Alkinylquinazoline compounds

Abstract

This disclosure relates to a compound of formula (I'), This relates to JPEG2026063185000295.jpg43152 and its pharmaceutically acceptable salts and stereoisomers. [Solution] This disclosure also relates to methods for producing these compounds, compositions containing these compounds, and methods for using them in the prevention or treatment of abnormal cell proliferation in mammals, particularly humans.

Description

[Technical Field]

[0001] Related applications This application claims priority and benefits from U.S. applications No. 63 / 065,028, filed on 13 August 2020, and No. 62 / 887,392, filed on 15 August 2019, the entire contents of which are incorporated herein by reference.

[0002] This disclosure relates to novel compounds as inhibitors of receptor tyrosine kinases (RTKs) in specific oncogenic variants of the ErbB receptor. This disclosure also relates to methods for preparing these compounds, compositions containing these compounds, and methods for using them in the prevention or treatment of abnormal cell proliferation in mammals, particularly humans. [Background technology]

[0003] Mutations affecting either the intracellular catalytic domain or the extracellular ligand-binding domain of the ErbB receptor can result in 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 several cancers. However, not all patients respond well to this treatment. Therefore, there has been a long-standing need in the art for novel therapies that can address the variable responsiveness of cancer patients to known therapies. This disclosure provides compositions and methods for preventing or treating cancer in patients with these oncogenic mutations without the responsiveness variations observed when patients with these ErbB variants are treated with existing standard therapies. [Overview of the project]

[0004] In some embodiments, this disclosure relates to a compound of the following formula (I'), [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, and W is CH or N, Z is a 3- to 12-member heterocycloalkyl optionally substituted with one or more R Z where each R is independently 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, C Z 3-Cycloalkyl, C6-C 3- C 10 aryl, a 3- to 10-member heterocycloalkyl, or a 5- to 10-member heteroaryl, and -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 10 3-Cycloalkyl, C6-C 3- aryl, a 3- to 10-member heterocycloalkyl, or a 5- to 10-member heteroaryl are optionally substituted with one or more R 10 where each R 10 is independently 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 Za cycloalkyl, C6-C aryl, a 3- to 10-member heterocycloalkyl, or a 5- to 10-member heteroaryl, and Za T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more R 10 [[ID=SO]]where each R 10 is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C~-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C cycloalkyl, C6-C T aryl, a 3- to 10-member heterocycloalkyl, or a 5- to 10-member heteroaryl, and each R TThese are independently halogens, 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, C 3- C 10 Cycloalkyl, C6-C 10 These are aryl groups, 3-10 membered heterocycloalkyl groups, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C 3- C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R Ta It is optionally replaced with, Each R Ta These are independently halogens, 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, and C3-C 10 Cycloalkyl, C6-C 10 These are aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl compounds. Ar 1 is one or more R A1 C6-C is optionally replaced by 10 It is Ariel, Each R A1 These are independently 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 alkynyl, C3-C 10 Cycloalkyl, C6-C 10These are aryl groups, 3-10 membered heterocycloalkyl groups, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R A1a It is optionally replaced with, Each R A1a These are independently halogens, 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, C 3- C 10 Cycloalkyl, C6-C 10 These are aryl groups, 3-10 membered heterocycloalkyl groups, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C 3- C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R A1b It is optionally replaced with, and Each R A1b These are independently halogen, CN, -OH, or -NH2.

[0005] In some embodiments, this disclosure provides compounds of the following formula I or pharmaceutically acceptable salts or stereoisomers thereof: [ka] During the ceremony, W is CH or N, preferably CH. X 1 -O-, -S-, or -NR 3 -and, R a , Rb They are independent of each other, hydrogen or C 1-4 Alkyl, or R a One of them is X 1 NR 3 If that is the case, X 1 Together, they form a ring - (CH2) p - and R a One of them is R 2 Together, they form a ring - (CH2) p -and, R c , R d They are independent of each other, hydrogen or C 1-4 It is alkyl, R 1 is H or F, R 2 is hydrogen or C 1-4 Alkyl or R 3 It forms a ring together with R a Forms a ring with one of them - (CH2) q -and, R 3 is hydrogen or C 1-4 Alkyl, preferably hydrogen or methyl, or R 2 Together, they form a ring - (CH2) p -and, m is 1, 2, or 3. n is 0, 1, or 2. p is either 1 or 2. q is 0, 1 or 2, and Ar 1 is either unsubstituted or halogen, -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 1-6Alkylamino, 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 Is a 6-membered aryl substituted with one or more of the groups selected from alkoxy, or C6 aryl.

[0006] In some embodiments, X 1 Is, -NR 3 -, when R 2 Is not hydrogen.

[0007] In some embodiments, X 1 Is -, NR 3 -, when R 2 Is C 1-4 Alkyl, or R 3 Forms a ring with, or R a Forms a ring with one of -(CH2) q -.

[0008] In some embodiments, X 1 Is, -NR 3 -, and R 2 Is not hydrogen.

[0009] In some embodiments, X 1 Is -, NR 3 -, and R 2 Is C 1-4 Alkyl, or R 3 Forms a ring with, or R a Forms a ring with one of -(CH2) q -.

[0010] In some embodiments, X 1 Is, NR 3 Or O, wherein R 3 Is methyl, ethyl, n-propyl or n-butyl.

[0011] In some embodiments, R 1 It is hydrogen.

[0012] In some embodiments, R 2 is methyl, ethyl, n-propyl or n-butyl-, preferably methyl, or R 2 R 3 It is either -(CH2)- or -(CH2)2- which form a ring together with R 2 R a It is a -(CH2)- or -(CH2)2- which forms a ring with one of the others.

[0013] R a One of them is R 3 In some embodiments where a ring is formed together, the formed ring is a 4, 5, or 6-membered ring, or a 5 or 6-membered ring, or a 5-membered ring.

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

[0015] R 2 One of them is R 3 In some embodiments where a ring is formed together, the formed ring is a 4, 5, or 6-membered ring, or a 5, 6, or 6-membered ring.

[0016] In some embodiments, Ar 1 is the compound of formula i, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, R 4 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, C1-6 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 Alkoxyaminocarbonyl, aryl C 1-6 It is an alkoxy or C6 aryl compound. R 5 , R 5’ , R 6 , R 6’ These are, independently of each other, hydrogen, -CF3, or halogen, preferably F, Cl.

[0017] In some embodiments, R 1 It is hydrogen.

[0018] In some embodiments, R c and R d is hydrogen. In some embodiments, R b , R c and R d It is hydrogen.

[0019] In some embodiments, R 2 is methyl or R 2 R 3 It is either -(CH2)- or -(CH2)2- which form a ring together with R 2 R a It is a -(CH2)- or -(CH2)2- which forms a ring with one of the others.

[0020] In some embodiments, Ar 1 This is formula ii-1, ii-2, ii-3, or ii-4, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, X 2 is O, NH, or NMe, X 3 is CH or N, o is either 0 or 1, R 4 is hydrogen or halogen, preferably F or Cl. R 5 , R 5 ', R 6 , R 6 ' is independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl, R 7 is hydrogen or a halogen, preferably F.

[0021] In some embodiments, R 5 is F and / or R 6 It is either F or Cl.

[0022] In some embodiments, R 1 It is hydrogen.

[0023] In some embodiments, R 2 is methyl or R 2 R 3 It is either -(CH2)- or -(CH2)2- which form a ring together with R 2 R a It is a -(CH2)- or -(CH2)2- which forms a ring with one of the others.

[0024] In some embodiments, R c and R d is hydrogen. In some embodiments, R b , R c and R d It is hydrogen.

[0025] In some embodiments, Ar 1This is formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, X 3 is CH or N, o is either 0 or 1, R 4 is hydrogen or halogen, preferably F or Cl. R 5 , R 6 These are, independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl. R 7 is hydrogen or a halogen, preferably F.

[0026] In some embodiments, R 5 is F and / or R 6 It is either F or Cl.

[0027] In some embodiments, R 1 It is hydrogen.

[0028] In some embodiments, R c and R d is hydrogen. In some embodiments, R b , R c and R d It is hydrogen.

[0029] In some embodiments, R 2 is methyl or R 2 R 3 It is either -(CH2)- or -(CH2)2- which form a ring together with R 2 R a It is a -(CH2)- or -(CH2)2- which forms a ring with one of the others.

[0030] In some embodiments, Ar 1This is formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, X 3 is C or N, preferably N. o is either 0 or 1, R 4 is hydrogen or halogen, preferably F or Cl. R 5 , R 6 These are, independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl. R 7 is hydrogen or a halogen, preferably F.

[0031] In some embodiments, R 5 is F, and / or R in this case 6 It is either F or Cl.

[0032] In some embodiments, R 1 It is hydrogen.

[0033] In some embodiments, R c and R d is hydrogen. In some embodiments, R b , R c and R d It is hydrogen.

[0034] In some embodiments, R 2 is methyl or R 2 R 3 It is either -(CH2)- or -(CH2)2- which form a ring together with R 2 R a It is a -(CH2)- or -(CH2)2- which forms a ring with one of the others.

[0035] In some embodiments, Ar1 This is formula iv-1, iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, o is either 0 or 1, R 4 is hydrogen or halogen, preferably F or Cl. R 5 , R 6 These are, independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl. R 7 is hydrogen or a halogen, preferably F.

[0036] In some embodiments, R 5 is F and / or R 6 It is either F or Cl.

[0037] In some embodiments, R 1 It is hydrogen.

[0038] In some embodiments, R c and R d is hydrogen. In some embodiments, R b , R c and R d It is hydrogen.

[0039] In some embodiments, R 2 is methyl or R 2 R 3 It is either -(CH2)- or -(CH2)2- which form a ring together with R 2 R a It is -(CH2)- or -(CH2)2- which forms a ring with one of them. In some embodiments, R 7 It is F.

[0040] In some embodiments, the present disclosure provides compounds of formula IIa or IIb below, or pharmaceutically acceptable salts or stereoisomers thereof: [ka] During the ceremony, X 1 -O- or -NR 3 -and, R 1 is H or F, R 2 is hydrogen or C 1-4 Alkyl, preferably methyl, or R 3 Together, they form a ring - (CH2) q -and, R 3 is hydrogen or C 1-4 Alkyl, preferably hydrogen or methyl, or R 2 Together, they form a ring - (CH2) p -and, m is 1, 2, or 3. n is 0, 1, or 2. p is either 1 or 2. q is 0, 1, or 2. r is either 0 or 1. s is 1 or 2, and Ar 1 is either unsubstituted or halogen, -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, C1-6 Alkoxycarbonyl, C 1-6 Alkoxyaminocarbonyl, aryl C 1-6 A six-membered aryl group that is substituted with one or more groups selected from alkoxys or C6 aryls.

[0041] In some embodiments, R 1 It is hydrogen.

[0042] In some embodiments, R 2 is methyl or R 2 R 3 It is a -(CH2)- or -(CH2)2- which forms a ring together with .

[0043] In some embodiments, X 1 However, -NR 3 -If R 2 It is not hydrogen.

[0044] In some embodiments, X 1 But, NR 3 -If R 2 C 1-4 Alkyl or R 3 It forms a ring together with R a Forms a ring with one of them - (CH2) q - is

[0045] In some embodiments, X 1 -NR 3 - and R 2 It is not hydrogen.

[0046] In some embodiments, X 1 Ha-, NR 3 - and R 2 C 1-4 Alkyl or R 3 It forms a ring together with R a Forms a ring with one of them - (CH2) q - is

[0047] In some embodiments, the present disclosure provides compounds of formula III below or pharmaceutically acceptable salts or stereoisomers thereof: [ka] During the ceremony, R 1 is H or F, Ar 1 is either unsubstituted or halogen, -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 A six-membered aryl substituted with one or more groups selected from alkoxyaminocarbonyl or C6 aryl, and Z is selected from the following: [ka]

[0048] In some embodiments, R 1 It is hydrogen.

[0049] In some embodiments, the present disclosure provides compounds of formula IV below or pharmaceutically acceptable salts or stereoisomers thereof: [ka] During the ceremony, R 1is H or F, R 4 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 It is an alkoxyaminocarbonyl or C6 aryl, R 5 , R 5 ', R 6 , R 6 ' is independently of each other, hydrogen, -CF3 or halogen, preferably F or Cl, and Z is selected from the following: [ka]

[0050] In some embodiments, R 5 is F and / or R 6 It is either F or Cl.

[0051] In some embodiments, R 1 It is hydrogen.

[0052] In some embodiments, the present disclosure provides compounds of the following formulas V-1, V-2, V-3, or V-4, or pharmaceutically acceptable salts or stereoisomers thereof: [ka] During the ceremony, X 2 is O, NH, or NMe, X 3 is C or N, R 1 is H or F, R 4 is hydrogen or halogen, preferably F or Cl. R 5 , R 5 ', R 6 , R 6 ' is independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl, o is either 0 or 1, R 7 is hydrogen or halogen, preferably F, and Z is selected from the following: [ka]

[0053] In some embodiments, R 5 is F and / or R 6 It is either F or Cl.

[0054] In some embodiments, R 1 It is hydrogen.

[0055] In some embodiments, the present disclosure provides compounds of the following formulas VI-1, VI-2, VI-3, or VI-4, or pharmaceutically acceptable salts or stereoisomers thereof: [ka] During the ceremony, X 2 is O, NH, or NMe, X 3 is C or N, R 1 is H or F, o is either 0 or 1, R 4is hydrogen or halogen, preferably F or Cl. R 5 , R 6 These are, independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl. R 7 is hydrogen or halogen, preferably F, and Z is selected from the following: [ka]

[0056] In some embodiments, R 5 is F and / or R 6 It is either F or Cl.

[0057] In some embodiments, R 1 It is hydrogen.

[0058] In some embodiments, the present disclosure provides compounds of the following formulas VII-1, VII-2, VII-3 or VII-4, VII-5, VII-6, VII-7, VII-8 or VII-9, or pharmaceutically acceptable salts or stereoisomers thereof: [ka] During the ceremony, R 1 is H or F, o is either 0 or 1, R 4 is hydrogen or halogen, preferably F or Cl. R 5 , R 6 These are, independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl. R 7 is hydrogen or halogen, preferably F. Z is selected from the following: [ka]

[0059] In some embodiments, R 5 is F and / or R 6 It is either F or Cl.

[0060] In some embodiments, R 1 is hydrogen. In a particular embodiment, R 7 It is F.

[0061] In some embodiments, this disclosure covers compositions comprising a compound described in any of the embodiments described herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0062] In some embodiments, the composition comprises a pharmaceutically acceptable carrier.

[0063] In some embodiments, the composition comprises a second therapeutic agent.

[0064] In some embodiments, the present disclosure relates to methods for inhibiting oncogenic variants of the ErbB receptor (e.g., oncogenic variants of EGFR), which include administering a therapeutically effective amount of a compound described herein to a subject in need thereof.

[0065] In some embodiments, the present disclosure relates to methods for inhibiting oncogenic variants of the ErbB receptor (e.g., oncogenic variants of EGFR), which include administering compositions described herein to subjects requiring such inhibition.

[0066] In some embodiments, the Disclosure relates to methods for preventing or treating cancer, which include administering a therapeutically effective amount of a compound described herein to a subject in need thereof.

[0067] In some embodiments, the Disclosure relates to methods for preventing or treating cancer, which include administering compositions described herein to subjects in need thereof.

[0068] In some embodiments, this disclosure relates to compounds described herein for use in inhibiting oncogenic variants of the ErbB receptor (e.g., oncogenic variants of EGFR).

[0069] In some embodiments, this disclosure covers compounds described herein for use in the prevention or treatment of cancer.

[0070] In some embodiments, this disclosure relates to compositions described herein for use in inhibiting oncogenic variants of the ErbB receptor (e.g., oncogenic variants of EGFR).

[0071] In some embodiments, this disclosure covers compositions described herein for use in the prevention or treatment of cancer.

[0072] In some embodiments, this disclosure relates to the use of the compounds described herein in the manufacture of agents for inhibiting oncogenic variants of the ErbB receptor (e.g., oncogenic variants of EGFR).

[0073] In some aspects, this disclosure covers the use of the compounds described herein in the manufacture of agents for the prevention or treatment of cancer.

[0074] In some embodiments, the cancer is a gliablastoma.

[0075] In some embodiments, the Disclosure relates to methods for preventing or treating gliablastoma, which include administering a therapeutically effective dose of a compound described in any of the embodiments described herein to a subject in need.

[0076] In some embodiments, this disclosure relates to compounds described in any of the embodiments described herein for use in the prevention or treatment of gliablastoma.

[0077] In some embodiments, the Disclosure relates to methods for preventing or treating gliablastoma, which include administering to a subject in need of such treatment a composition described in any of the embodiments described herein.

[0078] In some embodiments, this disclosure relates to compositions described in any of the embodiments described herein for use in the prevention or treatment of gliablastoma. [Modes for carrying out the invention]

[0079] This disclosure relates to compounds useful as inhibitors of receptor tyrosine kinases (RTKs) in specific oncogenic variants of the ErbB receptor. In some embodiments of the present invention, the oncogenic variant of the ErbB receptor is also an allosteric variant of the ErbB receptor. In some embodiments, the allosteric variant comprises or may comprise an ErbB receptor variant having a mutation in the sequence outside the ATP binding site. In some embodiments, the allosteric variant comprises or may comprise an ErbB receptor variant having a mutation in one or more sequences within exon 19, exon 20, or the C1-C2 extracellular dimerization interface.

[0080] Mutations affecting either the intracellular catalytic domain or the 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). Extracellular variants of the ErbB receptor in cancers, including EGFR-Viii (and EGFR-V3) and HER2-S310F, are constitutively activated in the absence of ligands, exhibiting persistent signaling resistant to downregulation, and are both transformative and oncogenic (Nishikawa, Ji et al. 1994, 2013, Francis, Zhang et al. 2014). Their expression is associated with metastasis and poor long-term overall survival.

[0081] In gliablastoma (also known as pleomorphic gliablastoma 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 tends to be mutually exclusive with the expression of other RTK oncogenes co-expressed with EGFR variants in only 7% of GBM tumors (Furnari, Cloughesy et al. 2015). These data demonstrate how EGFR-Viii has 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 cell NSCLC (Ji, Zhao et al. 2006, Sasaki, Kawano et al. 2007), and is associated with resistance to current therapies, 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.

[0082] RNA sequencing data revealed that this was only one of several abnormally spliced ​​variants of EGFR expressed in GBM tumors. The other two resulted in exons 12-13 (EGFR-Vvi) and truncation of exons 14-15 (EGFR-Vii). Like EGFR-Viii, EGFR-Vii is both transformative and oncogenic. In addition to splice variants, GBM tumors also express a group of EGFR point mutations, including C620Y, A289V, and G598V, which are both transformative and oncogenic.

[0083] HER2-S310F is the most common HER2 mutation expressed in human tumors, representing approximately 0.5% of all tumors. Expression of HER2-S310F is mutually exclusive with HER2 amplification. HER2-S310F is highly oncogenic and transforms BaF3 cells (a mouse interleukin-3 (IL-3)-dependent pro-B cell line) into IL-3-independent cells, promoting tumor growth in vivo.

[0084] Short insertions within exon 20 of EGFR and HER2 are expressed by lung adenocarcinoma tumors and other tumor groups. ErbB exon 20 insertion mutants are expressed by 4–5% of lung adenocarcinoma tumors. Examples include HER2-YVMA, EGFR-SVD, and EGFR-NPH. These ErbB exon 20 insertion mutants are highly oncogenic and transform BaF3 cells independently of IL-3, promoting tumor growth in vivo.

[0085] ErbB inhibitors are a known treatment for several cancers. However, not all patients respond well to this treatment. Therefore, there has been a long-standing need in the art for novel therapies that can address the variable responses of cancer patients to known therapies. The present invention can overcome some of these shortcomings of standard treatments that existed prior to the development of the compositions and methods disclosed herein.

[0086] Paradoxical ErbB receptor activation The mechanisms described herein apply to any form of cancer in which these EGFR variants of the Disclosure are expressed, but the spread of these variants in gliablastoma (GBM) is provided as an example. Other cancers that express the EGFR variants of the Disclosure include, but are not limited to, solid tumors, epithelial cancers and / or cancers of epithelial origin, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, gliablastoma (GBM), head and neck cancer, lung cancer, and non-small cell lung cancer (NSCLC).

[0087] In GBM tumors, EGFR is often a target for genomic mutations and alternative splicing events that result in alterations at the extracellular dimer interface. Many tumors express two or more aberrant isoforms. This disclosure provides the mechanisms of activation for the most commonly occurring variants: EGFR-Viii, EGFR-Vii, EGFR-Vvi, EGFR-G598V, and EGFR-A289V. Each isoform / point mutation is the result of a unique external domain alteration, but all are activated by a common mechanism involving covalent ligand-dependent dimerization.

[0088] AMG-595 (Amgen) is an EGFR-Viii isoform selective antibody that is inactive against wild-type EGFR or other splice-activating variants. Rindopepimut (Celldex) is a vaccine that selectively induces an immunological response against tumor cells that express EGFR-Viii but do not express wild-type EGFR or other splice-activating isoforms. Other EGFR isoforms 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 of ErbB inhibitors that are selective only for EGFR-Viii. Therefore, it may be useful to exclude patients whose tumors express EGFR-Vii, EGFR-Vvi, or EGFR external domain point mutants from treatment with EGFR-Viii selective therapy.

[0089] Heterogeneous genotypic expression patterns of multiple external domain variants of the ErbB receptor in tumors indicate a preference for small molecule inhibitors that inhibit all variants. The family of covalently activated EGFR isoforms responds very differently to small molecule ErbB inhibitors compared to EGFR catalytic domain mutations observed in NSCLC. Importantly, all type I inhibitors, including erlotinib, induce the formation of covalently bound EGFR dimers and increase EGFR phosphorylation at subsaturated concentrations, an activity further enhanced when the ErbB inhibitor is flushed out. This manifests as paradoxical activation of proliferation at subsaturated concentrations.

[0090] The discovery of paradoxical activation of proliferation at subsaturated concentrations of type I ErbB inhibitors further demonstrates this for a range of extracellular variants of HER2 prevalent in several cancers, including breast and bladder cancer. Levels of all variants existing as covalently activated receptors, as well as covalent dimers, increased after treatment with type I inhibitors, including sapitinib and afatinib. Similar to covalently activated EGFR variants, subsaturated doses of type I inhibitors paradoxically increased phosphorylation of HER2 variants, leading to increased proliferation of cells expressing them.

[0091] In contrast to type I inhibitors, this disclosure demonstrates that non-type I (e.g., type II) inhibitors, including neratinib, do not exhibit paradoxical activation in cells expressing ErbB extradomain variants. Neratinib has proven to be a prime example of a preferred molecule that is both potent and selective against each member of the covalently activated EGFR family compared to wild-type EGFR.

[0092] In summary, this disclosure provides structure / function relationships to predict how structural variations affecting the distal receptor region to the active site may confer dramatically different responses to small molecule active-site inhibitors. The findings described herein regarding the paradoxical activation of covalently activated ErbB receptor variants by type I inhibitors have significant clinical implications. The data in this disclosure provide a mechanistic explanation for the failures of clinical studies of type I inhibitors in tumor types where covalently activated ErbB receptor expression is widespread. This includes erlotinib and gefitinib in GBM tumors, erlotinib in SCCHN tumors, and sapitinib in breast tumors.

[0093] Gliablastoma Gliablastoma (GBM), a grade IV astrocytoma, is the most common form of brain cancer. The prognosis for this disease is poor. The standard treatment regimen is surgery followed by radiation and temozolomide, but the median overall survival (OS) with this regimen is only 14.6 months, and most patients do not survive for 5 years. There has been little progress in extending the survival of GBM patients over the past decade. In the relapse setting, bevacizumab showed an improvement in progression-free survival, but the addition of bevacizumab to the standard treatment regimen in the cutting-edge setting did not result in an OS benefit.

[0094] EGFR is the most frequently altered oncogene in GBM. In addition to EGFR gene amplification, many tumors express variants generated by abnormal splicing or genomic mutations. The first recognized variant was EGFR-Viii, resulting from truncation of exons 2-7, and is expressed in approximately 20% of GBM tumors. EGFR-Viii is oncogenic. EGFR-Viii is constitutively activated in the absence of EGF ligands and exhibits persistent signaling that is resistant to downregulation. Therefore, EGFR-Viii is both transformative and tumorigenic. Expression of EGFR-Viii is associated with poor long-term overall survival in GBM.

[0095] RNA sequencing data revealed that the EGFR variant expressed in GBM tumors was only one of several abnormally spliced ​​variants. The other two result in exons 12-13 (EGFR-Vvi) and a shortening of exons 14-15 (EGFR-Vii). Like EGFR-Viii, EGFR-Vii is both transformative and oncogenic. In addition to splice variants, GBM tumors also express a group of EGFR point mutations, including C620Y, A289V, and G598V, which are both transformative and oncogenic. The complex situation of EGFR alterations in GBM is further complicated by the finding that many tumors express two or more receptor variants.

[0096] Because the expression of multiple EGFR variants in GBM leads to transformation and oncogenic 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) in NSCLC tumors carrying activating mutations in EGFR, these drugs were tested in GBM. Despite an intensive clinical investigation of ErbB inhibitors in this group of GBM patients, involving >30 clinical trials and >1500 patients, none of them yielded any benefit, even in those tumors expressing EGFR-Viii. Surprisingly, some evidence suggests that erlotinib may have accelerated disease progression. A phase II trial evaluating erlotinib in combination with radiation and temozolomide showed median progression-free survival (mPFS) of 2.8 months and median overall survival (mOS) of 8.6 months, compared to 6.9 months and 14.6 months, respectively, in patients receiving radiation and temozolomide alone. Another randomized phase II trial with erlotinib showed that patients treated with erlotinib, including those with tumors expressing EGFR-Viii, experienced less progression compared to patients receiving standard treatment. The clinical failure of ErbB inhibitors such as erlotinib in GBM tumors has raised questions about the role of EGFR as a driver of tumor growth in GBM and has led to an investigation into why ErbB inhibitors, which were highly effective in treating EGFR mutations in lung cancer, were so ineffective in treating EGFR variants in GBM.

[0097] A distinctive feature of EGFR variants expressed in GBM is their location within the extracellular domain. This contrasts with activating mutations of EGFR seen in lung cancer, which are often located in the intracellular catalytic domain. EGFR consists of four extracellular domains (two ligand-binding domains and two cysteine-rich regions), a transmembrane domain, and an intracellular catalytic domain. Ligand binding promotes dimerization of the extracellular cysteine-rich domains (CR1 and CR2), an event that confers dimerization of the intracellular domain and activation of receptor catalytic activity. Almost all EGFR splicing events and mutations in GBM affect the extracellular domain, particularly the two cysteine-rich regions (CR1 and CR2) that form the extracellular dimer interface. The CR region contains >40 cysteine ​​residues, all of which form intramolecular disulfide bonds. In EGFR-Viii, truncation of exons 2-7 results in partial loss of the sequence encoding the CR1 region. The result is the loss of one cysteine ​​from the Cys295-Cys307 pair, leaving Cys307 as a free, unpaired cysteine. For EGFR-Viii, this cysteine ​​forms an intermolecular disulfide bond with another EGFR monomer, leading to covalent dimerization and constitutively activated receptor formation. Mutation of cysteine ​​307 to serine (C307S) prevents the formation of EGFR-Viii, which is covalently dimerized and inactive.

[0098] Recent preclinical studies have suggested that EGFR kinase inhibitors such as erlotinib are not very effective in inhibiting EGFR-Viii, but no proposed mechanism has been established for this effect. Current understanding of the mechanisms involved in the activation of other external domain variants in GBM, including EGFR-Vii and EGFR-A289V, is also lacking. This disclosure provides the mechanisms of receptor activation and their effects on ErbB inhibitor activity for four groups of the most common external domain variants in GBM: EGFR-Viii, EGFR-Vii, EGFR-Vvi, EGFR-G598V, and EGFR-A289V.

[0099] This disclosure shows that, similar to EGFR-Viii, a further group of EGFR variants commonly occurring in GBM (EGFR-Vii, EGFR-Vvi, EGFR-G598V, and EGFR-A289V) all exist as constitutively active covalent dimers, forming a family of EGFR isoforms activated by 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 and confers unique activity to a class of small molecule inhibitors that bind to this distal site. Inhibitors that stabilize the active conformation of kinases (including type I inhibitors, erlotinib) induce covalent dimerization for all covalently activated EGFR isoforms. This is related to the tendency of type I inhibitors to increase EGFR phosphorylation at subsaturated concentrations, paradoxically stimulating the proliferation of cells expressing covalently activated EGFR isoforms.

[0100] Neither enhanced dimerization nor paradoxical activation of EGFR is observed with small molecule inhibitors that stabilize the inactive kinase structure (including type II inhibitors, lapatinib, and neratinib). Examples of type II inhibitors that are potent inhibitors of covalently activated EGFR isoforms and are selective to this family compared to WT-EGFR have been identified.

[0101] Similar to mutations identified for EGFR, this disclosure identifies a group of splice events and mutations affecting the CR domains of HER2 and HER4. This disclosure shows that this group of splice events and mutations affecting the CR domains of HER2 and HER4 exist as covalent dimers and are paradoxically activated by type I-binding drugs. These data provide a mechanistic explanation for the failures of multiple clinical trials involving type I inhibitors, including >30 clinical trials of type I ErbB inhibitors in GBM. Taken together, these data suggest that tumors expressing covalently activated EGFR isoforms should be excluded from treatment with type I ErbB inhibitors such as erlotinib due to paradoxical activation. These data further demonstrate the usefulness of optimizing type II ErbB inhibitors for the covalently activated ErbB family.

[0102] definition Unless otherwise specified, the following general definitions apply to the compounds described herein.

[0103] As used herein, the term “compounds of the disclosure” means compounds represented by any of the formulas described herein (e.g., formulas (I') to (IV') and formulas (I) to (VII)) and any of the specific examples disclosed herein.

[0104] However, it should be understood that the compounds disclosed herein may be represented by a particular structure. Such a particular structure should not be interpreted as being limited to one or another isomer, tautomer, regioisomer, or stereoisomer, much less exclude mixtures of isomers, tautomers, regioisomers, or stereoisomers. In some embodiments, the representation of a compound herein by a particular structure is intended to encompass and refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof, while such representation is also intended to refer to a particular structure of the compound.

[0105] Furthermore, it is understood that the compounds disclosed herein may be represented without a specific structure (for example, without a specific stereochemistry). Such representations are intended to encompass all available isomers, tautomers, regioisomers, and stereoisomers of the compound. In some embodiments, a representation of a compound herein without a specific structure is intended to refer to any of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof.

[0106] As used herein, the term "isomer" means a compound having the same molecular formula but differing in the bonding order of its atoms or the spatial arrangement of its atoms. Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers." Stereoiomers that are not mirror images of each other are called "diastereoisomers," and stereoisomers that are mirror images of each other but cannot be superimposed are called "enantiomers" or, in some cases, optical isomers. A mixture containing equal amounts of individual enantiomers of opposite chirality is called a "racemic mixture."

[0107] As used herein, the term “chiral center” refers to a carbon atom bonded to four non-identical substituents.

[0108] As used herein, the term “chiral isomer” means a compound having at least one chiral center. Compounds having two or more chiral centers may exist as individual diastereomers or as a mixture of diastereomers called a “diastereomer mixture.” When a single chiral center is present, stereoisomers can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. Substituents attached to the chiral center under consideration are ranked according to the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0109] As used herein, the term “geometric isomer” means a diastereomer whose presence prevents rotation with respect to a double bond or cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are named according to the Cahn-Ingold-Prelog rule, with prefixes cis and trans, or Z and E, indicating that the group is on the same or opposite side of the double bond within the molecule.

[0110] "Independently of each other" is understood to mean that if a group occurs more than once in any compound, the definition of each occurrence is independent of any other occurrence.

[0111] The dashed lines (or waves perpendicular to the bonds) are further understood to indicate the binding sites (i.e., subformulas) of residues.

[0112] As used herein, the terms "halogen" or "hal" may be fluoro, chloro, bromo, or iodine, preferably fluoro or chloro.

[0113] As used herein, “alkyl,” “C1, C2, C3, C4, C5 or C6 alkyl,” or “C1-C6 alkyl” is intended to include “linear saturated aliphatic hydrocarbon groups of C1, C2, C3, C4, C5 or C6, and branched saturated aliphatic hydrocarbon groups of C3, C4, C5 or C6.” For example, C1-C6 alkyl is intended to include alkyl groups of C1, C2, C3, C4, C5, and C6. Examples of alkyls, but not limited to, include moieties having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, linear or branched alkyls have 6 or fewer carbon atoms (for example, C for linear groups). 1- C6, regarding branching chains, C 3- C) is present, and in another embodiment, a linear or branched alkyl has four or fewer carbon atoms. In some embodiments, the term “alkyl” refers to a fully saturated branched or unbranched hydrocarbon moiety. 1-4 The term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety having one, two, three, or four carbon atoms. Typical examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.

[0114] As used herein, the term “optionally substituted alkyl” means an unsubstituted alkyl, or an alkyl in which the specified substituent substitutes one or more hydrogen atoms on one or more carbons of the hydrocarbon skeleton. Examples of such substituents include alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylates, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphates, phosphonates, phosphinates, aminos (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylaminos (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylates, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0115] As used herein, the term “alkenyl” includes unsaturated aliphatic groups that are similar to the alkyls described above in length and substitution possibilities, but contain at least one double bond. For example, the term “alkenyl” includes linear alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In certain embodiments, linear or branched alkenyl groups have six or fewer carbon atoms in their skeleton (e.g., C2-C6 for linear groups, C3-C6 for branched groups). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms.

[0116] As used herein, the term “optionally substituted alkenyl” refers to an unsubstituted alkenyl, or an alkenyl in which a specified substituent substitutes one or more hydrogen atoms on carbons of one or more hydrocarbon skeletons. Examples of such substituents include alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylates, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphates, phosphonates, phosphinates, aminos (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylaminos (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylates, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0117] As used herein, the term “alkynyl” includes unsaturated aliphatic groups that are similar to the alkyls described above in length and substitution possibilities, but contain at least one triple bond. For example, the term “alkynyl” includes linear alkynyl groups (e.g., elinyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, noninyl, desynyl) and branched alkynyl groups. In certain embodiments, linear or branched alkynyl groups have six or fewer carbon atoms in their skeleton (e.g., C2-C6 for linear groups, C3-C6 for branched groups). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “C3-C6” includes alkynyl groups containing three to six carbon atoms. As used herein, "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to contain a divalent unsaturated aliphatic hydrocarbon group of C2, C3, C4, C5, or C6 in a chain (straight or branched). For example, a C2-C6 alkenylene linker is intended to contain an alkenylene linker group of C2, C3, C4, C5, or C6.

[0118] As used herein, the term “optionally substituted alkynyl” refers to an unsubstituted alkynyl, or an alkynyl in which the specified substituents substitute one or more hydrogen atoms on carbons of one or more hydrocarbon skeletons. Examples of such substituents include alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylates, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphates, phosphonates, phosphinates, aminos (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylaminos (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylates, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0119] Other optionally substituted moieties (e.g., optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both an unsubstituted moiety and a moiety having one or more of the specified substituents. For example, substituted heterocycloalkyls include 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.

[0120] As used herein, the terms “alkoxy” or “alkoxyl” include substituted and unsubstituted alkyl groups covalently bonded to an oxygen atom. Examples of alkoxy or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups.

[0121] As used herein, the term “cycloalkyl” refers to monocyclic or polycyclic (e.g., fusion, cross-linking, or spirocyclic) systems of saturated or partially unsaturated hydrocarbons having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, adamantyl, and hexahydroindacenyl. For polycyclic (e.g., fusion, cross-linking, or spirocyclic) systems, it is understood that only one of the rings must be non-aromatic.

[0122] As used herein, the term “aryl” refers to an aromatic group, including a “conjugated” or polycyclic system having one or more aromatic rings, and which does not contain heteroatoms in the ring structure. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. In some embodiments, the aryl is phenyl.

[0123] As used herein, the term "heterocycloalkyl" means, unless otherwise specified, one or more heteroatoms (e.g., O, N, S, P, or Se) independently selected from the group consisting of nitrogen, oxygen, and sulfur, for example, one, one-two, one-three, one-four, one-five, or one-six heteroatoms, for example, saturated or partially unsaturated 3- to 8-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spiro-ring), or 11- to 14-membered tricyclic ring systems (fused, bridged, or spiro-ring) having one, two, three, four, five, or six heteroatoms.Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxyranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4 -Diazepanyl, 1,4-Oxazepanyl, 2-Oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-Diazabicyclo[2.2.1]heptanyl, 2-Oxa-6-azaspiro[3.3]heptanyl, 2,6-Diazaspiro[3.3]heptanyl, 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'-Isobe [Nzofuran]-yl, 7'H-spiro[cyclohexane-1,5'-flo[3,4-b]pyridine]-yl, 3'H-spiro[cyclohexane-1,1'-flo[3,4-c]pyridine]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexane-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-pyrazolyl Examples include [3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxazaspiro[3.4]octanyl, and 2-oxazaspiro[3.4]octan-6-yl. In the case of polycyclic heterocycloalkyls, only one of the rings in the heterocycloalkyl must be non-aromatic.In some embodiments, the heterocycloalkyl is oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azabispiro[3.3]heptanyl, 2-oxa-5-azabispiro[3.4]octanyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azabispiro[3.3]heptanyl, or 2-oxa-5-azabispiro[3.4]octanyl.

[0124] As used herein, the term “heteroaryl” is intended to include a carbon atom and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, for example, one or one-two or one-three or one-four or one-five or one-six heteroatoms, or a stable five-membered, six-membered, or seven-membered monocyclic or seven-membered, eight-membered, nine-membered, ten-membered, eleven-membered, or twelve-membered bicyclic aromatic heterocycle consisting of one, two, three, four, five, or six heteroatoms. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other defined substituents). The nitrogen heteroatom and sulfur heteroatom may optionally be oxidized (i.e., N → O, and S(O) p(wherein p=1 or 2). Note that the total number of S and O atoms in the aromatic heterocycle is 1 or less. In some embodiments, the term “heteroaryl” refers to a (complete) aromatic ring system having 3, 4, 5, or 6 ring atoms, preferably 6 ring atoms, selected from C, N, O, or S, preferably C, N, or O, more preferably C, N, with the number of N atoms preferably 0, 1, 2, or 3, and the number of O atoms and S atoms each 0, 1, or 2. Examples of “heteroaryl” include furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyradazinyl), pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl, etc. A preferred example of a “heteroaryl” is pyridinyl.

[0125] In some embodiments, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is a ring-forming carbon or a heteroatom such as N, with the above substituents at one or more ring positions (e.g., ring-forming carbons or heteroatoms such as N). Substituted with an aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moiety. In some embodiments, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with a halogen (e.g., F or Cl).

[0126] As used herein, the term “substituted” means that any one or more hydrogen atoms on a designated atom are substituted with a group of choice from the designated group, provided that the substitution does not exceed the normal valence of the designated atom and that the substitution results in a stable compound. If the substituent is oxo or keto (i.e., =O), two hydrogen atoms on the atom are substituted. Keto substituents are not present in aromatic moieties. A ring double bond, as used herein, is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0127] The terms “nucleic acid” and “polynucleotide” are used herein synonymously to refer to single-stranded or double-stranded RNA, DNA, or mixed polymers. Polynucleotides may include genomic sequences, extragenomic and plasmid sequences, and smaller engineered gene segments that express or can be adapted to express polypeptides.

[0128] "Isolated nucleic acids" are nucleic acids that are substantially separated from other genomic DNA sequences naturally associated with a native sequence, as well as from proteins or complexes such as ribosomes and polymerases. This term encompasses nucleic acid sequences removed from their naturally occurring environment, and includes recombinant or cloned DNA isolates, and chemically synthesized analogs or biologically synthesized analogs from heterologous systems. Substantially pure nucleic acids include isolated forms of nucleic acids. This, of course, refers to the original isolated nucleic acid, but does not exclude genes or sequences later added by humans to such isolated nucleic acid.

[0129] The term "polypeptide" is used in its conventional sense, i.e., as a sequence of amino acids. Polypeptides are not limited to a specific length of product. Peptides, oligopeptides, and proteins are included within the definition of polypeptide, and such terms may be used synonymously herein unless specifically indicated otherwise. This term also does not refer to, or excludes, post-expression modifications of polypeptides, such as glycosylation, acetylation, phosphorylation, etc., both naturally occurring and unnatural, as well as other modifications known in the art. A polypeptide may be an entire protein or a portion thereof.

[0130] "Isolated polypeptide" is identified, separated from its natural environment components, and / or recovered. In preferred embodiments, the isolated polypeptide is purified to a homogeneous level by SDS-PAGE under reducing or non-reducing conditions, (1) to more than 95% by weight, most preferably more than 99% by weight, of the polypeptide as determined by the Lowry method, (2) to a level sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence using a spinning cup sequencer, or (3) using Coomassie blue, or preferably silver staining. The isolated polypeptide contains the polypeptide in situ within recombinant cells because at least one component of the polypeptide's natural environment is absent. However, typically, the isolated polypeptide is prepared by at least one purification step.

[0131] A "natural sequence" polynucleotide is one that has the same nucleotide sequence as a naturally occurring polynucleotide. A "natural sequence" polypeptide is one that has the same amino acid sequence as a polypeptide derived from nature (e.g., any species) (e.g., EGFR). Such naturally sequence polynucleotides and polypeptides can be isolated from nature or produced by recombinant or synthetic means.

[0132] A “variant” of a polynucleotide, as used herein, is typically a polynucleotide that differs from a polynucleotide specifically disclosed herein by one or more substitutions, deletions, additions, and / or insertions.

[0133] Where the term is used herein, a "variant" of a polypeptide is typically a polypeptide that differs from the polypeptide specifically disclosed herein by one or more substitutions, deletions, additions, insertions, or inversions. Such variants may occur naturally, unnaturally, or synthetically.

[0134] Mutations (or variants) of EGFR as disclosed herein may include one or more substitutions, deletions, additions, and / or insertions or inversions of amino acid sequences that alter the function of the resulting protein. Mutations may be detected, for example, by comparison or alignment of a nucleic acid or amino acid sequence with a wild-type sequence.

[0135] When comparing polynucleotide and polypeptide sequences, two sequences are said to be “identical” if, when aligned for maximum match as described below, the sequences of nucleotides or amino acids in the two sequences are the same. Comparison between two sequences is typically performed by comparing the sequences on 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 consecutive positions, typically 30 to about 75, or 40 to about 50 consecutive positions, within which the two sequences can be optimally aligned and then compared to a reference sequence of the same number of consecutive positions.

[0136] Optimal alignment of sequences for comparison can be performed using the Megalign program in the Lasergene suite of bioinformatics software (DNASTAR, Inc., Madison, WI) with default parameters. This program implements several alignment schemes described in the following references. Dayhoff, MO (1978) A model of evolutionary change in protein-Matrices for detecting distant relationships. In Dayhoff, MO (ed.) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington DC Vol. 5, Suppl. 3, pp. 345-358; Hein J. (1990) Unified Approach to Alignment and Phylogenes pp. 626-645 Methods in Enzymology vol.183,Academic Press,Inc.,San Diego,CA;Higgins,DGand ​​Sharp,PM(1989)CABIOS 5:151-153;Myers,EWand Muller W.(1988)CABIOS 4:11-17;Robinson,ED(1971)Comb.Theor 11:105;Santou,N.Nes,M.(1987)Mol.Biol.Evol.4:406-425;Sneath,PHAand Sokal,RR(1973)Numerical Taxonomy-the Principles and Practice of Numerical Taxonomy,Freeman Press,San Francisco,CA;Wilbur,WJand Lipman, DJ (1983) Proc. Natl. Acad., Sci. USA 80:726-730.

[0137] Alternatively, optimal sequence alignment for comparison may be performed by the local identity algorithm of Smith and Waterman (1981) Add.APL.Math 2:482, by the identity alignment algorithm of Needleman and Wunsch (1970) J.Mol.Biol.48:443, by the similarity search method of Pearson and Lipman (1988) Proc.Natl.Acad.Sci.USA 85:2444, by computer implementations of these algorithms (GAP, BESTFIT, BLAST, FASTA, and TFASTA from Wisconsin Genetics Software Package, Genetics Computer Group (GCG), 575 Science Dr., Madison, WI), or by visual inspection.

[0138] One preferred example of an algorithm suitable for determining sequence identity percentage and sequence similarity percentage is the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. Nucl. (1977) Nucl. Acids Res. 25:3389-3402 and Altschul et al. (1990) J. Mol. Biol. 215:403-410, respectively. BLAST and BLAST 2.0 can be used, for example, to determine the sequence identity percentage of the polynucleotides and polypeptides of the present invention using the parameters described herein. Software for performing BLAST analysis is publicly available through the National Center for Biotechnology Information.

[0139] In one example, the cumulative score for a nucleotide sequence can be calculated using the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for a pair of mismatched residues; always < 0). The expansion of word hits in each direction stops if the cumulative alignment score falls by an amount X from its maximum achieved value, if the cumulative score becomes zero or less due to the accumulation of one or more negative score residue alignments, or if either sequence reaches its end. The parameters W, T, and X of the BLAST algorithm determine the sensitivity and speed of alignment. The BLASTN program (for nucleotide sequences) uses word length (W) 11, expected value (E) 10, and the BLOSUM62 score matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89:10915) as defaults, with word length (W) 50, expected value (E) 10, M=5, N=-4, and comparison of both strands.

[0140] For amino acid sequences, a score matrix can be used to calculate the cumulative score. The expansion of word hits in each direction stops if the cumulative alignment score decreases by an amount X from its maximum achieved value, if the cumulative score becomes zero or less due to the accumulation of one or more negative score residue alignments, or if any sequence reaches its end. The parameters W, T, and X of the BLAST algorithm determine the sensitivity and speed of the alignment.

[0141] One method determines the "percentage of sequence identity" by comparing two optimally aligned sequences over a comparison window of at least 20 positions, in which case some of the polynucleotide or polypeptide sequences within the comparison window may contain 20% or less, typically 5-15%, or 10-12% additions or deletions (i.e., gaps), compared to the reference sequence (which is ignorant of additions or deletions), for optimal alignment of the two sequences. The percentage of sequence identity is calculated by determining the number of positions in which identical nucleic acid bases or amino acid residues occur in both sequences to obtain 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.

[0142] The wild-type EGFR sequence of this disclosure comprises, or may consist of, the following amino acid sequence: 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 kedsflqrys sdptgalted 1081 siddtflpvp eyinqsvpkr pagsvqnpvy hnqplnpaps rdphyqdphs tavgnpeyln 1141 tvqptcvnst fdspahwaqk gshqisldnp dyqqdffpke akpngifkgs taenaeylrv 1201 apqssefiga (SEQ ID NO: 1, corresponding to epidermal growth factor receptor [Homo sapiens] and Genbank accession number CAA25240).

[0143] The wild-type HER2 receptor sequence of this disclosure comprises or may comprise the following amino acid sequence: 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 dcqsltrttvc 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 lglepseeea prsplapseg 1081 agsdvfdgdl gmgaakglqs lpthdpsplq rysedptvpl psetdgyvap ltcspqpeyv 1141 nqpdvrpqpp spregplpaa rpagatlerp ktlspgkngv vkdvfafgga venpeyltpq 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).

[0144] The wild-type HER2 receptor sequence of this disclosure comprises or may comprise the following amino acid sequence: 1 mklrlpaspe thldmlrhly qgcqvvqgnl eltylptnas lsflqdiqev qgyvliahnq 61 vrqvplqrlr ivrgtqlfed nyalavldng dplnnttpvt gaspgglrel qlrslteilk 121 ggvliqrnpq lcyqdtilwk difhknnqla ltlidtnrsr achpcspmck gsrcwgesse 181 dcqsltrttvc 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 gmgaakglqs lpthdpsplq 1081 rysedptvpl psetdgyvap ltcspqpeyv nqpdvrpqpp spregplpaa rpagatlerp 1141 ktlspgkngv vkdvfafgga venpeyltpq ggaapqphpp pafspafdnl yywdqdpper 1201 gappstfkgt ptaenpeylg ldvpv (SEQ ID NO: 3, corresponding to receptor tyrosine-protein kinase erbB-2 isoform b [Homo sapiens] and GenBank accession number NP_001005862).

[0145] The wild-type HER2 receptor sequence of this disclosure comprises or may comprise the following amino acid sequence: 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 eggerlpqpp ictidvymim vkcwmidsec rprfrelvse 961 fsrmardpqr fvviqnedlg paspldstfy rslledddmg dlvdaeeylv pqqgffcpdp 1021 apgaggmvhh rhrssstrsg ggdltlglep seeeaprspl apsegagsdv fdgdlmgaa 1081 kglqslpthd psplqrysed ptvplpsetd gyvapltcsp qpeyvnqpdv rpqppspreg 1141 plpaarpaga tlerpktlsp gkngvvkdvf afggavenpe yltpqggaap qphpppafsp 1201 afdnlyywdq dppergapps tfkgtptaen peylgldvpv (SEQ ID NO: 4, corresponding to receptor tyrosine-protein kinase erbB-2 isoform c [Homo sapiens] and GenBank accession number NP_001276865).

[0146] The wild-type HER2 receptor sequence of this disclosure comprises or may comprise the following amino acid sequence: 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 dcqsltrttvc 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 isoform d precursor [Homo sapiens] and GenBank accession number NP_001276866).

[0147] The wild-type HER2 receptor sequence of this disclosure comprises or may comprise the following amino acid sequence: 1 mklrlpaspe thldmlrhly qgcqvvqgnl eltylptnas lsflqdiqev qgyvliahnq 61 vrqvplqrlr ivrgtqlfed nyalavldng dplnnttpvt gaspgglrel qlrslteilk 121 ggvliqrnpq lcyqdtilwk difhknnqla ltlidtnrsr achpcspmck gsrcwgesse 181 dcqsltrttvc 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 isoform e [Homo sapiens] and GenBank accession number NP_001276867).

[0148] Based on the definitions given throughout this application, those skilled in the art will see which combinations are synthetically feasible and practical, for example, that typical combinations of groups resulting in heteroatoms that are directly linked to each other are not intended.

[0149] Compounds of the Disclosure In some embodiments, this disclosure relates to a compound of the following formula (I'), [ka] or to provide a pharmaceutically acceptable salt or stereoisomer thereof, W is either CH or N. Z is one or more R Z It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Z These are independently halogens, 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, C 3- C 10 Cycloalkyl, C6-C 10 These are aryl groups, 3-10 membered heterocycloalkyl groups, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C 3- C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R Za It is optionally replaced with, Each R Za These are independently halogens, 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, and C3-C 10 Cycloalkyl, C6-C 10 These are aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl compounds. T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R T These are independently halogens, 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, C 3- C 10 Cycloalkyl, C6-C 10 These are aryl groups, 3-10 membered heterocycloalkyl groups, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C 3- C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R Ta It is optionally replaced with, Each R Ta These are independently halogens, 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, and C3-C 10 Cycloalkyl, C6-C 10 These are aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl compounds. Ar 1 is one or more R A1 C6-C which is optionally replaced by 10 It is Ariel, Each R A1 These are independently 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 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 These are aryl groups, 3-10 membered heterocycloalkyl groups, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R A1a It is optionally replaced with, Each R A1a These are independently halogens, 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, C 3- C 10 Cycloalkyl, C6-C 10 These are aryl groups, 3-10 membered heterocycloalkyl groups, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C 3- C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R A1b It is optionally replaced with, and Each R A1b These are independently halogen, CN, -OH, or -NH2.

[0150] In some embodiments, the compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, where: W is either CH or N. Z is one or more R ZIt is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Z These are independently halogens, 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, C 3- C 10 Cycloalkyl, C6-C 10 These are aryls or 5-10 membered heteroaryls, including -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C 3- C 10 Cycloalkyl, C6-C 10 Aryls, 3- or 5-10 member heteroaryls, one or more R Za It is optionally replaced with, Each R Za These are independently halogens, 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, and C3-C 10 Cycloalkyl, C6-C 10 These are aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl compounds. T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R T These are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10These are aryl groups, 3-7 membered heterocycloalkyl groups, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may have one or more R Ta It can be optionally replaced with this. Each R Ta These are independently halogens, 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 These are aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl compounds. Ar 1 is one or more R A1 C6-C which is optionally replaced by 10 It is Ariel, Each R A1 These are independently 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, and -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R A1a It is optionally replaced with, and Each R A1a These are independently halogens, 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, and -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl are one or more R A1b It is optionally replaced with, and Each RA1b These are independently halogen, CN, -OH, or -NH2, However, Z is [ka] When that is the case, Ar 1 C6-C is optionally substituted with one or more halogens. 10 It is Ariel.

[0151] In some embodiments, the compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, where: W is either CH or N. Z is one or more R Z It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Z These are independently halogens, 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, C 3- C 10 Cycloalkyl, C6-C 10 These are aryls or 5-10 membered heteroaryls, including -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C 3- C 10 Cycloalkyl, C6-C 10 Aryls, 3- or 5-10 member heteroaryls, one or more R Za It is optionally replaced with, Each R Za These are independently halogens, 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, and C3-C 10 Cycloalkyl, C6-C 10 These are aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl compounds. T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R T These are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 These are aryl groups, 3-7 membered monocyclic heterocycloalkyl groups, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may have one or more R Ta It can be optionally replaced with this. Each R Ta These are independently halogens, 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 These are aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl compounds. Ar 1 is one or more R A1 C6-C which is optionally replaced by 10 It is Ariel, Each R A1 These are independently 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, and -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R A1a It is optionally replaced with, and Each R A1a These are independently halogens, 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, and -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl are one or more R A1b It is optionally replaced with, and Each R A1b These are independently halogen, CN, -OH, or -NH2, However, Z is [ka] When that is the case, Ar 1 C6-C is optionally substituted with one or more halogens. 10 It is Ariel.

[0152] In some embodiments, the compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, where: W is CH, Z is one or more R Z It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Z These are independently a halogen, -O-(C1-C6 alkyl), C1-C6 alkyl, or a 3- to 10-membered heterocycloalkyl, where the -O-(C1-C6 alkyl), C1-C6 alkyl, or 3- to 10-membered heterocycloalkyl 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 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R T These are independently a halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or a 3- to 7-membered heterocycloalkyl, where the -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH groups. Ar 1 is one or more R A1 C6-C which is optionally replaced by 10 It is Ariel, Each R A1 These are independently halogen, -OR A1a , or one or more R A1a It is an optionally substituted -O-(C1-C6 alkyl), and Each R A1a It is independent, C6-C 10 It is an aryl or 5-10 member heteroaryl, C6-C 10 The aryl or 5- to 10-membered heteroaryl can be optionally substituted with one or more halogens.

[0153] In some embodiments, the compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, where: W is CH, Z is one or more R Z It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Z These are independently a halogen, -O-(C1-C6 alkyl), C1-C6 alkyl, or a 3- to 10-membered heterocycloalkyl, where the -O-(C1-C6 alkyl), C1-C6 alkyl, or 3- to 10-membered heterocycloalkyl 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 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R T These are independently a halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or a 3- to 7-membered monocyclic heterocycloalkyl, and the -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or a 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH groups. Ar 1 is one or more R A1 C6-C which is optionally replaced by 10 It is Ariel, Each R A1 These are independently halogen, -OR A1a , or one or more R A1a It is an optionally substituted -O-(C1-C6 alkyl), and Each R A1a It is independent, C6-C 10 It is an aryl or 5-10 member heteroaryl, C6-C 10 The aryl or 5- to 10-membered heteroaryl can be optionally substituted with one or more halogens.

[0154] In some embodiments, the compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, where: W is CH, Z is one or more R Z It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Z independently, is a halogen, -O-(C1-C6 alkyl), or C1-C6 alkyl, where -O-(C1-C6 alkyl) or 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 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R T These are independently a halogen, -OH, -O-(C1-C6 alkyl), or a 3- to 7-membered heterocycloalkyl, and the -O-(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH groups. Ar 1 is one or more R A1 C6-C which is optionally replaced by 10 It is Ariel, Each R A1 These are independently halogen, -OR A1a , or one or more R A1a It is an optionally substituted -O-(C1-C6 alkyl), and Each R A1a It is independent, C6-C 10 It is an aryl or 5-10 member heteroaryl, C6-C 10 Aryl or 5- to 10-membered heteroaryls are optionally substituted with one or more halogens. However, Z is [ka] When that is the case, Ar 1 C6-C is optionally substituted with one or more halogens. 10 It is Ariel.

[0155] In some embodiments, the compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, where: W is CH, Z is one or more R Z It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Zindependently, is a halogen, -O-(C1-C6 alkyl), or C1-C6 alkyl, where -O-(C1-C6 alkyl) or 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 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R T These are independently a halogen, -OH, -O-(C1-C6 alkyl), or a 3- to 7-membered monocyclic heterocycloalkyl, and the -O-(C1-C6 alkyl) or the 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH groups. Ar 1 is one or more R A1 C6-C which is optionally replaced by 10 It is Ariel, Each R A1 These are independently halogen, -OR A1a , or one or more R A1a It is an optionally substituted -O-(C1-C6 alkyl), and Each R A1a It is independent, C6-C 10 It is an aryl or 5-10 member heteroaryl, C6-C 10 Aryl or 5- to 10-membered heteroaryls are optionally substituted with one or more halogens. However, Z is [ka] When that is the case, Ar 1 C6-C is optionally substituted with one or more halogens. 10 It is Ariel.

[0156] In some embodiments, the compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, where: W is CH, Z is one or more RZ It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Z independently, is a halogen, -O-(C1-C6 alkyl), or C1-C6 alkyl, where -O-(C1-C6 alkyl) or 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 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R T These are independently a halogen, -OH, -O-(C1-C6 alkyl), or a 3- to 7-membered heterocycloalkyl, and the -O-(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH groups. Ar 1 C6-C is optionally substituted with one or more halogens. 10 It is Ariel.

[0157] In some embodiments, the compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, where: W is CH, Z is one or more R Z It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Z independently, is a halogen, -O-(C1-C6 alkyl), or C1-C6 alkyl, where -O-(C1-C6 alkyl) or 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 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R TThese are independently a halogen, -OH, -O-(C1-C6 alkyl), or a 3- to 7-membered monocyclic heterocycloalkyl, and the -O-(C1-C6 alkyl) or the 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH groups. Ar 1 C6-C is optionally substituted with one or more halogens. 10 It is Ariel.

[0158] In some embodiments, the compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, where: W is CH, Z is a 3- to 12-membered heterocycloalkyl group optionally substituted with one or more C1-C6 alkyl groups. T is a C2-C6 alkenyl optionally substituted with one or more 6-membered heterocycloalkyl groups, and Ar 1 It is a C6 aryl that can be optionally substituted with one or more halogens.

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

[0160] Variable W In some embodiments, W is CH.

[0161] In some embodiments, W is N.

[0162] Variables Z, R Z、 and R Za In some embodiments, Z is one or more R Z It is a 3- to 12-membered heterocycloalkyl that is optionally substituted with, and Each R Z Each of these is independently a halogen, a -O-(C1-C6 alkyl), a C1-C6 alkyl, or a 3- to 10-membered heterocycloalkyl, where the -O-(C1-C6 alkyl), C1-C6 alkyl, or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogens.

[0163] In some embodiments, Z is a 3- to 12-membered heterocycloalkyl group.

[0164] In some embodiments, Z is one or more R Z These are 3- to 12-membered heterocycloalkyl groups that are substituted with [a specific compound].

[0165] In some embodiments, Z is oxetanil, tetrahydrofuranil, pyrrolidinil, piperidinil, morpholinil, 3-oxabicyclo[3.1.0]hexanil, 3-azabicyclo[3.1.0]hexanil, 2-azaspiro[3.3]heptanil, or 2-oxa-5-azaspiro[3.4]octanil, and oxetanil, tetrahydrofuranil, pyrrolidinil, piperidinil, morpholinil, 3-oxabicyclo[3.1.0]hexanil, 3-azabicyclo[3.1.0]hexanil, 2-azaspiro[3.3]heptanil, or 2-oxa-5-azaspiro[3.4]octanil is one or more R Z It can be optionally replaced with this.

[0166] In some embodiments, Z is oxetanil, tetrahydrofuranil, pyrrolidinil, piperidinil, morpholinil, 3-oxabicyclo[3.1.0]hexanil, 3-azabicyclo[3.1.0]hexanil, 2-azaspiro[3.3]heptanil, or 2-oxa-5-azaspiro[3.4]octanil, and oxetanil, tetrahydrofuranil, pyrrolidinil, piperidinil, morpholinil, 3-azabicyclo[3.1.0]hexanil, 2-azaspiro[3.3]heptanil, or 2-oxa-5-azaspiro[3.4]octanil is one or more R Z It can be optionally replaced with this.

[0167] In some embodiments, Z is [ka] That is the case.

[0168] In some embodiments, Z is [ka] That is the case.

[0169] In some embodiments, Z is [ka] That is the case.

[0170] In some embodiments, Z is [ka] That is the case.

[0171] In some embodiments, Z is [ka] That is the case.

[0172] In some embodiments, Z is [ka] That is the case.

[0173] In some embodiments, Z is [ka] That is the case.

[0174] In some embodiments, Z is [ka] That is the case.

[0175] In some embodiments, Z is [ka] That is the case.

[0176] In some embodiments, Z is [ka] That is the case.

[0177] In some embodiments, Z is [ka] That is the case.

[0178] In some embodiments, Z is [ka] That is the case.

[0179] In some embodiments, at least one R Z It is a halogen.

[0180] In some embodiments, at least one R Z It is either F or Cl.

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

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

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

[0184] In some embodiments, at least one R Z It is CN, -OH, or -NH2.

[0185] In some embodiments, at least one R Z These include -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 These are aryl groups, 3-10 membered heterocycloalkyl groups, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 An aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, with one or more R Za It can be optionally replaced with this.

[0186] In some embodiments, at least one R Z is one or more R Za It is an optionally substituted -O-(C1-C6 alkyl) group.

[0187] In some embodiments, at least one R Z It is -O-(C1-C6 alkyl).

[0188] In some embodiments, at least one R Z It is -OCH3.

[0189] In some embodiments, at least one R Z is one or more R Za It is a -O-(C1-C6 alkyl) that is substituted with

[0190] In some embodiments, at least one R Z It is a -O-(C1-C6 alkyl) substituted with one or more halogens (e.g., F or Cl).

[0191] In some embodiments, at least one R Z is -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2, and -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2 is one or more R Za It can be optionally replaced with this.

[0192] In some embodiments, at least one R Z is one or more R Za It is a C1-C6 alkyl group that can be optionally substituted.

[0193] In some embodiments, at least one R Z It is a C1-C6 alkyl group.

[0194] In some embodiments, at least one R Z This is methyl, ethyl, or propyl (e.g., i-propyl).

[0195] In some embodiments, at least one R Z is one or more R Za It is a C1-C6 alkyl group that is substituted with [a specific compound].

[0196] In some embodiments, at least one R Z This is a C1-C6 alkyl group substituted with one or more halogens (e.g., F or Cl).

[0197] In some embodiments, at least one R Z This is a C1-C6 alkyl group substituted with one or more fluorine atoms.

[0198] In some embodiments, at least one R Z This is CF3.

[0199] In some embodiments, at least one R Z is a C2-C6 alkenyl or C2-C6 alkynyl, in which case the C2-C6 alkenyl or C2-C6 alkynyl is one or more R Za It can be optionally replaced with this.

[0200] In some embodiments, at least one R Z C3-C 10 Cycloalkyl, C6-C 10 It is an aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R Za It can be optionally replaced with this.

[0201] In some embodiments, at least one R Z is one or more R Za C3-C which is optionally replaced by 10 It is a cycloalkyl group.

[0202] In some embodiments, at least one R Z is one or more R Za C6-C which is optionally replaced by 10 It is Ariel.

[0203] In some embodiments, at least one R Z is one or more R Za It is a 3- to 10-membered heterocycloalkyl group that can be optionally substituted.

[0204] In some embodiments, at least one R Z is one or more R Za It is a four-membered heterocycloalkyl that can be optionally substituted.

[0205] In some embodiments, at least one R Z It is a four-membered heterocycloalkyl group.

[0206] In some embodiments, at least one R Z It is oxetanil.

[0207] In some embodiments, at least one R Z is one or more R Za It is a 5-10 member heteroaryl that can be optionally substituted.

[0208] In some embodiments, at least one R Za It is a halogen.

[0209] In some embodiments, at least one R Za It is either F or Cl.

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

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

[0212] In some embodiments, at least one R Za These are 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 They are aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[0213] Variables T, R T , and RTa In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R T These are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 These are aryl groups, 3-7 membered heterocycloalkyl groups, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may have one or more R Ta It is optionally replaced with, and Each R Ta These are independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 They are aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[0214] In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R TThese are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 These are aryl groups, 3-7 membered monocyclic heterocycloalkyl groups, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 Aryls, 3- to 7-membered monocyclic heterocycloalkyls, or 5- to 10-membered heteroaryls include one or more R Ta It is optionally replaced with, and Each R Ta These are independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 They are aryl, 3- to 10-membered heterocycloalkyl, 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 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, and Each R T The elements are independently a halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or a 3- to 7-membered heterocycloalkyl, where the -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or 3- to 7-membered heterocycloalkyl are optionally substituted with one or more -C(=O)OH groups.

[0216] In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, and Each R T The elements are independently a halogen, -OH, -O-(C1-C6 alkyl), or a 3- to 7-membered heterocycloalkyl, and the -O-(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl may be optionally substituted with one or more -C(=O)OH groups.

[0217] In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, and Each R T These are independently a halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or a 3- to 7-membered monocyclic heterocycloalkyl, where the -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or a 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH groups.

[0218] In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, and Each R T The elements are independently a halogen, -OH, -O-(C1-C6 alkyl), or a 3- to 7-membered heterocycloalkyl, and the -O-(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl may be optionally substituted with one or more -C(=O)OH groups.

[0219] In some embodiments, T is one or more R T It is an optionally substituted -O-(C1-C6 alkyl) group.

[0220] In some embodiments, T is -O-(C1-C6 alkyl).

[0221] In some embodiments, T is -OCH3.

[0222] In some embodiments, T is one or more R T It is an optionally substituted -NH-(C1-C6 alkyl) group.

[0223] In some embodiments, T is -NH-(C1-C6 alkyl).

[0224] In some embodiments, T is -NHCH3.

[0225] In some embodiments, T is one or more R T It is a C1-C6 alkyl group that can be optionally substituted.

[0226] In some embodiments, T is a C1-C6 alkyl group.

[0227] In some embodiments, T is methyl or ethyl.

[0228] In some embodiments, T is methyl.

[0229] In some embodiments, T is ethyl.

[0230] In some embodiments, T is one or more R T It is a C1-C6 alkyl group that is substituted with [a specific compound].

[0231] In some embodiments, T is a C1-C6 alkyl group substituted with one or more halogens (e.g., F or Cl).

[0232] In some embodiments, T is a methyl molecule substituted with one or more halogens (e.g., F or Cl).

[0233] In some embodiments, T is -CHFCl.

[0234] In some embodiments, T is a C1-C6 alkyl group substituted with one or more CNs.

[0235] In some embodiments, T is -CH2CN.

[0236] In some embodiments, T is one or more R T It is a C2-C6 alkenyl that can be optionally substituted.

[0237] In some embodiments, T is a C2-C6 alkenyl.

[0238] In some embodiments, T is ethenyl (i.e., -CH=CH2).

[0239] In some embodiments, T is propenyl (e.g., -C(CH3)=CH2 or -CH=CH-CH3).

[0240] In some embodiments, T is pentenyl (e.g., -CH=CH-C(CH3)2).

[0241] In some embodiments, T is one or more R T It is a C2-C6 alkenyl that is substituted with [the specified compound].

[0242] In some embodiments, T is a C2-C6 alkenyl substituted with one or more -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or 3- to 10-membered heterocycloalkyl groups, in which case the 3- to 10-membered heterocycloalkyl group is optionally substituted with one or more -C(=O)OH groups.

[0243] In some embodiments, T is a C2-C6 alkenyl substituted with one or more -OH groups.

[0244] In some embodiments, T is a C2-C6 alkenyl substituted with one or more -O-(C1-C6 alkyl) groups.

[0245] In some embodiments, T is a C2-C6 alkenyl substituted with one or more -OCH3 groups.

[0246] In some embodiments, T is a C2-C6 alkenyl substituted with one or more -N(C1-C6 alkyl)2 groups.

[0247] In some embodiments, T is a C2-C6 alkenyl substituted with one or more -N(CH3)2 groups.

[0248] In some embodiments, T is a C2-C6 alkenyl substituted with one or more 3- to 10-membered heterocycloalkyl groups.

[0249] In some embodiments, T is a C2-C6 alkenyl substituted with one or more 3- to 10-membered heterocycloalkyl groups, in which case the 3- to 10-membered heterocycloalkyl groups are optionally substituted with one or more -C(=O)OH groups.

[0250] In some embodiments, T is a C2-C6 alkenyl substituted with one or more 3- to 7-membered heterocycloalkyl groups.

[0251] In some embodiments, T is a C2-C6 alkenyl substituted with one or more 3- to 7-membered heterocycloalkyl groups, in which case the 3- to 7-membered heterocycloalkyl groups are optionally substituted with one or more -C(=O)OH groups.

[0252] In some embodiments, T is a C2-C6 alkenyl substituted with one or more 3- to 7-membered heterocycloalkyl groups.

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

[0254] In some embodiments, T is a C2-C6 alkenyl substituted with one or more 3- to 7-membered monocyclic heterocycloalkyl groups, in which case the 3- to 7-membered monocyclic heterocycloalkyl groups are optionally substituted with one or more -C(=O)OH groups.

[0255] In some embodiments, T is a C2-C6 alkenyl substituted with one or more 3- to 7-membered monocyclic heterocycloalkyl groups.

[0256] In some embodiments, T is a C2-C6 alkenyl substituted with one or more six-membered heterocycloalkyl groups, in which case the six-membered heterocycloalkyl groups are optionally substituted with one or more -C(=O)OH groups.

[0257] In some embodiments, T is a C2-C6 alkenyl substituted with one or more six-membered heterocycloalkyl groups.

[0258] In some embodiments, T is a C2-C6 alkenyl substituted with one or more six-membered monocyclic heterocycloalkyl groups, in which case the six-membered monocyclic heterocycloalkyl groups are optionally substituted with one or more -C(=O)OH groups.

[0259] In some embodiments, T is a C2-C6 alkenyl substituted with one or more six-membered monocyclic heterocycloalkyl groups.

[0260] In some embodiments, T is one or more R T It is a C2-C6 alkynyl that can be optionally substituted.

[0261] In some embodiments, T is a C2-C6 alkynyl.

[0262] In some embodiments, T is propynyl (e.g., -C≡C-CH3).

[0263] In some embodiments, T is one or more R T It is a C2-C6 alkynyl that is substituted with [the specified compound].

[0264] In some embodiments, T is one or more R T It is propynyl that is substituted with [the specified compound].

[0265] In some embodiments, T is -C≡C-CH2-R T That is the case.

[0266] In some embodiments, T is a C2-C6 alkynyl substituted with one or more 3- to 10-membered heterocycloalkyl groups.

[0267] In some embodiments, T is propynyl substituted with one or more 3- to 10-membered heterocycloalkyl groups.

[0268] In some embodiments, T is a C2-C6 alkynyl substituted with one or more 3- to 7-membered heterocycloalkyl groups.

[0269] In some embodiments, T is propynyl substituted with one or more 3- to 7-membered heterocycloalkyl groups.

[0270] In the Party embodiment, T is [ka] That is the case.

[0271] In the Party embodiment, T is [ka] That is the case.

[0272] In the Party embodiment, T is [ka] That is the case.

[0273] In the Party embodiment, T is [ka] That is the case.

[0274] In the Party embodiment, T is [ka] That is the case.

[0275] In the Party embodiment, T is [ka] That is the case.

[0276] In the Party embodiment, T is [ka] That is the case.

[0277] In the Party embodiment, T is [ka] That is the case.

[0278] In some embodiments, at least one R T This is a halogen (for example, F or Cl).

[0279] In some embodiments, at least one R T It is F.

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

[0281] In some embodiments, at least one R T It is CN, -OH, or -NH2.

[0282] In some embodiments, at least one R T This is CN.

[0283] In some embodiments, at least one R T It is -OH.

[0284] In some embodiments, at least one R T is -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2, in which case -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2 is one or more R Ta It can be optionally replaced with this.

[0285] In some embodiments, at least one R T is -O-(C1-C6 alkyl) or -N(C1-C6 alkyl)2, in which case O-(C1-C6 alkyl) or -N(C1-C6 alkyl)2 is one or more R Ta It can be optionally replaced with this.

[0286] In some embodiments, at least one R T This is -O-(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

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

[0288] In some embodiments, at least one R T It is -N(C1-C6 alkyl)2.

[0289] In some embodiments, at least one R T is a C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, in which case the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R Ta It can be optionally replaced with this.

[0290] In some embodiments, at least one R T C3-C 10 Cycloalkyl, C6-C 10 It is an aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R Ta It can be optionally replaced with this.

[0291] In some embodiments, at least one R T is one or more R Ta It is a 3- to 10-membered heterocycloalkyl group that can be optionally substituted.

[0292] In some embodiments, at least one R T is one or more R Ta These are 3- to 10-membered heterocycloalkyl groups that are substituted with [the specified character].

[0293] In some embodiments, at least one R T These are 3- to 10-membered heterocycloalkyl groups substituted with one or more C(=O)OH groups.

[0294] In some embodiments, at least one R T is one or more R Ta It is a 3- to 7-membered heterocycloalkyl group that can be optionally substituted.

[0295] In some embodiments, at least one R T These are heterocycloalkyl groups with 3 to 7 members.

[0296] In some embodiments, at least one R T is one or more R Ta It is a 3- to 7-membered heterocycloalkyl group that is substituted with [a specific component].

[0297] In some embodiments, at least one RT These are 3- to 7-membered heterocycloalkyl groups substituted with one or more C(=O)OH groups.

[0298] In some embodiments, at least one R T is one or more R Ta It is a 6-membered heterocycloalkyl group that can be optionally substituted.

[0299] In some embodiments, at least one R T It is a six-membered heterocycloalkyl group.

[0300] In some embodiments, at least one R T is one or more R Ta It is a six-membered heterocycloalkyl group that is substituted with [a specific compound].

[0301] In some embodiments, at least one R T It is a six-membered heterocycloalkyl group substituted with one or more C(=O)OH groups.

[0302] In some embodiments, at least one R T is one or more R Ta It is a 3- to 7-membered monocyclic heterocycloalkyl group that can be optionally substituted.

[0303] In some embodiments, at least one R T These are monocyclic heterocycloalkyl groups with 3 to 7 members.

[0304] In some embodiments, at least one R T is one or more R Ta These are 3- to 7-membered monocyclic heterocycloalkyl groups that are substituted with [the specified compound].

[0305] In some embodiments, at least one R T These are 3- to 7-membered monocyclic heterocycloalkyl groups substituted with one or more C(=O)OH groups.

[0306] In some embodiments, at least one RT is one or more R Ta It is a 6-membered monocyclic heterocycloalkyl that can be optionally substituted.

[0307] In some embodiments, at least one R T It is a 6-membered monocyclic heterocycloalkyl compound.

[0308] In some embodiments, at least one R T is one or more R Ta It is a six-membered monocyclic heterocycloalkyl that is substituted with [a specific compound].

[0309] In some embodiments, at least one R T It is a six-membered monocyclic heterocycloalkyl group substituted with one or more C(=O)OH groups.

[0310] In some embodiments, at least one R Ta This is C(=O)OH.

[0311] In some embodiments, at least one R Ta These include halogens, 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, and C3-C 10 Cycloalkyl, C6-C 10 They are aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[0312] Variable Ar 1 , R A1 , R A1a , and R A1b In some embodiments, Ar 1 is one or more R A1 C6-C which is optionally replaced by 10 It is Ariel, Each R A1 These are independently 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, and -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R A1a It is optionally replaced with, Each R A1a These are independently halogens, 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, and -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl are one or more R A1b It is optionally replaced with, and Each R A1b These are independently halogen, CN, -OH, or -NH2.

[0313] In some embodiments, Ar 1 C6-C 10 It is Ariel.

[0314] In some embodiments, Ar 1 is one or more R A1 C6-C is replaced by 10 It is Ariel.

[0315] In some embodiments, Ar 1 is one or more R A1 It is a phenyl compound that is substituted with [a specific compound].

[0316] In some embodiments, Ar 1 is one or more halogens, -OR A1a , or phenyl substituted with -O-(C1-C6 alkyl), in which case -O-(C1-C6 alkyl) is one or more R A1a It is optionally replaced by and each R A1aIt is independent, C6-C 10 It is an aryl or a 5-10 member heteroaryl, in this case C6-C 10 The aryl or 5- to 10-membered heteroaryl can optionally be substituted with one or more halogens.

[0317] In some embodiments, Ar 1 This is a phenyl compound substituted with one or more halogens.

[0318] In some embodiments, Ar 1 This is a phenyl compound substituted with one or more F or Cl atoms.

[0319] In some embodiments, Ar 1 This is a phenyl compound substituted with one F and one Cl.

[0320] In some embodiments, Ar 1 is a phenyl compound optionally substituted with one or more halogens, in which case the phenyl compound is -O-(C6-C 10 Further substituted with -O-(aryl) or -O-(5-10 member heteroaryl), in this case -O-(C6-C 10 The aryl (-O-) or -O- (5-10 member heteroaryl) is optionally substituted with one or more halogens.

[0321] In some embodiments, Ar 1 is a phenyl molecule optionally substituted with one or more halogens, in which case the phenyl molecule is further substituted with -O-phenyl or -O-pyridinyl, in which case the -O-phenyl molecule or -O-pyridinyl molecule is optionally substituted with one or more halogens.

[0322] In some embodiments, Ar 1 is a phenyl molecule optionally substituted with one or more halogens, in which case the phenyl molecule is further substituted with -O-phenyl, in which case the -O-phenyl molecule is optionally substituted with one or more halogens.

[0323] In some embodiments, Ar 1 is a phenyl molecule optionally substituted with one or more halogens, in which case the phenyl molecule is further substituted with -O-pyridinyl, in which case the -O-pyridinyl molecule is optionally substituted with one or more halogens.

[0324] In some embodiments, Ar 1 teeth, [ka] That is the case.

[0325] In some embodiments, Ar 1 teeth, [ka] That is the case.

[0326] In some embodiments, Ar 1 teeth, [ka] That is the case.

[0327] In some embodiments, Ar 1 teeth, [ka] That is the case.

[0328] In some embodiments, Ar 1 teeth, [ka] That is the case.

[0329] In some embodiments, Ar 1 teeth, [ka] That is the case.

[0330] In some embodiments, Ar1 teeth, [ka] That is the case.

[0331] In some embodiments, Ar 1 teeth, [ka] That is the case.

[0332] In some embodiments, Ar 1 teeth, [ka] That is the case.

[0333] In some embodiments, Ar 1 teeth, [ka] That is the case.

[0334] In some embodiments, Ar 1 teeth, [ka] That is the case.

[0335] In some embodiments, Ar 1 teeth, [ka] That is the case.

[0336] In some embodiments, Ar 1 teeth, [ka] That is the case.

[0337] In some embodiments, Ar 1 teeth, [ka] That is the case.

[0338] In some embodiments, at least one R A1 This is a halogen (for example, F or Cl).

[0339] In some embodiments, at least one R A1 It is F.

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

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

[0342] In some embodiments, at least one R A1 It is CN, -OH, or -NH2.

[0343] In some embodiments, at least one R A1 is -OR A1a That is the case.

[0344] In some embodiments, at least one R A1 is -O-(C6-C 10 It is an aryl or -O-(5-10 member heteroaryl), in which case -O-(C6-C 10 aryl) or -O- (5-10 member heteroaryl) is one or more R A1b It can be optionally replaced with this.

[0345] In some embodiments, at least one R A1 is -O-(C6-C 10 It is an aryl or -O-(5-10 member heteroaryl), in which case -O-(C6-C 10The aryl (-O-) or -O- (5-10 member heteroaryl) is optionally substituted with one or more halogens.

[0346] In some embodiments, at least one R A1 is -O-phenyl or -O-pyridinyl, in which case -O-phenyl or -O-pyridinyl is optionally substituted with one or more halogens.

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

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

[0349] In some embodiments, at least one R A1 is -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, in which case -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R A1a It can be optionally replaced with this.

[0350] In some embodiments, at least one R A1 is one or more R A1a It is an optionally substituted -O-(C1-C6 alkyl) group.

[0351] In some embodiments, at least one R A1 is one or more R A1a It is a -O-(C1-C6 alkyl) that is substituted with

[0352] In some embodiments, at least one R A1 is one or more C6-C 10-O-(C1-C6 alkyl) substituted with an aryl or 5-10 member heteroaryl, in this case C6-C 10 The aryl or 5- to 10-membered heteroaryl can optionally be substituted with one or more halogens.

[0353] In some embodiments, at least one R A1 is -O-CH2-R A1a That is the case.

[0354] In some embodiments, at least one R A1 is -O-CH2-(C6-C 10 It is an aryl) or -O-CH2-(5-10 member heteroaryl), in this case -O-CH2-(C6-C 10 The aryl (-O-CH2-) or -O-CH2- (5-10 member heteroaryl) group is optionally substituted with one or more halogens.

[0355] In some embodiments, at least one R A1 is -O-CH2-phenyl or -O-CH2-pyridinyl, in which case -O-CH2-phenyl or -O-CH2-pyridinyl is optionally substituted with one or more halogens.

[0356] In some embodiments, at least one R A1 This is a -O-CH2-phenyl compound optionally substituted with one or more halogens.

[0357] In some embodiments, at least one R A1 It is a -O-CH2-pyridinyl compound that is optionally substituted with one or more halogens.

[0358] In some embodiments, at least one R A1 C3-C 10 Cycloalkyl, C6-C 10 It is an aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, C6-C 10Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R A1a It can be optionally replaced with this.

[0359] In some embodiments, at least one R A1a 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, and -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R A1b It can be optionally replaced with this.

[0360] In some embodiments, at least one R A1a C3-C 10 Cycloalkyl, C6-C 10 It is an aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R A1b It can be optionally replaced with this.

[0361] In some embodiments, at least one R A1a C3-C 10 Cycloalkyl, C6-C 10 It is an aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, C6-C 10 The aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may optionally be substituted with one or more halogens.

[0362] In some embodiments, at least one R A1a C6-C 10 It is an aryl or 5-10 member heteroaryl, C6-C10 The aryl or 5- to 10-membered heteroaryl can optionally be substituted with one or more halogens.

[0363] In some embodiments, at least one R A1a is phenyl or pyridinyl, in which case phenyl or pyridinyl may be optionally substituted with one or more halogens.

[0364] In some embodiments, at least one R A1a This is a phenyl compound optionally substituted with one or more halogens.

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

[0366] In some embodiments, at least one R A1b It is a halogen.

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

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

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

[0370] In some embodiments, at least one R A1b It is CN, -OH, or -NH2.

[0371] Exemplary embodiments of compounds In some embodiments, Z [ka] When that is the case, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, in which case -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, or C2-C6 alkynyl is one or more R T It is optionally substituted with, and in this case the C2-C6 alkenyl is one or more R T Replaced by, Each R T These are independently halogens, CN, -OH, -NH2, -O-(C1-C6 alkyl), -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 These are aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R Ta It is optionally replaced with, and Each R Ta These are independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 They are aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[0372] In some embodiments, Z [ka] When that is the case, T is [ka] isn't it.

[0373] In some embodiments, Z [ka] When that is the case, Ar 1 C6-C is optionally substituted with one or more halogens. 10 It is Ariel.

[0374] In some embodiments, Z is [ka] isn't it.

[0375] In some embodiments, Z is [ka] isn't it.

[0376] In the Party embodiment, T is [ka] isn't it.

[0377] In some embodiments, the compound is a compound of the following formula (II'). [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0378] In some embodiments, the compound is a compound of the following formula (II'). [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0379] In some embodiments, the compound is a compound of the following formula (III') or (III'-a). [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0380] In some embodiments, the compound is a compound of the following formula (IV') or (IV'-a). [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0381] In some embodiments, the present disclosure provides compounds of the following formula I or pharmaceutically acceptable salts or stereoisomers thereof: [ka] During the ceremony, W is CH or N, preferably CH. X 1 -O-, -S-, -NR 3 -and, R a , R b They are independent of each other, hydrogen or C 1-4 Alkyl, or R a One of them is X 1 NR 3 If that is the case, X 1 Together, they form a ring - (CH2) p - and R a One of them is R 2 Together, they form a ring - (CH2) p -and, R c , R d They are independent of each other, hydrogen or C 1-4 It is alkyl, R 1 is H or F, R 2 is hydrogen or C 1-4 Alkyl or R 3 It forms a ring together with R a Forms a ring with one of them - (CH2) q -and, R 3is hydrogen or C 1-4 Alkyl, preferably hydrogen or methyl, or R 2 Together, they form a ring - (CH2) p -and, m is 1, 2, or 3. n is 0, 1, or 2. p is either 1 or 2. q is 0, 1 or 2, and Ar 1 is either unsubstituted or halogen, -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 A six-membered aryl group that is substituted with one or more groups selected from alkoxys or C6 aryls.

[0382] In some embodiments of the compound of formula I, W is CH.

[0383] In some embodiments, when n is 0, R 2 R 3 Along with, or R a Forms a ring with one of them - (CH2) q- That is the case.

[0384] In some embodiments, when n is 0, R 2 R 3that forms a ring together with -(CH2) q- is.

[0385] In some embodiments, n is 0 and R 2 is such that R 3 forms a ring together with, or one of R a is -(CH2) q- that forms a ring together with it.

[0386] In some embodiments, n is 0 and R 2 is such that R 3 forms a ring together with -(CH2) q- which is.

[0387] In some embodiments of the compound of formula I, X 1 is -O- or -NR 3 -, more preferably -NR 3 -.

[0388] In some embodiments of the compound of formula I, R b is always hydrogen, so that only R a may not be hydrogen. For example, R b may be hydrogen, and R a is such that R 2 forms a ring together with methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl, or may be selected from -(CH2)- or -(CH2)2-. Preferably, R b may be hydrogen, and R a is such that R 2 forms a ring together with methyl or -(CH2)- or -(CH2)2-. Further, both R a and R b may be hydrogen.

[0389] In some embodiments, the ring of which X 1 is a part is monocyclic or bicyclic.

[0390] In some embodiments of the compound of formula I, R cIt is always hydrogen, therefore R d It's not always the case that only hydrogen is present. For example, R c R may be hydrogen, d R may be selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. Preferably, c R may be hydrogen, d R may be methyl. Furthermore, R c and R d Both may be hydrogen.

[0391] In some embodiments of the compound of formula I, R 1 It is hydrogen.

[0392] In some embodiments of the compound of formula I, R c and R d R is hydrogen. In some embodiments of the compounds of formula I, R b , R c , and R d R is hydrogen. In some embodiments of the compounds of formula I, R 1 , R b , R c and R d It is hydrogen.

[0393] R a One of them is R 3 In some embodiments of the compound of formula I that forms a ring together, the formed ring is a 4, 5, or 6-membered ring, or a 5 or 6-membered ring, or a 5-membered ring.

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

[0395] R 2 One of them is R 3 In some embodiments of the compound of formula I that forms a ring together, the formed ring is a 4, 5, or 6-membered ring, or a 5, 6, or 6-membered ring. In some embodiments of the compound of formula I, R 2 C 1-4 Alkyl or R 3 Or R a Together, they form a ring - (CH2) q For example, R 2 may be selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl, or R 2 R 3 It is either -(CH2)- or -(CH2)2- which form a ring together with R 2 R a It is -(CH2)- or -(CH2)2- which forms a ring together with R. Preferably, 2 may be selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, or i-butyl, or R 2 R 3 It is either -(CH2)- or -(CH2)2- which form a ring together with R 2 R a It is a -(CH2)- or -(CH2)2- that forms a ring together with R. 2 It may also be methyl.

[0396] In some embodiments of the compound of formula I, R 3 is either hydrogen or methyl, or R 3 R 2 It is a -(CH2)- or -(CH2)2- which forms a ring together with .

[0397] 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, 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.

[0398] In some embodiments of the compound of formula I, X 1 R 2 It may form a heterocycle with the carbon that it directly bonds to. For example, X 1 It may form a 4, 5, 6, or 7-membered heterocycle. In some embodiments of the compounds of formula I, X 1 These may form substituted or unsubstituted oxetanil, thiatanil, azetidinil, pyrrolidinil, tetrahydrofuranil, tetrahydrothiopyranil, dihydropyranil, tetrahydropyranil, piperidinil, oxepanil, thiepanil, azepanil, azabicyclo[2.2.1]heptane, or azabicyclo[2.2.2]octane, preferably azetidinil, pyrrolidinil, tetrahydrofuranil, piperidinil, more preferably azetidinil, pyrrolidinil, or piperidinil.

[0399] In some embodiments of the compound of formula I, Ar 1 is the compound of formula i, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, R 4 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C3-7 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 Is alkoxy, or C6 aryl, and R 5 、R 5’ 、R 6 、R 6’ are, independently of each other, hydrogen, -CF3 or halogen, preferably F, Cl.

[0400] Ar 1 In some embodiments of the compound of formula I, where Ar is a compound of formula i, R 4 is hydrogen, fluoro, chloro, 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[[ID=?]] 1-4 Alkoxycarbonyl, C 1-4 )Alkoxyaminocarbonyl, or C6 aryl.

[0401] Ar 1In some embodiments of the compound of formula I, where is the compound of formula i, R 4 is hydrogen, fluoro, chloro, 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 It is a heteroaryl or C6aryl compound.

[0402] Ar 1 In some embodiments of the compound of formula I, where is the compound of formula i, R 4Generally, hydrogen, fluoro, chloro, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, n-hexyl, i-hexyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-propoxy, n-butoxy, i-butoxy, n-pentoxy, i-pentoxy, n-hexoxy, i-hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclofeptyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl Butoxymethyl, Methoxyethyl, Methoxypropyl, Methoxybutyl, Methoxypentyl, Methoxyhexyl, Ethoxymethyl, Ethoxyethyl, Ethoxypropyl, Ethoxybutyl, Ethoxypentyl, Ethoxyhexyl, Propoxymethyl, Propoxyethyl, Propoxypropyl, Propoxybutyl, Propoxypentyl, Propoxyhexyl, Butoxymethyl, Butoxyethyl, Butoxypropyl, Butoxybutyl, Butoxypentyl, Butoxyhexyl, Pentoxymethyl, Pentoxyethyl, Pentoxypropyl, Pentoxbutyl, Penthoxypentyl, pentoxyhexyl, hexoxymethyl, hexoxyethyl, hexoxypropyl, hexoxybutyl, hexoxypentyl, hexoxyhexyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, methoxyaminocarbonyl, ethoxyamino Carbonyl, propoxyaminocarbonyl, butoxyaminocarbonyl, pentoxyaminocarbonyl, hexoxyaminocarbonyl, phenylmethoxy, phenylethoxy, phenylpropoxy, phenylbutoxy, phenylpentoxy, phenylhexoxy, m-fluorophenylmethoxy, m-fluorophenylphenylethoxy, m-fluorophenylphenylpropoxy, m-fluorophenylphenylbutoxy, m-fluorophenylphenylpentoxy, m-fluorophenylphenylhexoxy, pyridinylmethoxy, pyridinylethoxy,These are pyridinylpropoxy, pyridinylbutoxy, pyridinylpentoxy, pyridinylhexoxy, phenyl, pyridinyl, or naphthyl. Ar 1 In some embodiments of the compound of formula I, where is the compound of formula i, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ is hydrogen. Preferably, R 4 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 It is an alkoxy or C6 aryl compound.

[0403] Ar 1 In some embodiments of the compound of formula I, where is the compound of formula i, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ is hydrogen. Preferably, R 4 is hydrogen, fluoro, chloro, 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, C1-4 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 It is an alkoxyaminocarbonyl or C6 aryl compound.

[0404] Ar 1 In some embodiments of the compound of formula I, where is the compound of formula i, Ar 1 It contains only one, two, or three substituents that are not hydrogen. Therefore, R 4 , R 5 , R 5’ , R 6 , or R 6’ At least two of these may be hydrogen.

[0405] Ar 1 In some embodiments of the compound of formula I, where is the compound of formula i, R 1 may be hydrogen, and / or R 2 may be methyl, or R 2 R 3 It is -(CH2)- or -(CH2)2- that forms a ring with R 2 R a It is a -(CH2)- or -(CH2)2- which forms a ring together with .

[0406] Ar 1 In some embodiments of the compound of formula I, where is the compound of formula i, R c and R d It is hydrogen. 1 In some embodiments of the compound of formula I, where is the compound of formula i, R b , R c and R d It is hydrogen.

[0407] Ra One of them is R 3 Together, they form a ring, Ar 1 In some embodiments of the compound of formula I, where is a compound of formula i, the formed ring is a 4, 5, or 6-membered ring, or a 5 or 6-membered ring, or a 5-membered ring.

[0408] R a One of them is R 3 Together, they form a ring, Ar 1 In some embodiments of the compound of formula I, where is the compound of formula i, the formed ring is a 3, 4, 5, or 6-membered ring.

[0409] R 2 One of them is R 3 Together, they form a ring, Ar 1 In some embodiments of the compound of formula I, where is a compound of formula i, the formed ring is a 4, 5, or 6-membered ring, or a 5, 6, or 6-membered ring.

[0410] In some embodiments of the compound of formula I, Ar 1 is the compound of formula ii-1, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, R 4 is hydrogen, F or Cl, R 5 , R 5’ , R 6 , R 6’ These are, independently of each other, hydrogen, -CF3, or halogen, preferably F, Cl.

[0411] In some embodiments of the compound of formula I, Ar 1 is a compound of formula ii-2, ii-3, or ii-4, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, X 2is O, NH, or NMe, X 3 is CH or N, o is either 0 or 1, R 5 , R 5 ', R 6 , R 6 ' is independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl, R 7 is hydrogen or a halogen, preferably F.

[0412] A person skilled in the art will know X 3 If CH represents R 7 In general, this carbon may also be bonded, thereby X 3 CR 7 It is important to understand that this is possible. Preferably, the corresponding aryl or heteroaryl is a single R 7 It is replaced only by X. 3 If R is N, 7 It is generally understood that it cannot be coupled to N.

[0413] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1, ii-2, ii-3, or ii-4, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ It is hydrogen.

[0414] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1, ii-2, ii-3, or ii-4, R 7 X 3 If is N, then it is hydrogen, and / or R 7 X 3 If it is CH, then it is F.

[0415] Ar 1However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1, ii-2, ii-3, or ii-4, o is 1.

[0416] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1, ii-2, ii-3, or ii-4, R 5 is F and / or R 6 It is either F or Cl.

[0417] Ar 1 In some embodiments of the compounds of formula I, where is a compound of formula ii-1, ii-2, ii-3, or ii-4, R c and R d It is hydrogen. 1 In some embodiments of the compounds of formula I, where is a compound of formula ii-1, ii-2, ii-3, or ii-4, R b , R c and R d It is hydrogen.

[0418] R a One of them is R 3 Together, they form a ring, Ar 1 In some embodiments of the compounds of formula I, where is a compound of formula ii-1, ii-2, ii-3, or ii-4, the formed ring is a 4, 5, or 6-membered ring, or a 5-membered ring.

[0419] R a One of them is R 3 Together, they form a ring, Ar 1 In some embodiments of the compounds of formula I, where is a compound of formula ii-1, ii-2, ii-3, or ii-4, the formed ring is a 3, 4, 5, or 6-membered ring.

[0420] R 2 One of them is R 3 Together, they form a ring, Ar 1In some embodiments of the compounds of formula I, where is a compound of formula ii-1, ii-2, ii-3, or ii-4, the formed ring is a 4, 5, or 6-membered ring, or a 5, 6, or 6-membered ring.

[0421] Ar 1 In some embodiments of the compounds of formula I, where is a compound of formula ii-1, ii-2, ii-3, or ii-4, R 2 is methyl or R 2 R 3 It is either -(CH2)- or -(CH2)2- which form a ring together with R 2 R a It is a -(CH2)- or -(CH2)2- which forms a ring together with .

[0422] In some embodiments, X 2 It is O, and therefore Ar 1 is the compound of formula ii-1a, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, R 4 is hydrogen, F or Cl, R 5 , R 5’ , R 6 , R 6’ These are, independently of each other, hydrogen, -CF3, or halogen, preferably F, Cl.

[0423] In some embodiments, X 2 It is O, and therefore Ar 1 is a compound of formula ii-2a, ii-3a, or ii-4a, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, X 3 is CH or N, preferably N. o is either 0 or 1, R 5 , R 5 ', R 6 , R 6 ' is independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl, R 7 is hydrogen or a halogen, preferably F.

[0424] Ar 1 In some embodiments of the compounds of formula I, where is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ It is hydrogen.

[0425] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1a, ii-2a, ii-3a, or ii-4a, o is 1.

[0426] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1a, ii-2a, ii-3a, or ii-4a, R 5 is F and / or R 6 It is either F or Cl.

[0427] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1a, ii-2a, ii-3a, or ii-4a, R 7 X 3 If is N, then it is hydrogen, and / or R 7 X 3 If it is CH, then it is F.

[0428] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1a, ii-2a, ii-3a, or ii-4a, R 2 is methyl or R 2 R3 It is either -(CH2)- or -(CH2)2- which form a ring together with R 2 R a It is a -(CH2)- or -(CH2)2- which forms a ring together with .

[0429] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1a, ii-2a, ii-3a, or ii-4a, R c and R d It is hydrogen. 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1a, ii-2a, ii-3a, or ii-4a, R b , R c and R d It is hydrogen.

[0430] R a One of them is R 3 Together, they form a ring, Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1a, ii-2a, ii-3a, or ii-4a, the ring formed is a 4, 5, or 6-membered ring, or a 5-membered ring.

[0431] R a One of them is R 3 Together, they form a ring, Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1a, ii-2a, ii-3a, or ii-4a, the ring formed is a 3, 4, 5, or 6-membered ring.

[0432] R 2 One of them is R 3 Together, they form a ring, Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1a, ii-2a, ii-3a, or ii-4a, the ring formed is a 4, 5, or 6-membered ring, or a 5, or 6-membered ring, or a 6-membered ring.

[0433] In some embodiments, X 3is N, and therefore Ar 1 is the compound of formula ii-1b, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, R 4 is hydrogen, F or Cl, R 5 , R 5’ , R 6 , R 6’ These are, independently of each other, hydrogen, -CF3, or halogen, preferably F, Cl.

[0434] In some embodiments, X 3 is N, and therefore Ar 1 These are compounds of formulas ii-2b, ii-3b, ii-4b, ii-5b, or pharmaceutically acceptable salts or stereoisomers thereof. [ka] During the ceremony, X 2 is O, NH or NMe, preferably O. o is either 0 or 1, R 5 , R 5 ', R 6 , R 6 ' is independently of each other, hydrogen, -CF3, or halogen, preferably F, Cl, R 7 is hydrogen or a halogen, preferably F.

[0435] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ It is hydrogen.

[0436] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, o is 1.

[0437] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of 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.

[0438] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, R 7 It is F.

[0439] Ar 1 In some embodiments of the compounds of formula I, where is a compound of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, R 2 is methyl or R 2 R 3 It is either -(CH2)- or -(CH2)2- which form a ring together with R 2 R a It is a -(CH2)- or -(CH2)2- which forms a ring together with .

[0440] Ar 1 In some embodiments of the compounds of formula I, where is a compound of formula ii-1b, ii-2b, ii-3b, or ii-4b, R c and R d It is hydrogen. 1 In some embodiments of the compounds of formula I, where is a compound of formula ii-1b, ii-2b, ii-3b, or ii-4b, R b , R c and R d It is hydrogen.

[0441] R a One of them is R 3 Together, they form a ring, Ar1 In some embodiments of the compounds of formula I, where is a compound of formula ii-1b, ii-2b, ii-3b, or ii-4b, the formed ring is a 4, 5, or 6-membered ring, or a 5-membered ring.

[0442] R a One of them is R 3 Together, they form a ring, Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1b, ii-2b, ii-3b, or ii-4b, the ring formed is a 3, 4, 5, or 6-membered ring.

[0443] R 2 One of them is R 3 Together, they form a ring, Ar 1 In some embodiments of the compounds of formula I, where is a compound of formula ii-1b, ii-2b, ii-3b, or ii-4b, the formed ring is a 4, 5, or 6-membered ring, or a 5, 6, or 6-membered ring.

[0444] In some embodiments, X 2 is O, and X 3 is N, and therefore Ar 1 is the compound of formula ii-1c, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, R 4 is hydrogen, F or Cl, R 5 , R 5’ , R 6 , R 6’ These are, independently of each other, hydrogen, -CF3, or halogen, preferably F, Cl.

[0445] In some embodiments, X 2 is O, and X 3 is N, and therefore Ar 1These are compounds of formulas ii-2c, ii-3c, ii-4c, ii-5c, or pharmaceutically acceptable salts or stereoisomers thereof. [ka] During the ceremony, o is either 0 or 1, R 4 is hydrogen, F or Cl, R 5 , R 5 ', R 6 , R 6 ' is independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl, R 7 is hydrogen or a halogen, preferably F.

[0446] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1c, ii-2c, ii-3c, ii-4c, or ii-5c, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ It is hydrogen.

[0447] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1c, ii-2c, ii-3c, ii-4c, or ii-5c, o is 1.

[0448] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of 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.

[0449] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1c, ii-2c, ii-3c, ii-4c, or ii-5c, R 7 It is F.

[0450] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1c, ii-2c, ii-3c, ii-4c, or ii-5c, R 2 is methyl or R 2 R 3 It is either -(CH2)- or -(CH2)2- which form a ring together with R 2 R a It is a -(CH2)- or -(CH2)2- which forms a ring together with .

[0451] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1c, ii-2c, ii-3c, or ii-4c, R c and R d It is hydrogen. 1 However, in some embodiments of the compounds of formula I, which are compounds of formula ii-1c, ii-2c, ii-3c, or ii-4c, R b , R c and R d It is hydrogen.

[0452] R a One of them is R 3 Together, they form a ring, Ar 1 In some embodiments of the compounds of formula I, where is a compound of formula ii-1c, ii-2c, ii-3c, or ii-4c, the formed ring is a 4, 5, or 6-membered ring, or a 5-membered ring.

[0453] R a One of them is R 3 Together, they form a ring, Ar 1 In some embodiments of the compounds of formula I, where is a compound of formula ii-1c, ii-2c, ii-3c, or ii-4c, the ring formed is a 3, 4, 5, or 6-membered ring.

[0454] R 2 One of them is R 3 Together, they form a ring, Ar 1In some embodiments of the compounds of formula I, where is a compound of formula ii-1c, ii-2c, ii-3c, or ii-4c, the formed ring is a 4, 5, or 6-membered ring, or a 5, 6, or 6-membered ring.

[0455] In some embodiments of the compound of formula I, Ar 1 is the compound of formula iii-1, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, R 4 is hydrogen or halogen, preferably F or Cl. R 5 , R 6 These are, independently of each other, hydrogen, -CF3, or halogen, preferably F, Cl.

[0456] In some embodiments of the compound of formula I, Ar 1 is a compound of formula iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, X 3 is CH or N, preferably N. o is either 0 or 1, R 5 , R 6 These are, independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl. R 7 is hydrogen or a halogen, preferably F.

[0457] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, R 5 and R 6These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ It is hydrogen.

[0458] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, o is 1.

[0459] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula 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.

[0460] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula iii-1, iii-2, iii-3, or iii-4, R 7 X 3 If is N, then it is hydrogen, and / or R 7 X 3 If it is CH, then it is F.

[0461] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, R 2 is methyl or R 2 R 3 It is either -(CH2)- or -(CH2)2- which form a ring together with R 2 R a It is a -(CH2)- or -(CH2)2- which forms a ring together with .

[0462] Ar 1However, in some embodiments of the compounds of formula I, which are compounds of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, R c and R d It is hydrogen. 1 However, in some embodiments of the compounds of formula I, which are compounds of formula 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.

[0463] R a One of them is R 3 Together, they form a ring, Ar 1 In some embodiments of the compounds of formula I, where is a compound of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, the formed ring is a 4, 5, or 6-membered ring, or a 5-membered ring.

[0464] R a One of them is R 3 Together, they form a ring, Ar 1 In some embodiments of the compounds of formula I, where is a compound of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, the ring formed is a 3, 4, 5, or 6-membered ring.

[0465] R 2 One of them is R 3 Together, they form a ring, Ar 1 In some embodiments of the compounds of formula I, where is a compound of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, the formed ring is a 4, 5, or 6-membered ring, or a 5, or 6-membered ring, or a 6-membered ring.

[0466] In some embodiments, X 3 is N, and therefore Ar 1However, it is a compound of formula iv-2, iv-3, or iv-4, iv-5, iv-6, or iv-7, or X 3 It is C, and therefore Ar 1 However, it is a compound of formula iv-8 or iv-9. [ka] During the ceremony, o is either 0 or 1, R 5 , R 6 These are, independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl. R 7 is hydrogen or a halogen, preferably F.

[0467] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ It is hydrogen.

[0468] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, o is 1.

[0469] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula 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.

[0470] Ar 1However, in some embodiments of the compounds of formula I, which are compounds of formula iiv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, R 7 It is F.

[0471] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, R 2 is methyl or R 2 R 3 It is either -(CH2)- or -(CH2)2- which form a ring together with R 2 R a It is a -(CH2)- or -(CH2)2- which forms a ring together with .

[0472] Ar 1 However, in some embodiments of the compounds of formula I, which are compounds of formula 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. 1 However, in some embodiments of the compounds of formula I, which are compounds of formula 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.

[0473] R a One of them is R 3 Together, they form a ring, Ar 1 In some embodiments of the compounds of formula I, where is a compound of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, the formed ring is a 4, 5, or 6-membered ring, or a 5-membered ring.

[0474] R a One of them is R 3 Together, they form a ring, Ar 1In some embodiments of the compounds of formula I, where is a compound of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, the formed ring is a 3, 4, 5, or 6-membered ring.

[0475] R 2 One of them is R 3 Together, they form a ring, Ar 1 In some embodiments of the compounds of formula I, where is a compound of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, the formed ring is a 4, 5, or 6-membered ring, or a 5, 6-membered ring, or a 6-membered ring.

[0476] In some embodiments, the present disclosure provides compounds of formula IIa or IIb below, or pharmaceutically acceptable salts or stereoisomers thereof: [ka] During the ceremony, X 1 -O-, -NR 3 -and, R 1 is H or F, R 2 is hydrogen or C 1-4 Alkyl, preferably methyl, or R 3 Together, they form a ring - (CH2) q -and, R 3 is hydrogen or C 1-4 Alkyl, preferably hydrogen or methyl, or R 2 Together, they form a ring - (CH2) p -and, m is 1, 2, or 3. n is 0, 1, or 2. p is either 1 or 2. q is 0, 1, or 2. r is either 0 or 1. s is 1 or 2, and Ar 1is either unsubstituted or halogen, -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 A six-membered aryl group that is substituted with one or more groups selected from alkoxys or C6 aryls.

[0477] In some embodiments of the compound of formula IIa or formula IIb, X 1 -NR 3 - is

[0478] In some embodiments of the compounds of formula IIa or formula IIb, R 1 It is hydrogen.

[0479] In some embodiments of the compounds of formula IIa or formula IIb, R 2 C 1-4 Alkyl or R 3 Together, they form a ring - (CH2) q - For example, R 2 R 3 Methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl R are -(CH2)- or -(CH2)2- that form a ring together with -(CH2)- or -(CH2)2-. 2 They may be selected from. Preferably, R 2 R 3Methyl, ethyl, n-propyl, i-propyl, n-butyl, or i-butyl R, which are -(CH2)- or -(CH2)2- that form a ring with -(CH2)-. 2 You may choose from the following. More preferably, R 2 R 2 R 3 It may also be methyl -(CH2)- or -(CH2)2 which forms a ring together with it.

[0480] In some embodiments of the compounds of formula IIa or formula IIb, R 3 R 2 It is a hydrogen atom or methyl atom that forms a ring with -(CH2)- or -(CH2)2-.

[0481] In some embodiments of the compound of formula IIa or formula IIb, X 1 , NR 3 That is the case.

[0482] 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, 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.

[0483] 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.

[0484] In some embodiments of the compound of formula IIa or formula IIb, X 1 R 2 It may form a heterocycle with the carbon that it directly bonds to. For example, X 1 It may form a 4, 5, 6, or 7-membered heterocycle or heterobicycle. In some embodiments of the compounds of formula I, X 1 These may form substituted or unsubstituted oxetanil, thiatanil, azetidinil, pyrrolidinil, tetrahydrofuranil, tetrahydrothiopyranil, dihydropyranil, tetrahydropyranil, piperidinil, oxepanil, thiepanil, azepanil, azabicyclo[2.2.1]heptane, or azabicyclo[2.2.2]octane, preferably azetidinil, pyrrolidinil, tetrahydrofuranil, piperidinil, more preferably azetidinil, pyrrolidinil, or piperidinil.

[0485] In some embodiments of the compound of formula IIa or formula IIb, Ar 1 is the compound of formula i, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, R 4 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 Alkoxyaminocarbonyl, aryl C 1-6It is an alkoxy or C6 aryl compound. R 5 , R 5’ , R 6 , R 6’ These are, independently of each other, hydrogen, -CF3, or halogen, preferably F, Cl.

[0486] Ar 1 In some embodiments of compounds of formula IIa or formula IIb, where is a compound of formula i, R 4 is hydrogen, fluoro, chloro, 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 It is an alkoxyaminocarbonyl or C6 aryl compound.

[0487] Ar 1 In some embodiments of compounds of formula IIa or formula IIb, where is the compound of formula i, R 4 is hydrogen, fluoro, chloro, 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 It is a heteroaryl or C6aryl compound.

[0488] Ar 1In some embodiments of compounds of formula IIa or formula IIb, where is the compound of formula i, R 4Generally, hydrogen, fluoro, chloro, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, n-hexyl, i-hexyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-propoxy, n-butoxy, i-butoxy, n-pentoxy, i-pentoxy, n-hexoxy, i-hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclofeptyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl Butoxymethyl, Methoxyethyl, Methoxypropyl, Methoxybutyl, Methoxypentyl, Methoxyhexyl, Ethoxymethyl, Ethoxyethyl, Ethoxypropyl, Ethoxybutyl, Ethoxypentyl, Ethoxyhexyl, Propoxymethyl, Propoxyethyl, Propoxypropyl, Propoxybutyl, Propoxypentyl, Propoxyhexyl, Butoxymethyl, Butoxyethyl, Butoxypropyl, Butoxybutyl, Butoxypentyl, Butoxyhexyl, Pentoxymethyl, Pentoxyethyl, Pentoxypropyl, Pentoxbutyl, Penthoxypentyl, pentoxyhexyl, hexoxymethyl, hexoxyethyl, hexoxypropyl, hexoxybutyl, hexoxypentyl, hexoxyhexyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, methoxyaminocarbonyl, ethoxyamino Carbonyl, propoxyaminocarbonyl, butoxyaminocarbonyl, pentoxyaminocarbonyl, hexoxyaminocarbonyl, phenylmethoxy, phenylethoxy, phenylpropoxy, phenylbutoxy, phenylpentoxy, phenylhexoxy, m-fluorophenylmethoxy, m-fluorophenylphenylethoxy, m-fluorophenylphenylpropoxy, m-fluorophenylphenylbutoxy, m-fluorophenylphenylpentoxy, m-fluorophenylphenylhexoxy, pyridinylmethoxy, pyridinylethoxy,These are pyridinylpropoxy, pyridinylbutoxy, pyridinylpentoxy, pyridinylhexoxy, phenyl, pyridinyl, or naphthyl.

[0489] Ar 1 In some embodiments of compounds of formula IIa or formula IIb, where is the compound of formula i, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ is hydrogen. Preferably, R 4 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 It is an alkoxy or C6 aryl compound.

[0490] Ar 1 In some embodiments of compounds of formula IIa or formula IIb, where is the compound of formula i, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ is hydrogen. Preferably, R 4 is hydrogen, fluoro, chloro, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, hydroxy C 1-5 Alkyl, C1-4 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 It is an alkoxyaminocarbonyl or C6 aryl compound.

[0491] Ar 1 In some embodiments of compounds of formula IIa or formula IIb, where is the compound of formula i, Ar 1 It contains only one, two, or three substituents that are not hydrogen. Therefore, R 4 , R 5 , R 5’ , R 6 , or R 6’ At least two of these may be hydrogen.

[0492] In some embodiments of the compound of formula IIa or formula IIb, Ar 1 is a compound of formula i, and R 1 may be hydrogen, and / or R 2 may be methyl, or R 3 It may also be -(CH2)- or -(CH2)2- which form a ring together.

[0493] In some embodiments of the compound of formula IIa or formula IIb, Ar 1 is the compound of formula ii-1, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, R 4 is hydrogen, F or Cl, R 5 , R 5’ , R6 , R 6’ These are, independently of each other, hydrogen, -CF3, or halogen, preferably F, Cl.

[0494] In some embodiments of the compound of formula IIa or formula IIb, Ar 1 is a compound of formula ii-2, ii-3, or ii-4, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, X 2 is O, NH, or NMe, X 3 is C or N, o is either 0 or 1, R 5 , R 5 ', R 6 , R 6 ' is independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl, R 7 is hydrogen or a halogen, preferably F.

[0495] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula ii-1, ii-2, ii-3, or ii-4, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ It is hydrogen.

[0496] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula ii-1, ii-2, ii-3, or ii-4, o is 1.

[0497] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula ii-1, ii-2, ii-3, or ii-4, R 5is F and / or R 6 It is either F or Cl.

[0498] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula ii-1, ii-2, ii-3, or ii-4, R 2 is methyl or R 3 It is a -(CH2)- or -(CH2)2- which forms a ring together with .

[0499] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula ii-1, ii-2, ii-3, or ii-4, R 7 X 3 If is N, then it is hydrogen, and / or R 7 X 3 If it is CH, then it is F.

[0500] Ar 1 However, in some embodiments of the compounds of formula IIa, which are compounds of formula ii-1, ii-2, ii-3, or ii-4, 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, 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.

[0501] Ar 1However, in some embodiments of the compounds of formula IIb, which are compounds of formula ii-1, ii-2, ii-3, or ii-4, 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.

[0502] In some embodiments, X 2 It is O, and therefore Ar 1 is the compound of formula ii-1a, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, R 4 is hydrogen, F or Cl, R 5 , R 5’ , R 6 , R 6’ These are, independently of each other, hydrogen, -CF3, or halogen, preferably F, Cl.

[0503] In some embodiments, X 2 It is O, and therefore Ar 1 is a compound of formula ii-2a, ii-3a, or ii-4a, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, X 3 is CH or N, preferably N. o is either 0 or 1, R 5 , R 5 ', R 6 , R 6 ' is independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl, R 7 is hydrogen or a halogen, preferably F.

[0504] Ar 1In some embodiments of compounds of formula IIa or formula IIb, where is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ It is hydrogen.

[0505] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula ii-1a, ii-2a, ii-3a, or ii-4a, o is 1.

[0506] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula ii-1a, ii-2a, ii-3a, or ii-4a, R 5 is F and / or R 6 It is either F or Cl.

[0507] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula ii-1a, ii-2a, ii-3a, or ii-4a, R 7 X 3 If is N, then it is hydrogen, and / or R 7 X 3 If it is CH, then it is F.

[0508] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula ii-1a, ii-2a, ii-3a, or ii-4a, R 2 is methyl or R 3 It is a -(CH2)- or -(CH2)2- which forms a ring together with .

[0509] Ar 1However, in some embodiments of the compounds of formula IIa, which are compounds of formula ii-a-1, ii-2a, ii-3a, or ii-4a, 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, 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.

[0510] Ar 1 However, in some embodiments of the compounds of formula IIb, which are compounds of formula ii-1a, ii-2a, ii-3a, or ii-4a, 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.

[0511] In some embodiments of the compound of formula IIa or formula IIb, X 3 is N, and therefore Ar 1 is the compound of formula ii-1b, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, R 4 is hydrogen, F or Cl, R 5 , R 5’ , R 6 , R 6’ These are, independently of each other, hydrogen, -CF3, or halogen, preferably F, Cl.

[0512] In some embodiments of the compound of formula IIa or formula IIb, X 3 is N, and therefore Ar 1 These are compounds of formulas ii-2b, ii-3b, ii-4b, ii-5b, or pharmaceutically acceptable salts or stereoisomers thereof. [ka] During the ceremony, X 2 is O, NH or NMe, preferably O. o is either 0 or 1, R 5 , R 5 ', R 6 , R 6 ' is independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl, R 7 is hydrogen or a halogen, preferably F.

[0513] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ It is hydrogen.

[0514] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, o is 1.

[0515] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of 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.

[0516] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, R 7 It is F.

[0517] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, R 2 is methyl or R 3 It is a -(CH2)- or -(CH2)2- which forms a ring together with .

[0518] Ar 1 However, in some embodiments of the compounds of formula IIa, which are compounds of formula ii-1b, ii-2b, ii-3b, or ii-4b, 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, 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.

[0519] Ar 1 However, in some embodiments of the compounds of formula IIb, which are compounds of formula ii-1b, ii-2b, ii-3b, or ii-4b, 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.

[0520] In some embodiments of the compound of formula IIa or formula IIb, Ar1 is the compound of formula ii-1c, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, R 4 is hydrogen, F or Cl, R 5 , R 5’ , R 6 , R 6’ These are, independently of each other, hydrogen, -CF3, or halogen, preferably F, Cl.

[0521] In some embodiments of the compound of formula IIa or formula IIb, X 2 is O, and X 3 is N, and therefore Ar 1 These are compounds of formulas ii-2c, ii-3c, ii-4c, ii-5c, or pharmaceutically acceptable salts or stereoisomers thereof. [ka] During the ceremony, o is either 0 or 1, R 5 , R 5 ', R 6 , R 6 ' is independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl, R 7 is hydrogen or a halogen, preferably F.

[0522] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ It is hydrogen.

[0523] Ar 1However, in some embodiments of compounds of formula IIa or formula IIb that are compounds of formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, o is 1.

[0524] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of 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.

[0525] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 7 It is F.

[0526] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 2 is methyl or R 3 It is a -(CH2)- or -(CH2)2- which forms a ring together with .

[0527] Ar 1However, in some embodiments of the compounds of formula IIa, which are compounds of formula ii-1c, ii-2c, ii-3c, or ii-4c, 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, 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.

[0528] Ar 1 However, in some embodiments of the compounds of formula IIb, which are compounds of formula ii-1c, ii-2c, ii-3c, or ii-4c, 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.

[0529] In some embodiments of the compound of formula IIa or formula IIb, Ar 1 is the compound of formula iii-1, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, R 4 is hydrogen or halogen, preferably F or Cl. R 5 , R 6 These are, independently of each other, hydrogen, -CF3, or halogen, preferably F, Cl.

[0530] In some embodiments of the compound of formula IIa or formula IIb, Ar 1is a compound of formula iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, X 3 is CH or N, preferably N. o is either 0 or 1, R 5 , R 6 These are, independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl. R 7 is hydrogen or a halogen, preferably F.

[0531] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ It is hydrogen.

[0532] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb that are compounds of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, o is 1.

[0533] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula 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.

[0534] Ar 1However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula iii-1, iii-2, iii-3, or iii-4, R 7 X 3 If is N, then it is hydrogen, and / or R 7 X 3 If it is CH, then it is F.

[0535] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, R 2 is methyl or R 3 It is a -(CH2)- or -(CH2)2- which forms a ring together with .

[0536] Ar 1 However, in some embodiments of the compounds of formula IIa, which are compounds of formula iii-1, iii-2, iii-3, or iii-4, 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, 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.

[0537] Ar 1 However, in some embodiments of the compounds of formula IIb, which are compounds of formula iii-1, iii-2, iii-3, or iii-4, 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.

[0538] In some embodiments, X 3 is N, and therefore Ar 1 However, it is a compound of formula iv-2, iv-3, or iv-4, iv-5, iv-6, or iv-7, or X 3 It is C, and therefore Ar 1 However, it is a compound of formula iv-8 or iv-9. [ka] During the ceremony, o is either 0 or 1, R 5 , R 6 These are, independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl. R 7 is hydrogen or a halogen, preferably F.

[0539] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb, which are compounds of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ It is hydrogen.

[0540] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb that are compounds of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, o is 1.

[0541] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb that are compounds of formula 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.

[0542] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb that are compounds of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, R 7 It is F.

[0543] Ar 1 However, in some embodiments of compounds of formula IIa or formula IIb that are compounds of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, R 2 is methyl or R 3 It is a -(CH2)- or -(CH2)2- which forms a ring together with .

[0544] Ar 1 However, in some embodiments of the compounds of formula IIa, which are compounds of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, n is 0 and m is 1, 2, or 3, or n is 0 and m is 1, or n is 1 and m is 1, 2, or 3, or n is 1 and m is 1, 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.

[0545] Ar 1However, in some embodiments of the compounds of formula IIb, which are compounds of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, 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.

[0546] In some embodiments, the present disclosure provides compounds of formula III below or pharmaceutically acceptable salts or stereoisomers thereof: [ka] During the ceremony, R 1 is H or F, Ar 1 is either an unsubstituted 6-membered aryl or a halogen, -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 A six-membered aryl group substituted with one or more groups selected from alkoxy or C6 aryl groups, Z is a compound selected from the following, according to any one of the embodiments described above: [ka]

[0547] In some embodiments of the compound of formula III, R 1 It is hydrogen.

[0548] In some embodiments, the present disclosure provides compounds of formula IV below or pharmaceutically acceptable salts or stereoisomers thereof: [ka] During the ceremony, R 1 is H or F, R 4 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 Alkoxyaminocarbonyl, aryl C 1-6 It is an alkoxy or C6 aryl compound. R 5 , R 5 ', R 6 , R 6 ' is independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl, Z is a compound selected from the following, according to any one of the embodiments described above: [ka]

[0549] In some embodiments of the compound of formula IV, R 4is hydrogen, fluoro, chloro, 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 It is an alkoxyaminocarbonyl or C6 aryl compound.

[0550] In some embodiments of the compound of formula VI, R 4 is hydrogen, fluoro, chloro, 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 It is a heteroaryl or C6aryl compound.

[0551] In some embodiments of the compound of formula IV, R 4Generally, hydrogen, fluoro, chloro, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, n-hexyl, i-hexyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-propoxy, n-butoxy, i-butoxy, n-pentoxy, i-pentoxy, n-hexoxy, i-hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclofeptyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl Butoxymethyl, Methoxyethyl, Methoxypropyl, Methoxybutyl, Methoxypentyl, Methoxyhexyl, Ethoxymethyl, Ethoxyethyl, Ethoxypropyl, Ethoxybutyl, Ethoxypentyl, Ethoxyhexyl, Propoxymethyl, Propoxyethyl, Propoxypropyl, Propoxybutyl, Propoxypentyl, Propoxyhexyl, Butoxymethyl, Butoxyethyl, Butoxypropyl, Butoxybutyl, Butoxypentyl, Butoxyhexyl, Pentoxymethyl, Pentoxyethyl, Pentoxypropyl, Pentoxbutyl, Penthoxypentyl, pentoxyhexyl, hexoxymethyl, hexoxyethyl, hexoxypropyl, hexoxybutyl, hexoxypentyl, hexoxyhexyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, methoxyaminocarbonyl, ethoxyamino Carbonyl, propoxyaminocarbonyl, butoxyaminocarbonyl, pentoxyaminocarbonyl, hexoxyaminocarbonyl, phenylmethoxy, phenylethoxy, phenylpropoxy, phenylbutoxy, phenylpentoxy, phenylhexoxy, m-fluorophenylmethoxy, m-fluorophenylphenylethoxy, m-fluorophenylphenylpropoxy, m-fluorophenylphenylbutoxy, m-fluorophenylphenylpentoxy, m-fluorophenylphenylhexoxy, pyridinylmethoxy, pyridinylethoxy,These are pyridinylpropoxy, pyridinylbutoxy, pyridinylpentoxy, pyridinylhexoxy, phenyl, pyridinyl, or naphthyl.

[0552] In some embodiments of the compound of formula IV, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ is hydrogen. Preferably, R 4 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 It is an alkoxy or C6 aryl compound.

[0553] In some embodiments of the compound of formula IV, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ is hydrogen. Preferably, R 4 is hydrogen, fluoro, chloro, 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, C1-4 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 It is an alkoxyaminocarbonyl or C6 aryl compound.

[0554] In some embodiments of the compound of formula IV, Ar 1 It contains only one, two, or three substituents that are not hydrogen. Therefore, R 4 , R 5 , R 5’ , R 6 , or R 6’ At least two of these may be hydrogen.

[0555] In some embodiments of the compound of formula IV, R 1 It may be hydrogen.

[0556] In some embodiments, the present disclosure provides compounds of the following formula V-1 or pharmaceutically acceptable salts or stereoisomers thereof: [ka] During the ceremony, R 1 is H or F, R 4 is hydrogen or halogen, preferably F or Cl. R 5 , R 5 ', R 6 , R 6 ' is independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl, Z is selected from the following: [ka]

[0557] In some embodiments, the present disclosure provides compounds of the following formulas V-2, V-3, or V-4, or pharmaceutically acceptable salts or stereoisomers thereof: [ka] During the ceremony, X 2 is O, NH, or NMe, X 3 is CH or N, R 1 is H or F, R 5 , R 5 ', R 6 , R 6 ' is independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl, o is either 0 or 1, R 7 is hydrogen or halogen, preferably F. Z is selected from the following: [ka]

[0558] In some embodiments of the compounds of formula V-1, V-2, V-3, or V-4, R 4 These are hydrogen, chloro, or fluoro.

[0559] In some embodiments of compounds of formula V-1, V-2, V-3, or V-4, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ is hydrogen. Preferably, R 4 These are hydrogen, chloro, or fluoro.

[0560] In some embodiments of compounds of formula V-1, V-2, V-3, or V-4, R 5 and R 6These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ is hydrogen. Preferably, R 4 These are hydrogen, chloro, or fluoro.

[0561] In some embodiments of the compounds of formula V-1, V-2, V-3, or V-4, Ar 1 It contains only one, two, or three substituents that are not hydrogen. Therefore, R 4 , R 5 , R 5’ , R 6 , or R 6’ At least two of these may be hydrogen.

[0562] In some embodiments of the compounds of formula V-1, V-2, V-3, or V-4, R 7 X 3 If is N, then it is hydrogen, and / or R 7 X 3 If it is CH, then it is F.

[0563] In some embodiments of the compounds of formula V-1, V-2, V-3, or V-4, o is 1.

[0564] In some embodiments of the compounds of formula V-1, V-2, V-3, or V-4, R 1 It may be hydrogen.

[0565] In some embodiments of the compounds of formula V-2, V-3, or V-4, X 2 is O, which gives rise to compounds of formula V-2a, V-3a, or V-4a or their pharmaceutically acceptable salts or stereoisomers. [ka] During the ceremony, X 3 is CH or N, R 1 is H or F, R 5 , R5 ', R 6 , R 6 ' is independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl, o is either 0 or 1, R 7 is hydrogen or halogen, preferably F. Z is selected from the following: [ka]

[0566] In some embodiments of the compounds of formula V-1, V-2a, V-3a, or V-4a, R 4 These are hydrogen, fluoro, or chloro.

[0567] In some embodiments of the compounds of formula V-1, V-2a, V-3a, or V-4a, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ is hydrogen. Preferably, R 4 These are hydrogen, chloro, or fluoro.

[0568] In some embodiments of the compounds of formula V-1, V-2a, V-3a, or V-4a, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ is hydrogen. Preferably, R 4 These are hydrogen, chloro, or fluoro.

[0569] In some embodiments of the compounds of formula V-1, V-2a, V-3a, or V-4a, Ar 1 It contains only one, two, or three substituents that are not hydrogen. Therefore, R 4 , R 5 , R 5’ , R 6 , or R 6’At least two of these may be hydrogen.

[0570] In some embodiments of the compounds of formula V-1, V-2a, V-3a, or V-4a, R 7 X 3 If is N, then it is hydrogen, and / or R 7 X 3 If it is CH, then it is F.

[0571] In some embodiments of the compounds of formula V-1, V-2a, V-3a, or V-4a, o is 1.

[0572] In some embodiments of the compounds of formula V-1, V-2a, V-3a, or V-4a, R 1 It may be hydrogen.

[0573] In some embodiments of the compounds of formula V-2, V-3, or V-4, X 3 is N, which gives rise to compounds of formulas V-2b, V-3b, V-4b or their pharmaceutically acceptable salts or stereoisomers, or X 3 This is C, which gives rise to the compound of formula V-5b or its pharmaceutically acceptable salt or stereoisomer. [ka] During the ceremony, X 2 is O, NH, or NMe, R 1 is H or F, R 5 , R 5 ', R 6 , R 6 ' is independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl, o is either 0 or 1, R 7 is hydrogen or halogen, preferably F. Z is selected from the following: [ka]

[0574] In some embodiments of the compounds of formula V-1, V-2b, V-3b, V-4b, or V-5b, R 4 These are hydrogen, fluoro, and chloro.

[0575] In some embodiments of the compounds of formula V-1, V-2b, V-3b, V-4b, or V-5b, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ is hydrogen. Preferably, R 4 These are hydrogen, chloro, or fluoro.

[0576] In some embodiments of the compounds of formula V-1, V-2b, V-3b, V-4b, or V-5b, R 5 and R 6 These are independently hydrogen, -CF3, F, or Cl, and R 5’ and R 6’ is hydrogen. Preferably, R 4 is hydrogen, fluoro, chloro, 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 C 1-4 Alkyl, heteroaryl C 1-4 It is an alkoxy or aryl compound.

[0577] In some embodiments of the compounds of formula V-1, V-2b, V-3b, V-4b, or V-5b, Ar 1 It contains only one, two, or three substituents that are not hydrogen. Therefore, R 4 , R5 , R 5’ , R 6 , or R 6’ At least two of these may be hydrogen.

[0578] In some embodiments of V-2b, V-3b, V-4b, or V-5b, o is 1.

[0579] In some embodiments of the compounds of formula V-1, V-2b, V-3b, V-4b, or V-5b, R 7 It is F.

[0580] In some embodiments of the compounds of formula V-1, V-2b, V-3b, V-4b, or V-5b, R 1 It may be hydrogen.

[0581] In some embodiments, the present disclosure provides compounds of the following formula VI-1 or pharmaceutically acceptable salts or stereoisomers thereof: [ka] During the ceremony, R 1 is H or F, R 4 is hydrogen or halogen, preferably F or Cl. R 5 , R 6 These are, independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl. R 7 is hydrogen or halogen, preferably F. Z is selected from the following: [ka]

[0582] In some embodiments, the present disclosure provides compounds of formulas VI-2, VI-3, or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof: [ka] During the ceremony, X 2 is O, NH, or NMe, X 3 is CH or N, R 1 is H or F, o is either 0 or 1, R 5 , R 6 These are, independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl. R 7 is hydrogen or halogen, preferably F. Z is selected from the following: [ka]

[0583] In some embodiments of the compounds of formula VI-1, VI-2, VI-3, or VI-4, R 4 These are hydrogen, chloro, or fluoro.

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

[0585] In some embodiments of the 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.

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

[0587] In some embodiments of the compounds of formula VI-1, VI-2, VI-3, or VI-4, R1 It may be hydrogen.

[0588] In some embodiments of the compounds of formula VI-2, VI-3, or VI-4, X 2 is O, which gives rise to compounds of formula VI-2a, VI-3a, or VI-4a or their pharmaceutically acceptable salts or stereoisomers. [ka] During the ceremony, X 3 is CH or N, R 1 is H or F, R 5 , R 6 These are, independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl. o is either 0 or 1, R 7 is hydrogen or halogen, preferably F. Z is selected from the following: [ka]

[0589] In some embodiments of the compounds of formula VI-1, VI-2a, VI-3a, or VI-4a, R 4 These are hydrogen, fluoro, or chloro.

[0590] In some embodiments of the compounds of formula VI-1, VI-2a, VI-3a, or VI-4a, o is 1.

[0591] In some embodiments of the 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.

[0592] In some embodiments of the compounds of formula VI-1, VI-2a, VI-3a, or VI-4a, R 7X 3 If is N, then it is hydrogen, and / or R 7 X 3 If it is CH, then it is F.

[0593] In some embodiments of the compounds of formula VI-1, VI-2a, VI-3a, or VI-4a, R 1 It may be hydrogen.

[0594] In some embodiments of the compounds of formula VI-2, VI-3, or VI-4, X 3 is N, which gives rise to compounds of formula VI-2b, VI-3b, or VI-4b or their pharmaceutically acceptable salts or stereoisomers, or X 3 This is C, which gives rise to the compound of formula VI-5b or its pharmaceutically acceptable salt or stereoisomer. [ka] During the ceremony, X 2 is O, NH, or NMe, R 1 is H or F, R 5 , R 6 These are, independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl. o is either 0 or 1, R 7 is hydrogen or halogen, preferably F. Z is selected from the following: [ka]

[0595] In some embodiments of the compounds of formula VI-1, VI-2b, VI-3b, VI-4b, or VI-5b, R 4 These are hydrogen, fluoro, or chloro.

[0596] In some embodiments of the compounds of formulas VI-1, VI-2b, VI-3b, VI-4b, or VI-5b, o is 1.

[0597] In some embodiments of the compounds of formula VI-1, VI-2b, VI-3b, VI-4b, or VI-5b, R 5 is F and / or R 6 It is either F or Cl.

[0598] In some embodiments of the compounds of formula VI-1, VI-2b, VI-3b, VI-4b, or VI-5b, R 7 It is F.

[0599] In some embodiments of the compounds of formula VI-1, VI-2b, VI-3b, VI-4b, or VI-5b, R 1 It may be hydrogen.

[0600] In some embodiments, the present disclosure provides compounds of the following formula VII-1 or pharmaceutically acceptable salts or stereoisomers thereof: [ka] During the ceremony, R 1 is H or F, preferably H. R 4 is hydrogen or halogen, preferably F or Cl. R 5 , R 6 These are, independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl. Z is selected from the following: [ka]

[0601] In some embodiments, the present disclosure provides compounds of the following formulas VII-2, VII-3 or VII-4, VII-5, VII-6, VII-7, VII-8 or VII-9, or pharmaceutically acceptable salts or stereoisomers thereof: [ka] During the ceremony, R 1 is H or F, preferably H. o is either 0 or 1, R 5 , R 6 These are, independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl. R 7 is hydrogen or halogen, preferably F. Z is selected from the following: [ka]

[0602] In some embodiments of the 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 These are hydrogen, fluoro, or chloro.

[0603] In some embodiments of the compounds of formulas VII-1, VII-2, VII-3, or VII-4, VII-5, VII-6, VII-7, VII-8, or VII-9, o is 1.

[0604] In some embodiments of the compounds of formula VII-1, VII-2, VII-3, or VII-4, VII-5, VII-6, VII-7, VII-8, or VII-9, R 5 is F, and / or R in this case 6 It is either F or Cl.

[0605] In some embodiments of the 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.

[0606] In some embodiments of the compounds of formula VII-1, VII-2, VII-3, or VII-4, VII-5, VII-6, VII-7, VII-8, or VII-9, R 1 It may be hydrogen.

[0607] In some embodiments, the compounds are selected from the compounds listed in Tables 1 and 2, their pharmaceutically acceptable salts, and stereoisomers.

[0608] In some embodiments, the compounds are selected from the compounds listed in Tables 1 and 2, as well as their pharmaceutically acceptable salts.

[0609] In some embodiments, the compound is selected from the compounds listed in Tables 1 and 2.

[0610] In some embodiments, the compound is selected from the compounds listed in Table 1, their pharmaceutically acceptable salts, and stereoisomers.

[0611] In some embodiments, the compound is selected from the compounds listed in Table 1 and their pharmaceutically acceptable salts.

[0612] In some embodiments, the compound is selected from the compounds listed in Table 1.

[0613] In some embodiments, the compound is selected from the compounds listed in Table 2, their pharmaceutically acceptable salts, and stereoisomers.

[0614] In some embodiments, the compound is selected from the compounds listed in Table 2 and their pharmaceutically acceptable salts.

[0615] In some embodiments, the compound is selected from the compounds listed in Table 2. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15] [Table 2-16] [Table 2-17] [Table 2-18]

[0616] In some embodiments, the Disclosure provides compounds that are isotopic derivatives (e.g., isotope-labeled compounds) of any one of the compounds of the formulas disclosed herein.

[0617] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Tables 1 and 2, their pharmaceutically acceptable salts, and stereoisomers.

[0618] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Tables 1 and 2, or any pharmaceutically acceptable salt thereof.

[0619] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Tables 1 and 2.

[0620] It is understood that isotopic derivatives can be prepared using any of the various techniques recognized in the art. For example, isotopic derivatives can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein, by substituting an isotope-labeled reagent with an isotope-labeled reagent.

[0621] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0622] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulas disclosed herein.

[0623] In some embodiments, the compound is a deuterium-labeled compound, one of the compounds listed in Tables 1 and 2, their pharmaceutically acceptable salts, and stereoisomers.

[0624] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds listed in Tables 1 and 2, or a pharmaceutically acceptable salt thereof.

[0625] In some embodiments, the compound is one of the deuterium-labeled compounds listed in Tables 1 and 2.

[0626] In some embodiments, the compound is selected from the compounds listed in Table 3, their pharmaceutically acceptable salts, and stereoisomers.

[0627] In some embodiments, the compound is selected from the compounds listed in Table 3 and their pharmaceutically acceptable salts.

[0628] In some embodiments, the compound is one of the compounds listed in Table 3. [Table 3]

[0629] Deuterium-labeled compounds contain deuterium atoms with a deuterium abundance of 0.015%, which is far greater than the natural abundance of deuterium.

[0630] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor of at least 3500 (52.5% deuterium uptake at each deuterium atom), at least 4000 (60% deuterium uptake), at least 4500 (67.5% deuterium uptake), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium uptake), at least 6000 (90% deuterium uptake), at least 6333.3 (95% deuterium uptake), at least 6466.7 (97% deuterium uptake), at least 6600 (99% deuterium uptake), or at least 6633.3 (99.5% deuterium uptake) per deuterium atom. As used herein, the term “deuterium enrichment factor” means the ratio between the abundance of deuterium and the natural abundance of deuterium.

[0631] It is understood that deuterium-labeled compounds can be prepared using any of the various 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, and by substituting a non-deuterium-labeled reagent with a deuterium-labeled reagent.

[0632] The compounds of the present invention containing the aforementioned deuterium atom, or their pharmaceutically acceptable salts or solvates, are within the scope of the present invention. Furthermore, deuterium (i.e.) 2 Substitution with H) may result in certain therapeutic benefits stemming from its high metabolic stability, such as an extended in vivo half-life or a reduction in the required dose.

[0633] The compounds of this disclosure may contain one or more chiral centers in their molecules. Compounds not designated as stereochemical should be understood to include all optical isomers (e.g., diastereomers, enantiomers, etc.) in pure or substantially pure forms, as well as mixtures thereof (e.g., racemic mixtures or enantiomerically enriched mixtures). Methods for preparing such optically active forms (e.g., by recrystallization techniques to separate racemic forms, by synthesis from optically active starting materials, by chiral synthesis, by chromatographic separation using a chiral stationary phase, and other methods) are well known in the art.

[0634] The compounds may be isotope-labeled compounds, such as compounds containing various isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine, or chlorine. The compounds of this disclosure may exist in tautomeristic forms, and mixtures and distinct individual tautomers are intended. In addition, some compounds may exhibit polymorphism.

[0635] The compounds disclosed herein include their free forms, as well as their pharmaceutically acceptable salts and stereoisomers. The pharmaceutically acceptable salts include all typical pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds may be synthesized from the compounds disclosed herein containing basic or acidic moieties by conventional chemical methods; see, for example, Berge et al., “Pharmaceutical Salts,” J. Pharm. ScL, 1977:66:1-19.

[0636] For example, conventional pharmaceutically acceptable salts of basic compounds include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., as well as 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, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc. Conventionally pharmaceutically acceptable salts of acidic compounds include those derived from inorganic bases, as well as those derived from aluminum, ammonium, calcium, copper, ferric acid, ferrous acid, lithium, magnesium, manganese salts, manganese, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as salts of arginine, betaine caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.

[0637] The compounds of this disclosure may exist in solid form, i.e., crystalline or amorphous form (optionally as solvates), or in liquid form. In the solid state, it may exist in or as a mixture thereof. In crystalline solvates, solvent molecules are incorporated into the crystal lattice during crystallization. The formation of solvates may include, but are not limited to, non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or aqueous solvents such as water (also called "hydrates"). It is common knowledge that crystalline forms (and their solvates) may exhibit polymorphism, i.e., exist in different crystalline structures known as "polymorphs," having the same chemical composition but differing in packing, geometric arrangement, and other descriptive properties of the crystal in the solid state. Thus, polymorphs may have different physical properties such as shape, density, hardness, morphogenesis, stability, and solubility, and may exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. Such different polymorphs can be generated during the preparation of the compounds of this disclosure, for example, by changing or adjusting reaction conditions or reagents.

[0638] In some embodiments, the Disclosure also provides methods for preparing the compounds of the Disclosure. Typically, the compounds of the Disclosure are prepared according to the synthesis shown in the Experimental Section.

[0639] It is understood that the synthesis process of this disclosure can tolerate a wide range of functional groups and therefore can use a variety of substitutional initiating materials. The process generally provides the desired final compound at or near the end of the entire process, but in certain examples, it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0640] It is understood that the compounds of this disclosure can be prepared in various ways using commercially available starting materials, compounds known in the literature, or readily prepared intermediates by employing standard synthetic methods and procedures that are known to those skilled in the art or that will become obvious to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and the transformation and manipulation of functional groups can be obtained from relevant scientific literature or standard textbooks in the field. Not limited to any one or more sources, but for example, Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th edition,John Wiley & Sons:New York,2001;Greene,TW,Wuts,PGM,Protective Groups in Organic Synthesis,3 rd Classical texts such as John Wiley & Sons, New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) are useful and widely recognized references on organic synthesis known to those skilled in the art, and are incorporated herein by reference.

[0641] Those skilled in the art will note that the order of certain steps may change during the reaction sequences and synthesis schemes described herein, such as the introduction and removal of protecting groups. Those skilled in the art will also recognize that certain groups may require protection from reaction conditions through the use of protecting groups. Protecting groups may also be used to distinguish similar functional groups in a molecule. A list of protecting groups, and methods for introducing and removing these protecting groups, can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3. rd This can be found in edition, John Wiley & Sons: New York, 1999.

[0642] Biological assays Compounds designed, selected, and / or optimized by the methods described herein may, once produced, be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, molecules may be characterized by conventional assays, including, but not limited to, those assays described below, to determine whether they have predicted activity, binding activity, and / or binding specificity.

[0643] Furthermore, high-throughput screening can be used to speed up analyses using such assays. As a result, it may be possible to rapidly screen for the activity of the molecules described herein using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays may be one or more different assay techniques, including, but are not limited to, those described below.

[0644] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of this disclosure. These in vitro or in vivo biological assays may include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell survival assays, and assays described herein.

[0645] Pharmaceutical composition In some embodiments, the Disclosure further provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds of the Disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients (also referred to as diluents). The excipients are acceptable in the sense that they are compatible with the other components of the formulation and are not harmful to the recipient (i.e., the patient). As used herein, the term “therapeutically effective amount” means an amount of the compound of the Disclosure (either in itself or in the form of a pharmaceutical composition) that is effective in producing a desired therapeutic effect.

[0646] The pharmaceutical composition may be in unit dose form containing a predetermined amount of the compound of the Disclosure per unit dose. Such a unit may contain a therapeutically effective amount of the compound of the Disclosure or a salt thereof, or a therapeutically effective amount of fraction such that multiple unit dosage forms can be administered in a given time to achieve a desired therapeutically effective amount. Preferred unit dose formulations contain a daily dose or sub-dose of the compound of the Disclosure or a salt thereof, or an appropriate fraction thereof.

[0647] The compounds of this disclosure may be administered by any acceptable means in solid or liquid form, including (1) oral administration, e.g., drenches (aqueous or non-aqueous solutions, or suspensions), tablets, e.g., targeted boluses for oral, sublingual, and systemic absorption, powders, granules, pastes for application to the tongue, (2) parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, or sustained-release formulations, e.g., sterile solutions or suspensions, (3) topical application, e.g., creams, ointments, or controlled-release patches or sprays applied to the skin, (4) intravaginal or rectal administration, e.g., pessaries, creams, or foams, (5) sublingual, (6) ocular, (7) transdermal, (8) transnasal, (9) pulmonary, or (10) intrathecal.

[0648] As used herein, the phrase “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, magnesium talc, calcium or zinc stearate, or stearic acid), or solvent encapsulation material involved in transporting or carrying a compound of interest from one organ or part of body to another. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is not harmful to the patient. Some examples of substances that can serve as pharmaceutically acceptable carriers include: (1) sugars, e.g., lactose, glucose, and sucrose; (2) starches, e.g., corn starch and potato starch; (3) cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, e.g., cocoa butter and suppository waxes; (9) oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, e.g. Examples include (11) propylene glycol, (12) polyols, such as glycerin, 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) alginic acid, (17) pyrogen-free water, (18) isotonic saline, (19) Ringer's solution, (20) ethyl alcohol, (21) pH buffers, (22) polyesters, polycarbonates, and / or polyanhydrides, as well as other non-toxic and suitable substances used in pharmaceutical compositions.

[0649] Such compositions may further contain components commonly used in pharmaceutical preparations, such as wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents, preservatives and antioxidants, pH adjusters, bulking agents, and further activators. Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; (2) lipid-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0650] Such compositions may be prepared by any method known in the art, for example, by bringing an active ingredient into association with one or more carriers and / or excipients. Examples of different compositions and carriers and / or excipients are well known to those skilled in the art and are described in detail, for example, Remington: The Science and Practice of Pharmacy. Pharmaceutical Press, 2013 and Rowe, Sheskey, Quinn: Handbook of Pharmaceutical Excipients. Pharmaceutical Press, 2009. Excipients that may be used in the preparation of pharmaceutical compositions may include buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, flow enhancers, processing aids, colorants, sweeteners, flavoring agents, diluents, and other known additives to provide compositions suitable for selected dosages.

[0651] As described above, the compounds of this disclosure may be in solid or liquid form and may be administered by any conventional dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, and various other routes.

[0652] In the solid dosage forms of the present disclosure for oral administration (capsules, tablets, pills, sugar-coated tablets, powders, granules, lozenges, etc.), 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 bulking agents, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) agar, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate. (5) Disintegrants such as thorium; (6) Solution retarders such as paraffin; (7) Absorption enhancers such as quaternary ammonium compounds, and surfactants such as poloxamer and sodium lauryl sulfate; (8) Wetting agents such as cetyl alcohol, glycerol monostearate, and nonionic surfactants; (9) Absorbents such as kaolin and bentonite clay; (10) Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (11) Colorants, and (22) Controlled release agents such as crospovidone or ethylcellulose. In the case of capsules, tablets, and pills, the pharmaceutical composition may also include buffers. Similar types of solid compositions can also be used as excipients such as lactose, and as fillers in soft-shell and hard-shell gelatin capsules using high molecular weight polyethylene glycol, etc. Tablets may optionally be made by compression or molding with one or more auxiliary components. Compressed tablets may be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium glycolate starch or cross-linked sodium carboxymethylcellulose), a surfactant, or a dispersant.Molded tablets may be produced by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets and other solid preparations of the pharmaceutical compositions of this disclosure, such as sugar-coated tablets, capsules, pills, and granules, may optionally be prepared with coatings and shells, such as notches or enteric coatings and other coatings well known in the pharmaceutical formulation field. They may also be formulated, for example, using hydroxypropyl methylcellulose in various proportions to provide a slow or controlled release of the active ingredient therein to provide a desired release profile, other polymer matrices, liposomes, and / or microspheres. They may be formulated for immediate release and may be lyophilized, for example. They may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injection medium immediately before use. The composition may optionally contain an opaque agent, or it may be a composition that releases only the active ingredient, or preferably, optionally, it may be a composition that releases only the active ingredient in a delayed manner to a specific part of the gastrointestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, together with one or more of the excipients described above, where appropriate.

[0653] Liquid formulations for oral administration of the compounds of this disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredients, the liquid formulations may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, as well as mixtures thereof. Oral compositions may also contain adjuvants, such as humectants, emulsifiers, and suspending agents, sweeteners, flavorings, colorants, tasters, and preservatives.

[0654] In suspension form, the compound may contain suspending agents such as ethoxylated isostearyl alcohol, polyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0655] Dosage forms for rectal or vaginal administration of the compounds of the Disclosure include suppositories that may be prepared by mixing one or more of the compounds of the Disclosure with one or more suitable non-irritating excipients or carriers, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylate, which are solid at room temperature but liquid at body temperature, and therefore melt in the rectum or vaginal cavity to release the active compound. Other suitable forms include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing carriers known to be suitable in the art.

[0656] Dosage forms for topical or transdermal administration of the compounds of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compounds may be mixed under sterile conditions with pharmaceutically acceptable carriers and any preservatives, buffers, or propellants as required. Such ointments, pastes, creams, and gels may contain, in addition to the compounds of this disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0657] Dosage forms of the compounds of this disclosure, such as powders and sprays, may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powders, or mixtures thereof. Sprays may also contain common propellants such as chlorofluorocarbons, as well as volatile unsubstituted hydrocarbons such as butane and propane.

[0658] Dosage forms of the compounds of this disclosure, such as transdermal patches, may include absorption enhancers or retarders to increase or decrease the flow of the compounds across the skin. Such flow rates can be controlled by either providing a rate-controlled membrane or by dispersing the compounds in a polymer matrix or gel. Other dosage forms intended include eye drops, eye ointments, powders, solutions, etc. It is understood that all intended compositions must be stable under manufacturing and storage conditions and must be preserved against microbial contamination such as bacteria and fungi.

[0659] The dosage levels of the compounds of the Disclosure in the pharmaceutical compositions of the Disclosure may be adjusted to obtain an amount of the compounds of the Disclosure that is effective in achieving a desired therapeutic response for a particular patient, compound, and mode of administration without causing harm to the patient. The dosage of choice depends on various factors, including the nature of the particular compound of the Disclosure used, the route of administration, the time of administration, the rate of elimination or metabolism of the particular compound used, the rate and extent of absorption, the duration of treatment or prevention, other drugs, compounds, and / or materials used in combination with the particular compound, the age, sex, weight, condition, overall health, and prior medical history of the patient being treated, as well as similar factors well known in the medical field. Physicians in the art can readily determine and prescribe the effective amount of the required pharmaceutical composition.

[0660] Typically, the preferred daily dose of the compounds of this disclosure is the amount of the compound that is the minimum effective dose to produce a therapeutic effect. Such an effective dose generally depends on the factors described above. Generally, oral, intravenous, intraventricular, and subcutaneous doses of the compounds of this disclosure to a patient, when used for the indicated analgesic effect, range from about 0.0001 to about 100 mg per kilogram of body weight of the recipient (patient, mammal) per day, more typically in the range of 0.1 to 100 mg / kg. An acceptable daily dose may be about 1 to about 1000 mg / day, for example, about 1 to about 100 mg / day.

[0661] The effective dose of the compounds disclosed herein may be optionally administered as two, three, four, five, six or more secondary doses in a single dosage form, administered separately at appropriate intervals (per day, per week, or per month) throughout a specified period. The preferred dose depends on the factors described above, such as the administration method, and can be readily achieved by those skilled in the art of medicine and pharmaceutical technology.

[0662] Use of compounds and compositions The compounds of this disclosure inhibit or modulate the activity of receptor tyrosine kinases, particularly extracellular variants of ErbB receptors, such as, but not limited to, EGFR-Viii, EGFR-Vii, EGFR-Vvi, EGFR-A289V, and EGFR-G598V, as well as HER2-S310F. Therefore, the compounds and compositions of this disclosure may be useful as pharmaceuticals, i.e., as pharmaceuticals in therapeutics for the prevention or treatment of cancer, as detailed below. Thus, in a further embodiment, this disclosure provides methods for the prevention or treatment of cancer in mammals, such as humans, as detailed below.

[0663] The terms “prevention” or “prevention” refer 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 a mammal, such as a human.

[0664] The terms “treatment” or “treating” are intended to encompass therapy and cure. Such treatment comprises the step of administering a therapeutic 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 a mammal, such as a human.

[0665] Accordingly, this disclosure provides the use of the compounds of this disclosure, or pharmaceutically acceptable salts or stereoisomers thereof, or pharmaceutical compositions thereof, for the treatment of cancer in mammals, such as humans, as detailed below.

[0666] In some embodiments, the present disclosure relates to methods for inhibiting oncogenic variants of the ErbB receptor (e.g., oncogenic variants of EGFR), which include administering a therapeutically effective amount of a compound described herein to a subject in need thereof.

[0667] In some embodiments, the present disclosure relates to methods for inhibiting oncogenic variants of the ErbB receptor (e.g., oncogenic variants of EGFR), which include administering compositions described herein to subjects requiring such inhibition.

[0668] In some embodiments, the Disclosure relates to methods for preventing or treating cancer, which include administering a therapeutically effective amount of a compound described herein to a subject in need thereof.

[0669] In some embodiments, the Disclosure relates to methods for preventing or treating cancer, which include administering compositions described herein to subjects in need thereof.

[0670] In some embodiments, this disclosure relates to compounds described herein for use in inhibiting oncogenic variants of the ErbB receptor (e.g., oncogenic variants of EGFR).

[0671] In some embodiments, this disclosure covers compounds described herein for use in the prevention or treatment of cancer.

[0672] In some embodiments, this disclosure relates to compositions described herein for use in inhibiting oncogenic variants of the ErbB receptor (e.g., oncogenic variants of EGFR).

[0673] In some embodiments, this disclosure covers compositions described herein for use in the prevention or treatment of cancer.

[0674] In some embodiments, this disclosure relates to the use of the compounds described herein in the manufacture of agents for inhibiting oncogenic variants of the ErbB receptor (e.g., oncogenic variants of EGFR).

[0675] In some aspects, this disclosure covers the use of the compounds described herein in the manufacture of agents for the prevention or treatment of cancer.

[0676] In some embodiments, the compounds are selected from the compounds listed in Tables 1 and 2, their pharmaceutically acceptable salts, and stereoisomers.

[0677] In some embodiments, the compounds are selected from the compounds listed in Tables 1 and 2, as well as their pharmaceutically acceptable salts.

[0678] In some embodiments, the compound is selected from the compounds listed in Tables 1 and 2.

[0679] In some embodiments, cancer includes solid tumors.

[0680] In some embodiments, cancer is bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, gliablastoma (GBM), head and neck cancer, lung cancer, non-small cell lung cancer (NSCLC), or any subtype thereof.

[0681] In some embodiments, the cancer is gliablastoma (GBM) or any subtype thereof.

[0682] In some embodiments, the cancer is a gliablastoma.

[0683] In some embodiments, cancer, or tumors, or their cells express oncogenic variants of the ErbB receptor.

[0684] In some embodiments, oncogenic variants of the ErbB receptor include allosteric mutations.

[0685] In some embodiments, the oncogenic variant of the ErbB receptor is an allosteric variant of the ErbB receptor.

[0686] In some embodiments, the ErbB receptor is the epidermal growth factor receptor (EGFR) or the human epidermal growth factor receptor 2 (HER2) receptor.

[0687] In some embodiments, the ErbB receptor is the epidermal growth factor receptor (EGFR).

[0688] In some embodiments, the ErbB receptor is the HER2 receptor.

[0689] In some embodiments, cancer, or tumors, or their cells express oncogenic variants of the epidermal growth factor receptor (EGFR).

[0690] In some embodiments, the oncogenic variant of EGFR is an allosteric variant of EGFR.

[0691] In some embodiments, oncogenic variants of EGFR include allosteric mutations.

[0692] In some embodiments, cancer, or tumors, or their cells express oncogenic variants of the HER2 receptor.

[0693] In some embodiments, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor.

[0694] In some embodiments, oncogenic variants of the HER2 receptor include allosteric mutations.

[0695] In some embodiments, the oncogenic variant of EGFR includes the EGFR variant III (EGFR-Viii) mutation.

[0696] In some embodiments, the oncogenic variant of EGFR includes the EGFR variant II (EGFR-Vii) mutation.

[0697] In some embodiments, the oncogenic variant of EGFR includes the EGFR variant VI (EGFR-Vvi) mutation.

[0698] In some embodiments, the oncogenic variant of EGFR includes an alanine (A) and valine (V) substitution at position 289 of SEQ ID NO: 1.

[0699] In some embodiments, the oncogenic variant of EGFR includes a glycine (G) to valine (V) substitution at position 598 of SEQ ID NO: 1.

[0700] In some embodiments, cancer, or tumors, or their cells express an oncogenic variant of EGFR, in which case the oncogenic variant of EGFR is an allosteric variant of EGFR, and the oncogenic variant of EGFR comprises a structural modification of EGFR, in which case the oncogenic variant of EGFR can form a covalent dimer, in which case the covalent dimer is structurally active, in which case the covalent dimer enhances the activity of EGFR when exposed to a type I ErbB inhibitor. In some embodiments, the structural modification of EGFR comprises one or more modifications of the nucleic acid sequence, amino acid sequence, secondary structure, tertiary structure, and quaternary structure. In some embodiments, the oncogenic variant comprises mutation, splicing events, posttranslational processes, conformational changes, or any combination thereof. In some embodiments, the structural modification of EGFR occurs within the primary cysteine-rich (CR1) and / or secondary cysteine-rich (CR2) regions of EGFR. In some embodiments, the first cysteine-rich (CR1) and / or second cysteine-rich (CR2) regions of EGFR each contain amino acid residues T211-R334 and / or C526-S645 of SEQ ID NO: 1, respectively. In some embodiments, the oncogenic variant of EGFR generates a physical barrier to the formation of disulfide bonds within the CR1 and / or CR2 regions. In some embodiments, the oncogenic variant of EGFR removes the physical barrier to the formation of disulfide bonds within the CR1 and / or CR2 regions. In some embodiments, the oncogenic variant of EGFR contains one or more free or unpaired cysteine ​​(C) residues located at the dimer interface of EGFR.In some embodiments, the oncogenic variants of EGFR are C190-C199, C194-C207, C215-C223, C219-C231, C232-C240, C236-C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C333, according to SEQ ID NO: 1. The molecule contains one or more free or unpaired cysteine ​​(C) residues at a site selected from the group consisting of 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 intramolecular disulfide bonds of 10 angstroms or less at sites selected from the group consisting of 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 as defined by SEQ ID NO: 1.

[0701] In some embodiments, cancer, or tumors, or their cells express an oncogenic variant of EGFR, the oncogenic variant of EGFR being a mutation of EGFR, and the nucleotide sequence encoding the oncogenic variant of EGFR includes a deletion or substitution containing one or more amino acids encoding an adenosine triphosphate (ATP) binding site. In some embodiments, the ATP binding site includes amino acids E746-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, lysine (K) is substituted with arginine (R) at position 858 of SEQ ID NO: 1 (K858R).

[0702] In some embodiments, cancer, or tumors, or their cells express an oncogenic variant of EGFR, in which case 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 the sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof includes the sequence encoding KEILDEAYVMASVDNPHVCAR (SEQ ID NO: 7). In some embodiments, the sequence encoding exon 20 or a portion thereof includes the sequence encoding a C-helix, the end of a C-helix, or a loop after a C-helix. In some embodiments, the insertion includes the amino acid sequence 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) insertion of amino acid sequence ASV between positions V769 to D770 of SEQ ID NO: 1, (b) insertion of amino acid sequence SVD between positions D770 to N771 of SEQ ID NO: 1, (c) insertion of amino acid sequence NPH between positions H773 to V774 of SEQ ID NO: 1, (d) insertion of amino acid sequence FQEA between positions A763 to Y764 of SEQ ID NO: 1, (e) insertion of amino acid sequence PH between positions H773 to V774 of SEQ ID NO: 1, (f) insertion of amino acid G between positions D770 to N771 of SEQ ID NO: 1, (g) insertion of amino acid H between positions H773 to V774 of SEQ ID NO: 1, (h) insertion of amino acid sequence HV between positions V774 to C775 of SEQ ID NO: 1, (i) SEQ ID NO: (j) Insertion of amino acid sequence AH between positions H773-V774 of SEQ ID NO: 1, (k) Insertion of amino acid sequence SVA between positions A767-S768 of SEQ ID NO: 1, (l) Insertion of amino acid H between positions N771-P772 of SEQ ID NO: 1, (m) Insertion of amino acid Y between positions H773-V774 of SEQ ID NO: 1, (n) Insertion of amino acid sequence PHVC between positions C775-R776 of SEQ ID NO: 1, (o) Substitution of H at position 773 of SEQ ID NO: 1 with amino acid sequence YNPY, (p) Insertion of amino acid sequence DNP between positions P772-H773 of SEQ ID NO: 1, (q) Insertion of amino acid sequence VDS between positions S768-V769 of SEQ ID NO: 1, (r) Insertion of amino acid H between positions D770-N771 of SEQ ID NO: 1,(s) Insertion of amino acid N between positions N771 and P772 of SEQ ID NO: 1, (t) Insertion of amino acid sequence PNP between positions P772 and H773 of SEQ ID NO: 1, (u) Substitution of DN between positions 770 and 771 of SEQ ID NO: 1 with amino acid sequence GSVDN, (v) Substitution of NP between positions 771 and 772 of SEQ ID NO: 1 with amino acid sequence GYP, (w) Insertion of amino acid G between positions N771 and P772 of SEQ ID NO: 1, (x) P772 to H773 (y) Insertion of amino acid sequence GNP between positions V769-D770 of SEQ ID NO: 1, (z) Substitution of VC and amino acid sequence GNPHVC between positions 774-775 of SEQ ID NO: 1, (aa) Insertion of amino acid sequence LQEA between positions A763-Y764 of SEQ ID NO: 1, (bb) Insertion of amino acid sequence GL between positions D770-N771 of SEQ ID NO: 1, (cc) Insertion of amino acid Y between positions D770-N771 of SEQ ID NO: 1, (dd) Insertion of amino acid sequence NPY between positions H773-V774 of SEQ ID NO: 1 Insertion of (ee) amino acid sequence TH between positions H773-V774 of SEQ ID NO: 1, (ff) substitution of NP with amino acid sequence KGP between positions 771-772 of SEQ ID NO: 1, (gg) substitution of NP with amino acid sequence SVDNP between positions 771-772 of SEQ ID NO: 1, (hh) insertion of amino acid sequence NN between positions N771-P772 of SEQ ID NO: 1, (ii) insertion of amino acid T between positions N771-P772 of SEQ ID NO: 1, and (jj) substitution of SV with amino acid sequence STLASV between positions 768-769 of SEQ ID NO: 1.

[0703] In some embodiments, cancer, tumors, or their cells express oncogenic variants of EGFR, in which case the oncogenic variants of EGFR are allosteric variants of EGFR, and the oncogenic variants of EGFR are EGFR-Vii, EGFR-Vvi, EGFR-R222C, EGFR-R252C, EGFR-R252P, EGFR-R256Y, EGFR-T263P, EGFR-Y270C, EGFR-A289T, EGFR-A This includes 289V, 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.

[0704] In some embodiments, cancer, or tumors, or their cells express one or more of the following: (a) wild-type human epidermal growth factor receptor 2 (HER2) receptor or oncogenic variants of the HER-2 receptor.

[0705] In some embodiments, cancer, or tumors, or their cells express the wild-type HER-2 receptor, which comprises the amino acid sequence of SEQ ID NOs: 2, 3, 4, 5, or 6.

[0706] In some embodiments, cancer, or tumors, or their cells express an oncogenic variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor.

[0707] In some embodiments, cancer, or tumors, or their cells express an oncogenic variant of the HER2 receptor, in which case the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes a serine (S) to phenylalanine (F) substitution at position 310 of SEQ ID NO: 2 or 5.

[0708] In some embodiments, cancer, or tumors, or their cells express an oncogenic variant of the HER2 receptor, in which case the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes a serine (S) to tyrosine (Y) substitution at position 310 of SEQ ID NO: 2 or 5.

[0709] In some embodiments, cancer, or tumors, or their cells express an oncogenic variant of the HER2 receptor, in which case the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes an arginine (R) to glutamine (Q) substitution at position 678 of SEQ ID NO: 2 or 5.

[0710] In some embodiments, cancer, or tumors, or their cells express an oncogenic variant of the HER2 receptor, in which case the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes a valine (V) to leucine (L) substitution at position 777 of SEQ ID NO: 2 or 5.

[0711] In some embodiments, cancer, or tumors, or their cells express an oncogenic variant of the HER2 receptor, in which case the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes a valine (V) to methionine (M) substitution at position 777 of SEQ ID NO: 2 or 5.

[0712] In some embodiments, cancer, or tumors, or their cells express an oncogenic variant of the HER2 receptor, in which case the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes a valine (V) to isoleucine (I) substitution at position 842 of SEQ ID NO: 2 or 5.

[0713] In some embodiments, cancer, or tumors, or their cells express an oncogenic variant of the HER2 receptor, in which case the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes a leucine (L) to alanine (A) substitution at position 755 of SEQ ID NO: 2 or 5.

[0714] In some embodiments, cancer, or tumors, or their cells express an oncogenic variant of the HER2 receptor, in which case the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes a leucine (L) to proline (P) substitution at position 755 of SEQ ID NO: 2 or 5.

[0715] In some embodiments, cancer, or tumors, or their cells express an oncogenic variant of the HER2 receptor, in which case the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes a leucine (L) to serine (S) substitution at position 755 of SEQ ID NO: 2 or 5.

[0716] In some embodiments, cancer, or tumors, or their cells express an oncogenic variant of the HER2 receptor, in which case 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 the sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof includes the sequence encoding KEILDEAYVMAGVGSPYVSR (SEQ ID NO: 8). In some embodiments, the sequence encoding exon 20 or a portion thereof includes the sequence encoding a C-helix, the terminal of a C-helix, or a loop after a C-helix. In some embodiments, the insertion includes the amino acid sequence of GSP or YVMA. In some embodiments, the sequence encoding exon 20 or a portion thereof includes one or more of the following: (a) insertion of amino acid sequence YVMA between positions A775-G776 of SEQ ID NO: 2, (b) insertion of amino acid sequence GSP between positions P780-Y781 of SEQ ID NO: 2, (c) insertion of amino acid sequence YVMA between positions A771-Y772 of SEQ ID NO: 2, (d) insertion of amino acid sequence YVMA between positions A775-G776 of SEQ ID NO: 2, (e) insertion of amino acid V between positions V777-G778 of SEQ ID NO: 2, (f) insertion of amino acid V between positions V777-G778 of SEQ ID NO: 2, (g) substitution of GV between positions 776-777 of SEQ ID NO: 2 with amino acid sequence AVGCV, (h) substitution of G between position 776 of SEQ ID NO: 2 with amino acid sequence LC Substitutions: (i) substitution of G between position 776 of SEQ ID NO: 2 with amino acid sequence LCV; (j) insertion of amino acid sequence GSP between positions V777-G778 of SEQ ID NO: 2; (k) substitution of LRE between positions 755-757 of SEQ ID NO: 2 with amino acid sequence PS; (l) substitution of SP between positions 779-780 of SEQ ID NO: 2 with amino acid sequence CPGSP; (m) insertion of amino acid C between positions V777-G778 of SEQ ID NO: 2; (n) substitution of AG between positions 775-776 of SEQ ID NO: 2 with amino acid sequence VVMA; (o) substitution of G at position 776 of SEQ ID NO: 2 with amino acid sequence VV; (p) substitution of GV between positions 776-777 of SEQ ID NO: 2 with amino acid sequence AVCV; (q) substitution of GV between positions 776-777 of SEQ ID NO: 2 with amino acid sequence VCV.(r) Insertion of amino acid G between positions G778 and S779 of SEQ ID NO: 2, (s) Insertion of LRE and amino acid sequence PK between positions 755 and 757 of SEQ ID NO: 2, (t) Insertion of amino acid V between positions A775 and G776 of SEQ ID NO: 2, (u) Insertion of amino acid sequence YAMA between positions A775 and G776 of SEQ ID NO: 2, (v) Substitution of G at position 776 of SEQ ID NO: 2 with amino acid sequence CV, (w) Substitution of GVG and amino acid sequence AVCGG between positions 776 and 778 of SEQ ID NO: 2, (x) Positions 776 and 778 of SEQ ID NO: 2 (y) Substitution of GVG between positions 776-778 of SEQ ID NO: 2 and amino acid sequence VVVG, (z) Substitution of GVGS between positions 776-779 of SEQ ID NO: 2 and amino acid sequence SVGG, (aa) Substitution of GVGS between positions 776-779 of SEQ ID NO: 2 and amino acid sequence VVGES, (bb) Substitution of GV between positions 776-777 of SEQ ID NO: 2 and amino acid sequence AVGSGV, (cc) Substitution of GV between positions 776-777 of SEQ ID NO: 2 and amino acid sequence CVC, ( (dd) Substitution of GV between positions 776-777 of SEQ ID NO: 2 and amino acid sequence HVC, (ee) Substitution of GV between positions 776-777 of SEQ ID NO: 2 and amino acid sequence VAAGV, (ff) Substitution of GV between positions 776-777 of SEQ ID NO: 2 and amino acid sequence VAGV, (gg) Substitution of GV between positions 776-777 of SEQ ID NO: 2 and amino acid sequence VVV, (hh) Insertion of amino acid sequence FPG between positions G778-S779 of SEQ ID NO: 2, (ii) Insertion of amino acid sequence GS between positions S779-P780 of SEQ ID NO: 2 Insertion, (jj) substitution of VLRE between positions 754-757 of SEQ ID NO: 2 with amino acid sequence VPS, (kk) insertion of amino acid sequence E between positions V777-G778 of SEQ ID NO: 2, (ll) insertion of amino acid sequence MAGV between positions V777-G778 of SEQ ID NO: 2, (mm) insertion of amino acid S between positions V777-G778 of SEQ ID NO: 2, (nn) insertion of amino acid sequence SCV between positions V777-G778 of SEQ ID NO: 2, and (oo) insertion of amino acid sequence LMAY between positions Y772-V773 of SEQ ID NO: 2.

[0717] In some embodiments, cancer, or tumors, or their cells express an oncogenic variant of the HER2 receptor, in which case the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes HER2-Δ16, HER2-C311R, HER2-S310F, p95-HER2-M611, or any combination thereof.

[0718] In some embodiments, cancer, or tumors, or their cells express an oncogenic variant of the HER4 receptor. In some embodiments, the oncogenic variant of the HER4 receptor is an allosteric variant of the HER4 receptor. In some embodiments, the oncogenic variant of the HER4 receptor includes a deletion of exon 16 (HER4-Δ16).

[0719] In some embodiments, cancer, tumors, or their cells express an oncogenic variant of EGFR, in which case the sequence encoding the oncogenic variant of EGFR includes a deletion of exon 20 or a portion thereof, and in which case cancer, tumors, or their cells do not contain a second oncogenic diversity in sequences other than exon 20 of EGFR. In some embodiments, the second oncogenic diversity includes a sequence encoding one or more of the EGFR kinase domain (KD), BRAF, NTRK, and KRAS.

[0720] In some embodiments, cancer, tumors, or their 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 in this case, cancer, tumors, or their cells do not contain markers suggesting responsiveness to immunotherapy.

[0721] In some embodiments, oncogenic variants (e.g., allosteric variants) or oncogenic mutations (e.g., allosteric mutations) are detected by a diagnostic method approved by the Food and Drug Administration (FDA).

[0722] In some embodiments, the subject is treated with a therapeutic agent different from the compound of the disclosure prior to treatment with the compound of the disclosure.

[0723] In some embodiments, cancer, tumors, or their cells are insensitive to or resistant to treatment with therapeutic agents other than the compounds of this disclosure. In some embodiments, cancer, tumors, or their cells are insensitive to or resistant to treatment with type I inhibitors. In some embodiments, cancer, tumors, or their cells are insensitive to or resistant to treatment with one or more of the following: gefinitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, peritinib, WZ4002, WZ8040, WZ3146, CO-1686, and AZD9291.

[0724] In some embodiments, subjects have adverse reactions to treatment with therapeutic agents other than the compounds of this disclosure. In some embodiments, subjects have adverse reactions to treatment with type I inhibitors. In some embodiments, subjects have adverse reactions to treatment with one or more of the following: gefinitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, peritinib, WZ4002, WZ8040, WZ3146, CO-1686, and AZD9291. In some embodiments, the adverse reaction is activation of an oncogenic variant of EGFR, the oncogenic variant includes a mutation in the extracellular domain of the receptor. In some embodiments, the adverse reaction is the activation of an oncogenic variant of the HER-2 receptor, the oncogenic variant involves a mutation in the extracellular domain of the receptor.

[0725] In some embodiments, the method further comprises administering a therapeutically effective dose of a non-type I inhibitor to a subject requiring it. In some embodiments, the non-type I inhibitor includes a small molecule type II inhibitor.

[0726] In some embodiments, the method further comprises administering a therapeutically effective dose of a non-type I inhibitor to a subject requiring it. In some embodiments, the non-type I inhibitor includes a small molecule type II inhibitor.

[0727] In some embodiments, the compound is used in combination with a therapeutically effective dose of a non-type I inhibitor. In some embodiments, the non-type I inhibitor includes a small molecule type II inhibitor.

[0728] 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.

[0729] In some embodiments, the therapeutically effective dose reduces the severity of signs or symptoms of cancer.

[0730] In some embodiments, signs of cancer include tumor malignancy, and a reduction in the severity of signs includes a decrease in tumor malignancy.

[0731] In some embodiments, signs of cancer include tumor metastasis, and reduction of the severity of signs includes elimination of metastasis or reduction of the rate or extent of metastasis.

[0732] In some embodiments, signs of cancer include tumor volume, and reduction of the severity of signs includes tumor elimination or reduction of volume.

[0733] In some embodiments, the symptoms of cancer include pain, and the reduction of the severity of the symptoms includes the elimination or reduction of pain.

[0734] In some embodiments, the therapeutically effective dose induces a remission period.

[0735] In some embodiments, the therapeutically effective dose improves the prognosis of the subject.

[0736] Such use of the subject matter (or method of treatment or prevention) involves administering a therapeutically effective amount of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, to a subject in need of such prevention or treatment by targeting allosteric and / or oncogenic variants of the EGFR and HER-2 receptors.

[0737] This disclosure describes the administration of the compounds disclosed alone or with one or more additional therapeutic agents, e.g., other tyrosine kinase inhibitors: erlotinib hydrochloride (e.g., Tarceva® by Genentech / Roche), linifanib (or ABT 869 by Genentech), sunitinib malate (e.g., Sutent® by Pfizer), bosutinib (or SKI-606, as described in US 6,780,996), dasatinib (e.g., Bristol-Myers Sprycel® by Squibb, armala (e.g., pazopanib, e.g., Votrient® by GlaxoSmithKline), imatinib and imatinib mesylate (e.g., Gilvec® and Gleevec® by Novartis); vascular endothelial growth factor (VEG) receptor inhibitors (bevacizumab, or Avastin® by Genentech / Roche, axitinib (or as described in AG013736, WO01 / 002369), brivanib alaninate (or BMS-582664), motesanib (or AMG-706, PCT)(as described in WO02 / 066470), pasireotide (e.g., SOM230, as described in WO02 / 010192), sorafenib (e.g., Nexavar®); HER2 receptor inhibitors: trastuzumab (e.g., Herceptin® by Genentech / Roche), neratinib (or HKI-272, as described in WO05 / 028443), lapatinib or lapatinib nitosylate (e.g., Tykerb® by GlaxoSmithKline); CD20 antibody: rituximab (e.g., G Riuxan® and MabThera® by enentech / Roche, tositumomab (e.g., Bexxar® by GlaxoSmithKline), ofatumumab by GlaxoSmithKline (e.g., Arzerra®); Bcr / Abl kinase inhibitors: nilotinib hydrochloride (e.g., Tasigna® by Novartis); DNA synthesis inhibitors: capecitabine (e.g., Xeloda® by Roche), gemcitabine hydrochloride (e.g., Eli Gemzar® by Lilly and Company, nelarabine (or Arranon® and Atriance® by GlaxoSmithKline); antitumor agents: oxaliplatin (e.g., Eloxatin® by Sanofi-Aventis as described in US4,169,846); epidermal growth factor receptor (EGFR) inhibitors: gefitinib (or Iressa®), afatinib (or Tovok® by Boehringer Ingelheim), cetuximab (e.g., Bristol-MyersErbitux (registered trademark) by Squibb, panitumumab (e.g., Vectibix (registered trademark) by Amgen); HER dimerization inhibitors: pertuzumab (e.g., Omnitarg (registered trademark) by Genentech); human granulocyte colony-stimulating factor (G-CSF) modifiers: filgrastim (e.g., Neupogen (registered trademark) by Amgen); immunomodulators: aftuzumab (registered trademark by Roche), pegfilgrastim (e.g., Neulasta (registered trademark) by Amgen), lenalidomide (e.g., CC-5013, e.g., Revlimid (registered trademark)), thalidomide (e.g., Thalomid (registered trademark)); (m)CD40 inhibitors: dasetuzumab (e.g., Seattle SGN-40 or huS2C6 by Genetics, Inc.; Pro-apoptotic receptor agonists (PARAs): Duranermin (e.g., AMG-951 by Amgen / Genentech); Hedgehog antagonists: Bismodegib (or GDC-0449, as described in WO06 / 028958); PI3K inhibitors: Pictilisib (or GDC-0941 as described in WO09 / 036082 and WO09 / 055730), Dactrisib (or BEZ 235 or NVP-BEZ) 235, as described in WO06 / 122806); phospholipase A2 inhibitors: anagrelide (e.g., Agrylin®); BCL-2 inhibitors: navitoclax (or ABT-263, as described in WO09 / 155386); mitogen-activated protein kinase (MEK) inhibitors: XL-518 (ACCCAS number 1029872-29-4 by Corp.; Aromatase inhibitors: exemestane (e.g., Aromasin® by Pfizer), letrozole (e.g., Femara® by Novartis), anastrozole (e.g., Arimidex®), topoisomerase I inhibitors: irinotecan (e.g., Camptosar® by Pfizer), topotecan hydrochloride (e.g., Hycamt by GlaxoSmithKline) in(registered trademark)); Topoisomerase II inhibitors: Etoposide (e.g., VP-16 and phosphate etoposide, e.g., Toposar(registered trademark), VePesid(registered trademark), and Etopophos(registered trademark)), Teniposide (e.g., VM-26, e.g., Vamon(registered trademark)), mTOR inhibitors: Temsirolimus (e.g., Torisel(registered trademark), Pfizer), Ridaholorumus (formerly known as deferolimus, (or AP23573 and MK8669, WO (as described in 03 / 064383), everolimus (e.g., Afinitor®, Novartis), osteoclast bone resorption inhibitors: zoledronic acid (or Zometa®, Novartis), CD33 antibody drug conjugate: gemtuzumab ozogamicin (e.g., Mylotarg®, Pfizer / Wyeth), CD22 antibody drug conjugate: inotuzumab ozogamicin (also known as CMC-544 and WAY-207294, Hangzhou Sage Chemical Co., Ltd.), CD20 antibody drug conjugate: ibritumomab tiuxetan (e.g., Zevalin®), somatostatin analogs: octreotide (e.g., octreotide acetate, e.g., Sandostatin® and SandostatinLAR(registered trademark), synthetic interleukin-11 (IL-11): oprelbequin (e.g., Neumega(registered trademark), Pfizer / Wyeth), synthetic erythropoietin: darbepoetin alfa (e.g., Aranesp(registered trademark), Amgen), nuclear factor kappa B receptor activator (RANK) inhibitor: denosumab (e.g., Prolia(registered trademark), Amgen), thrombopoietin mimic peptide body: romiplostim (e.g., Nplate(registered trademark), Amgen), cell proliferation stimulant: parifermin (e.g., Kepivance(registered trademark), Amgen), anti-insulin-like growth factor 1 receptor (IGF-1R) antibody: figtumumab (e.g., CP-751, 871, ACC Corp), lobatumumab (CAS No. 934235-44-6), Anti-CS1 antibody: elotuzumab (HuLuc63, CAS No. 915296-00-3), CD52 antibody: alemtuzumab (e.g., Campath®), CTLA-4 inhibitor: tremelimumab (IgG2 monoclonal antibody, Pfizer, formerly known as tisilimmab, CP-675,206), ipilimumab (CTLA-4 antibody, e.g., MDX-010, CASNo. 477202-00-9), Histone deacetylase inhibitors (HDIs): Boninostat (e.g., Zolinza®, Merck), Alkylating agents: Temozolomide (e.g., Temodar® and Temodar®, Schering-Plough / Merck), Dactinomycin (e.g., Actinomycin D and e.g., Cosmegen®), Melphalan (e.g., L-PAM, L-sarcolicin and phenylalanine mustard, e.g., Alkeran®), Altoretamine (e.g., Hexamethylmelamine (HMM), e.g., Hexalen®), Carmustine (e.g., BiCNU®), Bendamustine (e.g., Treanda®), Busulfan (e.g., Busulfex® and Myleran®), Carboplatin (e.g., Parapl atin(registered trademark)), lomustine (e.g., CCNU, e.g., CeeNU(registered trademark)), cisplatin (e.g., CDDP, e.g., Platinol(registered trademark) and Platinol(registered trademark)-AQ), chlorambucil (e.g., Leukeran(registered trademark)), cyclophosphamide (e.g., Cytoxan(registered trademark) and Neosar(registered trademark)), decarbazine (e.g., DTIC, DIC and imidazole-carboxamide, e.g., DTIC-Dome(registered trademark)), altretamine (e.g., hexamethylmelamine (HMM), e.g., Hexalen(registered trademark)), ifosfamide (e.g., Ifex(registered trademark)), procarbazine (e.g., Matulane(registered trademark)), mechlorethamine (e.g., nitrogen mustard, mustine, and mechloroethamine hydrochloride (mechloroethamine) Hydrochloride), e.g., Mustargen (registered trademark), streptozocin (e.g., Zanosar (registered trademark)), thiotepa (e.g., thiophosphoamide, TESPA and TSPA, e.g., Thioplex (registered trademark), biological response modifiers: Calmette-Guéran bacilli (e.g., theraCys (registered trademark) and TICE (registered trademark) BCG), denileukinDifutitex (e.g., Ontak®), antitumor antibiotics: doxorubicin (e.g., Adriamycin® and Rubex®), bleomycin (e.g., lenoxane®), daunorubicin (e.g., daunorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, e.g., Cerubidine®), daunorubicin liposomes (daunorubicin citrate liposomes, e.g., DaunoXome®), mitoxantrone (e.g., DHAD, e.g., Novantrone®), epirubicin (e.g., Ellence®), idarubicin (e.g., Idamycin®, Idamycin®) PFS(registered trademark), mitomycin C (e.g., Mutamycin(registered trademark)), microtubule-enhancing agents: estramustine (e.g., Emcyl(registered trademark)), cathepsin K inhibitors: odanacatib (or MK-0822, Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, as described in WO 03 / 075836), epothyron B analogs: ixabepyrone (e.g., Lxempra(registered trademark), Bristol-Myers Squibb), heat shock protein (HSP) inhibitors: tanespimycin (17-allylamino-17-demethoxygeldanamycin, e.g., KOS-953 and 17-AAG, SIGMA, US (Listed in 4,261,989), TpoR agonist: eltrombopag (e.g., Promacta® and Revolade®, GlaxoSmithKline), anti- Streptococcal agents: Docetaxel (e.g., Taxotere®, Sanofi-Aventis), adrenal steroid inhibitors: Aminoglutethimide (e.g., Cytadren®), antiandrogens: Nilutamide (e.g., Nilandron® and Anandron®), bicalutamide (trade name Casodex®), flutamide (e.g., Fulexin®), androgens: Fluoxymesterone (e.g., halotestin®), proteasome inhibitors: Bortezomib (e.g., Velcade®), CDK1 inhibitors: Arbocidib (e.g., flovopirdol or HMR-1275, as described in US 5,621,002), gonadotropin-releasing hormone (GnRH) receptor agonists: Leuprolide or leuprolide acetate (e.g., Viadure®, Bayer) AG, Eligard®, Sanofi-Aventis, and Lupron®, Abbott Labs), Taxane antineoplastic agents: cabazitaxel, larotaxel, 5HT1a receptor agonist: xaliproden (or SR57746, US (Listed in 5,266,573), HPC vaccines: Cervarix®, marketed by GlaxoSmithKline; Gardasil®, marketed by Merck; iron chelators: Deferasinox (e.g., Exjade®, marketed by 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., arabinosylcytosine (Ara-C), e.g., Cytosar-U®), cytarabine liposomes (e.g., Liposomal)Ara-C (e.g., DepoCyt®), decitabine (e.g., Dacogen®), hydroxyurea (e.g., Hydrea®, Droxia®, and Mylocel®), fludarabine (e.g., Fludara®), floxuridine (e.g., FUDR®), cladribine (e.g., 2-chlorodeoxyadenosine (2-CdA), e.g., Leustatin®), methotrexate (e.g., ametopterin, methotrexate sodium (MTX), e.g., Rheumatrex®, and Trexall®), pentostatin (e.g., Nipent®) ), bisphosphonates: pamidronate (e.g., Aredia®), zoledronic acid (e.g., Zometa®), demethylating agents: 5-azacitidine (e.g., Vidaza®), decitabine (e.g., Dacogen®), plant alkaloids: paclitaxel protein-bound (e.g., Abraxane®), vinblastine (e.g., vinblastine sulfate, vincaloicoblastine and VLB, e.g., Alkaban-AQ® and Velban®), vincristine (e.g., vincristine sulfate, LCR and VCR, e.g., Oncovin® and Vincasar)Pfs(registered trademark), vinorelbine (e.g., Navelbine(registered trademark)), paclitaxel (e.g., Taxol and Onxal(registered trademarks)), retinoids: alitretinoin (e.g., Panretin(registered trademark)), tretinoin (total-trans retinoic acid, e.g., ATRA, e.g., Vesanoid(registered trademark)), isotretinoin (13-cis-retinoic acid, e.g., Accutane(registered trademark), Amnesteem(registered trademark), Claravis(registered trademark), Clarus(registered trademark), De cutan(registered trademark), Isotane(registered trademark), Izotech(registered trademark), Oratane(registered trademark), Isotret(registered trademark), and Sotret(registered trademark), bexarotene (e.g., Targretin(registered trademark)), glucocorticosteroids: hydrocortisone (e.g., cortisone, sodium hydrocortisone succinate, sodium hydrocortisone phosphate, and e.g., Ala-Cort(registered trademark), hydrocortisone phosphate, Solu-Cortef(registered trademark), Hydrocort Acetate(registered trademark), and Lanacort(registered trademark)), dexamethasone, prednisolone (e.g., Delta-Cortel(registered trademark), Orapred(registered trademark), Pediapred(registered trademark), and Prelone(registered trademark)), prednisone (e.g., Deltasone(registered trademark), LiquidRed (registered trademark), Meticorten (registered trademark), and Orasone (registered trademark)), methylprednisolone (e.g., 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, e.g., Duralone (registered trademark), Medralone (registered trademark), Medrol (registered trademark), M-Prednisol (registered trademark), and Solu-Medrol (registered trademark)), cytokines: interleukin-2 (e.g., aldesleukin and IL-2, e.g., Proleukin (registered trademark)), interleukin-11 ( For example, oprelbequine (e.g., Neumega®), alpha-interferon alpha (e.g., IFN-alpha, e.g., Intron® A, and Roferon-A®); luteinizing hormone-releasing hormone (LHRH) agonists: goserelin (e.g., Zoladex®), progesterone megestrol (e.g., megestrol acetate, e.g., Megace®); mixed cytotoxic agents: arsenic trioxide (e.g., Trisenox®), asparaginase (e.g., L-asparaginase, Elwinia) It is anticipated that this drug will be administered in combination with L-asparaginases, e.g., Elspar® and Kidrolase®; anti-nausea agents: NK-1 receptor antagonists: casopitants (e.g., Rezonic® and Zunrisa®, GlaxoSmithKline); and cytoprotective agents: amiphostin (e.g., Ethyol®), leucovorin (e.g., leucovorin calcium, citroborum factor, and folinic acid). [Embodiment] Exemplary Embodiments Embodiment 1: The compound of the following formula (I'), [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, W is either CH or N. Z is one or more RZ It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Z These are independently halogens, 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, C 3- C 10 Cycloalkyl, C6-C 10 These are aryl groups, 3-10 membered heterocycloalkyl groups, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C 3- C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R Za It is optionally replaced with, Each R Za These are independently halogens, 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, and C3-C 10 Cycloalkyl, C6-C 10 These are aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl compounds. T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R T These are independently halogens, 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, C 3- C10 Cycloalkyl, C6-C 10 These are aryl groups, 3-10 membered heterocycloalkyl groups, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C 3- C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R Ta It is optionally replaced with, Each R Ta These are independently halogens, 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, and C3-C 10 Cycloalkyl, C6-C 10 These are aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl compounds. Ar 1 is one or more R A1 C6-C is optionally replaced by 10 It is Ariel, Each R A1 These are independently 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 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 These are aryl groups, 3-10 membered heterocycloalkyl groups, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R A1a It is optionally replaced with, Each R A1a These are independently halogens, 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, C 3- C 10 Cycloalkyl, C6-C 10 These are aryl groups, 3-10 membered heterocycloalkyl groups, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C 3- C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R A1b It is optionally replaced with, and Each R A1b These are independently halogen, CN, -OH, or -NH2. Embodiment 2: The compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, as described in any one of the above embodiments, wherein the formula is: W is either CH or N. Z is one or more R Z It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Z These are independently halogens, 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, C 3- C 10 Cycloalkyl, C6-C 10 These are aryls or 5-10 membered heteroaryls, including -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C 3- C 10 Cycloalkyl, C6-C10 Aryls, 3- or 5-10 member heteroaryls, one or more R Za It is optionally replaced with, Each R Za These are independently halogens, 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, and C3-C 10 Cycloalkyl, C6-C 10 These are aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl compounds. T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R T These are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 These are aryl, 3-7 membered heterocycloalkyl, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may have one or more R Ta It is optionally replaced with, Each R Ta These are independently halogens, 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 These are aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl compounds. Ar1 is one or more R A1 C6-C is optionally replaced by 10 It is Ariel, Each R A1 These are independently 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, and -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R A1a It is optionally replaced with, and Each R A1a These are independently halogens, 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, and -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl are one or more R A1b It is optionally replaced with, and Each R A1b These are independently halogen, CN, -OH, or -NH2, However, Z is [ka] When that is the case, Ar 1 C6-C is optionally substituted with one or more halogens. 10 It is Ariel. Embodiment 3: The compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, as described in any one of the above embodiments, wherein the formula is: W is either CH or N. Z is one or more R Z It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each RZ These are independently halogens, 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, C 3- C 10 Cycloalkyl, C6-C 10 These are aryls or 5-10 membered heteroaryls, including -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C 3- C 10 Cycloalkyl, C6-C 10 Aryls, 3- or 5-10 member heteroaryls, one or more R Za It is optionally replaced with, Each R Za These are independently halogens, 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, and C3-C 10 Cycloalkyl, C6-C 10 These are aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl compounds. T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R T These are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 These are aryl, 3-7 membered monocyclic heterocycloalkyl, or 5-10 membered heteroaryl, and include -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C10 Cycloalkyl, C6-C 10 Aryls, 3- to 7-membered monocyclic heterocycloalkyls, or 5- to 10-membered heteroaryls include one or more R Ta It is optionally replaced with, Each R Ta These are independently halogens, 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 These are aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl compounds. Ar 1 is one or more R A1 C6-C is optionally replaced by 10 It is Ariel, Each R A1 These are independently 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, and -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R A1a It is optionally replaced with, and Each R A1a These are independently halogens, 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, and -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl are one or more R A1b It is optionally replaced with, and Each R A1b These are independently halogen, CN, -OH, or -NH2, However, Z is [ka] When that is the case, Ar 1 C6-C is optionally substituted with one or more halogens. 10 It is Ariel. Embodiment 4: The compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, as described in any one of the above embodiments, wherein the formula is: W is CH, Z is one or more R Z It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Z These are independently a halogen, -O-(C1-C6 alkyl), C1-C6 alkyl, or a 3- to 10-membered heterocycloalkyl, where the -O-(C1-C6 alkyl), C1-C6 alkyl, or 3- to 10-membered heterocycloalkyl 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 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R T These are independently a halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or a 3- to 7-membered heterocycloalkyl, where the -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH groups. Ar 1 is one or more R A1 C6-C is optionally replaced by 10 It is Ariel, Each R A1 These are independently halogen, -OR A1a , or one or more R A1a It is an optionally substituted -O-(C1-C6 alkyl), and Each R A1a It is independent, C6-C 10It is an aryl or 5-10 member heteroaryl, C6-C 10 The aryl or 5- to 10-membered heteroaryl can be optionally substituted with one or more halogens. Embodiment 5: The compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, as described in any one of the above embodiments, wherein the formula is: W is CH, Z is one or more R Z It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Z These are independently a halogen, -O-(C1-C6 alkyl), C1-C6 alkyl, or a 3- to 10-membered heterocycloalkyl, where the -O-(C1-C6 alkyl), C1-C6 alkyl, or 3- to 10-membered heterocycloalkyl 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 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R T These are independently a halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or a 3- to 7-membered monocyclic heterocycloalkyl, and the -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or a 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH groups. Ar 1 is one or more R A1 C6-C is optionally replaced by 10 It is Ariel, Each R A1 These are independently halogen, -OR A1a , or one or more R A1a It is an optionally substituted -O-(C1-C6 alkyl), and Each R A1a It is independent, C6-C 10It is an aryl or 5-10 member heteroaryl, C6-C 10 The aryl or 5- to 10-membered heteroaryl can be optionally substituted with one or more halogens. Embodiment 6: The compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, as described in any one of the above embodiments, wherein the formula is: W is CH, Z is one or more R Z It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Z independently, is a halogen, -O-(C1-C6 alkyl), or C1-C6 alkyl, where -O-(C1-C6 alkyl) or 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 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R T These are independently a halogen, -OH, -O-(C1-C6 alkyl), or a 3- to 7-membered heterocycloalkyl, and the -O-(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH groups. Ar 1 is one or more R A1 C6-C is optionally replaced by 10 It is Ariel, Each R A1 These are independently halogen, -OR A1a , or one or more R A1a It is an optionally substituted -O-(C1-C6 alkyl), and Each R A1a It is independent, C6-C 10 It is an aryl or 5-10 member heteroaryl, C6-C 10 Aryl or 5- to 10-membered heteroaryls are optionally substituted with one or more halogens. However, Z is [ka] When that is the case, Ar 1 C6-C is optionally substituted with one or more halogens. 10 It is Ariel. Embodiment 7: The compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, as described in any one of the above embodiments, wherein the formula is: W is CH, Z is one or more R Z It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Z independently, is a halogen, -O-(C1-C6 alkyl), or C1-C6 alkyl, where -O-(C1-C6 alkyl) or 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 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R T These are independently a halogen, -OH, -O-(C1-C6 alkyl), or a 3- to 7-membered monocyclic heterocycloalkyl, and the -O-(C1-C6 alkyl) or the 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH groups. Ar 1 is one or more R A1 C6-C is optionally replaced by 10 It is Ariel, Each R A1 These are independently halogen, -OR A1a , or one or more R A1a It is an optionally substituted -O-(C1-C6 alkyl), and Each R A1a It is independent, C6-C 10It is an aryl or 5-10 member heteroaryl, C6-C 10 Aryl or 5- to 10-membered heteroaryls are optionally substituted with one or more halogens. However, Z is [ka] When that is the case, Ar 1 C6-C is optionally substituted with one or more halogens. 10 It is Ariel. Embodiment 8: The compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, as described in any one of the above embodiments, wherein the formula is: W is CH, Z is one or more R Z It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Z independently, is a halogen, -O-(C1-C6 alkyl), or C1-C6 alkyl, where -O-(C1-C6 alkyl) or 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 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R T These are independently a halogen, -OH, -O-(C1-C6 alkyl), or a 3- to 7-membered heterocycloalkyl, and the -O-(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH groups. Ar 1 C6-C is optionally substituted with one or more halogens. 10 It is Ariel. Embodiment 9: The compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, as described in any one of the above embodiments, wherein the formula is: W is CH, Z is one or more R Z It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Z independently, is a halogen, -O-(C1-C6 alkyl), or C1-C6 alkyl, where -O-(C1-C6 alkyl) or 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 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R T These are independently a halogen, -OH, -O-(C1-C6 alkyl), or a 3- to 7-membered monocyclic heterocycloalkyl, and the -O-(C1-C6 alkyl) or the 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH groups. Ar 1 C6-C is optionally substituted with one or more halogens. 10 It is Ariel. Embodiment 10: The compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, as described in any one of the above embodiments, wherein the formula is: W is CH, Z is a 3- to 12-membered heterocycloalkyl group optionally substituted with one or more C1-C6 alkyl groups. T is a C2-C6 alkenyl optionally substituted with one or more 6-membered heterocycloalkyl groups, and Ar 1 It is a C6 aryl that can be optionally substituted with one or more halogens. Embodiment 11: The compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, as described in any one of the above embodiments, wherein the formula is: W is CH, Z is a 3- to 12-membered heterocycloalkyl group optionally substituted with one or more C1-C6 alkyl groups. T is a C2-C6 alkenyl optionally substituted with one or more 6-membered monocyclic heterocycloalkyl groups, and Ar 1 It is a C6 aryl that can be optionally substituted with one or more halogens. Embodiment 12: A compound according to any one of the embodiments described above, wherein W is CH. Embodiment 13: The compound according to any one of the above embodiments, wherein W is N. Embodiment 14: Z is one or more R Z It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Z The compound according to any one of the above embodiments, wherein is independently a halogen, a -O-(C1-C6 alkyl), a C1-C6 alkyl, or a 3- to 10-membered heterocycloalkyl, and the -O-(C1-C6 alkyl), C1-C6 alkyl, or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogens. Embodiment 15: Z is oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azaspiro[3.3]heptanyl, or 2-oxa-5-azaspiro[3.4]octanyl, and oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azaspiro[3.3]heptanyl, or 2-oxa-5-azaspiro[3.4]octanyl is one or more R Z The compound according to any one of the above embodiments, which is optionally substituted with. Embodiment 16: Z is oxetanil, tetrahydrofuranil, pyrrolidinil, piperidinil, morpholinil, 3-oxabicyclo[3.1.0]hexanil, 3-azabicyclo[3.1.0]hexanil, 2-azaspiro[3.3]heptanil, or 2-oxa-5-azaspiro[3.4]octanil, and oxetanil, tetrahydrofuranil, pyrrolidinil, piperidinil, morpholinil, 3-azabicyclo[3.1.0]hexanil, 2-azaspiro[3.3]heptanil, or 2-oxa-5-azaspiro[3.4]octanil is one or more R Z The compound according to any one of the above embodiments, which is optionally substituted with. Embodiment 17: Z [ka] The compound described in any one of the embodiments described above. Embodiment 18: Z [ka] The compound described in any one of the embodiments described above. Embodiment 19: At least one R Z However, the compound described in any one of the embodiments above is a halogen. Embodiment 20: At least one R Z The compound according to any one of the embodiments described above, wherein the compound is F or Cl. Embodiment 21: At least one R Z The compound according to any one of the embodiments described above, wherein the group is CN, -OH, or -NH2. Embodiment 22: At least one R Z These include -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C10 These are aryl groups, 3-10 membered heterocycloalkyl groups, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 An aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, with one or more R Za The compound according to any one of the above embodiments, which is optionally substituted with. Embodiment 23: At least one R Z is one or more R Za The compound according to any one of the embodiments described above, wherein the -O-(C1-C6 alkyl) is optionally substituted. Embodiment 24: At least one R Z However, the compound is -OCH3 as described in any one of the embodiments above. Embodiment 25: At least one R Z The compound according to any one of the embodiments described above, wherein the compound is an -O-(C1-C6 alkyl) substituted with one or more halogens. Embodiment 26: At least one R Z However, the compound is a C1-C6 alkyl compound as described in any one of the embodiments above. Embodiment 27: At least one R Z The compound according to any one of the embodiments described above, wherein the compound is methyl, ethyl, or propyl. Embodiment 28: At least one R Z The compound according to any one of the embodiments described above, wherein the compound is a C1-C6 alkyl group substituted with one or more halogens. Embodiment 29: At least one R Z However, the compound is CF3, as described in any one of the embodiments described above. Embodiment 30: At least one R Z C3-C 10 Cycloalkyl, C6-C 10 It is an aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R Za The compound according to any one of the above embodiments, which is optionally substituted with. Embodiment 31: At least one R Z is one or more R Za The compound according to any one of the embodiments described above, which is a 3-membered to 10-membered heterocycloalkyl group that is optionally substituted with [the specified compound]. Embodiment 32: At least one R Z is one or more R Za The compound according to any one of the embodiments described above, which is a four-membered heterocycloalkyl that is optionally substituted with [the specified compound]. Embodiment 33: At least one R Z However, the compound described in any one of the embodiments above is oxetanyl. Embodiment 34: At least one R Za However, the compound described in any one of the embodiments above is a halogen. Embodiment 35: At least one R Za The compound according to any one of the embodiments described above, wherein the compound is F or Cl. Embodiment 36: At least one R Za These are 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 10The compound according to any one of the embodiments described above, which is an aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl. Embodiment 37: T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, Each R T These are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 These are aryl, 3-7 membered heterocycloalkyl, or 5-10 membered heteroaryl groups, including -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may have one or more R Ta It is optionally replaced with, and Each R Ta These are independently 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 The compound according to any one of the embodiments described above, which is an aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl. Embodiment 38: T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more RT It is optionally replaced with, Each R T These are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 These are aryl, 3-7 membered monocyclic heterocycloalkyl, or 5-10 membered heteroaryl, and include -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 Cycloalkyl, C6-C 10 Aryls, 3- to 7-membered monocyclic heterocycloalkyls, or 5- to 10-membered heteroaryls include one or more R Ta It is optionally replaced with, and Each R Ta These are independently 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 They are aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl. Embodiment 39: T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, and Each R T The compound according to any one of the above embodiments, wherein is independently a halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or a 3- to 7-membered heterocycloalkyl, and the -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH groups. Embodiment 40: T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, and Each R T These are independently a halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or a 3- to 7-membered monocyclic heterocycloalkyl, where the -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or a 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH groups. Embodiment 41: T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, and Each R T The elements are independently a halogen, -OH, -O-(C1-C6 alkyl), or a 3- to 7-membered heterocycloalkyl, and the -O-(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl may be optionally substituted with one or more -C(=O)OH groups. Embodiment 42: T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R T It is optionally replaced with, and Each R T The compound according to any one of the above embodiments, wherein is independently a halogen, -OH, -O-(C1-C6 alkyl), or a 3- to 7-membered monocyclic heterocycloalkyl, and the -O-(C1-C6 alkyl) or the 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH groups. Embodiment 43: T is one or more R T The compound according to any one of the embodiments described above, wherein the -O-(C1-C6 alkyl) is optionally substituted. Embodiment 44: The compound according to any one of the embodiments described above, wherein T is -OCH3. Embodiment 45: T is one or more R T The compound according to any one of the embodiments described above, wherein the compound is a -NH-(C1-C6 alkyl) which is optionally substituted. Embodiment 46: A compound according to any one of the embodiments described above, wherein T is -NHCH3. Embodiment 47: T is one or more R T The compound according to any one of the embodiments described above, wherein the C1-C6 alkyl group is optionally substituted. Embodiment 48: A compound according to any one of the embodiments described above, wherein T is a C1-C6 alkyl group. Embodiment 49: The compound according to any one of the embodiments described above, wherein T is methyl or ethyl. Embodiment 50: The compound according to any one of the embodiments described above, wherein T is a C1-C6 alkyl group substituted with one or more halogens. Embodiment 51: The compound according to any one of the embodiments described above, wherein T is -CHFCl. Embodiment 52: T is one or more R T The compound according to any one of the embodiments described above, which is a C2-C6 alkenyl optionally substituted with. Embodiment 53: The compound according to any one of the embodiments described above, wherein T is a C2-C6 alkenyl. Embodiment 54: The compound according to any one of the above embodiments, wherein T is ethenyl. Embodiment 55: The compound according to any one of the above embodiments, wherein T is propenyl. Embodiment 56: The compound according to any one of the above embodiments, wherein T is pentenyl. Embodiment 57: T is one or more R T The compound according to any one of the embodiments described above, which is a C2-C6 alkenyl substituted with [a specific compound]. Embodiment 58: The compound according to any one of the embodiments described above, wherein T is a C2-C6 alkenyl substituted with one or more -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or a 3- to 10-membered heterocycloalkyl, in which case the 3- to 10-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH. Embodiment 59: The compound according to any one of the embodiments described above, wherein T is a C2-C6 alkynyl compound. Embodiment 60: The compound according to any one of the embodiments described above, wherein T is propynyl. Embodiment 61: T is one or more R T The compound according to any one of the embodiments described above, which is a C2-C6 alkynyl substituted with [a specific compound]. Embodiment 62: T is one or more R T The compound according to any one of the above embodiments, wherein the propynyl is substituted with [a specific compound]. Embodiment 63: The compound according to any one of the embodiments described above, wherein T is a propynyl substituted with one or more 3- to 10-membered heterocycloalkyl groups. Embodiment 64: T is [ka] The compound described in any one of the embodiments described above. Embodiment 65: T is [ka] The compound described in any one of the embodiments described above. Embodiment 66: At least one R T However, the compound described in any one of the embodiments above is a halogen. Embodiment 67: At least one R T The compound according to any one of the embodiments described above, wherein the group is CN, -OH, or -NH2. Embodiment 68: At least one R T is -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2, in which case -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2 is one or more R Ta The compound according to any one of the above embodiments, which is optionally substituted with. Embodiment 69: At least one R T The compound according to any one of the embodiments described above, wherein is -O-(C1-C6 alkyl) or -N(C1-C6 alkyl)2. Embodiment 70: At least one R T is a C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, in which case the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is one or more R Ta The compound according to any one of the above embodiments, which is optionally substituted with. Embodiment 71: At least one R T C3-C 10 Cycloalkyl, C6-C 10 It is an aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more RTa The compound according to any one of the above embodiments, which is optionally substituted with. Embodiment 72: At least one R T The compound according to any one of the embodiments described above, wherein is a 3-membered to 10-membered heterocycloalkyl group substituted with one or more C(=O)OH groups. Embodiment 73: At least one R Ta The compound is C(=O)OH, as described in any one of the embodiments described above. Embodiment 74: At least one R Ta These include halogens, 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, and C3-C 10 Cycloalkyl, C6-C 10 The compound according to any one of the embodiments described above, which is an aryl, a 3- to 10-membered heterocycloalkyl...

Claims

1. The compound of the following formula (I'), 【Chemistry 1】 or a pharmaceutically acceptable salt or stereoisomer thereof, W is CH or N, Z is one or more R Ｚ It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Ｚ is independently halogen, CN, -OH, -NH ２ , -O-(C １ -C ６ alkyl), -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３－ C １０ cycloalkyl, C ６ -C １０ aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the -O-(C １ -C ６ alkyl), -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３－ C １０ cycloalkyl, C ６ -C １０ aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl are optionally substituted with one or more R Ｚａ and Each R Ｚａ These are independently halogen, CN, -OH, and -NH ２ , -O-(C １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ The aryl group is a 3- to 10-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group. T is -O-(C １ -C ６ Alkyl), -NH-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ It is an alkynyl, and the -O-(C １ -C ６ Alkyl), -NH-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is one or more R Ｔ It is optionally replaced with, Each R Ｔ is independently halogen, CN, -OH, -NH ２ , -O-(C １ -C ６ alkyl), -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , C １ [[ID=2o]]-C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３－ C １０ cycloalkyl, C ６ -C<000009?aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, and the -O-(C １ -C ６ alkyl), -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３－ C １０ cycloalkyl, C ６ -C １０ aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl are optionally substituted with one or more R Ｔａ s, Each R Ｔａ These are independently halogen, CN, -OH, and -NH ２ , -C(=O)OH, -O-(C １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ The aryl group is a 3- to 10-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group. Ar １ is one or more R Ａ１ C is optionally replaced by ６ -C １０ It is Ariel, Each R Ａ１ These are independently halogen, CN, -OH, and -NH ２ , -OR Ａ１ａ , -O-(C １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ The aryl group is a 3- to 10-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group, and the -O-(C １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may have one or more R Ａ１ａ It is optionally replaced with, Each R Ａ１ａ These are independently halogen, CN, -OH, and -NH ２ , -O-(C １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３－ C １０ Cycloalkyl, C ６ -C １０ The aryl group is a 3- to 10-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group, and the -O-(C １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３－ C １０ Cycloalkyl, C ６ -C １０ An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may have one or more R Ａ１ｂ It is optionally replaced with, and Each R Ａ１ｂ These are independently halogen, CN, -OH, or -NH ２ It is a compound.

2. The compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof. W is CH or N, Z is one or more R Ｚ It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Ｚ These are independently halogen, CN, -OH, and -NH ２ , -O-(C １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３－ C １０ Cycloalkyl, C ６ -C １０ The aryl or 5-10 member heteroaryl, and the -O-(C １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３－ C １０ Cycloalkyl, C ６ -C １０ Aryls, 3- or 5- to 10-membered heteroaryls, one or more R Ｚａ It is optionally replaced with, Each R Ｚａ These are independently halogen, CN, -OH, and -NH ２ , -O-(C １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ The aryl group is a 3- to 10-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group. T is -O-(C １ -C ６ Alkyl), -NH-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ It is an alkynyl, and the -O-(C １ -C ６ Alkyl), -NH-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is one or more R Ｔ It is optionally replaced with, Each R Ｔ These are independently halogen, CN, -OH, and -NH ２ , -O-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ The aryl group is a 3- to 7-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group, and the -O-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ Aryl, 3- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, one or more R Ｔａ It is optionally replaced with, Each R Ｔａ These are independently halogen, CN, -OH, and -NH ２ , -C(=O)OH, -O-(C １ -C ６ Alkyl C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ The aryl group is a 3- to 10-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group. Ar １ is one or more R Ａ１ C is optionally replaced by ６ -C １０ It is Ariel, Each R Ａ１ These are independently halogen, CN, -OH, and -NH ２ , -OR Ａ１ａ , -O-(C １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ It is an alkynyl, and the -O-(C １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is one or more R Ａ１ａ It is optionally replaced with, and Each R Ａ１ａ These are independently halogen, CN, -OH, and -NH ２ , -O-(C １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ It is an alkynyl, and the -O-(C １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is one or more R Ａ１ｂ It is optionally replaced with, and Each R Ａ１ｂ These are independently halogen, CN, -OH, or -NH ２ And, However, Z 【Chemistry 2】 When Ar １ C is optionally substituted with one or more halogens. ６ -C １０ The compound according to claim 1, wherein it is an aryl compound.

3. The compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof. W is CH, Z is one or more R Ｚ It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Ｚ These are independently halogen, -O-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, or 3- to 10-membered heterocycloalkyl, and the -O-(C １ -C ６ Alkyl), C １ -C ６ Alkyl or 3- to 10-membered heterocycloalkyl groups are optionally substituted with one or more halogens. T is -O-(C １ -C ６ Alkyl), -NH-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ It is an alkynyl, and the C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is one or more R Ｔ It is optionally replaced with, Each R Ｔ These are independently halogen, -OH, -O-(C) １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , or a 3- to 7-membered heterocycloalkyl, the -O-(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , or a 3- to 7-membered heterocycloalkyl group, optionally substituted with one or more -C(=O)OH groups, Ar １ is one or more R Ａ１ C is optionally replaced by ６ -C １０ It is Ariel, Each R Ａ１ These are independently halogen, -OR Ａ１ａ , or one or more R Ａ１ａ -O-(C) is optionally substituted. １ -C ６ alkyl) and Each R Ａ１ａ C is independent ６ -C １０ The C is an aryl or a 5-10 member heteroaryl, ６ -C １０ The compound according to claim 1 or 2, wherein the aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogens.

4. The compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof. W is CH, Z is one or more R Ｚ It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Ｚ These are independently halogen, -O-(C １ -C ６ Alkyl), or C １ -C ６ It is alkyl, and the -O-(C １ -C ６ Alkyl) or C １ -C ６ Alkyl is optionally substituted with one or more halogens, T is -O-(C １ -C ６ Alkyl), -NH-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ It is an alkynyl, and the C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is one or more R Ｔ It is optionally replaced with, Each R Ｔ These are independently halogen, -OH, -O-(C) １ -C ６ Alkyl), or a 3- to 7-membered heterocycloalkyl, wherein the -O-(C １ -C ６ Alkyl groups, or 3- to 7-membered heterocycloalkyl groups, are optionally substituted with one or more -C(=O)OH groups. Ar １ is one or more R Ａ１ C is optionally replaced by ６ -C １０ It is Ariel, Each R Ａ１ These are independently halogen, -OR Ａ１ａ , or one or more R Ａ１ａ -O-(C) is optionally substituted. １ -C ６ alkyl) and Each R Ａ１ａ C is independent ６ -C １０ The C is an aryl or a 5-10 member heteroaryl, ６ -C １０ Aryl or 5- to 10-membered heteroaryls are optionally substituted with one or more halogens. However, Z 【Transformation 3】 When Ar １ C is optionally substituted with one or more halogens. ６ -C １０ A compound according to any one of claims 1 to 3, wherein the compound is an aryl compound.

5. The compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof. W is CH, Z is one or more R Ｚ It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Ｚ These are independently halogen, -O-(C １ -C ６ Alkyl), or C １ -C ６ It is alkyl, and the -O-(C １ -C ６ Alkyl) or C １ -C ６ Alkyl is optionally substituted with one or more halogens, T is -O-(C １ -C ６ Alkyl), -NH-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ It is an alkynyl, and the C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is one or more R Ｔ It is optionally replaced with, Each R Ｔ These are independently halogen, -OH, -O-(C) １ -C ６ Alkyl), or a 3- to 7-membered heterocycloalkyl, wherein the -O-(C １ -C ６ Alkyl groups, or 3- to 7-membered heterocycloalkyl groups, are optionally substituted with one or more -C(=O)OH groups. Ar １ C is optionally substituted with one or more halogens. ６ -C １０ The compound according to any one of claims 1 to 4, wherein it is an aryl compound.

6. The compound is the compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof. W is CH, Z is one or more C １ -C ６ A 3- to 12-membered heterocycloalkyl group that is optionally substituted with alkyl groups. T is optionally substituted with one or more six-membered heterocycloalkyl groups. ２ -C ６ Alkenyl reaches, and Ar １ C is optionally substituted with one or more halogens. ６ The compound according to any one of claims 1 to 5, wherein it is an aryl compound.

7. The compound according to any one of claims 1 to 6, wherein W is CH.

8. Z is one or more R Ｚ It is a 3- to 12-membered heterocycloalkyl that can be optionally substituted with, Each R Ｚ These are independently halogen, -O-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, or 3- to 10-membered heterocycloalkyl, and the -O-(C １ -C ６ Alkyl), C １ -C ６ The compound according to any one of claims 1 to 7, wherein the alkyl or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogens.

9. Z is oxetanil, tetrahydrofuranil, pyrrolidinil, piperidinil, morpholinil, 3-oxabicyclo[3.1.0]hexanil, 3-azabicyclo[3.1.0]hexanil, 2-azaspiro[3.3]heptanil, or 2-oxa-5-azaspiro[3.4]octanil, and the oxetanil, tetrahydrofuranil, pyrrolidinil, piperidinil, morpholinil, 3-oxabicyclo[3.1.0]hexanil, 3-azabicyclo[3.1.0]hexanil, 2-azaspiro[3.3]heptanil, or 2-oxa-5-azaspiro[3.4]octanil is one or more R Ｚ The compound according to any one of claims 1 to 8, which is optionally substituted with

10. Z is oxetanil, tetrahydrofuranil, pyrrolidinil, piperidinil, morpholinil, 3-oxabicyclo[3.1.0]hexanil, 3-azabicyclo[3.1.0]hexanil, 2-azaspiro[3.3]heptanil, or 2-oxa-5-azaspiro[3.4]octanil, and the oxetanil, tetrahydrofuranil, pyrrolidinil, piperidinil, morpholinil, 3-azabicyclo[3.1.0]hexanil, 2-azaspiro[3.3]heptanil, or 2-oxa-5-azaspiro[3.4]octanil is one or more R Ｚ A compound according to any one of claims 1 to 9, which is optionally substituted with

11. Z is 【Chemistry 4】 The compound according to any one of claims 1 to 10.

12. Z is 【Transformation 5】 The compound according to any one of claims 1 to 11.

13. At least one R Ｚ The compound according to any one of claims 1 to 12, wherein the compound is a halogen.

14. At least one R Ｚ The compound according to any one of claims 1 to 13, wherein the compound is F or Cl.

15. At least one R Ｚ is one or more R Ｚａ -O-(C) is optionally substituted. １ -C ６ A compound according to any one of claims 1 to 14, wherein it is alkyl.

16. At least one R Ｚ However, -OCH ３ The compound according to any one of claims 1 to 15.

17. At least one R Ｚ However, C １ -C ６ A compound according to any one of claims 1 to 16, wherein it is alkyl.

18. At least one R Ｚ The compound according to any one of claims 1 to 17, wherein the compound is methyl, ethyl, or propyl.

19. At least one R Ｚ However, C is replaced by one or more halogens. １ -C ６ A compound according to any one of claims 1 to 18, wherein it is alkyl.

20. At least one R Ｚ However, CF ３ The compound according to any one of claims 1 to 19.

21. At least one R Ｚ is one or more R Ｚａ The compound according to any one of claims 1 to 20, wherein the compound is a 3- to 10-membered heterocycloalkyl group that is optionally substituted.

22. At least one R Ｚ The compound according to any one of claims 1 to 21, wherein the compound is oxetanyl.

23. T is -O-(C １ -C ６ Alkyl), -NH-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ It is an alkynyl, and the -O-(C １ -C ６ Alkyl), -NH-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is one or more R Ｔ It is optionally replaced with, Each R Ｔ These are independently halogen, CN, -OH, and -NH ２ , -O-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ The aryl group is a 3- to 7-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group, and the -O-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ Aryl, 3- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, one or more R Ｔａ It is optionally replaced with, and Each R Ｔａ These are independently halogen, CN, -OH, and -NH ２ , -C(=O)OH, -O-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ The compound according to any one of claims 1 to 22, wherein the compound is an aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl.

24. T is -O-(C １ -C ６ Alkyl), -NH-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ It is an alkynyl, and the C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is one or more R Ｔ It is optionally replaced with, and Each R Ｔ These are independently halogen, -OH, -O-(C) １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , or a 3- to 7-membered heterocycloalkyl, the -O-(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ The compound according to any one of claims 1 to 23, wherein the heterocycloalkyl group, or a 3- to 7-membered group, is optionally substituted with one or more -C(=O)OH groups.

25. T is -O-(C １ -C ６ Alkyl), -NH-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ It is an alkynyl, and the C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is one or more R Ｔ It is optionally replaced with, and Each R Ｔ These are independently halogen, -OH, -O-(C) １ -C ６ Alkyl), or a 3- to 7-membered heterocycloalkyl, wherein the -O-(C １ -C ６ The compound according to any one of claims 1 to 24, wherein the alkyl group, or a 3- to 7-membered heterocycloalkyl group, is optionally substituted with one or more -C(=O)OH groups.

26. T is one or more R Ｔ -O-(C) is optionally substituted. １ -C ６ A compound according to any one of claims 1 to 25, wherein it is alkyl.

27. T is one or more R Ｔ -NH-(C) is optionally replaced by １ -C ６ A compound according to any one of claims 1 to 26, wherein it is an alkyl compound.

28. T is one or more R Ｔ C is optionally replaced by １ -C ６ A compound according to any one of claims 1 to 27, wherein it is alkyl.

29. T is C １ -C ６ A compound according to any one of claims 1 to 28, wherein it is alkyl.

30. T is C which is replaced by one or more halogens. １ -C ６ A compound according to any one of claims 1 to 29, wherein it is an alkyl compound.

31. The compound according to any one of claims 1 to 30, wherein T is -CHHCl.

32. T is C ２ -C ６ The compound according to any one of claims 1 to 31, wherein it is an alkenyl.

33. T is one or more -OH, -O-(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , or C substituted with a 3- to 10-membered heterocycloalkyl group ２ -C ６ The compound according to any one of claims 1 to 32, wherein the compound is an alkenyl, and the 3 to 10-membered heterocycloalkyl group is optionally substituted with one or more -C(=O)OH groups.

34. T is C ２ -C ６ The compound according to any one of claims 1 to 33, wherein it is an alkynyl compound.

35. The compound according to any one of claims 1 to 34, wherein T is propynyl.

36. The compound according to any one of claims 1 to 35, wherein T is propynyl substituted with one or more 3- to 10-membered heterocycloalkyl groups.

37. T is, 【Transformation 6】 The compound according to any one of claims 1 to 36.

38. T is, 【Transformation 7】 The compound according to any one of claims 1 to 37.

39. At least one R Ｔ The compound according to any one of claims 1 to 38, wherein the compound is a halogen.

40. At least one R Ｔ However, CN, -OH, or -NH ２ The compound according to any one of claims 1 to 39.

41. At least one R Ｔ is -O-(C １ -C ６ Alkyl) or -N(C １ -C ６ Alkyl) ２ The compound according to any one of claims 1 to 40.

42. At least one R Ｔ The compound according to any one of claims 1 to 41, wherein is a 3- to 10-membered heterocycloalkyl group substituted with one or more C(=O)OH groups.

43. At least one R Ｔａ The compound according to any one of claims 1 to 42, wherein is C(=O)OH.

44. Ar １ is one or more R Ａ１ C is optionally replaced by ６ -C １０ It is Ariel, Each R Ａ１ These are independently halogen, CN, -OH, and -NH ２ , -OR Ａ１ａ , -O-(C １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ It is an alkynyl, and the -O-(C １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is one or more R Ａ１ａ It is optionally replaced with, Each R Ａ１ａ These are independently halogen, CN, -OH, and -NH ２ , -O-(C １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ It is an alkynyl, and the -O-(C １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkinyl is one or more R Ａ１ｂ It is optionally replaced with, and Each R Ａ１ｂ These are independently halogen, CN, -OH, or -NH ２ The compound according to any one of claims 1 to 43.

45. Ar １ However, one or more R Ａ１ C is replaced by ６ -C １０ The compound according to any one of claims 1 to 44, wherein it is an aryl compound.

46. Ar １ The compound according to any one of claims 1 to 45, wherein is a phenyl substituted with one or more halogens.

47. Ar １ The compound according to any one of claims 1 to 46, wherein is a phenyl substituted with one F and one Cl.

48. Ar １ is a phenyl compound optionally substituted with one or more halogens, wherein the phenyl compound is -O-(C ６ -C １０ Further substituted with aryl) or -O- (5-10 member heteroaryl), and the -O- (C ６ -C １０ The compound according to any one of claims 1 to 47, wherein the aryl) or -O- (5- to 10-membered heteroaryl) is optionally substituted with one or more halogens.

49. Ar １ The compound according to any one of claims 1 to 48, wherein is a phenyl optionally substituted with one or more halogens, wherein the phenyl is further substituted with -O-phenyl or -O-pyridinyl, and the -O-phenyl or -O-pyridinyl is optionally substituted with one or more halogens.

50. Ar １ teeth, 【Transformation 8】 The compound according to any one of claims 1 to 49.

51. Ar １ teeth, 【Chemistry 9】 The compound according to any one of claims 1 to 50.

52. Ar １ teeth, 【Chemistry 10】 The compound according to any one of claims 1 to 51.

53. Ar １ teeth, 【Chemistry 11】 The compound according to any one of claims 1 to 52.

54. At least one R Ａ１ The compound according to any one of claims 1 to 53, wherein the compound is a halogen.

55. At least one R Ａ１ However, F is and at least one R Ａ１ The compound according to any one of claims 1 to 54, wherein the compound is Cl.

56. At least one R Ａ１ The compound according to any one of claims 1 to 55, wherein is -O-phenyl or -O-pyridinyl, and the -O-phenyl or -O-pyridinyl is optionally substituted with one or more halogens.

57. At least one R Ａ１ is -O-CH ２ -phenyl or -O-CH ２ -Pyridinyl, and the -O-CH ２ -phenyl or -O-CH ２ - The compound according to any one of claims 1 to 56, wherein the pyridinyl is optionally substituted with one or more halogens.

58. At least one R Ａ１ａ The compound according to any one of claims 1 to 57, wherein is phenyl or pyridinyl, and the phenyl or pyridinyl is optionally substituted with one or more halogens.

59. At least one R Ａ１ｂ The compound according to any one of claims 1 to 58, wherein the compound is a halogen.

60. At least one R Ａ１ｂ However, F is and at least one R Ａ１ｂ The compound according to any one of claims 1 to 59, wherein the compound is Cl.

61. The compound is a compound of the following formula (II'). 【Chemistry 12】 The compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt or stereoisomer thereof.

62. The compound is a compound of the following formula (II'). 【Chemistry 13】 The compound according to any one of claims 1 to 61, or a pharmaceutically acceptable salt or stereoisomer thereof.

63. The compound is a compound of the following formula (III') or (III'-a). 【Chemistry 14】 The compound according to any one of claims 1 to 62, or a pharmaceutically acceptable salt or stereoisomer thereof.

64. The compound is a compound of the following formula (IV') or (IV'-a). 【Chemistry 15】 The compound according to any one of claims 1 to 63, or a pharmaceutically acceptable salt or stereoisomer thereof.

65. The aforementioned compound is a compound of formula I. 【Chemistry 16】 or a pharmaceutically acceptable salt or stereoisomer thereof, W is CH or N, X １ -O-, -S-, -NR ３ - and R ａ , R ｂ They are independent of each other, hydrogen or C １－４ Alkyl, or R ａ One of them is X １ NR ３ If that is the case, X １ Together they form a ring - (CH ２ ) ｐ - and R ａ One of them is R ２ Together they form a ring - (CH ２ ) ｐ - and R ｃ , R ｄ They are independent of each other, hydrogen or C １－４ It is alkyl, R １ is H or F, R ２ is hydrogen or C １－４ Alkyl or R ３ It forms a ring together with R ａ Forms a ring with one of them - (CH ２ ) ｑ - and R ３ is hydrogen or C １－４ Alkyl, preferably hydrogen or methyl, or R ２ Together they form a ring - (CH ２ ) ｐ - and m is 1, 2, or 3. n is 0, 1, or 2. p is either 1 or 2, q is 0, 1 or 2, and Ar １ is either unsubstituted or halogen, -CF ３ , 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-C ６ Ariel, C １－６ Alkoxy-C ５－６ Heteroaryl, amino, amino C １－４ Alkyl, C １－６ Alkylamino, C １－６ Aminoalkyl-C ６ Ariel, C １－６ Aminoalkyl-C ５－６ Heteroaryl, C １－６ Alkoxycarbonyl, C １－６ Alkoxyaminocarbonyl, aryl C １－６ Alkoxy, or C ６ The compound according to any one of claims 1 to 64, which is a six-membered aryl substituted with one or more groups selected from aryl groups.

66. Ar １ However, it is the compound of formula i, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Chemistry 17】 During the ceremony, R ４ 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-C ６ Ariel, C １－６ Alkoxy-C ５－６ Heteroaryl, amino C １－４ Alkyl, C １－６ Alkylamino, C １－６ Aminoalkyl-C ６ Ariel, C １－６ Aminoalkyl-C ５－６ Heteroaryl, C １－６ Alkoxycarbonyl, C １－６ Alkoxyaminocarbonyl, aryl C １－６ Alkoxy, or C ６ It is Ariel, R ５ , R ５ ', R ６ , R ６ ' are independent of each other, hydrogen, -CF ３ The compound according to any one of claims 1 to 65, or a halogen, preferably F or Cl.

67. Ar １ However, the compound is of formula ii-1, ii-2, ii-3, or ii-4, or a pharmaceutically acceptable salt or stereoisomer thereof. [Chemistry 18] During the ceremony, X ２ is O, NH, or NMe, X ３ is CH or N, o is either 0 or 1, R ４ is hydrogen or a halogen, preferably F or Cl, and R ５ , R ５ ', R ６ , R ６ ' are independent of each other, hydrogen, -CF ３ Alternatively, a halogen, preferably F or Cl, R ７ The compound according to any one of claims 1 to 66, wherein is hydrogen or a halogen, preferably F.

68. Ar １ is a compound of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, or a pharmaceutically acceptable salt or stereoisomer thereof, 【Chemistry 19】 During the ceremony, X ３ is CH or N, preferably N. o is either 0 or 1, R ４ is hydrogen or halogen, preferably F or Cl. R ５ , R ６ These are, independently of each other, hydrogen, -CF ３ , or halogen, preferably F or Cl, R ７ The compound according to any one of claims 1 to 67, wherein is hydrogen or a halogen, preferably F.

69. Ar １ This is formula iv-1, iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Chemistry 20】 During the ceremony, o is either 0 or 1, R ４ is hydrogen or halogen, preferably F or Cl. R ５ , R ５ ', R ６ , R ６ ' are independent of each other, hydrogen, -CF ３ Alternatively, a halogen, preferably F or Cl, R ７ The compound according to any one of claims 1 to 68, wherein is hydrogen or a halogen, preferably F.

70. Compounds of formula IIa or formula IIb, 【Chemistry 21】 or a pharmaceutically acceptable salt or stereoisomer thereof, X １ is -O- or -NR ３ - and R １ is H or F, R ２ is hydrogen or C １－４ Alkyl, preferably methyl, or R ３ Together they form a ring - (CH ２ ) ｑ - and R ３ is hydrogen or C １－４ Alkyl, preferably hydrogen or methyl, or R ２ Together they form a ring - (CH ２ ) ｐ - and m is 1, 2, or 3. n is 0, 1, or 2. p is either 1 or 2, q is 0, 1, or 2. r is either 0 or 1, s is 1 or 2, and Ar １ is either unsubstituted or halogen, -CF ３ , 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-C ６ Ariel, C １－６ Alkoxy-C ５－６ Heteroaryl, amino, amino C １－４ Alkyl, C １－６ Alkylamino, C １－６ Aminoalkyl-C ６ Ariel, C １－６ Aminoalkyl-C ５－６ Heteroaryl, C １－６ Alkoxycarbonyl, C １－６ Alkoxyaminocarbonyl, aryl C １－６ Alkoxy, or C ６ The compound according to any one of claims 1 to 69, wherein the compound is a six-membered aryl substituted with one or more groups selected from aryl groups.

71. Compound of formula III, 【Chemistry 22】 or a pharmaceutically acceptable salt or stereoisomer thereof, R １ is H or F, Ar １ is unsubstituted or is substituted with one or more of the groups selected from halogen, -CF ３ , 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-C ６ aryl, C １－６ alkoxy-C ５－６ heteroaryl, amino, amino C １－４ alkyl, C １－６ alkylamino, C １－６ aminoalkyl-C ６ aryl, C １－６ aminoalkyl-C ５－６ heteroaryl, C １－６ alkoxycarbonyl, C １－６ alkoxyaminocarbonyl, or C ６ aryl, and is a 6-membered aryl substituted with one or more of the groups selected therefrom Z is a compound according to any one of claims 1 to 70, selected from the following: 【Chemistry 23】

72. Compound of formula IV, 【Chemistry 24】 or a pharmaceutically acceptable salt or stereoisomer thereof, R １ is H or F, R ４ 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-C ６ Ariel, C １－６ Alkoxy-C ５－６ Heteroaryl, amino C １－４ Alkyl, C １－６ Alkylamino, C １－６ Aminoalkyl-C ６ Ariel, C １－６ Aminoalkyl-C ５－６ Heteroaryl, C １－６ Alkoxycarbonyl, C １－６ Alkoxyaminocarbonyl, or C ６ It is Ariel, R ５ , R ５ ', R ６ , R ６ ' are independent of each other, hydrogen, -CF ３ Alternatively, a halogen, preferably F or Cl, Z is a compound according to any one of claims 1 to 71, selected from the following: 【Chemistry 25】

73. Compounds of formula V-1, V-2, V-3, or V-4, 【Chemistry 26】 or a pharmaceutically acceptable salt or stereoisomer thereof, R １ is H or F, X ２ is O, NH, or NMe, X ３ is C or N, o is either 0 or 1, R ４ is hydrogen or halogen, preferably F or Cl. R ５ , R ５ ', R ６ , R ６ ' are independent of each other, hydrogen, -CF ３ Alternatively, a halogen, preferably F or Cl, R ７ is hydrogen or halogen, preferably F. Z is a compound according to any one of claims 1 to 72, selected from the following: 【Chemistry 27】

74. Compounds of formula VI-1, VI-2, VI-3, or VI-4, 【Chemistry 28】 or a pharmaceutically acceptable salt or stereoisomer thereof, R １ is H or F, X ２ is O, NH, or NMe, X ３ is C or N, o is either 0 or 1, R ４ is hydrogen or halogen, preferably F or Cl. R ５ , R ６ These are, independently of each other, hydrogen, -CF ３ , or halogen, preferably F or Cl, R ７ is hydrogen or halogen, preferably F. Z is a compound according to any one of claims 1 to 73, selected from the following: 【Chemistry 29】

75. Compounds of formula VII-1, VII-2, VII-3, or VII-4, VII-5, VII-6, VII-7, VII-8, or VII-9, 【Transformation 30】 or a pharmaceutically acceptable salt or stereoisomer thereof, R １ is H or F, o is either 0 or 1, R ４ is hydrogen or halogen, preferably F or Cl. R ５ , R ６ These are, independently of each other, hydrogen, -CF ３ , or halogen, preferably F or Cl, R ７ is hydrogen or halogen, preferably F. Z is a compound according to any one of claims 1 to 74, selected from the following: 【Chemistry 31】

76. A compound according to any one of claims 1 to 75, selected from the compounds listed in Tables 1 and 2, pharmaceutically acceptable salts thereof, and stereoisomers.

77. A composition comprising a compound according to any one of claims 1 to 76, and a pharmaceutically acceptable carrier.

78. A method for inhibiting an oncogenic variant of the ErbB receptor, comprising administering a therapeutically effective amount of the compound described in any one of claims 1 to 77 to a subject in need of such inhibition.

79. A method for preventing or treating cancer, comprising administering a therapeutically effective amount of a compound described in any one of claims 1 to 78 to a subject in need thereof.

80. A compound according to any one of claims 1 to 76, for use in the prevention or treatment of cancer.

81. A compound according to any one of claims 1 to 76, for use in inhibiting oncogenic variants of the ErbB receptor.

82. The method or compound according to any one of claims 1 to 81, wherein the cancer is a solid tumor.

83. The method or compound according to any one of claims 1 to 82, wherein the cancer is bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, gliablastoma (GBM), head and neck cancer, lung cancer, non-small cell lung cancer (NSCLC), or any subtype thereof.

84. The method or compound according to any one of claims 1 to 83, wherein the cancer is gliablastoma (GBM) or any subtype thereof.

85. The method or compound according to any one of claims 1 to 84, wherein the cancer is a gliablastoma.

86. The method or compound according to any one of claims 1 to 85, wherein the cancer, tumor, or its cells express an oncogenic variant of the ErbB receptor.

87. The method or compound according to any one of claims 1 to 86, wherein the oncogenic variant of the ErbB receptor comprises an allosteric mutation.

88. The method or compound according to any one of claims 1 to 87, wherein the oncogenic variant of the ErbB receptor is an allosteric variant of the ErbB receptor.

89. The method or compound according to any one of claims 1 to 88, wherein the oncogenic variant or oncogenic mutation is detected by a diagnostic method approved by the Food and Drug Administration (FDA).

90. A method for preventing or treating gliablastoma, comprising administering a therapeutically effective amount of a compound described in any one of claims 1 to 89 to a subject in need of such treatment.

91. A compound according to any one of claims 1 to 89, for use in the prevention or treatment of gliablastoma.

92. The method or compound according to any one of claims 1 to 91, wherein the compound is selected from the compounds listed in Tables 1 and 2, pharmaceutically acceptable salts thereof, and stereoisomers.

93. The method or compound according to any one of claims 1 to 92, wherein the compound is selected from the compounds listed in Tables 1 and 2, and pharmaceutically acceptable salts thereof.

94. The method or compound according to any one of claims 1 to 93, wherein the compound is selected from the compounds listed in Tables 1 and 2.

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