membered rings, or 5-membered rings.

[0456] In some embodiments of the compound of formula I, where Ar 1 It has the formula ii-1c, ii-2c, ii-3c or ii-4c, where R a One of them with R 3 The rings formed are 3-membered, 4-membered, 5-membered, or 6-membered rings.

[0457] In some embodiments of the compound of formula I, where Ar 1 It has ii-1c, ii-2c, ii-3c or ii-4c, where R 2 One of them with R 3 The formed rings are 4-membered, 5-membered, or 6-membered rings.

[0458] In some embodiments of the compound of formula I, Ar 1 Having formula iii-1 or its pharmaceutically acceptable salt or stereoisomer, in R 4 It is hydrogen or halogen, preferably F or Cl; R 5 R 6 They are hydrogen, -CF3 or halogens, and preferably F or Cl.

[0459] In some embodiments of the compound of formula I, Ar 1 Having formula iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7 or their pharmaceutically acceptable salts or stereoisomers, in X 3 It is CH or N, preferably N; o is 0 or 1; R 5 R 6 They are hydrogen, -CF3, or halogens, each independent of the other, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F.

[0460] In some embodiments of the compound of formula I, where Ar 1 Having equations iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen.

[0461] In some examples of compounds of formula I, wherein Ar 1 If it has the formulas iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, then o is 1.

[0462] In some examples of compounds of formula I, wherein Ar 1 Having equations iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, R 5 Is F and / or R 6 It is either F or Cl.

[0463] In some embodiments of the compound of formula I, where Ar 1 If X has equations iii-1, iii-2, iii-3, or iii-4, then X 3 If it is N, then R 7 Is it hydrogen and / or if X 3 If it is CH, then R 7 It is F.

[0464] In some examples of compounds of formula I, wherein Ar 1 Having equations iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, R 2 Is it methyl or R? 2 Is with R 3 -(CH2)- or -(CH2)2- that form a ring, or R 2 Is with R a One of them forms a ring -(CH2)- or -(CH2)2-.

[0465] In some embodiments of the compound of formula I, where Ar 1 Having equations iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, R c and / or R d It is hydrogen. In some embodiments of the compound of formula I, where Ar... 1 Having equations iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, R b R c and R d It is hydrogen.

[0466] In some examples of compounds of formula I, wherein Ar 1 It has equations iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, where R a One of them with R 3 The formed rings are 4-membered, 5-membered, or 6-membered rings, or 5-membered or 6-membered rings, or 5-membered rings.

[0467] In some examples of compounds of formula I, wherein Ar 1 It has iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, where R a One of them with R 3 The rings formed are 3-membered, 4-membered, 5-membered, or 6-membered rings.

[0468] In some embodiments of the compound of formula I, where Ar 1 It has iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, where R 2 One of them with R 3 The formed rings are 4-membered, 5-membered, or 6-membered rings.

[0469] In some embodiments, X 3 It is N such that Ar 1 It has formula iv-2, iv-3 or iv-4, iv-5, iv-6 or iv-7, or X 3 It is C that makes Ar 1 It has formula IV-8 or IV-9, in o is 0 or 1; R 5 R 6 They are hydrogen, -CF3, or halogens, each independent of the other, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F.

[0470] In some embodiments of the compound of formula I, where Ar 1 Having formulas iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen.

[0471] In some embodiments of the compound of formula I, where Ar 1 If it has iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, o is 1.

[0472] In some embodiments of the compound of formula I, where Ar 1 Having formulas iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, R 5 Is F and / or R 6 It is either F or Cl.

[0473] In some embodiments of the compound of formula I, where Ar 1 With IV-2, IV-3 or IV-4, IV-5, IV-6, IV-7, IV-8 or IV-9, R 7 It is F.

[0474] In some embodiments of the compound of formula I, where Ar 1 With IV-2, IV-3 or IV-4, IV-5, IV-6, IV-7, IV-8 or IV-9, R 2 Is it methyl or R? 2 Is with R 3-(CH2)- or -(CH2)2- that form a ring, or R 2 Is with R a One of them forms a ring -(CH2)- or -(CH2)2-.

[0475] In some embodiments of the compound of formula I, where Ar 1 With IV-2, IV-3 or IV-4, IV-5, IV-6, IV-7, IV-8 or IV-9, R c and R d It is hydrogen. In some embodiments of the compound of formula I, where Ar... 1 Having formulas iv-1, iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, R b R c and R d It is hydrogen.

[0476] In some embodiments of the compound of formula I, where Ar 1 It has formulas iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, where R a One of them with R 3 The formed rings are 4-membered, 5-membered, or 6-membered rings, or 5-membered or 6-membered rings, or 5-membered rings.

[0477] In some embodiments of the compound of formula I, where Ar 1 It has IV-2, IV-3 or IV-4, IV-5, IV-6, IV-7, IV-8 or IV-9, where R a One of them with R 3 The rings formed are 3-membered, 4-membered, 5-membered, or 6-membered rings.

[0478] In some examples of compounds of formula I, wherein Ar 1 It has IV-2, IV-3 or IV-4, IV-5, IV-6, IV-7, IV-8 or IV-9, where R 2 One of them with R 3 The formed rings are 4-membered, 5-membered, or 6-membered rings.

[0479] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof having formula IIa or IIb. in X 1 It is -O-, -NR 3 -; R 1 It is H or F; R 2 Is it hydrogen or C? 1-4 Alkyl, preferably methyl, or with R 3 -(CH2) forms a ring q -; R 3 Is it hydrogen or C? 1-4 Alkyl groups, preferably hydrogen or methyl, or those with R 2 -(CH2) forms a ring p -; m is 1, 2, or 3; n is 0, 1, or 2; p is 1 or 2; q is 0, 1, or 2; r is 0 or 1; s is 1 or 2; and Ar 1 It is a 6-membered aryl group that is either unsubstituted or substituted with one or more members selected from the group consisting of: halogens, -CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 heteroaryl, amino, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 Aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 alkoxyaminocarbonyl, aryl C 1-6 Alkyl or C6 aryl.

[0480] In some embodiments of compounds of formula IIa or IIb, X 1 Yes -NR 3 -

[0481] In some embodiments of compounds of formula IIa or IIb, R 1 It is hydrogen.

[0482] In some embodiments of compounds of formula IIa or IIb, R 2 It is C 1-4 Alkyl, or with R 3 -(CH2) forms a ringq -. For example, R 2 It can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, R 2 Is with R 3 Forming a ring -(CH2)- or -(CH2)2-. Preferably, R 2 It can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl, R 2 Is with R 3 Forming a ring -(CH2)- or -(CH2)2-. More preferably, R 2 It can be methyl, R 2 Is with R 3 -(CH2)- or -(CH2)2- form a ring.

[0483] In some embodiments of compounds of formula IIa or IIb, R 3 Is it hydrogen or methyl, or is it related to R? 2 -(CH2)- or -(CH2)2- form a ring.

[0484] In some embodiments of compounds of formula IIa or IIb, X 1 It is NR 3 .

[0485] In some embodiments of the compound of formula IIa, n is 0 and m is 1, 2 or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2 or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2 or 3; or n is 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1; or n is 1 or 2 and m is 1, 2 or 3; or n is 1 or 2 and m is 1 or 2; or n is 1 or 2 and m is 1 or 3; or n is 1 or 2 and m is 2 or 3.

[0486] In some embodiments of the compound of formula IIb, r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0487] In some embodiments of compounds of formula IIa or IIb, X 1 Can be combined with R 2 Directly bonded carbon atoms form heterocycles. For example, X 1 It can form 4-, 5-, 6-, or 7-membered heterocyclic or heterobicyclic rings. In some embodiments of the compounds of formula I, X 1It can form substituted or unsubstituted oxetane, thiaalkyl, azirnealkyl, pyrrolyl, tetrahydrofuranyl, tetrahydrothiaalkyl, dihydropyranyl, tetrahydropyranyl, piperidinyl, oxetane, thiophenyl, azirnealkyl, azirnebicyclo[2.2.1]heptane or azirnebicyclo[2.2.2]octane, preferably azirnealkyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, more preferably azirnealkyl, pyrrolyl or piperidinyl.

[0488] In some embodiments of compounds of formula IIa or IIb, Ar 1 Having formula i or its pharmaceutically acceptable salt or stereoisomer, in R 4 It is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 heteroaryl, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 Aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 Alkoxyamino-carbonyl, aryl C 1-6 alkoxy or C6 aryl; R 5 R 5' R 6 R 6' They are hydrogen, -CF3 or halogens, and preferably F or Cl.

[0489] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having the formula i, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy-C6 aryl, C 1-4 Alkoxy-C 5-6 heteroaryl, amino C1-4 Alkyl, C 1-4 Alkylamino, C 1-4 Aminoalkyl-C6 aryl, C 1-4 Aminoalkyl-C6 heteroaryl, C 1-4 alkoxycarbonyl, C 1-4 Alkoxyaminocarbonyl or C6 aryl.

[0490] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having the formula i, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy-C6 aryl, C 1-4 Alkoxy-C 5-6 Heteroaryl or C6 aryl.

[0491] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having the formula i, R 4Typically, these are hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-propoxy, n-butoxy, isobutoxy, n-pentoxy, isopentyloxy, n-hexyloxy, isohexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, methoxymethyl, methoxyethyl, methoxypropyl, methyl oxybutyl, methoxypentyl, methoxyhexyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, propoxyhexyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, butoxyhexyl, pentomethyl, pentoethyl, pentopropyl, pentobutyl, pentopentyl, pentohexyl, hexyl oxymethyl, hexoxyethyl, hexoxypropyl, hexoxybutyl, hexoxypentyl, hexoxyhexyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentooxycarbonyl, hexoxycarbonyl, methoxyaminocarbonyl, ethoxyaminocarbonyl, propoxyaminocarbonyl, butoxyaminocarbonyl , pentoxyaminocarbonyl, hexoxyaminocarbonyl, phenylmethoxy, phenylethoxy, phenylpropoxy, phenylbutoxy, phenylpentoxy, phenylhexyloxy, m-fluorophenylmethoxy, m-fluorophenylphenylethoxy, m-fluorophenylphenylpropoxy, m-fluorophenylphenylbutoxy, m-fluorophenylphenylpentoxy, m-fluorophenylphenylhexyloxy, pyridylmethoxy, pyridylethoxy, pyridylpropoxy, pyridylbutoxy, pyridylpentoxy, pyridylhexyloxy, phenyl, pyridyl or naphthyl.

[0492] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having the formula i, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen. Preferably, R 4 It is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 heteroaryl, amino C1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 Aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 Alkoxyamino-carbonyl, aryl C 1-6 Alkyl or C6 aryl.

[0493] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having the formula i, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen. Preferably, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy-C6 aryl, C 1-4 Alkoxy-C 5-6 heteroaryl, amino C 1-4 Alkyl, C 1-4 Alkylamino, C 1-4 Aminoalkyl-C6 aryl, C 1-4 Aminoalkyl-C6 heteroaryl, C 1-4 alkoxycarbonyl, C 1-4 Alkoxyaminocarbonyl or C6 aryl.

[0494] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having formula i, Ar 1 This includes substituents that are not hydrogen, whether there are only one, two, or three. Therefore, R 4 R 5 R 5' R 6 or R 6' At least two of them can be hydrogen.

[0495] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having the formula i, R 1 It can be hydrogen and / or R 2 It can be methyl or it can be with R 3 -(CH2)- or -(CH2)2- form a ring.

[0496] In some embodiments of compounds of formula IIa or IIb, Ar 1 Having formula ii-1 or its pharmaceutically acceptable salt or stereoisomer in R 4 It is hydrogen, F, or Cl; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3 or halogen, preferably F or Cl.'

[0497] In some embodiments of compounds of formula IIa or IIb, Ar 1 Having formula ii-2, ii-3 or ii-4 or their pharmaceutically acceptable salts or stereoisomers. in X 2 It is O, NH, or NMe; X 3 It is C or N; o is 0 or 1; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3, or halogen, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F.

[0498] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having formulas ii-1, ii-2, ii-3 or ii-4, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen.

[0499] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 It has the formula ii-1, ii-2, ii-3 or ii-4, where o is 1.

[0500] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having formulas ii-1, ii-2, ii-3 or ii-4, R 5 Is F and / or R 6 It is either F or Cl.

[0501] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having formulas ii-1, ii-2, ii-3 or ii-4, R 2 Is it methyl or related to R? 3 -(CH2)- or -(CH2)2- form a ring.

[0502] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 If X has the formula ii-1, ii-2, ii-3 or ii-4, then X 3 If it is N, then R 7 Is it hydrogen and / or if X 3 If it is CH, then R 7 It is F.

[0503] In some embodiments of the compound of formula IIa, Ar 1 It has the following formulas: ii-1, ii-2, ii-3, or ii-4, where n is 0 and m is 1, 2, or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2, or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2, or 3; or n is 2 and m is 1 or 2; or n is 0, 1, or 2 and m is 1 or 2; or n is 0, 1, or 2 and m is 1; or n is 1 or 2 and m is 1, 2, or 3; or n is 1 or 2 and m is 1 or 2; or n is 1 or 2 and m is 1 or 3; or n is 1 or 2 and m is 2 or 3.

[0504] In some embodiments of the compound of formula IIb, where Ar 1 It has the following formulas: ii-1, ii-2, ii-3 or ii-4, where r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0505] In some embodiments, X 2 It is O that makes Ar 1 Having formula ii-1a or a pharmaceutically acceptable salt or stereoisomer thereof in R 4 It is hydrogen, F, or Cl; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3 or halogen, preferably F or Cl.'

[0506] In some embodiments, X2 It is O that makes Ar 1 Having formula ii-2a, ii-3a or ii-4a or a pharmaceutically acceptable salt or stereoisomer thereof in X 3 It is CH or N, preferably N; o is 0 or 1; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3, or halogen, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F.

[0507] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having the formula ii-1a, ii-2a, ii-3a or ii-4a, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen.

[0508] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 It has the formula ii-1a, ii-2a, ii-3a or ii-4a, where o is 1.

[0509] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having the formula ii-1a, ii-2a, ii-3a or ii-4a, R 5 Is F and / or R 6 It is either F or Cl.

[0510] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having the formula ii-1a, ii-2a, ii-3a or ii-4a, if X 3 If it is N, then R 7 Is it hydrogen and / or if X 3 If it is CH, then R 7 It is F.

[0511] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having the formula ii-1a, ii-2a, ii-3a or ii-4a, R 2 Is it methyl or related to R? 3-(CH2)- or -(CH2)2- form a ring.

[0512] In some embodiments of the compound of formula IIa, Ar 1 It has the following formulas: ii-a-1, ii-2a, ii-3a, or ii-4a, where n is 0 and m is 1, 2, or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2, or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2, or 3; or n is 2 and m is 1 or 2; or n is 0, 1, or 2 and m is 1 or 2; or n is 0, 1, or 2 and m is 1; or n is 1 or 2 and m is 1, 2, or 3; or n is 1 or 2 and m is 1 or 2; or n is 1 or 2 and m is 1 or 3; or n is 1 or 2 and m is 2 or 3.

[0513] In some embodiments of the compound of formula IIb, where Ar 1 It has the following formulas: ii-1a, ii-2a, ii-3a or ii-4a, where r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0514] In some embodiments of compounds of formula IIa or IIb, X 3 It is N such that Ar 1 Having formula ii-1b or a pharmaceutically acceptable salt or stereoisomer thereof in R 4 It is hydrogen, F, or Cl; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3 or halogen, preferably F or Cl.'

[0515] In some embodiments of compounds of formula IIa or IIb, X 3 It is N such that Ar 1 Having the formula ii-2b, ii-3b, ii-4b, ii-5b or their pharmaceutically acceptable salts or stereoisomers, in X 2 It is O, NH or NMe, preferably O; o is 0 or 1; R 5 R 5 '、R 6 R6 'Independently hydrogen, -CF3, or halogen, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F.

[0516] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having the formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen.

[0517] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 It has the formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, where o is 1.

[0518] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having the formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 5 Is F and / or R 6 It is either F or Cl.

[0519] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having the formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 7 It is F.

[0520] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having the formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 2 Is it methyl or related to R? 3 -(CH2)- or -(CH2)2- form a ring.

[0521] In some embodiments of the compound of formula IIa, Ar 1It has the following formulas: ii-1b, ii-2b, ii-3b, or ii-4b, where n is 0 and m is 1, 2, or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2, or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2, or 3; or n is 2 and m is 1 or 2; or n is 0, 1, or 2 and m is 1 or 2; or n is 0, 1, or 2 and m is 1; or n is 1 or 2 and m is 1, 2, or 3; or n is 1 or 2 and m is 1 or 2; or n is 1 or 2 and m is 1 or 3; or n is 1 or 2 and m is 2 or 3.

[0522] In some embodiments of the compound of formula IIb, where Ar 1 It has the following formulas: ii-1b, ii-2b, ii-3b or ii-4b, where r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0523] In some embodiments of compounds of formula IIa or IIb, Ar 1 Having formula ii-1c or a pharmaceutically acceptable salt or stereoisomer thereof in R 4 It is hydrogen, F, or Cl; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3 or halogen, preferably F or Cl.'

[0524] In some embodiments of compounds of formula IIa or IIb, X 2 It is O, and X 3 It is N such that Ar 1 Having the formula ii-2c, ii-3c, ii-4c, ii-5c, or their pharmaceutically acceptable salts or stereoisomers, in o is 0 or 1; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3, or halogen, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F.

[0525] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having the formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen.

[0526] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 It has the formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, where o is 1.

[0527] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having the formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 5 Is F and / or R 6 It is either F or Cl.

[0528] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having the formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 7 It is F.

[0529] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having the formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 2 Is it methyl or related to R? 3 -(CH2)- or -(CH2)2- form a ring.

[0530] In some embodiments of the compound of formula IIa, Ar 1 It has the following formulas: ii-1c, ii-2c, ii-3c or ii-4c, where n is 0 and m is 1, 2 or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2 or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2 or 3; or n is 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1; or n is 1 or 2 and m is 1, 2 or 3; or n is 1 or 2 and m is 1 or 2; or n is 1 or 2 and m is 1 or 3; or n is 1 or 2 and m is 2 or 3.

[0531] In some embodiments of the compound of formula IIb, where Ar 1It has the following formulas: ii-1c, ii-2c, ii-3c or ii-4c, where r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0532] In some embodiments of compounds of formula IIa or IIb, Ar 1 Having formula iii-1 or its pharmaceutically acceptable salt or stereoisomer, in R 4 It is hydrogen or halogen, preferably F or Cl; R 5 R 6 They are hydrogen, -CF3 or halogens, and preferably F or Cl.

[0533] In some embodiments of compounds of formula IIa or IIb, Ar 1 Having formula iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7 or their pharmaceutically acceptable salts or stereoisomers, in X 3 It is CH or N, preferably N; o is 0 or 1; R 5 R 6 They are hydrogen, -CF3, or halogens, each independent of the other, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F.

[0534] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having equations iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen.

[0535] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 If it has the formulas iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, then o is 1.

[0536] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1Having equations iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, R 5 Is F and / or R 6 It is either F or Cl.

[0537] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 If X has equations iii-1, iii-2, iii-3, or iii-4, then X 3 If it is N, then R 7 Is it hydrogen and / or if X 3 If it is CH, then R 7 It is F.

[0538] In some examples of compounds of formula IIa or IIb, wherein Ar 1 Having equations iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, R 2 Is it methyl or related to R? 3 -(CH2)- or -(CH2)2- form a ring.

[0539] In some embodiments of the compound of formula IIa, Ar 1 It has equations iii-1, iii-2, ii-3, or iii-4, where n is 0 and m is 1, 2, or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2, or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2, or 3; or n is 2 and m is 1 or 2; or n is 0, 1, or 2 and m is 1 or 2; or n is 0, 1, or 2 and m is 1; or n is 1 or 2 and m is 1, 2, or 3; or n is 1 or 2 and m is 1 or 2; or n is 1 or 2 and m is 1 or 3; or n is 1 or 2 and m is 2 or 3.

[0540] In some embodiments of the compound of formula IIb, where Ar 1 It has equations iii-1, iii-2, iii-3 or iii-4, where r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0541] In some embodiments, X 3 It is N such that Ar 1 It has formula iv-2, iv-3 or iv-4, iv-5, iv-6 or iv-7, or X 3 It is C that makes Ar 1 It has formula IV-8 or IV-9, in o is 0 or 1; R 5 R 6 They are hydrogen, -CF3, or halogens, each independent of the other, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F.

[0542] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having formulas iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen.

[0543] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 If it has iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, o is 1.

[0544] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having formulas iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, R 5 Is F and / or R 6 It is either F or Cl.

[0545] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 With IV-2, IV-3 or IV-4, IV-5, IV-6, IV-7, IV-8 or IV-9, R 7 It is F.

[0546] In some embodiments of compounds of formula IIa or IIb, wherein Ar 1 Having formulas iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, R 2 Is it methyl or related to R? 3 -(CH2)- or -(CH2)2- form a ring.

[0547] In some embodiments of the compound of formula IIa, Ar 1Having formulas iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, where n is 0 and m is 1, 2 or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2 or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2 or 3; or n is 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1; or n is 1 or 2 and m is 1, 2 or 3; or n is 1 or 2 and m is 1 or 2; or n is 1 or 2 and m is 1 or 3; or n is 1 or 2 and m is 2 or 3.

[0548] In some embodiments of the compound of formula IIb, where Ar 1 It has the following formulas: iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, where r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0549] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof having formula III. in R 1 It is H or F; Ar 1 It is a 6-membered aryl group that is either unsubstituted or substituted with one or more members selected from the group consisting of: halogens, -CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 heteroaryl, amino, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 Aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 alkoxyaminocarbonyl, aryl C 1-6 alkoxy or C6 aryl; Z is selected from In some embodiments of the compound of formula III, R 1 It is hydrogen.

[0550] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof having formula IV. in R 1 It is H or F; R 4 It is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 heteroaryl, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 Aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 Alkoxyamino-carbonyl, aryl C 1-6 alkoxy or C6 aryl; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3, or halogen, preferably F or Cl; Z is selected from In some embodiments of the formula IV compound, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy-C6 aryl, C 1-4 Alkoxy-C 5-6 heteroaryl, amino C 1-4 Alkyl, C 1-4 Alkylamino, C 1-4 Aminoalkyl-C6 aryl, C 1-4 Aminoalkyl-C6 heteroaryl, C 1-4alkoxycarbonyl, C 1-4 Alkoxyaminocarbonyl or C6 aryl.

[0551] In some embodiments of the compound of formula VI, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy-C6 aryl, C 1-4 Alkoxy-C 5-6 Heteroaryl or C6 aryl.

[0552] In some embodiments of the formula IV compound, R 4 Typically, these are hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-propoxy, n-butoxy, isobutoxy, n-pentoxy, isopentyloxy, n-hexyloxy, isohexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, methoxymethyl, methoxyethyl, methoxypropyl, methyl oxybutyl, methoxypentyl, methoxyhexyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, propoxyhexyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, butoxyhexyl, pentomethyl, pentoethyl, pentopropyl, pentobutyl, pentopentyl, pentohexyl, hexyl oxymethyl, hexoxyethyl, hexoxypropyl, hexoxybutyl, hexoxypentyl, hexoxyhexyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentooxycarbonyl, hexoxycarbonyl, methoxyaminocarbonyl, ethoxyaminocarbonyl, propoxyaminocarbonyl, butoxyaminocarbonyl , pentoxyaminocarbonyl, hexoxyaminocarbonyl, phenylmethoxy, phenylethoxy, phenylpropoxy, phenylbutoxy, phenylpentoxy, phenylhexyloxy, m-fluorophenylmethoxy, m-fluorophenylphenylethoxy, m-fluorophenylphenylpropoxy, m-fluorophenylphenylbutoxy, m-fluorophenylphenylpentoxy, m-fluorophenylphenylhexyloxy, pyridylmethoxy, pyridylethoxy, pyridylpropoxy, pyridylbutoxy, pyridylpentoxy, pyridylhexyloxy, phenyl, pyridyl or naphthyl.

[0553] In some embodiments of the formula IV compound, R5和R 6 are independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen. Preferably, R 4 It is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 heteroaryl, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 Aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 Alkoxyamino-carbonyl, aryl C 1-6 Alkyl or C6 aryl.

[0554] In some embodiments of the compound of formula IV, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen. Preferably, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy-C6 aryl, C 1-4 Alkoxy-C 5-6 heteroaryl, amino C 1-4 Alkyl, C 1-4 Alkylamino, C 1-4 Aminoalkyl-C6 aryl, C 1-4 Aminoalkyl-C6 heteroaryl, C 1-4 alkoxycarbonyl, C 1-4 Alkoxyaminocarbonyl or C6 aryl.

[0555] In some embodiments of the formula IV compound, Ar 1 This includes substituents that are not hydrogen, whether there are only one, two, or three. Therefore, R 4 R 5 R 5' R 6or R 6' At least two of them can be hydrogen.

[0556] In some embodiments of the formula IV compound, R 1 It could be hydrogen.

[0557] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof having the formula V-1. in R 1 It is H or F; R 4 It is hydrogen or halogen, preferably F or Cl; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3, or halogen, preferably F or Cl; Z is selected from In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof having the formula V-2, V-3, or V-4. in X 2 It is O, NH, or NMe; X 3 It is CH or N; R 1 It is H or F; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3, or halogen, preferably F or Cl; o is 0 or 1; R 7 It is hydrogen or halogen, preferably F; Z is selected from In some embodiments of compounds of formula V-1, V-2, V-3, or V-4, R 4 It is hydrogen, chlorine, or fluorine.

[0558] In some embodiments of compounds of formula V-1, V-2, V-3, or V-4, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R5' and R 6' It is hydrogen. Preferably, R 4 It is hydrogen, chlorine, or fluorine.

[0559] In some embodiments of compounds of formula V-1, V-2, V-3, or V-4, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen. Preferably, R 4 It is hydrogen, chlorine, or fluorine.

[0560] In some embodiments of compounds of formula V-1, V-2, V-3, or V-4, Ar 1 This includes substituents that are not hydrogen, whether there are only one, two, or three. Therefore, R 4 R 5 R 5' R 6 or R 6' At least two of them can be hydrogen.

[0561] In some embodiments of compounds of formula V-1, V-2, V-3, or V-4, if X 3 If it is N, then R 7 Is it hydrogen and / or if X 3 If it is CH, then R 7 It is F.

[0562] In some embodiments of compounds of formula V-1, V-2, V-3 or V-4, o is 1.

[0563] In some embodiments of compounds of formula V-1, V-2, V-3, or V-4, R 1 It could be hydrogen.

[0564] In some embodiments of compounds of formula V-2, V-3, or V-4, X 2 It is O, producing compounds of formula V-2a, V-3a or V-4a or their pharmaceutically acceptable salts or stereoisomers. in X 3 It is CH or N; R 1 It is H or F; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3, or halogen, preferably F or Cl; o is 0 or 1; R7 It is hydrogen or halogen, preferably F; Z is selected from In some embodiments of compounds of formula V-1, V-2a, V-3a, or V-4a, R 4 It is hydrogen, fluorine, or chlorine.

[0565] In some embodiments of compounds of formula V-1, V-2a, V-3a, or V-4a, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen. Preferably, R 4 It is hydrogen, chlorine, or fluorine.

[0566] In some embodiments of compounds of formula V-1, V-2a, V-3a, or V-4a, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen. Preferably, R 4 It is hydrogen, chlorine, or fluorine.

[0567] In some embodiments of compounds of formula V-1, V-2a, V-3a, or V-4a, Ar 1 This includes substituents that are not hydrogen, whether there are only one, two, or three. Therefore, R 4 R 5 R 5' R 6 or R 6' At least two of them can be hydrogen.

[0568] In some embodiments of compounds of formula V-1, V-2a, V-3a, or V-4a, if X 3 If it is N, then R 7 Is it hydrogen and / or if X 3 If it is CH, then R 7 It is F.

[0569] In some embodiments of compounds of formula V-1, V-2a, V-3a or V-4a, o is 1.

[0570] In some embodiments of compounds of formula V-1, V-2a, V-3a, or V-4a, R 1 It could be hydrogen.

[0571] In some embodiments of compounds of formula V-2, V-3, or V-4, X 3It is N, producing compounds of formula V-2b, V-3b, V-4b or their pharmaceutically acceptable salts or stereoisomers, or X. 3 It is C, a compound of formula V-5b or a pharmaceutically acceptable salt or stereoisomer thereof. in X 2 It is O, NH, or NMe; R 1 It is H or F; R 5 R 5 '、R 6 R 6 'Independently hydrogen, -CF3, or halogen, preferably F or Cl; o is 0 or 1; R 7 It is hydrogen or halogen, preferably F; Z is selected from In some embodiments of compounds of formula V-1, V-2b, V-3b, V-4b, or V-5b, R 4 It consists of hydrogen, fluorine, and chlorine.

[0572] In some embodiments of compounds of formula V-1, V-2b, V-3b, V-4b, or V-5b, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen. Preferably, R 4 It is hydrogen, chlorine, or fluorine.

[0573] In some embodiments of compounds of formula V-1, V-2b, V-3b, V-4b, or V-5b, R 5 and R 6 Each of these can be independently hydrogen, -CF3, F, or Cl, and R 5' and R 6' It is hydrogen. Preferably, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkylamino, C 1-4 alkoxycarbonyl, C 1-4 alkoxyaminocarbonyl, aryl C1-4 Alkoxy, heteroaryl C 1-4 Alkyl or aryl.

[0574] In some embodiments of compounds of formula V-1, V-2b, V-3b, V-4b, or V-5b, Ar 1 This includes substituents that are not hydrogen, whether there are only one, two, or three. Therefore, R 4 R 5 R 5' R 6 or R 6' At least two of them can be hydrogen.

[0575] In some embodiments V-2b, V-3b, V-4b, or V-5b, o is 1.

[0576] In some embodiments of compounds of formula V-1, V-2b, V-3b, V-4b, or V-5b, R 7 It is F.

[0577] In some embodiments of compounds of formula V-1, V-2b, V-3b, V-4b, or V-5b, R 1 It could be hydrogen.

[0578] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof having the formula VI-1. in R 1 It is H or F; R 4 It is hydrogen or halogen, preferably F or Cl; R 5 R 6 They are hydrogen, -CF3, or halogens, each independent of the other, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F; Z is selected from In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof having the formula VI-2, VI-3, or VI-4. in X 2 It is O, NH, or NMe; X 3 It is CH or N; R 1 It is H or F; o is 0 or 1; R 5 R 6 They are hydrogen, -CF3, or halogens, each independent of the other, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F; Z is selected from In some embodiments of compounds of formula VI-1, VI-2, VI-3, or VI-4, R 4 It is hydrogen, chlorine, or fluorine.

[0579] In some embodiments of compounds of formula VI-1, VI-2, VI-3 or VI-4, o is 1.

[0580] In some embodiments of compounds of formula VI-1, VI-2, VI-3, or VI-4, R 5 Is F and / or R 6 It is either F or Cl.

[0581] In some embodiments of compounds of formula VI-1, VI-2, VI-3, or VI-4, if X 3 If it is N, then R 7 Is it hydrogen and / or if X 3 If it is CH, then R 7 It is F.

[0582] In some embodiments of compounds of formula VI-1, VI-2, VI-3, or VI-4, R 1 It could be hydrogen.

[0583] In some embodiments of compounds of formula VI-2, VI-3, or VI-4, X 2 It is O, producing compounds of formula VI-2a, VI-3a or VI-4a or their pharmaceutically acceptable salts or stereoisomers. in X 3 It is CH or N; R 1 It is H or F; R 5 R 6 They are hydrogen, -CF3, or halogens, each independent of the other, preferably F or Cl; o is 0 or 1; R 7 It is hydrogen or halogen, preferably F; Z is selected from In some embodiments of compounds of formula VI-1, VI-2a, VI-3a, or VI-4a, R 4 It is hydrogen, fluorine, or chlorine.

[0584] In some embodiments of compounds of formula VI-1, VI-2a, VI-3a or VI-4a, o is 1.

[0585] In some embodiments of compounds of formula VI-1, VI-2a, VI-3a, or VI-4a, R 5 Is F and / or R 6 It is either F or Cl.

[0586] In some embodiments of compounds of formula VI-1, VI-2a, VI-3a, or VI-4a, if X 3 If it is N, then R 7 Is it hydrogen and / or if X 3 If it is CH, then R 7 It is F.

[0587] In some embodiments of compounds of formula VI-1, VI-2a, VI-3a, or VI-4a, R 1 It could be hydrogen.

[0588] In some embodiments of compounds of formula VI-2, VI-3, or VI-4, X 3 It is N, producing compounds of formula VI-2b, VI-3b, VI-4b or their pharmaceutically acceptable salts or stereoisomers, or X. 3 It is C, a compound of formula VI-5b or a pharmaceutically acceptable salt or stereoisomer thereof. in X 2 It is O, NH, or NMe; R 1 It is H or F; R 5 R 6 They are hydrogen, -CF3, or halogens, each independent of the other, preferably F or Cl; o is 0 or 1; R 7 It is hydrogen or halogen, preferably F; Z is selected from In some embodiments of compounds of formula VI-1, VI-2b, VI-3b, VI-4b, or VI-5b, R 4 It is hydrogen, fluorine, or chlorine.

[0589] In some embodiments of compounds of formula VI-1, VI-2b, VI-3b, VI-4b, or VI-5b, o is 1.

[0590] In some embodiments of compounds of formula VI-1b, VI-2b, VI-3b, VI-4b, or VI-5b, R 5 Is F and / or R 6 It is either F or Cl.

[0591] In some embodiments of compounds of formula VI-1, VI-2b, VI-3b, VI-4b, or VI-5b, R 7 It is F.

[0592] In some embodiments of compounds of formula VI-1, VI-2b, VI-3b, VI-4b, or VI-5b, R 1 It could be hydrogen.

[0593] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof having the formula VII-1. in R 1 It is H or F, preferably H; R 4 It is hydrogen or halogen, preferably F or Cl; R 5 R 6 They are hydrogen, -CF3, or halogens, each independent of the other, preferably F or Cl; Z is selected from In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof having the formula VII-2, VII-3 or VII-4, VII-5, VII-6, VII-7, VII-8 or VII-9. in R 1 It is H or F, preferably H; o is 0 or 1; R 5 R 6 They are hydrogen, -CF3, or halogens, each independent of the other, preferably F or Cl; R 7 It is hydrogen or halogen, preferably F; Z is selected from In some embodiments of compounds of formula VII-1, VII-2, VII-3 or VII-4, VII-5, VII-6, VII-7, VII-8 or VII-9, R 4 It is hydrogen, fluorine, or chlorine.

[0594] In some embodiments of compounds of formula VII-1, VII-2, VII-3 or VII-4, VII-5, VII-6, VII-7, VII-8 or VII-9, o is 1.

[0595] In some embodiments of compounds of formulas VII-1, VII-2, VII-3 or VII-4, VII-5, VII-6, VII-7, VII-8 or VII-9, R 5 It is F and / or R. 6 It is either F or Cl.

[0596] In some embodiments of compounds of formula VII-1, VII-2, VII-3 or VII-4, VII-5, VII-6, VII-7, VII-8 or VII-9, R 7 It is F.

[0597] In some embodiments of compounds of formulas VII-1, VII-2, VII-3 or VII-4, VII-5, VII-6, VII-7, VII-8 or VII-9, R 1 It could be hydrogen.

[0598] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2, their pharmaceutically acceptable salts, and their stereoisomers.

[0599] In some embodiments, the compounds are selected from the compounds described in Tables 1 and 2 and their pharmaceutically acceptable salts.

[0600] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2.

[0601] In some embodiments, the compound is selected from the compounds described in Table 1, their pharmaceutically acceptable salts, and their stereoisomers.

[0602] In some embodiments, the compounds are selected from the compounds described in Table 1 and their pharmaceutically acceptable salts.

[0603] In some embodiments, the compound is selected from the compounds described in Table 1.

[0604] In some embodiments, the compound is selected from the compounds described in Table 2, their pharmaceutically acceptable salts, and their stereoisomers.

[0605] In some embodiments, the compounds are selected from the compounds described in Table 2 and their pharmaceutically acceptable salts.

[0606] In some embodiments, the compound is selected from the compounds described in Table 2.

[0607] Table 1

[0608] Table 2

[0609] In some aspects, this disclosure provides a compound that is an isotopic derivative (e.g., an isotopically labeled compound) of any of the compounds of the formula disclosed herein.

[0610] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Tables 1 and 2, a pharmaceutically acceptable salt thereof, and a stereoisomer thereof.

[0611] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Tables 1 and 2 and its pharmaceutically acceptable salt.

[0612] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Tables 1 and 2.

[0613] It should be understood that any of a variety of techniques recognized in the art can be used to prepare isotope derivatives. For example, isotope derivatives can generally be prepared by performing the schemes and / or procedures disclosed in the examples described herein using an isotopically labeled reagent instead of a non-isotopically labeled reagent.

[0614] In some embodiments, the isotope derivative is a deuterium-labeled compound.

[0615] In some embodiments, the isotope derivative is a deuterium-labeled compound of any of the compounds of the formulas disclosed herein.

[0616] In some embodiments, the compound is a deuterium-labeled compound of any of the compounds described in Tables 1 and 2, its pharmaceutically acceptable salt, and its stereoisomer.

[0617] In some embodiments, the compound is a deuterium-labeled compound of any of the compounds described in Tables 1 and 2 and its pharmaceutically acceptable salt.

[0618] In some embodiments, the compound is a deuterium-labeled compound of any of the compounds described in Tables 1 and 2.

[0619] In some embodiments, the compound is selected from the compounds described in Table 3, their pharmaceutically acceptable salts, and their stereoisomers.

[0620] In some embodiments, the compounds are selected from the compounds described in Table 3 and their pharmaceutically acceptable salts.

[0621] In some embodiments, the compound is one of the compounds described in Table 3.

[0622] Table 3

[0623] It is understood that deuterium-labeled compounds include deuterium atoms with a deuterium abundance that is substantially greater than the natural abundance of deuterium, which is 0.015%.

[0624] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium doping at each deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping). As used herein, the term "deuterium enrichment factor" refers to the ratio between the deuterium abundance and the natural abundance of deuterium.

[0625] It should be understood that deuterium-labeled compounds can be prepared using any of a variety of techniques recognized in the art. For example, deuterium-labeled compounds can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein, replacing the non-deuterium-labeled reagents with deuterium-labeled reagents.

[0626] Compounds of the present invention containing the aforementioned deuterium atoms, or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present invention. Further, deuterium (i.e., 2 H) substitution can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements.

[0627] The compounds disclosed herein may contain one or more asymmetric centers in their molecules. Compounds without specified stereochemistry should be understood to include all optical isomers (e.g., diastereomers, enantiomers, etc.) in pure or substantially pure form, as well as mixtures thereof (e.g., racemic mixtures, or mixtures rich in enantiomers). How to prepare such optically active forms is well known in the art (e.g., by recrystallization of racemic forms, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using chiral stationary phases and other methods).

[0628] The compounds can be isotopically labeled, for example, compounds containing various isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine, or chlorine. The disclosed compounds can exist as tautomers and mixtures, and separate, individual tautomers are contemplated. Additionally, some compounds may exhibit polymorphism.

[0629] The compounds disclosed herein comprise their free form as well as pharmaceutically acceptable salts and stereoisomers. Pharmaceutically acceptable salts include all typical pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this disclosure containing basic or acidic moieties by conventional chemical methods, see, for example, Berge et al., “Pharmaceutical Salts”, J. Pharm. ScL, 1977:66:1-19.

[0630] For example, pharmaceutically acceptable salts of basic compounds include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, and nitric acid; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, dihydroxynaphthyl acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylates, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethanesulfonic acid, and trifluoroacetic acid. Pharmaceutically acceptable salts of acidic compounds include those derived from inorganic bases, including aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, and zinc. Salts derived from pharmaceutically acceptable organic bases include primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and salts from basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, heparin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0631] The compounds of this disclosure can exist in solid, i.e., crystalline or amorphous form (optionally as solvates) or liquid form. In the solid state, they can exist as mixtures thereof or as mixtures thereof. In crystalline solvates, solvent molecules are incorporated into the crystal lattice during crystallization. The formation of solvates can involve 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 known as “hydrates”). It is well known that crystalline forms (and their solvates) can exhibit polymorphism, i.e., exist in different crystal structures known as “polymorphs”, which have the same chemical composition but differ in the packing, geometric arrangement, and other descriptive properties of the crystalline solid. Therefore, polymorphs may have different physical properties that can be used for identification, such as shape, density, hardness, deformability, stability, and solubility, and may exhibit different melting points, IR spectra, and X-ray powder diffraction patterns. For example, such different polymorphs can be produced during the preparation of the compounds of this disclosure by changing or adjusting the reaction conditions or reagents.

[0632] In some aspects, this disclosure also provides methods for preparing the compounds of this disclosure. Typically, they are prepared according to the synthetic methods shown in the experimental section.

[0633] It should be understood that the synthetic methods of this disclosure can accommodate a wide variety of functional groups, and therefore a wide variety of substituted starting materials can be used. The methods substantially provide the desired final compound at or near the end of the process, but in some cases may require further conversion of the compound into its pharmaceutically acceptable salt.

[0634] It should be understood that the compounds disclosed herein can be prepared in various ways using commercially available starting materials, compounds known in the literature or derived from readily prepared intermediates, and by employing standard synthetic methods and procedures known to those skilled in the art or obvious to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules, as well as for the transformation and manipulation of functional groups, are available from relevant scientific literature or from standard textbooks in the field. While not limited to any one or more sources, classic texts incorporated herein, such as Smith, MB, March, J., *March Advanced Organic Chemistry: Reactions, Mechanisms, and Structures*, are also cited. March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure ), 5th Edition, John Willie & Sons: New York, 2001; and Greene, TW, Wuts, PGM, Protecting Groups in Organic Synthesis ( Protective Groups in Organic Synthesis ), 3rd edition, John Willie & Sons: New York, 1999; and La Roch's Comprehensive Organic Transformation ( Comprehensive Organic Transformations(VCH Publishers Inc., (1989); L. Fieser and M. Fieser, Fisher and Fisher's Reagents for Organic Synthesis) Fieser and Fieser's Reagents for Organic Synthesis John Willie & Sons, (1994); and L. Paquette, ed., *Encyclopedia of Reagents for Organic Synthesis*. Encyclopedia of Reagents for Organic Synthesis John Willie & Sons (1995) is a known and widely accepted reference textbook on organic synthesis in the field of this art.

[0635] Those skilled in the art will notice that the order of certain steps, such as the introduction and removal of protecting groups, can be altered during the reaction sequence and synthetic scheme described herein. Those skilled in the art will recognize that certain groups may require protection from the effects of reaction conditions by using protecting groups. Protecting groups can also be used to distinguish similar functional groups in a molecule. A list of protecting groups and how to introduce and remove these groups can be found in Greene, TW, Wuts, PGM, *Protecting Groups in Organic Synthesis*, 3rd Edition, John Wiley & Sons: New York, 1999.

[0636] Bioassay Once compounds designed, selected, and / or optimized using the methods described herein are generated, they can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds possess biological activity. For example, molecules can be characterized by routine assays, including but not limited to those described below, to determine whether these molecules possess predicted activity, binding activity, and / or binding specificity.

[0637] Furthermore, high-throughput screening can be used to accelerate analyses utilizing such assays. Therefore, the activity of molecules described herein can be rapidly screened using techniques known in the art. For example, general methods for performing high-throughput screening are described in Devlin (1998) High-throughput Screening (… High Throughput Screening In Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays may use one or more different assay techniques, including, but not limited to, those described below.

[0638] Various in vitro or in vivo bioassays may be suitable for detecting the effects of the compounds disclosed herein. These in vitro or in vivo bioassays may include, but are not limited to, enzyme activity assays, electrophoretic mobility variation assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0639] Pharmaceutical Composition In some aspects, this disclosure further provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of this disclosure or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers and / or excipients (also referred to as diluents). Excipients are “acceptable” in the sense that they are compatible with the other components of the formulation and harmless to their recipient (i.e., the patient). As used herein, the term “therapeutically effective amount” refers to the amount of the compound of this disclosure (either in its own form or in the form of a pharmaceutical composition) that effectively produces some desired therapeutic effect.

[0640] Pharmaceutical compositions may be in unit dose form, containing a predetermined amount of the disclosed compound per unit dose. Such units may contain a therapeutically effective dose of the disclosed compound or a salt thereof, or a portion thereof, such that multiple unit dosage forms can be administered at a given time to achieve a desired therapeutically effective dose. Preferred unit dose formulations are those containing a daily dose or sub-dose of the disclosed compound or a salt thereof, or a suitable portion thereof.

[0641] The compounds disclosed herein may be administered in any acceptable manner in solid or liquid form, including (1) oral administration, e.g., oral administration (aqueous or non-aqueous solutions or suspensions); tablets, e.g., tablets intended for absorption via the buccal, sublingual and systemic routes; pills; powders; granules; pastes applied to the tongue; (2) parenteral administration, e.g., as a sterile solution or suspension or a formulation for sustained release via subcutaneous, intramuscular, intravenous or epidural injection; (3) topical application, e.g., as a cream, ointment or controlled-release patch or spray applied to the skin; (4) intravaginal or intrauterine administration, e.g., as a pessary, cream or foam; (5) sublingual; (6) ocular; (7) percutaneous; or (8) nasal; (9) pulmonary; or (10) intrathecal injection.

[0642] As used herein, the phrase “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or medium, such as liquid or solid fillers, diluents, excipients, manufacturing aids (e.g., lubricants, magnesium talc, calcium stearate, or zinc or stearic acid), or solvent encapsulation materials, that is involved in carrying or transporting a subject compound from one part of an organ or body to another part of another organ or body. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and harmless to the patient. Some examples of materials that 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 gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil and cottonseed oil. (10) Safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (11) Diols, such as propylene glycol; (12) Polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (13) Esters, such as ethyl oleate and ethyl laurate; (14) Agar; (15) Buffers, such as magnesium hydroxide and aluminum hydroxide; (16) Alginate; (17) Atherless water; (18) Isotonic saline; (19) Ringer's solution; (20) Ethanol; (21) pH buffer solution; (22) Polyesters, polycarbonates, and / or polyanhydrides; and (23) Other non-toxic and compatible substances used in pharmaceutical compositions.

[0643] Such compositions may contain additional components conventional to pharmaceutical preparations, such as wetting agents, emulsifiers and lubricants, such as sodium dodecyl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring and aroma agents, preservatives and antioxidants, pH adjusters, swelling agents and other active agents. Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0644] Such compositions can be prepared by any method known in the art, for example by associating the active ingredient with one or more carriers and / or excipients. Different compositions and examples of carriers and / or excipients are well known to those skilled in the art and are described in detail, for example, in: *Remington: The Science and Practice of Pharmacy.*, Pharmaceutical Press, 2013; Rowe, Sheskey, Quinn: *Handbook of Pharmaceutical Excipients*, Pharmaceutical Press, 2009. Excipients that can be used to prepare pharmaceutical compositions may include one or more of the following: buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavoring agents, diluents, and other known additives to provide a composition suitable for application selection.

[0645] As indicated above, the compounds disclosed herein may be in solid or liquid form and may be administered via various routes in any convenient manner, such as tablets, powders, capsules, solutions, dispersants, suspensions, syrups, sprays, suppositories, gels, emulsions, pastes, etc.

[0646] In the solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, pellets, etc.) disclosed herein for oral administration, the 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 starch, lactose, sucrose, glucose, mannitol, and / or silica; (2) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, such as glycerin; (4) disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, seaweed starch, etc. Alginic acid, certain silicates, and sodium carbonate; (5) solution blocking agents, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as cetyl alcohol, glyceryl monostearate, and nonionic surfactants; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) colorants; and (11) controlled-release agents, such as crospovidone or ethyl cellulose. In the case of capsules, tablets, and pills, the pharmaceutical composition may also include a buffer. Similar types of solid compositions may also use excipients such as lactose or toffee and high molecular weight polyethylene glycol as fillers in soft-shell gelatin capsules and hard-shell gelatin capsules. Tablets may be prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium glycolate starch or cross-linked sodium carboxymethyl cellulose), surfactants, or dispersants. Molded tablets can be manufactured by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms (such as sugar-coated pills, capsules, pellets, and granules) of the pharmaceutical compositions disclosed herein can optionally be coated or prepared using coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. The dosage forms can also be formulated using, for example, different proportions of hydroxypropyl methylcellulose to allow sustained or controlled release of the active ingredient to provide a desired release profile, other polymer matrices, liposomes, and / or microspheres. The dosage forms can be formulated for rapid release, for example, lyophilized. The dosage form can be sterilized, for example, by filtration through a bacterial trap or by incorporating a sterilizing agent in the form of a sterile solid composition soluble in sterile water or some other sterile injectable medium, and then used immediately. These compositions may also optionally contain an emulsifier and their composition may allow for the optional delayed release of one or more active ingredients, either only or preferably in a portion of the gastrointestinal tract. Examples of encapsulation compositions that can be used include polymers and waxes.The active ingredient may also be in microencapsulated form, and if appropriate, may contain one or more of the excipients mentioned above.

[0647] Liquid dosage forms for oral administration of the compounds disclosed herein comprise pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. Oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, aroma agents, and preservatives.

[0648] In the form of a suspension, the compound may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar-agar and tragacanth gum and mixtures thereof.

[0649] Dosage forms of the pharmaceutical compositions of this disclosure for rectal or vaginal application include suppositories, which are prepared by mixing one or more compounds of this disclosure with one or more suitable non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylates, and are solid at room temperature but liquid at body temperature and thus melt in the rectal or vaginal cavity to release the active compound. Other suitable forms include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing carriers known in the art as suitable.

[0650] Dosage forms for topical or transdermal application of the compounds of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active compounds may be mixed under aseptic conditions with pharmaceutically acceptable carriers and any preservatives, buffers, or propellants that may be required. In addition to the compounds of this disclosure, the ointments, pastes, creams, and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin wax, starch, astragalus gum, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0651] Formulations for applying the compounds of this disclosure, such as powders and sprays, may contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders or mixtures thereof. Sprays may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0652] Dosage forms such as transdermal patches for administering the compounds of this disclosure may contain absorption enhancers or delayers to increase or decrease the flux of the compound across the skin. The rate of such flux can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel. Other contemplated dosage forms include ophthalmic formulations, ointments, powders, solutions, etc. It should be understood that all contemplated compositions must be stable under manufacturing and storage conditions and be preserved against contamination by microorganisms such as bacteria and fungi.

[0653] The dosage level of the compound of this disclosure in the pharmaceutical composition can be adjusted to obtain an amount of the compound of this disclosure that is effective in achieving the desired therapeutic response and is harmless to the patient, specific to the patient, composition, and administration method. The selected dosage will depend on a variety of factors, including the nature of the specific compound of this disclosure used, the route of administration, the time of administration, the rate of excretion or metabolism of the specific compound used, the rate and extent of absorption, the duration of prevention or treatment, other drugs, compounds, and / or materials used in combination with the specific compound, the age, sex, weight, condition, general health status, and medical history of the patient being treated, and similar factors well known in the medical field. A physician with ordinary skills in the field can readily determine and prescribe the effective amount of the desired pharmaceutical composition.

[0654] Generally, the appropriate daily dose of the compounds disclosed herein will be the amount of the lowest dose of the compound that effectively produces a therapeutic effect. This effective dose typically depends on the factors described above. Generally, when used for the indicated analgesic effect, the oral, intravenous, intraventricular, and subcutaneous doses of the compounds disclosed herein for a patient will range from about 0.0001 to about 100 mg, more typically from 0.1 to 100 mg / kg per kilogram of recipient (patient, mammal) body weight per day. An acceptable daily dose can be from about 1 to about 1000 mg / day, and for example, from about 1 to about 100 mg / day.

[0655] The effective dose of the disclosed compound can be administered at appropriate intervals (daily, weekly, or monthly) throughout a specific time period, optionally in two, three, four, five, six, or more sub-dose doses administered in a unit dosage form. Preferred doses also depend on the factors described above; for example, those skilled in the medical or pharmaceutical field can readily derive the preferred doses in terms of administration.

[0656] Use of compounds and compositions The compounds disclosed herein inhibit or modulate the activity of receptor tyrosine kinases, specifically extracellular mutants of the ErbB-receptor, such as, but not limited to, EGFR-Viii, EGFR-Vii, EGFR-Vvi, EGFR-A289V, EGFR-G598V, and HER2-S310F. Therefore, the compounds and compositions of this disclosure can be used as pharmaceuticals, i.e., as medicines in therapy, and more specifically for the prevention or treatment of cancer, as detailed below. Accordingly, in another aspect, this disclosure provides a method for the prevention or treatment of cancer in mammals, such as humans, as detailed below.

[0657] The term "prevention" refers to reducing or eliminating the onset of symptoms or complications of a disease (e.g., cancer). Such prevention includes the step of administering a therapeutically effective amount of a compound of formula I or a salt thereof (or a pharmaceutical composition containing a compound of formula I or a salt thereof) to the mammal, such as a human.

[0658] The term "treatment" or "curative" is intended to encompass both therapeutic methods and cures. Such treatments involve the step of administering, to the mammal, such as a human, a therapeutically effective amount of a compound of formula I or a salt thereof (or a pharmaceutical composition containing a compound of formula I or a salt thereof).

[0659] Therefore, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts or stereoisomers thereof or pharmaceutical compositions thereof for the prevention or treatment of cancer in mammals, such as humans, as detailed below.

[0660] In some aspects, this disclosure relates to a method of inhibiting an oncogenic variant of the ErbB receptor (e.g., an oncogenic variant of EGFR), the method comprising administering a therapeutically effective amount of the compound described herein to a subject in need.

[0661] In some aspects, this disclosure relates to a method of inhibiting oncogenic variants of the ErbB receptor (e.g., oncogenic variants of EGFR), said method comprising administering the composition described herein to a subject in need.

[0662] In some aspects, this disclosure relates to a method for preventing or treating cancer, the method comprising administering a therapeutically effective amount of the compound described herein to a subject in need.

[0663] In some respects, this disclosure relates to a method for preventing or treating cancer, the method comprising administering the composition described herein to a subject in need.

[0664] In some respects, this disclosure relates to compounds described herein for inhibiting oncogenic variants of the ErbB receptor (e.g., oncogenic variants of EGFR).

[0665] In some respects, this disclosure relates to compounds described herein for the prevention or treatment of cancer.

[0666] In some respects, this disclosure relates to compositions described herein for inhibiting oncogenic variants of the ErbB receptor (e.g., oncogenic variants of EGFR).

[0667] In some respects, this disclosure relates to the compositions described herein for the prevention or treatment of cancer.

[0668] In some respects, this disclosure relates to the use of the compounds described herein for the manufacture of medicaments for inhibiting oncogenic variants of the ErbB receptor (e.g., oncogenic variants of EGFR).

[0669] In some respects, this disclosure relates to the use of the compounds described herein in the manufacture of medicaments for the prevention or treatment of cancer.

[0670] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2, their pharmaceutically acceptable salts, and their stereoisomers.

[0671] In some embodiments, the compounds are selected from the compounds described in Tables 1 and 2 and their pharmaceutically acceptable salts.

[0672] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2.

[0673] In some embodiments, cancer is a solid tumor.

[0674] In some embodiments, the cancer is bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma (GBM), head and neck cancer, lung cancer, non-small cell lung cancer (NSCLC), or any subtype thereof.

[0675] In some embodiments, the cancer is glioblastoma (GBM) or any subtype thereof.

[0676] In some embodiments, the cancer is glioblastoma.

[0677] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of the ErbB receptor.

[0678] In some embodiments, the oncogenic variants of the ErbB receptor include allosteric mutations.

[0679] In some embodiments, the oncogenic variant of the ErbB receptor is an allosteric variant of the ErbB receptor.

[0680] In some embodiments, the ErbB receptor is an epidermal growth factor receptor (EGFR) or a human epidermal growth factor receptor 2 (HER2) receptor.

[0681] In some embodiments, the ErbB receptor is the epidermal growth factor receptor (EGFR).

[0682] In some embodiments, the ErbB receptor is the HER2 receptor.

[0683] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of the epidermal growth factor receptor (EGFR).

[0684] In some embodiments, the carcinogenic variant of EGFR is an allosteric variant of EGFR.

[0685] In some embodiments, oncogenic variants of EGFR include allosteric mutations.

[0686] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of the HER2 receptor.

[0687] In some embodiments, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor.

[0688] In some embodiments, the oncogenic variants of the HER2 receptor include allosteric mutations.

[0689] In some embodiments, oncogenic variants of EGFR include EGFR variant III (EGFR-Viii) mutations.

[0690] In some embodiments, oncogenic variants of EGFR include EGFR variant II (EGFR-Vii) mutations.

[0691] In some embodiments, oncogenic variants of EGFR include EGFR variant VI (EGFR-Vvi) mutations.

[0692] In some embodiments, the carcinogenic variant of EGFR includes valine (V) that replaces alanine (A) at position 289 of SEQ ID NO: 1.

[0693] In some embodiments, the carcinogenic variant of EGFR includes valine (V) that replaces glycine (G) at position 598 of SEQ ID NO: 1.

[0694] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of EGFR, wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, the oncogenic variant of EGFR includes modifications to the EGFR structure, wherein the oncogenic variant of EGFR is capable of forming a covalently linked dimer, wherein the covalently linked dimer is constitutively active, and wherein the covalently linked dimer enhances the activity of EGFR upon contact with a type I ErbB inhibitor. In some embodiments, modifications to the EGFR structure include one or more modifications to nucleic acid sequences, amino acid sequences, secondary structures, tertiary structures, and quaternary structures. In some embodiments, the oncogenic variant includes mutations, splicing events, post-translational processes, conformational changes, or any combination thereof. In some embodiments, modifications to the EGFR structure occur within the first cysteine-rich (CR1) region and / or the second cysteine-rich (CR2) region of EGFR. In some embodiments, the first cysteine-rich (CR1) region and / or the second cysteine-rich (CR2) region of EGFR respectively comprise amino acid residues T211-R334 and / or C526-S645 of SEQ ID NO: 1. In some embodiments, oncogenic variants of EGFR create a physical barrier for disulfide bond formation within the CR1 and / or CR2 regions. In some embodiments, oncogenic variants of EGFR remove the physical barrier for disulfide bond formation within the CR1 and / or CR2 regions. In some embodiments, oncogenic variants of EGFR include one or more free or unpaired cysteine ​​(C) residues located at the dimer interface of EGFR. In some embodiments, oncogenic variants of EGFR include one or more free or unpaired cysteine ​​(C) residues at sites selected from the group consisting of: according to SEQ ID NO: 1. C190-C199, C194-C207, C215-C223, C219-C231, C232-C240, C236-C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C333, C506-C515, C510-C523, C526-C535, C539-C555, C558-C571, C562-C579, C582-C591, C595-C617, C620-C628 and C624-C636.In some embodiments, the modification occurs at sites selected from the group consisting of intramolecular disulfide bonds within a range of 10 angstroms or less: C190-C199, C194-C207, C215-C223, C219-C231, C232-C240, C236-C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C333, C506-C515, C510-C523, C526-C535, C539-C555, C558-C571, C562-C579, C582-C591, C595-C617, C620-C628, and C624-C636 according to SEQ ID NO: 1.

[0695] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of EGFR, and the oncogenic variant of EGFR is a mutation of EGFR, wherein the nucleotide sequence encoding the oncogenic variant of EGFR includes deletions or substitutions of one or more amino acids encoding an adenosine triphosphate (ATP) binding site. In some embodiments, the ATP binding site includes amino acids E746 to A750 of SEQ ID NO: 1. In some embodiments, the ATP binding site or its deletion or substitution includes K858 of SEQ ID NO: 1. In some embodiments, the deletion includes K858 of SEQ ID NO: 1. In some embodiments, arginine (R) substitutes for lysine (K) at position 858 of SEQ ID NO: 1 (K858R).

[0696] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of EGFR, wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, and the nucleotide sequence encoding the oncogenic variant of EGFR includes an insertion within a sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof includes a sequence encoding KEILDEAYVMASVDNPHVCAR (SEQ ID NO: 7). In some embodiments, the sequence encoding exon 20 or a portion thereof includes a sequence encoding a C-helix, the end of a C-helix, or a loop following a C-helix. In some embodiments, the insertion includes an amino acid sequence comprising ASV, SVD, NPH, or FQEA. In some embodiments, the sequence encoding exon 20 or a portion thereof includes one or more of the following: (a) the amino acid sequence ASV inserted between position V769 and D770 in SEQ ID NO: 1; (b) the amino acid sequence SVD inserted between position D770 and N771 in SEQ ID NO: 1; (c) the amino acid sequence NPH inserted between position H773 and V774 in SEQ ID NO: 1; (d) the amino acid sequence FQEA inserted between position A763 and Y764 in SEQ ID NO: 1; (e) the amino acid sequence PH inserted between position H773 and V774 in SEQ ID NO: 1; (f) the amino acid G inserted between position D770 and N771 in SEQ ID NO: 1; (g) the amino acid H inserted between position H773 and V774 in SEQ ID NO: 1; (h) the amino acid sequence HV inserted between position V774 and C775 in SEQ ID NO: 1; (i) the amino acid sequence NPH inserted between position D779 and N771 in SEQ ID NO: 1; (ii) the amino acid sequence NPH inserted between position D779 and N771 in SEQ ID NO: 1; (iii) the amino acid sequence NPH inserted between position D779 and N771 in SEQ ID NO: 1; (iv) the amino acid sequence NPH inserted between position D779 and N771 in SEQ ID NO: 1; (v ... (j) The amino acid sequence AH between positions H773 and V774 in SEQ ID NO: 1; (k) The amino acid sequence SVA inserted between positions A767 and S768 in SEQ ID NO: 1; (l) The amino acid sequence GYN replacing DN between positions 770 and 771 in SEQ ID NO: 1; (m) The amino acid H inserted between positions N771 and P772 in SEQ ID NO: 1; (n) The amino acid sequence PHVC inserted between positions C775 and R776 in SEQ ID NO: 1; (o) The amino acid sequence YNPY replacing H at position 773 in SEQ ID NO: 1; (p) The amino acid sequence DNP inserted between positions P772 and H773 in SEQ ID NO: 1; (q) The amino acid sequence VDS inserted between positions S768 and V769 in SEQ ID NO: 1;(r) Amino acid H inserted between positions D770 and N771 in SEQ ID NO: 1; (s) Amino acid N inserted between positions N771 and P772 in SEQ ID NO: 1; (t) Amino acid sequence PNP inserted between positions P772 and H773 in SEQ ID NO: 1; (u) Amino acid sequence GSVDN replacing DN between positions 770 and 771 in SEQ ID NO: 1; (v) Amino acid sequence GYP replacing NP between positions 771 and 772 in SEQ ID NO: 1; (w) Amino acid G inserted between positions N771 and P772 in SEQ ID NO: 1; (x) Amino acid sequence GNP inserted between positions P772 and H773 in SEQ ID NO: 1; (y) Amino acid sequence GSV inserted between positions V769 and D770 in SEQ ID NO: 1; (z) Amino acid sequence GNPHVC replacing VC between positions 774 and 775 in SEQ ID NO: 1; (aa) Amino acid sequence GSV inserted between positions D770 and D770 in SEQ ID NO: 1; (aa) Amino acid sequence GSV DN replacing DN between positions D770 and N771 ...b) Amino acid sequence GSV DN replacing DN between positions D770 and N771 in SEQ ID NO: 1; (c) Amino acid sequence GSV DN replacing DN between positions D770 and N771 in SEQ ID NO: 1; (d) Amino acid sequence GSV DN replacing DN between positions D770 and N771 in SEQ ID NO: 1 (ii) The amino acid sequence LQEA inserted between positions A763 and Y764 of SEQ ID NO: 1; (bb) The amino acid sequence GL inserted between positions D770 and N771 of SEQ ID NO: 1; (cc) The amino acid Y inserted between positions D770 and N771 of SEQ ID NO: 1; (dd) The amino acid sequence NPY inserted between positions H773 and V774 of SEQ ID NO: 1; (ee) The amino acid sequence TH inserted between positions H773 and V774 of SEQ ID NO: 1; (ff) The amino acid sequence KGP replacing the NP between positions 771 and 772 of SEQ ID NO: 1; (gg) The amino acid sequence SVDNP replacing the NP between positions 771 and 772 of SEQ ID NO: 1; (hh) The amino acid sequence NN inserted between positions N771 and P772 of SEQ ID NO: 1; (ii) The amino acid T inserted between positions N771 and P772 of SEQ ID NO: 1; and (jj) The amino acid T replacing the NP between positions N771 and P772 of SEQ ID NO: 1; The amino acid sequence of the SV between positions 768 and 769 is STLASV.

[0697] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of EGFR, wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, and the oncogenic variants of EGFR include EGFR-Vii, EGFR-Vvi, EGFR-R222C, EGFR-R252C, EGFR-R252P, EGFR-R256Y, EGFR-T263P, EGFR-Y270C, EGFR-A289T, EGFR-A289V, EGFR-A289D, EGFR-H304Y, EGFR-G331R, EGFR- P596S, EGFR-P596L, EGFR-P596R, EGFR-G598V, EGFR-G598A, EGFR-G614D, EGFR-C620Y, EGFR-C614W, EGFR-C628F, EGFR-C628Y, EGFR-C636Y, EGFR-G645C, EGFR-Δ660, EGFR-Δ768, or any combination thereof.

[0698] In some embodiments, the cancer or its tumor or cells express one or more of the following: (a) a wild-type human epidermal growth factor receptor 2 (HER2) receptor or an oncogenic variant of the HER-2 receptor.

[0699] In some embodiments, the cancer or its tumor or cells express a wild-type HER-2 receptor, which includes the amino acid sequence of SEQ ID NO: 2, 3, 4, 5 or 6.

[0700] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor.

[0701] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor comprising phenylalanine (F) replacing serine (S) at position 310 of SEQ ID NO: 2 or 5.

[0702] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor comprising a tyrosine (Y) replacing the serine (S) at position 310 of SEQ ID NO: 2 or 5.

[0703] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of the HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor comprising glutamine (Q) replacing arginine (R) at position 678 of SEQ ID NO: 2 or 5.

[0704] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor comprising leucine (L) replacing valine (V) at position 777 of SEQ ID NO: 2 or 5.

[0705] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor comprising methionine (M) replacing valine (V) at position 777 of SEQ ID NO: 2 or 5.

[0706] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor comprising isoleucine (I) replacing valine (V) at position 842 of SEQ ID NO: 2 or 5.

[0707] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of the HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor comprising alanine (A) replacing leucine (L) at position 755 of SEQ ID NO: 2 or 5.

[0708] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor comprising a proline (P) replacing leucine (L) at position 755 of SEQ ID NO: 2 or 5.

[0709] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor comprising a serine (S) that substitutes for leucine (L) at position 755 of SEQ ID NO: 2 or 5.

[0710] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the nucleotide sequence encoding the oncogenic variant of the HER2 receptor includes an insertion within a sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof includes a sequence encoding KEILDEAYVMAGVGSPYVSR (SEQ ID NO: 8). In some embodiments, the sequence encoding exon 20 or a portion thereof includes a sequence encoding a C-helix, the end of a C-helix, or a loop following a C-helix. In some embodiments, the insertion includes an amino acid sequence comprising GSP or YVMA. In some embodiments, the sequence encoding exon 20 or a portion thereof includes one or more of the following: (a) the amino acid sequence YVMA inserted between positions A775 and G776 of SEQ ID NO: 2; (b) the amino acid sequence GSP inserted between positions P780 and Y781 of SEQ ID NO: 2; (c) the amino acid sequence YVMA inserted between positions A771 and Y772 of SEQ ID NO: 2; (d) the amino acid sequence YVMA inserted between positions A775 and G776 of SEQ ID NO: 2; (e) the amino acid V inserted between positions V777 and G778 of SEQ ID NO: 2; (f) the amino acid V inserted between positions V777 and G778 of SEQ ID NO: 2; (g) the amino acid sequence AVGCV replacing GV between positions 776 and 777 of SEQ ID NO: 2; (h) the amino acid sequence LC replacing G between positions 776 and 777 of SEQ ID NO: 2; (i) the amino acid sequence LC replacing G between positions P780 and P781 of SEQ ID NO: 2; (j) The amino acid sequence LCV of G between positions 776 and 776 in SEQ ID NO: 2; (k) The amino acid sequence GSP inserted between positions V777 and G778 in SEQ ID NO: 2; (l) The amino acid sequence PS of LRE replacing positions 755 and 757 in SEQ ID NO: 2; (m) The amino acid C inserted between positions V777 and G778 in SEQ ID NO: 2; (n) The amino acid sequence VVMA of AG replacing positions 775 and 776 in SEQ ID NO: 2; (o) The amino acid sequence VV of G replacing position 776 in SEQ ID NO: 2; (p) The amino acid sequence AVCV of GV replacing positions 776 and 777 in SEQ ID NO: 2; (q) The amino acid sequence VCV of GV replacing positions 776 and 777 in SEQ ID NO: 2.(r) Amino acid G inserted between positions G778 and S779 of SEQ ID NO: 2; (s) Amino acid sequence PK replacing LRE between positions 755 and 757 of SEQ ID NO: 2; (t) Amino acid V inserted between positions A775 and G776 of SEQ ID NO: 2; (u) Amino acid sequence YAMA inserted between positions A775 and G776 of SEQ ID NO: 2; (v) Amino acid sequence CV replacing G at position 776 of SEQ ID NO: 2; (w) Amino acid sequence AVCGG replacing GVG between positions 776 and 778 of SEQ ID NO: 2; (x) Amino acid sequence CVCG replacing GVG between positions 776 and 778 of SEQ ID NO: 2; (y) Amino acid sequence VVVG replacing GVG between positions 776 and 778 of SEQ ID NO: 2; (z) Amino acid sequence PK replacing LRE between positions 755 and 757 of SEQ ID NO: 2; The amino acid sequence SVGG of GVGS between positions 776 and 779 of SEQ ID NO: 2 is replaced by (aa) VVGES of GVGS between positions 776 and 779 of SEQ ID NO: 2; (bb) AVGSGV of GV between positions 776 and 777 of SEQ ID NO: 2 is replaced by (cc) CVC of GV between positions 776 and 777 of SEQ ID NO: 2; (dd) HVC of GV between positions 776 and 777 of SEQ ID NO: 2 is replaced by (ee) VAAGV of GV between positions 776 and 777 of SEQ ID NO: 2; (ff) VAGV of GV between positions 776 and 777 of SEQ ID NO: 2 is replaced by (gg) VVV of GV between positions 776 and 777 of SEQ ID NO: 2; (hh) inserted into SEQ ID NO: (ii) The amino acid sequence FPG inserted between G778 and S779 at position 2 of SEQ ID NO: 2; (jj) The amino acid sequence VPS replacing VLRE at position 754 and 757 of SEQ ID NO: 2; (kk) The amino acid E inserted between V777 and G778 at position 2 of SEQ ID NO: 2; (ll) The amino acid sequence MAGV inserted between V777 and G778 at position 2 of SEQ ID NO: 2; (mm) The amino acid S inserted between V777 and G778 at position 2 of SEQ ID NO: 2; (nn) The amino acid sequence SCV inserted between V777 and G778 at position 2 of SEQ ID NO: 2;And (oo) the amino acid sequence LMAY inserted between Y772 and V773 at position SEQ ID NO: 2.

[0711] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, including HER2-Δ16, HER2-C311R, HER2-S310F, p95-HER2-M611, or any combination thereof.

[0712] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of the HER-4 receptor. In some embodiments, the oncogenic variant of the HER-4 receptor is an allosteric variant of the HER4 receptor. In some embodiments, the oncogenic variant of the HER4 receptor includes the deletion of exon 16 (HER4-Δ16).

[0713] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of EGFR, wherein the sequence encoding the oncogenic variant of EGFR includes a deletion of exon 20 or a portion thereof, and wherein the cancer, its tumor, or cells do not contain a second oncogenic variant in sequences other than EGFR exon 20. In some embodiments, the second oncogenic variant includes sequences encoding one or more of the EGFR kinase domain (KD), BRAF, NTRK, and KRAS.

[0714] In some embodiments, the cancer or its tumor or cells express an oncogenic variant of EGFR, wherein the sequence encoding the oncogenic variant of EGFR includes a deletion of exon 20 or a portion thereof, and wherein the cancer, its tumor or cells do not include biomarkers indicating responsiveness to immunotherapy.

[0715] In some embodiments, the oncogenic variant (e.g., allosteric variant) or the oncogenic mutation (e.g., allosteric mutation) is detected by a diagnostic test approved by the Food and Drug Administration (FDA).

[0716] In some embodiments, a subject is treated with a therapeutic agent different from the compounds disclosed herein prior to treatment with the compounds disclosed herein.

[0717] In some embodiments, the cancer or its tumor or cells are insensitive to or resistant to treatment with a therapeutic agent different from the compounds disclosed herein. In some embodiments, the cancer or its tumor or cells are insensitive to or resistant to treatment with a type I inhibitor. In some embodiments, the cancer or its tumor or cells are insensitive to or resistant to treatment with one or more of the following: gefinitinib, erlotinib, afatinib, osimertinib, necitumumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, saprinib, dacomitinib, canertinib, pemetinib, WZ4002, WZ8040, WZ3146, CO-1686, and AZD9291.

[0718] In some embodiments, the subject has an adverse reaction to treatment with a therapeutic agent different from the compounds disclosed herein. In some embodiments, the subject has an adverse reaction to treatment with a type I inhibitor. In some embodiments, the subject has an adverse reaction to treatment with one or more of the following: gefitinib, erlotinib, afatinib, osimertinib, nexituzumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, saprotinib, dacomitinib, canenatinib, peritinib, WZ4002, WZ8040, WZ3146, CO-1686, and AZD9291. In some embodiments, the adverse reaction is activation of an oncogenic variant of EGFR, wherein the oncogenic variant comprises a mutation in the extracellular domain of the receptor. In some embodiments, the adverse reaction is activation of an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant comprises a mutation in the extracellular domain of the receptor.

[0719] In some embodiments, the method further includes administering a therapeutically effective amount of a non-type I inhibitor to a subject in need. In some embodiments, the non-type I inhibitor includes a small molecule type II inhibitor.

[0720] In some embodiments, the method further includes administering a therapeutically effective amount of a non-type I inhibitor to a subject in need. In some embodiments, the non-type I inhibitor includes a small molecule type II inhibitor.

[0721] In some embodiments, the compound is used in combination with a therapeutically effective amount of a non-type I inhibitor. In some embodiments, the non-type I inhibitor includes a small molecule type II inhibitor.

[0722] In some embodiments, the composition further comprises a non-type I inhibitor. In some embodiments, the non-type I inhibitor comprises a small molecule type II inhibitor.

[0723] In some embodiments, the therapeutically effective dose reduces the severity of cancer signs or symptoms.

[0724] In some embodiments, signs of cancer include tumor grade, and a reduction in the severity of signs includes a reduction in tumor grade.

[0725] In some embodiments, signs of cancer include tumor metastasis, and a reduction in the severity of the signs includes the elimination of metastasis or a reduction in the rate or extent of metastasis.

[0726] In some embodiments, signs of cancer include tumor volume, and a reduction in the severity of the signs includes tumor elimination or reduction in volume.

[0727] In some embodiments, symptoms of cancer include pain, and a reduction in the severity of symptoms includes the elimination or relief of pain.

[0728] In some embodiments, the effective therapeutic dose induces a remission period.

[0729] In some embodiments, the therapeutically effective dose improves the outcome of the subject.

[0730] Such use (or prevention or treatment) in subjects includes administering a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a subject in need of such prevention or treatment by means of allosteric variants and / or oncogenic variants targeting EGFR and HER-2 receptors.

[0731] This disclosure contemplates the administration of the disclosed compounds, alone or in combination with one or more other therapeutic agents, such as other tyrosine kinase inhibitors: erlotinib hydrochloride (e.g., Tarceva® of Genentech / Roche), linifanib (or ABT 869, Genentech), sunitinib malate (e.g., Sutent® of Pfizer), bosutinib (or SKI-606, described in the US). 6,780,996), dasatinib (e.g., Sprycel(R) of Bristol-Myers Squibb), armala (e.g., pazopanib, e.g., Votrient(R) of GlaxoSmithKline), imatinib and imatinib mesylate (e.g., Gilvec(R) and Gleevec(R) of Novartis); vascular endothelial growth factor (VEG) receptor inhibitors (bevacizumab or Avastin(R) of Genentech / Roche), axitinib (or AG013736, described in WO 01 / 002369), brivanib alanine 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(R)); HER2 receptor inhibitors: trastuzumab (e.g., Herceptin(R) from Genentech / Roche), neratinib (or HKI-272, described in WO 02 / 066470). 05 / 028443 (in Chinese), lapatinib or lapatinib dimethylbenzenesulfate (e.g., Tykerb(R) from GlaxoSmithKline); CD20 antibodies: rituximab (e.g., Riuxan(R) and MabThera(R) from Genentech / Roche), tositumomab (e.g., Bexxar(R) from GlaxoSmithKline), oflamumab (e.g., Arzerra(R) from GlaxoSmithKline); Bcr / Abl kinase inhibitors: nilotinib hydrochloride (e.g., Tasigna(R) from Novartis);DNA synthesis inhibitors: Capecitabine (e.g., Roche's Xeloda(R)), gemcitabine hydrochloride (e.g., Eli Lilly's Gemzar(R)), nelarabine (or GlaxoSmithKline's Arranon(R) and Atriance(R))); Antitumor agents: oxaliplatin (e.g., Sanofi-Aventis' Eloxatin(R), described in the US). 4,169,846 (in Chinese); Epidermal growth factor receptor (EGFR) inhibitors: Gefitinib (or Iressa(R)), Afatinib (or Boehringer Ingelheim's Tovok(R))), Cetuximab (e.g., Bristol-Myers Squibb's Erbitux(R))), Panitumumab (e.g., Amgen's Vectibix(R))); HER dimer inhibitors: Pertuzumab (e.g., Genentech's Omnitarg(R)); Human granulocyte colony-stimulating factor (G-CSF) modulators: Filgrastim (e.g., Amgen's Neupogen(R)); Immunomodulators: Afto Afutuzumab (Roche(R)), pegfilgrastim (e.g., Neulasta(R) from Amgen), lenalidomide (e.g., CC-5013, Revlimid(R)), thalidomide (e.g., Thalomid(R)); (m) CD40 inhibitors: dacetuzumab (e.g., SGN-40 or huS2C6 from Seattle Genetics); pro-apoptotic receptor agonists (PARA): dulanermin (e.g., AMG-951 from Amgen / Genentech); Hedgehog antagonists (… Antagonist: Vismodegib (or GDC-0449, described in WO 06 / 028958); PI3K inhibitor: Pictilisib (or GDC-0941, described in WO 09 / 036082 and WO 09 / 055730), Dactolisib (or BEZ235 or NVP-BEZ 235, described in WO 06 / 122806); Phospholipase A2 inhibitor: Anagrelide (e.g., Agrylin(R));BCL-2 inhibitors: Navitoclax (or ABT-263, described in WO 09 / 155386); mitogen-activated protein kinase kinase (MEK) inhibitors: XL-518 (CAS No.: 1029872-29-4, ACC); aromatase inhibitors: exemestane (e.g., Pfizer's Aromasin®), letrozole (e.g., Novartis' Femara®), anastrozole (e.g., Arimidex®); topoisomerase I inhibitors: irinotecan (e.g., Pfizer's Camptosar®), topotecan hydrochloride. Hydrochlorides (e.g., Hycamtin(R) from GlaxoSmithKline); Topoisomerase II inhibitors: etoposide (e.g., VP-16 and etoposide phosphate, e.g., Toposar(R)), VePesid(R) and Etopophos(R)), teniposide (e.g., VM-26, e.g., Vumon(R)); mTOR inhibitors: sirolimus esters (Temsirolimus) (e.g., Torisel(R) from Pfizer), and ridaforol. imus (formerly known as deferolimus, (or AP23573 and MK8669, described in WO03 / 064383), everolimus (e.g., Novartis' Afinitor®); osteoclast resorption inhibitors: zoledronic acid (or Novartis' Zometa®); CD33 antibody drug conjugates: Gemtuzumabozogamicin (e.g., Pfizer / Wyeth's Mylotarg®); CD22 antibody drug conjugates: Inotuzumab ozogamicin (also known as CMC-544 and WAY-207294, Hangzhou Saiqi Chemical Co., Ltd.); CD20 antibody drug conjugates: Ibritumomab tiuxetan (e.g., Zevalin(R)); somatostatin analogs: octreotide (e.g., octreotide acetate, for example, Sandostatin(R) and Sandostatin LAR(R)); synthetic interleukin 11 (IL-11): oprelvekin (e.g., Neumega(R) of Pfizer / Wyeth).Synthetic erythropoietin: Darbepoetin alfa (e.g., Aranesp(R) by Amgen); Receptor activators of nuclear factor κB (RANK) inhibitors: denosumab (e.g., Prolia(R) by Amgen); Thrombopoietin mimic peptides: Romiplostim (e.g., Nplate(R) by Amgen); Cell growth stimulants: Palifermin (e.g., Kepivance(R) by Amgen); Anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies: Figitumumab (e.g., CP-751,871, ACC), robatumumab (CAS No.: 934235-44-6); Anti-CS1 antibody: Elotuzumab (HuLuc63, CAS No.: 915296-00-3); CD52 antibody: Alemtuzumab (e.g., Camppath(R)); CTLA-4 inhibitors: Tremelimumab (an IgG2 monoclonal antibody manufactured by Pfizer, formerly known as ticilimumab, CP-675,206), ipilimumab (a CTLA-4 antibody, e.g., MDX-010, CAS No.: 477202-00-9); Histone deacetylase inhibitors (HDI): Voninostat (e.g., Merck's Zolinza(R));Alkylating agents: Temozolomide (e.g., Temodar(R) and Temodal(R) from Schering-Plough / Merck), styromycin (e.g., actinomycin-D and, for example, Cosmegen(R)), melphalan (e.g., L-PAM, L-saccharin, and phenylalanine mustard, for example, Alkeran(R)), hexamethylmelamine (e.g., hexamethylmelamine (HMM), for example, Hexalen(R)), carmustine (e.g., BiCNU(R)), bendamustine (e.g., Treanda(R)), busulfan (e.g., Busulfex(R) and Myleran(R)), carboplatin (e.g., Paraplatin(R)), lomustine (e.g., CCNU, e.g., CeeNU(R)), cisplatin (e.g., CDDP, e.g., Platinol(R) and Platinol(R)-AQ), phenylbutyrate nitrogen Mustard (e.g., Leukeran(R)), cyclophosphamide (e.g., Cytoxan(R) and Neosar(R)), dacarbazine (e.g., DTIC, DIC, and imidazole carboxamide, e.g., DTIC-Dome(R)), atratramine (e.g., hexamethylpyrimidine (HMM), e.g., Hexalen(R)), ifosfamide (e.g., Ifex(R)), procarbazine (… bazine (e.g., Matulane(R)), dichloromethyldiethylamine (e.g., nitrogen mustard, sinigrin and methylchloroethylamine hydrochloride, e.g., Mustargen(R)), streptozotocin (e.g., Zanosar(R)), thiotepa (e.g., thiophosphoramide, TESPA and TSPA, e.g., Thioplex(R)); biological response modulators: BCG (e.g., theraCys(R) and TICE(R), denileukindiftitox (e.g., Ontak(R));Antitumor antibiotics: doxorubicin (e.g., Adriamycin(R) and Rubex(R)), bleomycin (e.g., lenoxane(R)), daunorubicin (e.g., daunorubicin hydrochloride, daunorubicin and erythromycin hydrochloride, e.g., Cerubidine(R)), daunorubicin liposomes (daunorubicin citrate liposomes, e.g., DaunoXome(R)), mitoxantrone (e.g., DHAD, e.g., Novantrone(R)), epirubicin (e.g., Ellence™), idarubicin (e.g., Idamycin(R)). PFS(R)), mitomycin C (e.g., Mustamycin(R)); antimicrotubule agents: Estramustine (e.g., Emcyl(R)); cathepsin K inhibitors: Odanacatib (or MK-0822, ACC Lanzhou Chon Chemical Co., Ltd. and ChemieTek, described in WO 03 / 075836); epothilone B analogs: Ixabepilone (e.g., Bristol-Myers Squibb's Lxempra(R)); heat shock protein (HSP) inhibitors: Tanespimycin (17-allylamino-17-demethoxygeldmycin, e.g., Sigma-Aldrich's KOS-953 and 17-AAG, described in US... 4,261,989 (in Chinese); TpoR agonists: eltrombopag (e.g., Promacta® and Revolade® from GlaxoSmithKline); antimitotics: docetaxel (e.g., Taxotere® from Sanofi-Aventis); adrenocorticosteroid inhibitors: aminoglutethimide (e.g., Cytadren®); antiandrogens: nilutamide (e.g., Nilandron® and Anandron®), bicalutamide (sold under the brand name Casodex®), flutamide (e.g., Fulexin™); androgens: fluoxymesterone (e.g., halotestin®); proteasome inhibitors: bortezomib (e.g., Velcade®).CDK1 inhibitors: Alvocidib (e.g., fluvopirdol or HMR-1275, described in US 5,621,002); Gonadotropin-releasing hormone (GnRH) receptor agonists: leuprolide or leuprolide acetate (e.g., Viadure® of Bayer AG, Eligard® of Sanofi-Aventis, and Lupron® of Abbott Laboratories); Taxane antitumor agents: Cabazitaxel, larotaxel; 5HT1a receptor agonists: Xaliproden (or SR57746, described in US 5,621,002). 5,266,573 (Chinese); HPC vaccines: Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck; iron chelators: iron chelators (Deferasinox) (e.g., Exjade® from Novartis); antimetabolites: Claribine (2-chlorodeoxyadenosine, e.g., leustatin®), 5-fluorouracil (e.g., Adrucil®), 6-thioguanine (e.g., Purinethol®), pemetrexed (e.g., Alimta®), cytarabine (e.g., cytarabine (Ara-C), e.g., Cytosar-U®), cytarabine liposomes (e.g., liposome Ara-C, e.g., DepoCyt™), decitabine (e.g., D... acogen(R)), hydroxyurea (e.g., Hydrea(R), Droxia™ and Mylocel™), fludarabine (e.g., Fludara(R)), fluorouracil (e.g., FUDR(R)), cladribine (e.g., 2-chlorodeoxyadenosine (2-CdA), e.g., Leustatin™), methotrexate (e.g., aminopterin, methotrexate sodium (MTX), e.g., Rheumatrex(R) and Trexall™), pentostatin (e.g., Nipent(R)); bisphosphonates: pamidronate (e.g., Aredia(R)), zoledronic acid (e.g., Zometa(R)); demethylating agents: 5-azacitidine (e.g., Vidaza(R)), decitabine (e.g., Dacogen(R));Plant alkaloids: Paclitaxel protein-bound (e.g., Abraxane(R)), vinblastines (e.g., vinblastine sulfate, vincristine and VLB, e.g., Alkaban-AQ(R) and Velban(R)), vincristines (e.g., vincristine sulfate, LCR and VCR, e.g., Oncovin(R) and Vincasar Pfs(R)), vinorelbine (e.g., Navebine(R)), paclitaxel (e.g., paclitaxel and Onxal™); Retinoids: Alitretinoin (e.g., Panretin(R)), retinoic acid (all-trans retinoic acid, e.g., ATRA, e.g., Vesanoid(R)), isotretinoin (13-cis-retinoic acid, e.g., Accutane(R), Amnesteem(R), Claravis(R), Clarus(R), Decutane (R), Isotane(R), Izotech(R), Oratane(R), Isotret(R) and Sotret(R)), bexarotene (e.g., Targretin(R)); glucocorticoids: hydrocortisone (e.g., cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and, for example, Ala-Cort(R), hydrocortisone phosphate, Solu-Cortef(R), Hydrocort Acetate(R) and Lanacort(R)), dexamethasone, prednisolone (e.g., Delta-Cortel(R), Orapred(R), Pediapred(R) and Prelone(R)), prednisone (e.g., Deltasone(R), Liquid Red(R), Meticorten(R) and Orasone(R)); Methylprednisolone (e.g., 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, e.g., Duralone(R), Medralone(R), Medrol(R), M-Prednisol(R) and Solu-Medrol(R)); Cytokines: Interleukin-2 (e.g., adeleukin and IL-2, e.g., Proleukin(R)), Interleukin-11 (e.g., oprevelkin, e.g., Neumega(R)), α-interferon-α (e.g., IFN-α, e.g., Intron(R) A and Roferon-A(R)); Luteinizing hormone-releasing hormone (LHRH) agonists: Goserelin (e.g., Zoladex(R));Progesterone: medroxyprogesterone acetate (e.g., megestrol acetate, e.g., Megace®); confounding cytotoxic agents: arsenic trioxide (e.g., Trisenox®), asparaginases (e.g., L-asparaginase, Erwinia L-asparaginase, e.g., Elspar® and Kidrolase®); antinausea drugs: NK-1 receptor antagonists: caspopitant (e.g., Promacta® and Revolade® from GlaxoSmithKline); and cytoprotective agents: amifostine (e.g., Ethyol®), folinic acid (e.g., calcium leucovorin, folinic acid factor, and folinic acid).

[0732] Exemplary embodiments Example 1: A compound of formula (I'): Or its pharmaceutically acceptable salt or stereoisomer, wherein: W is CH or N; Z is arbitrarily defined by one or more R. Z Substituted 3- to 12-membered heterocyclic alkyl groups; Each R Z Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R Za replace; Each R Za Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl is optionally replaced by one or more R. T replace; Each R T Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R Ta replace; Each R Ta Independently, it is a halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; Ar 1 It is optionally controlled by one or more R A1 Replacement C6-C 10 Aryl; Each R A1 Independently, it is halogen, CN, -OH, -NH2, -OR A1a -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10Aryl, 3- to 10-membered heterocyclic alkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R A1a Replace; and Each R A1a Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R A1b Replace; and Each R A1b It can be halogen, CN, -OH or -NH2 independently.

[0733] Example 2: The compound according to any one of the foregoing embodiments, wherein the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH or N; Z is arbitrarily defined by one or more R. Z Substituted 3- to 12-membered heterocyclic alkyl groups; Each R Z Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C10 cycloalkyl, the C6-C 10 aryl, the 3- or 5- to 10-membered heteroaryl, is optionally surrounded by one or more R Za replace; Each R Za Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl is optionally replaced by one or more R. T replace; Each R T Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 7-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 The aryl group, the 3- to 7-membered heterocyclic alkyl group, or the 5- to 10-membered heteroaryl group may optionally be separated by one or more R groups. Ta replace; Each R Ta Independently, it is a halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; Ar 1 It is optionally controlled by one or more R A1 Replacement C6-C 10 Aryl; Each R A1 Independently, it is halogen, CN, -OH, -NH2, -OR A1a-O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally replaced by one or more R A1a Replace; and Each R A1a Independently, it is a halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted by one or more R A1b Replace; and Each R A1b It can be halogen, CN, -OH, or -NH2 independently; The condition is when Z is At that time, then Ar 1 It is a C6-C that is optionally substituted with one or more halogens. 10 Aryl.

[0734] Example 3: The compound according to any one of the foregoing embodiments, wherein the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH or N; Z is arbitrarily defined by one or more R. Z Substituted 3- to 12-membered heterocyclic alkyl groups; Each R Z Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- or 5- to 10-membered heteroaryl, is optionally surrounded by one or more R Za replace; Each R Za Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl is optionally replaced by one or more R. T replace; Each R T Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3 to 7-membered monocyclic heterocyclic alkyl or 5 to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 7-membered monocyclic heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally separated by one or more R Ta replace; Each R Ta Independently, it is a halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; Ar 1 It is optionally controlled by one or more R A1 Replacement C6-C 10 Aryl; Each R A1 Independently, it is halogen, CN, -OH, -NH2, -OR A1a-O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally replaced by one or more R A1a Replace; and Each R A1a Independently, it is a halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted by one or more R A1b Replace; and Each R A1b It can be halogen, CN, -OH, or -NH2 independently; The condition is when Z is At that time, then Ar 1 It is a C6-C that is optionally substituted with one or more halogens. 10 Aryl.

[0735] Example 4: The compound according to any one of the foregoing embodiments, wherein the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is arbitrarily defined by one or more R. Z Substituted 3- to 12-membered heterocyclic alkyl groups; Each R Z Independently, it is a halogen, -O-(C1-C6 alkyl), C1-C6 alkyl, or a 3- to 10-membered heterocyclic alkyl; wherein the -O-(C1-C6 alkyl), the C1-C6 alkyl, or the 3- to 10-membered heterocyclic alkyl is optionally substituted by one or more halogens; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T replace; Each R TIndependently, it is a halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2 or a 3 to 7-membered heterocyclic alkyl; wherein the -O-(C1-C6 alkyl), the -N(C1-C6 alkyl)2 or the 3 to 7-membered heterocyclic alkyl is optionally substituted by one or more -C(=O)OH; Ar 1 It is optionally controlled by one or more R A1 Replacement C6-C 10 Aryl; Each R A1 Independently or optionally by one or more R A1a Substituted halogens, -OR A1a or -O-(C1-C6 alkyl); and Each R A1a Independently, it is C6-C 10 aryl or 5- to 10-membered heteroaryl; wherein the C6-C 10 The aryl group or the 5- to 10-membered heteroaryl group may optionally be substituted with one or more halogens.

[0736] Example 5: The compound according to any one of the foregoing embodiments, wherein the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is arbitrarily defined by one or more R. Z Substituted 3- to 12-membered heterocyclic alkyl groups; Each R Z Independently, it is a halogen, -O-(C1-C6 alkyl), C1-C6 alkyl, or a 3- to 10-membered heterocyclic alkyl; wherein the -O-(C1-C6 alkyl), the C1-C6 alkyl, or the 3- to 10-membered heterocyclic alkyl is optionally substituted by one or more halogens; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T replace; Each R T Independently, it is a halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2 or a 3 to 7-membered monocyclic heterocyclic alkyl; wherein the -O-(C1-C6 alkyl), the -N(C1-C6 alkyl)2 or the 3 to 7-membered monocyclic heterocyclic alkyl is optionally substituted by one or more -C(=O)OH; Ar 1 It is optionally controlled by one or more R A1 Replacement C6-C 10Aryl; Each R A1 Independently or optionally by one or more R A1a Substituted halogens, -OR A1a or -O-(C1-C6 alkyl); and Each R A1a Independently, it is C6-C 10 aryl or 5- to 10-membered heteroaryl; wherein the C6-C 10 The aryl group or the 5- to 10-membered heteroaryl group may optionally be substituted with one or more halogens.

[0737] Example 6: The compound according to any one of the foregoing embodiments, wherein the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is arbitrarily defined by one or more R. Z Substituted 3- to 12-membered heterocyclic alkyl groups; Each R Z It is independently a halogen, -O-(C1-C6 alkyl) or C1-C6 alkyl; wherein the -O-(C1-C6 alkyl) or the C1-C6 alkyl is optionally substituted with one or more halogens; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T replace; Each R T Independently, it is a halogen, -OH, -O-(C1-C6 alkyl) or a 3- to 7-membered heterocyclic alkyl; wherein the -O-(C1-C6 alkyl) or the 3- to 7-membered heterocyclic alkyl is optionally substituted by one or more -C(=O)OH; Ar 1 It is optionally controlled by one or more R A1 Replacement C6-C 10 Aryl; Each R A1 Independently or optionally by one or more R A1a Substituted halogens, -OR A1a or -O-(C1-C6 alkyl); and Each R A1a Independently, it is C6-C 10 aryl or 5- to 10-membered heteroaryl; wherein the C6-C 10 The aryl group or the 5- to 10-membered heteroaryl group may optionally be substituted with one or more halogens; The condition is when Z is At that time, then Ar 1 It is a C6-C that is optionally substituted with one or more halogens. 10 Aryl.

[0738] Example 7: The compound according to any one of the foregoing embodiments, wherein the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is arbitrarily defined by one or more R. Z Substituted 3- to 12-membered heterocyclic alkyl groups; Each R Z It is independently a halogen, -O-(C1-C6 alkyl) or C1-C6 alkyl; wherein the -O-(C1-C6 alkyl) or the C1-C6 alkyl is optionally substituted with one or more halogens; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T replace; Each R T Independently, it is a halogen, -OH, -O-(C1-C6 alkyl) or a 3- to 7-membered monocyclic heterocyclic alkyl; wherein the -O-(C1-C6 alkyl) or the 3- to 7-membered monocyclic heterocyclic alkyl is optionally substituted by one or more -C(=O)OH; Ar 1 It is optionally controlled by one or more R A1 Replacement C6-C 10 Aryl; Each R A1 Independently or optionally by one or more R A1a Substituted halogens, -OR A1a or -O-(C1-C6 alkyl); and Each R A1a Independently, it is C6-C 10 aryl or 5- to 10-membered heteroaryl; wherein the C6-C 10 The aryl group or the 5- to 10-membered heteroaryl group may optionally be substituted with one or more halogens; The condition is when Z is At that time, then Ar 1 It is a C6-C that is optionally substituted with one or more halogens. 10 Aryl.

[0739] Example 8:The compound according to any one of the foregoing embodiments, wherein the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is arbitrarily defined by one or more R. Z Substituted 3- to 12-membered heterocyclic alkyl groups; Each R Z It is independently a halogen, -O-(C1-C6 alkyl) or C1-C6 alkyl; wherein the -O-(C1-C6 alkyl) or the C1-C6 alkyl is optionally substituted with one or more halogens; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T replace; Each R T Independently, it is a halogen, -OH, -O-(C1-C6 alkyl) or a 3- to 7-membered heterocyclic alkyl; wherein the -O-(C1-C6 alkyl) or the 3- to 7-membered heterocyclic alkyl is optionally substituted by one or more -C(=O)OH; Ar 1 It is a C6-C that is optionally substituted with one or more halogens. 10 Aryl.

[0740] Example 9: The compound according to any one of the foregoing embodiments, wherein the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is arbitrarily defined by one or more R. Z Substituted 3- to 12-membered heterocyclic alkyl groups; Each R Z It is independently a halogen, -O-(C1-C6 alkyl) or C1-C6 alkyl; wherein the -O-(C1-C6 alkyl) or the C1-C6 alkyl is optionally substituted with one or more halogens; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T replace; Each R TIndependently, it is a halogen, -OH, -O-(C1-C6 alkyl) or a 3- to 7-membered monocyclic heterocyclic alkyl; wherein the -O-(C1-C6 alkyl) or the 3- to 7-membered monocyclic heterocyclic alkyl is optionally substituted by one or more -C(=O)OH; Ar 1 It is a C6-C that is optionally substituted with one or more halogens. 10 Aryl.

[0741] Example 10: The compound according to any one of the foregoing embodiments, wherein the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is a 3- to 12-membered heterocyclic alkyl group optionally substituted with one or more C1-C6 alkyl groups; T is a C2-C6 alkenyl group optionally substituted with one or more 6-membered heterocyclic alkyl groups; and Ar 1 It is a C6 aryl group that is optionally substituted with one or more halogens.

[0742] Example 11: The compound according to any one of the foregoing embodiments, wherein the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is a 3- to 12-membered heterocyclic alkyl group optionally substituted with one or more C1-C6 alkyl groups; T is a C2-C6 alkenyl group optionally substituted with one or more 6-membered monocyclic heterocyclic alkyl groups; and Ar 1 It is a C6 aryl group that is optionally substituted with one or more halogens.

[0743] Example 12: The compound according to any one of the foregoing embodiments, wherein W is CH.

[0744] Example 13: The compound according to any one of the foregoing embodiments, wherein W is N.

[0745] Example 14: The compound according to any one of the foregoing embodiments, wherein Z is optionally reacted by one or more R Z Substituted 3- to 12-membered heterocyclic alkyl groups; and Each R Z Independently, it is a halogen, -O-(C1-C6 alkyl), C1-C6 alkyl, or a 3- to 10-membered heterocyclic alkyl; wherein the -O-(C1-C6 alkyl), the C1-C6 alkyl, or the 3- to 10-membered heterocyclic alkyl is optionally substituted with one or more halogens.

[0746] Example 15: According to any one of the foregoing embodiments, in the compound, Z is an oxacyclobutane, tetrahydrofuranyl, pyrrolyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexane, 2-azaspiro[3.3]heptane, 2-oxa-5-azaspiro[3.4]octane, wherein the oxacyclobutane, the tetrahydrofuranyl, the pyrrolyl, the piperidinyl, the morpholinyl, the 3-oxabicyclo[3.1.0]hexane, the 3-azabicyclo[3.1.0]hexane, the 2-azaspiro[3.3]heptane, or the 2-oxa-5-azaspiro[3.4]octane is optionally replaced by one or more R Z replace.

[0747] Example 16: According to any one of the foregoing embodiments, in the compound, Z is an oxacyclobutane, tetrahydrofuranyl, pyrrolyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexane, 2-azaspiro[3.3]heptane, 2-oxa-5-azaspiro[3.4]octane, wherein the oxacyclobutane, the tetrahydrofuranyl, the pyrrolyl, the piperidinyl, the morpholinyl, the 3-oxabicyclo[3.1.0]hexane, the 2-azaspiro[3.3]hexane, or the 2-oxa-5-azaspiro[3.4]octane is optionally separated by one or more R Z replace.

[0748] Example 17: The compound according to any one of the foregoing embodiments, wherein Z is , , , , , , , , , , , , , , , , , , , , , , or .

[0749] Example 18:The compound according to any one of the foregoing embodiments, wherein Z is , , , , , , , , , , , , , , , , , , , , , or .

[0750] Example 19: According to any one of the foregoing embodiments, the compound wherein at least one R Z It is halogen.

[0751] Example 20: According to any one of the foregoing embodiments, the compound wherein at least one R Z It is either F or Cl.

[0752] Example 21: According to any one of the foregoing embodiments, the compound wherein at least one R Z It is CN, -OH, or -NH2.

[0753] Example 22: According to any one of the foregoing embodiments, the compound wherein at least one R Z It is -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclic alkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R Za replace.

[0754] Example 23: According to any one of the foregoing embodiments, the compound wherein at least one R Z It is optionally controlled by one or more R Za Substituted -O-(C1-C6 alkyl).

[0755] Example 24: According to any one of the foregoing embodiments, the compound wherein at least one R Z It is -OCH3.

[0756] Example 25: According to any one of the foregoing embodiments, the compound wherein at least one R Z It is an -O-(C1-C6 alkyl) substituted with one or more halogens.

[0757] Example 26: According to any one of the foregoing embodiments, the compound wherein at least one R Z It is a C1-C6 alkyl group.

[0758] Example 27: According to any one of the foregoing embodiments, the compound wherein at least one R Z It is methyl, ethyl, or propyl.

[0759] Example 28: According to any one of the foregoing embodiments, the compound wherein at least one R Z It is a C1-C6 alkyl group substituted with one or more halogens.

[0760] Example 29: According to any one of the foregoing embodiments, the compound wherein at least one R Z It's CF3.

[0761] Example 30: According to any one of the foregoing embodiments, the compound wherein at least one R Z It is C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; wherein the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R Za replace.

[0762] Example 31: According to any one of the foregoing embodiments, the compound wherein at least one R Z It is optionally controlled by one or more R Za Substituted 3 to 10-membered heterocyclic alkyl groups.

[0763] Example 32: According to any one of the foregoing embodiments, the compound wherein at least one R Z It is optionally controlled by one or more R Za Substituted 4-membered heterocyclic alkyl groups.

[0764] Example 33: According to any one of the foregoing embodiments, the compound wherein at least one R Z It is an oxocyclic butyl group.

[0765] Example 34: According to any one of the foregoing embodiments, the compound wherein at least one R Za It is halogen.

[0766] Example 35: According to any one of the foregoing embodiments, the compound wherein at least one R Za It is either F or Cl.

[0767] Example 36: According to any one of the foregoing embodiments, the compound wherein at least one R Za It is CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3 to 10-membered heterocyclic alkyl or 5 to 10-membered heteroaryl.

[0768] Example 37: According to any one of the foregoing embodiments, in the compound, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), the -NH-(C1-C6 alkyl), the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 alkynyl is optionally replaced by one or more R T replace; Each R T Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 7-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10The aryl group, the 3- to 7-membered heterocyclic alkyl group, or the 5- to 10-membered heteroaryl group may optionally be separated by one or more R groups. Ta Replace; and Each R Ta Independently, it is a halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3 to 10-membered heterocyclic alkyl or 5 to 10-membered heteroaryl.

[0769] Example 38: According to any one of the foregoing embodiments, in the compound, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), the -NH-(C1-C6 alkyl), the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 alkynyl is optionally replaced by one or more R T replace; Each R T Independently, it is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3 to 7-membered monocyclic heterocyclic alkyl or 5 to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 7-membered monocyclic heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally separated by one or more R Ta Replace; and Each R Ta Independently, it is a halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3 to 10-membered heterocyclic alkyl or 5 to 10-membered heteroaryl.

[0770] Example 39:According to any one of the foregoing embodiments, in the compound, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T Replace; and Each R T Independently, it is a halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2 or a 3 to 7-membered heterocyclic alkyl; wherein the -O-(C1-C6 alkyl), the -N(C1-C6 alkyl)2 or the 3 to 7-membered heterocyclic alkyl is optionally substituted by one or more -C(=O)OH.

[0771] Example 40: According to any one of the foregoing embodiments, in the compound, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T Replace; and Each R T Independently, it is a halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2 or a 3 to 7-membered monocyclic heterocyclic alkyl; wherein the -O-(C1-C6 alkyl), the -N(C1-C6 alkyl)2 or the 3 to 7-membered monocyclic heterocyclic alkyl is optionally substituted by one or more -C(=O)OH.

[0772] Example 41: According to any one of the foregoing embodiments, in the compound, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T Replace; and Each R T Independently, it is a halogen, -OH, -O-(C1-C6 alkyl), or a 3- to 7-membered heterocyclic alkyl; wherein the -O-(C1-C6 alkyl) or the 3- to 7-membered heterocyclic alkyl is optionally substituted with one or more -C(=O)OH.

[0773] Example 42:According to any one of the foregoing embodiments, in the compound, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 ynyl is optionally replaced by one or more R T Replace; and Each R T Independently, it is a halogen, -OH, -O-(C1-C6 alkyl) or a 3- to 7-membered monocyclic heterocyclic alkyl; wherein the -O-(C1-C6 alkyl) or the 3- to 7-membered monocyclic heterocyclic alkyl is optionally substituted with one or more -C(=O)OH.

[0774] Example 43: The compound according to any one of the foregoing embodiments, wherein T is optionally reacted with one or more R T Substituted -O-(C1-C6 alkyl).

[0775] Example 44: The compound according to any one of the foregoing embodiments, wherein T is -OCH3.

[0776] Example 45: The compound according to any one of the foregoing embodiments, wherein T is optionally reacted with one or more R T Substituted -NH-(C1-C6 alkyl).

[0777] Example 46: The compound according to any one of the foregoing embodiments, wherein T is -NHCH3.

[0778] Example 47: The compound according to any one of the foregoing embodiments, wherein T is optionally reacted with one or more R T Substituted C1-C6 alkyl groups.

[0779] Example 48: The compound according to any one of the foregoing embodiments, wherein T is a C1-C6 alkyl group.

[0780] Example 49: The compound according to any one of the foregoing embodiments, wherein T is methyl or ethyl.

[0781] Example 50: The compound according to any one of the foregoing embodiments, wherein T is a C1-C6 alkyl group substituted with one or more halogens.

[0782] Example 51: The compound according to any one of the foregoing embodiments, wherein T is -CHFCl.

[0783] Example 52:The compound according to any one of the foregoing embodiments, wherein T is optionally reacted with one or more R T 取代的C2 -C6 alkenyl.

[0784] Example 53: The compound according to any one of the foregoing embodiments, wherein T is a C2-C6 alkenyl group.

[0785] Example 54: The compound according to any one of the foregoing embodiments, wherein T is a vinyl group.

[0786] Example 55: The compound according to any one of the foregoing embodiments, wherein T is a propenyl group.

[0787] Example 56: The compound according to any one of the foregoing embodiments, wherein T is pentenyl.

[0788] Example 57: The compound according to any one of the foregoing embodiments, wherein T is reacted by one or more R T 取代的C2 -C6 alkenyl.

[0789] Example 58: According to any one of the foregoing embodiments, the compound T is a C2-C6 alkenyl group substituted with one or more -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2 or 3 to 10-membered heterocyclic alkyl groups; wherein the 3 to 10-membered heterocyclic alkyl group is optionally substituted with one or more -C(=O)OH groups.

[0790] Example 59: The compound according to any one of the foregoing embodiments, wherein T is a C2-C6 ynyl group.

[0791] Example 60: The compound according to any one of the foregoing embodiments, wherein T is a propynyl group.

[0792] Example 61: The compound according to any one of the foregoing embodiments, wherein T is reacted by one or more R T Substituted C2-C6 ynyl group.

[0793] Example 62: The compound according to any one of the foregoing embodiments, wherein T is reacted by one or more R T Substituted propynyl group.

[0794] Example 63: The compound according to any one of the foregoing embodiments, wherein T is a propynyl group substituted with one or more 3- to 10-membered heterocyclic alkyl groups.

[0795] Example 64: The compound according to any one of the foregoing embodiments, wherein T is , , , , , , , , , , , , , , , , , or .

[0796] Example 65: The compound according to any one of the foregoing embodiments, wherein T is , , , , , , , , , , , , , , , , or .

[0797] Example 66: According to any one of the foregoing embodiments, the compound wherein at least one R T It is halogen.

[0798] Example 67: According to any one of the foregoing embodiments, the compound wherein at least one R T It is CN, -OH, or -NH2.

[0799] Example 68: According to any one of the foregoing embodiments, the compound wherein at least one R T It is -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; wherein the O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), or the -N(C1-C6 alkyl)2 is optionally separated by one or more R Ta replace.

[0800] Example 69: According to any one of the foregoing embodiments, the compound wherein at least one R T It is -O-(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0801] Example 70: According to any one of the foregoing embodiments, the compound wherein at least one R T It is a C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 alkynyl is optionally surrounded by one or more R Ta replace.

[0802] Example 71: According to any one of the foregoing embodiments, the compound wherein at least one R T It is C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; wherein the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R Ta replace.

[0803] Example 72: According to any one of the foregoing embodiments, the compound wherein at least one R T It is a 3- to 10-membered heterocyclic alkyl group substituted with one or more C(=O)OH groups.

[0804] Example 73: According to any one of the foregoing embodiments, the compound wherein at least one R Ta It is C(=O)OH.

[0805] Example 74: According to any one of the foregoing embodiments, the compound wherein at least one R Ta It is a halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 3 to 10-membered heterocyclic alkyl or 5 to 10-membered heteroaryl.

[0806] Example 75: According to any one of the foregoing embodiments, the compound wherein Ar 1 It is optionally controlled by one or more R A1 Replacement C6-C 10 Aryl; Each R A1 Independently, it is halogen, CN, -OH, -NH2, -OR A1a -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally replaced by one or more R A1a replace; Each R A1a Independently, it is a halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted by one or more R A1b Replace; and Each R A1b It can be halogen, CN, -OH or -NH2 independently.

[0807] Example 76: According to any one of the foregoing embodiments, the compound wherein Ar 1 It is C6-C 10 Aryl.

[0808] Example 77: According to any one of the foregoing embodiments, the compound wherein Ar 1 It is by one or more R A1 Replacement C6-C 10 Aryl.

[0809] Example 78: According to any one of the foregoing embodiments, the compound wherein Ar 1 It is affected by one or more halogens, -OR A1a or -O-(C1-C6 alkyl)-substituted phenyl; wherein the -O-(C1-C6 alkyl) is optionally replaced by one or more R A1a Replace; and each R A1a Independently, it is C6-C 10 aryl or 5- to 10-membered heteroaryl; wherein the C6-C 10 The aryl group or the 5- to 10-membered heteroaryl group may optionally be substituted with one or more halogens.

[0810] Example 79:According to any one of the foregoing embodiments, the compound wherein Ar 1 It is a phenyl group that has been substituted with one or more halogens.

[0811] Example 80: According to any one of the foregoing embodiments, the compound wherein Ar 1 It is a phenyl group substituted with one F or one Cl.

[0812] Example 81: According to any one of the foregoing embodiments, the compound wherein Ar 1 It is a phenyl group optionally substituted with one or more halogens, wherein the phenyl group is further substituted with -O-(C6-C) halogens. 10 Aryl) or -O- (5 to 10 heteroaryl) substitution; wherein the -O- (C6-C 10 The aryl group or the -O- (5 to 10 heteroaryl group) may optionally be substituted with one or more halogens.

[0813] Example 82: According to any one of the foregoing embodiments, the compound wherein Ar 1 It is a phenyl group optionally substituted with one or more halogens, wherein the phenyl group is further substituted with -O-phenyl or -O-pyridyl; wherein the -O-phenyl or the -O-pyridyl is optionally substituted with one or more halogens.

[0814] Example 83: According to any one of the foregoing embodiments, the compound wherein Ar 1 yes , , , or .

[0815] Example 84: According to any one of the foregoing embodiments, the compound wherein Ar 1 yes , or .

[0816] Example 85: According to any one of the foregoing embodiments, the compound wherein Ar 1 yes or .

[0817] Example 86: According to any one of the foregoing embodiments, the compound wherein Ar 1 yes .

[0818] Example 87:According to any one of the foregoing embodiments, the compound wherein at least one R A1 It is halogen.

[0819] Example 88: According to any one of the foregoing embodiments, the compound wherein at least one R A1 It is F and at least one R A1 It is Cl.

[0820] Example 89: According to any one of the foregoing embodiments, the compound wherein at least one R A1 It is CN, -OH, or -NH2.

[0821] Example 90: According to any one of the foregoing embodiments, the compound wherein at least one R A1 Yes - OR A1a .

[0822] Example 91: According to any one of the foregoing embodiments, the compound wherein at least one R A1 It is -O-(C6-C) 10 aryl) or -O- (5 to 10-membered heteroaryl); wherein the -O- (C6-C 10 aryl) or -O- (5 to 10-membered heteroaryl) optionally constituting one or more R A1b replace.

[0823] Example 92: According to any one of the foregoing embodiments, the compound wherein at least one R A1 It is -O-(C6-C) 10 aryl) or -O- (5 to 10-membered heteroaryl); wherein the -O- (C6-C 10 The aryl group or the -O- (5 to 10 heteroaryl group) may optionally be substituted with one or more halogens.

[0824] Example 93: According to any one of the foregoing embodiments, the compound wherein at least one R A1 It is -O-phenyl or -O-pyridyl; wherein the -O-phenyl or the -O-pyridyl is optionally substituted with one or more halogens.

[0825] Example 94: According to any one of the foregoing embodiments, the compound wherein at least one R A1It is -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally separated by one or more R A1a replace.

[0826] Example 95: According to any one of the foregoing embodiments, the compound wherein at least one R A1 It is by one or more C6-C 10 Aryl or 5- to 10-membered heteroaryl-substituted -O-(C1-C6 alkyl), wherein the C6-C 10 The aryl group or the 5- to 10-membered heteroaryl group may optionally be substituted with one or more halogens.

[0827] Example 96: According to any one of the foregoing embodiments, the compound wherein at least one R A1 It is -O-CH2-(C6-C 10 aryl) or -O-CH2- (5 to 10-membered heteroaryl), wherein the -O-CH2- (C6-C 10 Aryl) or -O-CH2- (5 to 10 heteroaryl) may optionally be substituted with one or more halogens.

[0828] Example 97: According to any one of the foregoing embodiments, the compound wherein at least one R A1 It is -O-CH2-phenyl or -O-CH2-pyridyl, wherein the -O-CH2-phenyl or the -O-CH2-pyridyl is optionally substituted with one or more halogens.

[0829] Example 98: According to any one of the foregoing embodiments, the compound wherein at least one R A1 It is C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; wherein the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocyclic alkyl or the 5- to 10-membered heteroaryl, optionally with one or more R A1a replace.

[0830] Example 99: According to any one of the foregoing embodiments, the compound wherein at least one R A1aIt is a halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally separated by one or more R A1b replace.

[0831] Example 100: According to any one of the foregoing embodiments, the compound wherein at least one R A1a It is C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered he...

Claims

1. A compound selected from: And its pharmaceutically acceptable salts.

2. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

3. A compound, which is (Compound No. 37); Or its pharmaceutically acceptable salt.

4. A composition comprising the compound of claim 3 and a pharmaceutically acceptable carrier.

5. A compound, which is (Compound number 37A); Or its pharmaceutically acceptable salt.

6. A composition comprising the compound of claim 5 and a pharmaceutically acceptable carrier.

7. The compound according to claim 1, which is... (Compound number 37B); Or its pharmaceutically acceptable salt.

8. A composition comprising the compound of claim 7 and a pharmaceutically acceptable carrier.

9. A method of inhibiting an oncogenic variant of the ErbB receptor, comprising administering the compound of claim 1 to a subject in need.

10. A method of treating cancer, comprising administering the compound of claim 1 to a subject in need.

11. The method of claim 10, wherein the cancer is bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma (GBM), head and neck cancer, lung cancer, non-small cell lung cancer (NSCLC) or any subtype thereof.

12. A method of inhibiting an oncogenic variant of the ErbB receptor, comprising administering the compound of claim 3 to a subject in need.

13. A method of treating cancer, comprising administering the compound of claim 3 to a subject in need.

14. The method of claim 13, wherein the cancer is bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma (GBM), head and neck cancer, lung cancer, non-small cell lung cancer (NSCLC) or any subtype thereof.

15. A method of inhibiting an oncogenic variant of the ErbB receptor, comprising administering the compound of claim 5 to a subject in need.

16. A method of treating cancer, comprising administering the compound of claim 5 to a subject in need.

17. The method of claim 16, wherein the cancer is bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma (GBM), head and neck cancer, lung cancer, non-small cell lung cancer (NSCLC) or any subtype thereof.

18. A method of inhibiting an oncogenic variant of the ErbB receptor, comprising administering the compound of claim 7 to a subject in need.

19. A method of treating cancer, comprising administering the compound of claim 7 to a subject in need.

20. The method of claim 19, wherein the cancer is bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma (GBM), head and neck cancer, lung cancer, non-small cell lung cancer (NSCLC), or any subtype thereof.

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