Alkynylquinazoline Compounds

Abstract

To provide new compounds as inhibitors of receptor tyrosine kinases (RTK) in specific oncogenic mutants of ErbB-receptors.SOLUTION: The present disclosure relates to compounds of formula (I'), [wherein W is CH or N, and Z, T, and Ar1 each represent a specific group], and pharmaceutically acceptable salts and stereoisomers thereof.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] This disclosure relates to novel compounds as inhibitors of receptor tyrosine kinases (RTKs) in certain oncogenic mutants of ErbB receptors. This disclosure also relates to methods for preparing these compounds, compositions containing these compounds, and methods for their use in preventing or treating abnormal cell growth in mammals, particularly humans. [Background technology]

[0003] Mutations affecting either the intracellular catalytic domain or the extracellular ligand-binding domain of ErbB receptors can result in oncogenic activity. (The ErbB protein family consists of four members, including ErbB-1, also known as epidermal growth factor receptor (EGFR), and Erb-2, also known as HER2, in humans.) ErbB inhibitors are known treatments for some cancers. However, not all patients respond adequately to this treatment. Thus, there is a long-felt need in the art for new therapies that can address the variable responsiveness of cancer patients to known therapies. The present disclosure provides compositions and methods for preventing or treating cancer in patients with these oncogenic mutations without the variability in response observed when patients with these ErbB variants are treated using existing standard therapies. Summary of the Invention

[0004] In some aspects, the present disclosure provides a compound of formula (I'): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, W is CH or N; Z is one or more R Z is a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Z are independently selected from 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 3- C 10 Cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, and is selected from the group consisting of -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 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Za optionally replaced by Each R Za are independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R Tare independently selected from 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 3- C 10 Cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, and is selected from the group consisting of -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 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Ta optionally replaced by Each R Ta are independently selected from halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; Ar 1 is one or more R A1 C6-C optionally substituted with 10 is aryl, Each R A1 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 10Aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, and is selected from the group consisting of -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 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R A1a optionally replaced by Each R A1a are independently selected from 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 3- C 10 Cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, and is selected from the group consisting of -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 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R A1b optionally replaced by, and Each R A1b are independently halogen, CN, —OH, or —NH 2 .

[0005] In some aspects, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof: [ka] During the ceremony, W is CH or N, preferably CH; X 1 is -O-, -S-, or -NR 3 - and R a , Rb are independently hydrogen or C 1-4 alkyl, or R a One of the X 1 NR 3 If so, X 1 Forms a ring with -(CH2) p - or R a One of them is R 2 Forms a ring with -(CH2) p - and R c , R d are independently hydrogen or C 1-4 is alkyl, R 1 is H or F, R 2 is hydrogen or C 1-4 alkyl or R 3 Forms a ring with R a -(CH2) forms a ring with one of the q - and R 3 is hydrogen or C 1-4 alkyl, preferably hydrogen or methyl, or R 2 Forms a ring with -(CH2) p - and m is 1, 2 or 3; n is 0, 1 or 2; p is 1 or 2; q is 0, 1 or 2, and Ar 1 is unsubstituted or is 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 1-6Alkylamino, 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 It is a 6-membered aryl substituted with one or more groups selected from alkoxy, or C6 aryl.

[0006] In some embodiments, X 1 But, -NR 3 -If R 2 is not hydrogen.

[0007] In some embodiments, X 1 But-, NR 3 -If R 2 is C 1-4 alkyl or R 3 Forms a ring with R a -(CH2) forms a ring with one of the q -It is.

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

[0009] In some embodiments, X 1 Ha-, NR 3 - and R 2 is C 1-4 alkyl or R 3 Forms a ring with R a -(CH2) forms a ring with one of the q -It is.

[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 is hydrogen.

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

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

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

[0016] In some embodiments, Ar 1 is a 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 alkoxy, or C6 aryl; R 5 , R 5’ , R 6 , R 6’ are, independently of one another, hydrogen, —CF3 or halogen, preferably F, Cl.

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

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

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

[0020] In some embodiments, Ar 1 is of 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 0 or 1, R 4 is hydrogen or halogen, preferably F or Cl, R 5 , R 5 ', R 6 , R 6 ' are independently of each other hydrogen, -CF3 or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F.

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

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

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

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

[0025] In some embodiments, Ar 1is 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; [ka] During the ceremony, X 3 is CH or N, o is 0 or 1, R 4 is hydrogen or halogen, preferably F or Cl, R 5 , R 6 are, independently of one another, hydrogen, —CF or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F.

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

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

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

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

[0030] In some embodiments, Ar 1is 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; [ka] During the ceremony, X 3 is C or N, preferably N, o is 0 or 1, R 4 is hydrogen or halogen, preferably F or Cl, R 5 , R 6 are, independently of one another, hydrogen, —CF or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F.

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

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

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

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

[0035] In some embodiments, Ar1 is of 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 0 or 1, R 4 is hydrogen or halogen, preferably F or Cl, R 5 , R 6 are, independently of one another, hydrogen, —CF or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F.

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

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

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

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

[0040] In some embodiments, the disclosure provides a compound of Formula IIa or IIb, or a pharmaceutically acceptable salt or stereoisomer thereof: [ka] During the ceremony, 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 Forms a ring with -(CH2) q - and R 3 is hydrogen or C 1-4 alkyl, preferably hydrogen or methyl, or R 2 Forms a ring with -(CH2) p - and m is 1, 2 or 3; n is 0, 1 or 2; p is 1 or 2; q is 0, 1 or 2; r is 0 or 1, s is 1 or 2, and Ar 1 is unsubstituted or is 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, C1-6 Alkoxycarbonyl, C 1-6 Alkoxyaminocarbonyl, Aryl C 1-6 It is a 6-membered aryl substituted with one or more groups selected from alkoxy, or C6 aryl.

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

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

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

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

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

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

[0047] In some embodiments, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or stereoisomer thereof: [ka] During the ceremony, R 1 is H or F, Ar 1 is unsubstituted or is 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, or a 6-membered aryl substituted with one or more groups selected from C6 aryl, and Z is selected from: [ka]

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

[0049] In some embodiments, the present disclosure provides a compound of Formula IV, or a pharmaceutically acceptable salt or stereoisomer 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 alkoxyaminocarbonyl, or C6 aryl; R 5 , R 5 ', R 6 , R 6 ' are independently of each other hydrogen, -CF3 or halogen, preferably F or Cl, and Z is selected from: [ka]

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

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

[0052] In some embodiments, the present disclosure provides a compound of the following formula V-1, V-2, V-3, or V-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, R 1 is H or F, R 4 is hydrogen or halogen, preferably F or Cl, R 5 , R 5 ', R 6 , R 6 ' are independently of each other hydrogen, -CF3 or halogen, preferably F or Cl, o is 0 or 1, R 7 is hydrogen or halogen, preferably F, and Z is selected from: [ka]

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

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

[0055] In some embodiments, the disclosure provides a compound of the following formula VI-1, VI-2, VI-3, or VI-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, R 1 is H or F, o is 0 or 1, R 4is hydrogen or halogen, preferably F or Cl, R 5 , R 6 are, independently of one another, hydrogen, —CF or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F, and Z is selected from: [ka]

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

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

[0058] In some embodiments, the present disclosure provides a compound of formula VII-1, VII-2, VII-3 or VII-4, VII-5, VII-6, VII-7, VII-8 or VII-9, or a pharmaceutically acceptable salt or stereoisomer thereof: [ka] During the ceremony, R 1 is H or F, o is 0 or 1, R 4 is hydrogen or halogen, preferably F or Cl, R 5 , R 6 are, independently of one another, hydrogen, —CF or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F, Z is selected from: [ka]

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

[0060] In some embodiments, R 1 is hydrogen. In certain embodiments, R 7 is F.

[0061] In some aspects, the present disclosure is directed to compositions comprising a compound according to 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 therapeutically active agent.

[0064] In some aspects, the present disclosure is directed to a method of inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of EGFR), comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0065] In some aspects, the present disclosure is directed to a method of inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of EGFR), comprising administering to a subject in need thereof a composition described herein.

[0066] In some aspects, the present disclosure is directed to a method of preventing or treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0067] In some aspects, the present disclosure is directed to methods of preventing or treating cancer, comprising administering to a subject in need thereof a composition described herein.

[0068] In some aspects, the present disclosure is directed to compounds described herein for use in inhibiting oncogenic variants of ErbB receptors (eg, oncogenic variants of EGFR).

[0069] In some aspects, the present disclosure is directed to a compound described herein for use in the prevention or treatment of cancer.

[0070] In some aspects, the present disclosure is directed to a composition described herein for use in inhibiting an oncogenic variant of an ErbB receptor (eg, an oncogenic variant of EGFR).

[0071] In some aspects, the present disclosure is directed to a composition described herein for use in the prevention or treatment of cancer.

[0072] In some aspects, the present disclosure is directed to the use of a compound described herein in the manufacture of a medicament for inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of EGFR).

[0073] In some aspects, the present disclosure is directed to the use of a compound described herein in the manufacture of a medicament for preventing or treating cancer.

[0074] In some embodiments, the cancer is glioblastoma.

[0075] In some aspects, the present disclosure is directed to a method of preventing or treating glioblastoma, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described in any of the embodiments described herein.

[0076] In some aspects, the present disclosure is directed to a compound according to any of the embodiments described herein for use in the prevention or treatment of glioblastoma.

[0077] In some aspects, the present disclosure is directed to a method of preventing or treating glioblastoma, the method comprising administering to a subject in need thereof a composition described in any of the embodiments described herein.

[0078] In some aspects, the present disclosure is directed to a composition according to any of the embodiments described herein for use in the prevention or treatment of glioblastoma. DETAILED DESCRIPTION OF THE INVENTION

[0079] The present disclosure relates to compounds useful as receptor tyrosine kinase (RTK) inhibitors of specific oncogenic mutants of ErbB receptors. In some embodiments of the present invention, the oncogenic mutants of ErbB receptors are also allosteric mutants of ErbB receptors. In some embodiments, the allosteric mutants may comprise or consist of ErbB receptor variants having mutations in sequences outside the ATP-binding site. In some embodiments, the allosteric mutants may comprise or consist of ErbB receptor variants having mutations 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 ErbB receptors can result in oncogenic activity. (The ErbB protein family consists of four members, including ErbB-1, also known as epidermal growth factor receptor (EGFR), and Erb-2, also known as HER2 in humans.) Extracellular variants of ErbB receptors in cancer, including EGFR-VIII (also EGFR-V3) and HER2-S310F, are constitutively activated in the absence of ligand, exhibit persistent signaling that is resistant to downregulation, and are both transforming and tumorigenic (Nishikawa, Ji et al. 1994, 2013; Francis, Zhang et al. 2014). Their expression is associated with metastasis and poor long-term overall survival.

[0081] In glioblastoma (also known as glioblastoma multiforme or GBM), EGFR-VIII is expressed by 20% of tumors (Sugawa, Ekstrand et al. 1990, Brennan, Verhaak et al. 2013). EGFR-VIII expression in GBM tends to be mutually exclusive with that of other RTK oncogenes, which are co-expressed with EGFR variants in only 7% of GBM tumors (Furnari, Cloughesy et al. 2015). These data demonstrate how EGFR-VIII has a predominant and mutually exclusive expression pattern in GBM compared with other oncogenic drivers. EGFR-VIII is also expressed by approximately 30% of SCCHN tumors (Sok, Coppelli et al. 2006; Keller, Shroyer et al. 2010; Wheeler, Suzuki et al. 2010; Tinhofer, Klinghammer et al. 2011; Wheeler, Egloff et al. 2015) and 10% of squamous NSCLC (Ji, Zhao et al. 2006; Sasaki, Kawano et al. 2007) and is associated with resistance to current 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 only one of several aberrantly spliced ​​variants of EGFR was expressed in GBM tumors. The other two resulted in truncation of exons 12-13 (EGFR-Vvi) and 14-15 (EGFR-Vii). Like EGFR-Viii, EGFR-Vii is both transforming and tumorigenic. In addition to splice variants, GBM tumors also express a group of EGFR point mutations, including C620Y, A289V, and G598V, which are transforming and tumorigenic.

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

[0084] Short insertions within exon 20 of EGFR and HER2 are expressed by lung adenocarcinoma tumors and a range of other tumors. ErbB exon 20 insertion variants are expressed by 4-5% of lung adenocarcinoma tumors. Examples include HER2-YVMA, EGFR-SVD, and EGFR-NPH. These ErbB exon 20 insertion variants are highly oncogenic, transforming BaF3 cells into an IL-3-independent state and promoting tumor growth in vivo.

[0085] ErbB inhibitor is a known treatment for some cancers.However, not all patients respond well to this treatment.Therefore, there is a long-standing need in the art for new therapies that can address the variable response of cancer patients to known therapies.The present invention can overcome some of the shortcomings of standard treatment that exist before the development of the compositions and methods disclosed herein.

[0086] Paradoxical ErbB receptor activation Although the mechanisms described herein apply to any form of cancer in which these EGFR variants of the present disclosure are expressed, the prevalence of these variants in glioblastoma (GBM) is provided as an example. Other cancers that express the EGFR variants of the present 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, glioblastoma (GBM), head and neck cancer, lung cancer, and non-small cell lung cancer (NSCLC).

[0087] In GBM tumors, EGFR is frequently the target of genomic mutations and alternative splicing events that result in changes in the extracellular dimer interface. Many tumors express two or more abnormal 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 results from a unique ectodomain 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 has no activity 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 not 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 ectodomain point mutants from treatment with EGFR-Viii-selective therapy.

[0089] The heterogeneous genotypic expression patterns of multiple ectodomain variants of ErbB receptors in tumors suggest that small-molecule inhibitors that inhibit all variants are preferable. The family of covalently activated EGFR isoforms responds very differently to small-molecule ErbB inhibitors compared with EGFR catalytic domain mutations observed in NSCLC. Importantly, all type I inhibitors, including erlotinib, induce the formation of covalent EGFR dimers, increasing EGFR phosphorylation at subsaturating concentrations, an activity that is further enhanced when the ErbB inhibitor is washed out. This manifests as a paradoxical activation of proliferation at subsaturating concentrations.

[0090] The finding of paradoxical activation of proliferation at subsaturating concentrations of type I ErbB inhibitors was further demonstrated for a series of extracellular variants of HER2 that are prevalent in several cancers, including breast and bladder. The levels of all variants present 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, subsaturating doses of type I inhibitors paradoxically increased the phosphorylation of HER2 variants and increased proliferation of cells expressing them.

[0091] In contrast to type I inhibitors, the present disclosure demonstrates that non-type I (e.g., type II) inhibitors, including neratinib, lack paradoxical activation in cells expressing ErbB ectodomain variants. Neratinib has been found to exemplify a preferred molecule that is both potent and selective for covalently activated members of the EGFR family compared to wild-type EGFR.

[0092] In summary, this disclosure provides structure / function relationships for predicting how structural variations affecting receptor regions distal to the active site can 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 important clinical implications. The data disclosed provide a mechanistic explanation for the failed clinical trials of type I inhibitors in tumor types with widespread expression of covalently activated ErbB receptors. This includes erlotinib and gefitinib in GBM tumors, erlotinib in SCCHN tumors, and sapitinib in breast tumors.

[0093] Glioblastoma Glioblastoma (GBM), a grade IV astrocytoma, is the most common form of brain cancer. The disease has a poor outcome. Surgery followed by radiation and temozolomide is the standard of care, but this regimen results in a median overall survival (OS) of only 14.6 months, with most patients not surviving for 5 years. Over the past decade, there has been little progress in extending survival for GBM patients. In the recurrent setting, bevacizumab has demonstrated an improved progression-free survival benefit, but the addition of bevacizumab to standard-of-care therapy in the frontline setting did not confer 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 aberrant splicing or genomic mutations. The first recognized variant, EGFR-VIII, results from truncation of exons 2-7 and is expressed by approximately 20% of GBM tumors. EGFR-VIII is oncogenic. EGFR-VIII is constitutively activated in the absence of EGF ligand and exhibits persistent signaling that is resistant to downregulation. Thus, EGFR-VIII is both transforming and tumorigenic. EGFR-VIII expression is associated with poor long-term overall survival in GBM.

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

[0096] Because expression of multiple EGFR variants in GBM results in transforming and tumorigenic activity, and because EGFR is the most frequently altered oncogene present in GBM tumors, EGFR is a particularly attractive target for small-molecule ErbB inhibitors. Following the success of small-molecule EGFR therapeutics (erlotinib, gefitinib, and afatinib) against NSCLC tumors harboring activating mutations in EGFR, these drugs were tested in GBM. Despite intensive clinical investigation of this group of ErbB inhibitors in GBM, involving >30 clinical trials and >1500 patients, all have failed to provide any benefit, even for those tumors expressing EGFR-VIII. Surprisingly, some evidence suggests that erlotinib accelerated disease progression. A phase II trial evaluating erlotinib in combination with radiation and temozolomide demonstrated a median progression-free survival (mPFS) and median overall survival (mOS) of 2.8 and 8.6 months, compared with 6.9 and 14.6 months for patients receiving radiation and temozolomide alone. Another randomized phase II trial using erlotinib demonstrated that patients receiving erlotinib, including those whose tumors expressed EGFR-VIII, were less likely to progress than patients receiving standard therapy. 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 led to speculation as to why ErbB inhibitors, which have been highly effective in treating EGFR mutations in lung cancer, are so ineffective in treating EGFR variants in GBM.

[0097] A unique 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 intracellular domain dimerization and activation of receptor catalytic activity. Nearly 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. In EGFR-VIII, this cysteine ​​forms an intermolecular disulfide bond with another EGFR monomer, leading to a covalently dimerized, constitutively activated receptor. Mutation of cysteine ​​307 to serine (C307S) prevents the formation of covalently dimerized EGFR-VIII, which is inactive.

[0098] Some recent preclinical studies have suggested that EGFR kinase inhibitors such as erlotinib are not very effective in inhibiting EGFR-VIII, but there is no proposed mechanism for this effect.Currently, there is also a lack of understanding about the mechanisms involved in the activation of other ectodomain variants in GBM, including EGFR-Vii and EGFR-A289V.This disclosure provides the receptor activation mechanisms and the impact on ErbB inhibitor activity of the four most common ectodomain variants in GBM: EGFR-VIII, EGFR-Vii, EGFR-Vvi, EGFR-G598V and EGFR-A289V.

[0099] The present disclosure demonstrates that, like EGFR-Viii, an additional group of EGFR variants commonly occurring in GBM (EGFR-Vii, EGFR-Vvi, EGFR-G598V, and EGFR-A289V) all exist as constitutively active covalent dimers, together forming a family of EGFR isoforms activated by this common mechanism. Furthermore, the present disclosure demonstrates that the propensity 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 the kinase (including the type I inhibitor, erlotinib) induce covalent dimer formation for all covalently activated EGFR isoforms. This correlates with the tendency of type I inhibitors to increase EGFR phosphorylation at subsaturating concentrations, paradoxically stimulating proliferation of cells expressing covalently activated EGFR isoforms.

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

[0101] Similar to the mutations identified for EGFR, the present disclosure identifies a group of splice events and mutations affecting the CR domains of HER2 and HER4. The present 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 mode drugs. These data provide a mechanistic explanation for the failure of multiple clinical trials involving type I inhibitors, including more than 30 clinical trials of type I ErbB inhibitors in GBM. Collectively, these data indicate 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 utility of optimizing type II ErbB inhibitors against the covalently activated ErbB family.

[0102] definition Unless otherwise specified, the following general definitions apply to the compounds of this disclosure by way of illustration.

[0103] As used herein, the term "compound of the present disclosure" refers to a compound represented by any of the formulas described herein (e.g., Formulas (I')-(IV') and Formulas (I)-(VII)), and any of the specific examples disclosed herein.

[0104] However, it is understood that the compounds disclosed herein can be represented by one particular structure. Such a particular structure should not be construed as being limited to one or another isomer, tautomer, positional isomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, positional isomers, 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, positional isomers, and stereoisomers of the compound, or any mixture thereof, while also referring to the particular structure of the compound.

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

[0106] As used herein, the term "isomer" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms 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 can exist as individual diastereomers or as a mixture of diastereomers called a "diastereomeric mixture." When one chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked 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" refers to diastereomers whose presence hinders rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations differ in their designation by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite sides of the double bond in the molecule, according to the Cahn-Ingold-Prelog rules.

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

[0111] Dashed lines (or waves perpendicular to a bond) are further understood to indicate the binding site (ie, subformula) of a residue.

[0112] As used herein, the term "halogen" or "hal" may be fluoro, chloro, bromo, or iodo, 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 C1, C2, C3, C4, C5 or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups, and C3, C4, C5 or C6 branched-chain saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl include, but are not limited to, 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, a straight-chain or branched-chain alkyl has 6 or fewer carbon atoms (e.g., C for straight chain). 1- C6, C for branched chain 3- C6), and in another embodiment, the straight or branched chain alkyl has 4 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 1, 2, 3, or 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl.

[0114] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl or an alkyl in which specified substituents replace one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, 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, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0115] As used herein, the term "alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched-chain alkenyl groups. In certain embodiments, a straight-chain or branched-chain alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkenyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkenyl groups containing 3 to 6 carbon atoms.

[0116] As used herein, the term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or an alkenyl in which specified substituents replace one or more hydrogen atoms on one or more hydrocarbon backbone carbons. Such substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, 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, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0117] As used herein, the term "alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, the term "alkynyl" includes straight-chain alkynyl groups (e.g., erynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and branched-chain alkynyl groups. In certain embodiments, a straight-chain or branched-chain alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkynyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkynyl groups containing 3 to 6 carbon atoms. As used herein, a "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to include a C2, C3, C4, C5, or C6 chain (straight or branched) divalent unsaturated aliphatic hydrocarbon group. For example, a C2-C6 alkenylene linker is intended to include a C2, C3, C4, C5, or C6 alkenylene linker group.

[0118] As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl or an alkynyl in which specified substituents replace one or more hydrogen atoms on one or more hydrocarbon backbone carbons. Such substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, 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, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0119] Other optionally substituted moieties (e.g., optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both unsubstituted moieties and moieties with one or more of the specified substituents. For example, substituted heterocycloalkyl includes 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 linked 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 a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, adamantyl, and hexahydroindacenyl. For polycyclic (e.g., fused, bridged, or spirocyclic) systems, it is understood that only one of the rings therein need be non-aromatic.

[0122] As used herein, the term "aryl" refers to a group having aromatic character, including "conjugated" or polycyclic systems having one or more aromatic rings, and 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, naphthyl, and the like. In some embodiments, aryl is phenyl.

[0123] As used herein, the term "heterocycloalkyl," unless otherwise specified, refers to a saturated or partially unsaturated 3- to 8-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spirocyclic), or 11- to 14-membered tricyclic ring system (fused, bridged, or spirocyclic) having one or more heteroatoms (e.g., O, N, S, P, or Se) independently selected from the group consisting of nitrogen, oxygen, and sulfur, e.g., 1, 1-2, 1-3, 1-4, 1-5, or 1-6 heteroatoms, e.g., 1, 2, 3, 4, 5, or 6 heteroatoms.Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-tetrahydro ... -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'-isobenzyl] benzofuran]-yl, 7'H-spiro[cyclohexane-1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo [3,4-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-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like. In the case of polycyclic heterocycloalkyls, only one of the rings in the heterocycloalkyl need be non-aromatic.In some embodiments, heterocycloalkyl is oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-5-azaspiro[3.4]octanyl, 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.

[0124] As used herein, the term "heteroaryl" is intended to include a stable 5-, 6-, or 7-membered monocyclic, or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic heteroaromatic ring consisting of carbon atoms and one or more heteroatoms independently selected from the group consisting of, for example, nitrogen, oxygen, and sulfur, e.g., 1, or 1-2, or 1-3, or 1-4, or 1-5, or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituent as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O, and S(O)). p, where 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 (fully) 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, wherein the number of N atoms is preferably 0, 1, 2, or 3, and the number of O and S atoms is 0, 1, or 2, respectively. Examples of "heteroaryl" include furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl), pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl, etc. A preferred example of "heteroaryl" is pyridinyl.

[0125] In some embodiments, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may have at one or more ring positions (e.g., a ring carbon or a heteroatom, e.g., N) a substituent such as those described above, e.g., alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl In some embodiments, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with a halogen atom, an alkyl group ...

[0126] As used herein, the term "substituted" means that any one or more hydrogen atoms on the designated atom are replaced with a group selected from the designated group, provided that the normal valence of the designated atom is not exceeded and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =0), two hydrogen atoms on the atom are replaced. Keto substituents do not occur 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 interchangeably herein to refer to single- or double-stranded RNA, DNA, or mixed polymers. Polynucleotides can include genomic sequences, extragenomic and plasmid sequences, and smaller engineered gene segments that express or can be adapted to express a polypeptide.

[0128] An "isolated nucleic acid" is a nucleic acid that is substantially separated from other genomic DNA sequences and proteins or complexes, such as ribosomes and polymerases, that naturally accompany the native sequence. The term encompasses nucleic acid sequences that have been removed from their naturally occurring environment, including recombinant or cloned DNA isolates, as well as chemically synthesized analogs or biologically synthesized analogs produced in heterologous systems. A substantially pure nucleic acid includes isolated forms of nucleic acid. Of course, this refers to the original isolated nucleic acid, but does not exclude genes or sequences later added to the isolated nucleic acid by the hand of man.

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

[0130] An "isolated polypeptide" is one that has been identified and separated and / or recovered from a component of its natural environment. In preferred embodiments, an isolated polypeptide is purified (1) to greater than 95% by weight, and most preferably greater than 99% by weight, of the polypeptide as determined by the Lowry method; (2) to an extent sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence using a spinning cup sequencer; or (3) to homogeneity by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue, or preferably silver staining. Isolated polypeptides include polypeptides in situ within recombinant cells, since at least one component of the polypeptide's natural environment will be absent. Ordinarily, however, isolated polypeptides will be prepared by at least one purification step.

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

[0132] A "variant" of a polynucleotide, as that term is used herein, is a polynucleotide that typically differs from the polynucleotides specifically disclosed herein in one or more substitutions, deletions, additions, and / or insertions.

[0133] A "variant" of a polypeptide, as that term is used herein, is a polypeptide that typically differs from a polypeptide specifically disclosed herein in one or more substitutions, deletions, additions, insertions, or inversions. Such variants may be naturally occurring, non-naturally occurring, or synthetically produced.

[0134] Mutations (or variants) of EGFR of the present disclosure can include one or more substitutions, deletions, additions, and / or insertions, or inversions in the amino acid sequence that alter the function of the resulting protein. Mutations can be detected, for example, by comparison or alignment of the 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 the nucleotide or amino acid sequences in the two sequences are the same when aligned for maximum correspondence, as described below.Comparison between two sequences is typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity.As used herein, a "comparison window" refers to a segment of at least about 20 consecutive positions, usually 30 to about 75, 40 to about 50 consecutive positions, within which the two sequences can be optimally aligned and compared with 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) using default parameters, which embodies 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, the identity alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, the search for similarity method of Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85:2444, computer-implemented algorithms (GAP, BESTFIT, BLAST, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group (GCG), 575 Science Dr., Madison, WI), or by visual inspection.

[0138] One preferred example of algorithms suitable for determining percent sequence identity and percent sequence similarity are 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, with the parameters described herein to determine percent sequence identity of the polynucleotides and polypeptides of the invention. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information.

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

[0140] For amino acid sequences, a score matrix may be used to calculate the cumulative score. Extension of word hits in each direction is halted when the cumulative alignment score falls off by the amount X from its maximum achieved value, when the cumulative score falls below zero due to the accumulation of one or more negative-scoring residue alignments, or when either sequence reaches its end. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment.

[0141] In one method, "percent sequence identity" is determined by comparing two optimally aligned sequences over a comparison window of at least 20 positions, where the portion of the polynucleotide or polypeptide sequence in 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 does not contain additions or deletions) due to optimal alignment of the two sequences. The percentage of sequence identity is calculated by determining the number of positions where the same nucleic acid base or amino acid residue occurs 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 to obtain the percentage of sequence identity.

[0142] The wild-type EGFR sequence of the present disclosure may comprise or 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, corresponds to epidermal growth factor receptor [Homo sapiens] and Genbank accession number CAA25240).

[0143] The wild-type HER2 receptor sequence of the present disclosure may comprise or consist of 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, corresponds 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 the present disclosure may comprise or consist of 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 the present disclosure may comprise or consist of 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 the present disclosure may comprise or consist of 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, corresponds 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 the present disclosure may comprise or consist of 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 provided throughout this application, one of ordinary skill in the art will know which combinations are synthetically feasible and practical, e.g., typical combinations of groups resulting in heteroatoms directly linked to each other are not contemplated.

[0149] Compounds of the Disclosure In some aspects, the present disclosure provides a compound of formula (I'): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, W is CH or N; Z is one or more R Z is a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Z are independently selected from 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 3- C 10 Cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, and is selected from the group consisting of -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 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Za optionally replaced by Each R Za are independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R T are independently selected from 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 3- C 10 Cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, and is selected from the group consisting of -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 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Ta optionally replaced by Each R Ta are independently selected from halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; Ar 1 is one or more R A1 C6-C optionally substituted with 10 is aryl, Each R A1 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 Aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, and is selected from the group consisting of -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 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R A1a optionally replaced by Each R A1a are independently selected from 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 3- C 10 Cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, and is selected from the group consisting of -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 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R A1b optionally replaced by, and Each R A1b are independently halogen, CN, —OH, or —NH 2 .

[0150] In some embodiments, the compound is of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH or N; Z is one or more R Zis a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Z are independently selected from 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 3- C 10 Cycloalkyl, C6-C 10 Aryl, or 5-10 membered heteroaryl, and is selected from the group consisting of -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C 10 Cycloalkyl, C6-C 10 Aryl, 3- or 5- to 10-membered heteroaryl may be one or more R Za optionally replaced by Each R Za are independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R T are independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10aryl, 3-7 membered heterocycloalkyl, or 5-10 membered heteroaryl; and -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 An aryl, a 3- to 7-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Ta is optionally replaced by Each R Ta are independently selected from halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; Ar 1 is one or more R A1 C6-C optionally substituted with 10 is aryl, Each R A1 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 selected from the group consisting of one or more R A1a optionally replaced by, and Each R A1a are independently halogen, CN, -OH, -NH, -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 selected from the group consisting of one or more R A1b optionally replaced by, and Each RA1b are independently halogen, CN, -OH, or -NH; However, Z is [ka] When Ar 1 is a C6-C optionally substituted with one or more halogens 10 It is aryl.

[0151] In some embodiments, the compound is of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH or N; Z is one or more R Z is a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Z are independently selected from 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 3- C 10 Cycloalkyl, C6-C 10 Aryl, or 5-10 membered heteroaryl, and is selected from the group consisting of -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C 10 Cycloalkyl, C6-C 10 Aryl, 3- or 5- to 10-membered heteroaryl may be one or more R Za optionally replaced by Each R Za are independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R T are independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3-7 membered monocyclic heterocycloalkyl, or 5-10 membered heteroaryl, and is selected from the group consisting of -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 An aryl, a 3- to 7-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Ta is optionally replaced by Each R Ta are independently selected from halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; Ar 1 is one or more R A1 C6-C optionally substituted with 10 is aryl, Each R A1 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 selected from the group consisting of one or more R A1a optionally replaced by, and Each R A1a are independently halogen, CN, -OH, -NH, -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 selected from the group consisting of one or more R A1b optionally replaced by, and Each R A1b are independently halogen, CN, -OH, or -NH; However, Z is [ka] When Ar 1 is a C6-C optionally substituted with one or more halogens 10 It is aryl.

[0152] In some embodiments, the compound is a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is one or more R Z is a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Z are independently halogen, —O—(C1-C6 alkyl), C1-C6 alkyl, or 3-10 membered heterocycloalkyl, wherein —O—(C1-C6 alkyl), C1-C6 alkyl, or 3-10 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 the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R T are independently halogen, —OH, —O—(C1-C6 alkyl), —N(C1-C6 alkyl)2, or 3- to 7-membered heterocycloalkyl, wherein —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; Ar 1 is one or more R A1 C6-C optionally substituted with 10 is aryl, Each R A1 are independently halogen, -OR A1a , or one or more R A1a is —O—(C1-C6 alkyl) optionally substituted with Each R A1a independently, C6-C 10 aryl or 5- to 10-membered heteroaryl, C6-C 10 The aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogens.

[0153] In some embodiments, the compound is a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is one or more R Z is a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Z are independently halogen, —O—(C1-C6 alkyl), C1-C6 alkyl, or 3-10 membered heterocycloalkyl, wherein —O—(C1-C6 alkyl), C1-C6 alkyl, or 3-10 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 the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R T are independently halogen, —OH, —O—(C1-C6 alkyl), —N(C1-C6 alkyl)2, or 3- to 7-membered monocyclic heterocycloalkyl, wherein —O—(C1-C6 alkyl), —N(C1-C6 alkyl)2, or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more —C(═O)OH; Ar 1 is one or more R A1 C6-C optionally substituted with 10 is aryl, Each R A1 are independently halogen, -OR A1a , or one or more R A1a is —O—(C1-C6 alkyl) optionally substituted with Each R A1a independently, C6-C 10 aryl or 5- to 10-membered heteroaryl, C6-C 10 The aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogens.

[0154] In some embodiments, the compound is a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is one or more R Z is a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Z are independently halogen, —O—(C1-C6 alkyl), or C1-C6 alkyl, wherein —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 the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R T are independently halogen, —OH, —O—(C1-C6 alkyl), or 3- to 7-membered heterocycloalkyl, wherein —O—(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more —C(═O)OH; Ar 1 is one or more R A1 C6-C optionally substituted with 10 is aryl, Each R A1 are independently halogen, -OR A1a , or one or more R A1a is —O—(C1-C6 alkyl) optionally substituted with Each R A1a independently, C6-C 10 aryl or 5- to 10-membered heteroaryl, C6-C 10 the aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogens; However, Z is [ka] When Ar 1 is a C6-C optionally substituted with one or more halogens 10 It is aryl.

[0155] In some embodiments, the compound is a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is one or more R Z is a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Zare independently halogen, —O—(C1-C6 alkyl), or C1-C6 alkyl, wherein —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 the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R T are independently halogen, —OH, —O—(C1-C6 alkyl), or 3- to 7-membered monocyclic heterocycloalkyl, wherein —O—(C1-C6 alkyl) or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more —C(═O)OH; Ar 1 is one or more R A1 C6-C optionally substituted with 10 is aryl, Each R A1 are independently halogen, -OR A1a , or one or more R A1a is —O—(C1-C6 alkyl) optionally substituted with Each R A1a independently, C6-C 10 aryl or 5- to 10-membered heteroaryl, C6-C 10 the aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogens; However, Z is [ka] When Ar 1 is a C6-C optionally substituted with one or more halogens 10 It is aryl.

[0156] In some embodiments, the compound is a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is one or more RZ is a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Z are independently halogen, —O—(C1-C6 alkyl), or C1-C6 alkyl, wherein —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 the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R T are independently halogen, —OH, —O—(C1-C6 alkyl), or 3- to 7-membered heterocycloalkyl, wherein —O—(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more —C(═O)OH; Ar 1 is a C6-C optionally substituted with one or more halogens 10 It is aryl.

[0157] In some embodiments, the compound is a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is one or more R Z is a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Z are independently halogen, —O—(C1-C6 alkyl), or C1-C6 alkyl, wherein —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 the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R Tare independently halogen, —OH, —O—(C1-C6 alkyl), or 3- to 7-membered monocyclic heterocycloalkyl, wherein —O—(C1-C6 alkyl) or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more —C(═O)OH; Ar 1 is a C6-C optionally substituted with one or more halogens 10 It is aryl.

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

[0159] In some embodiments, the compound is a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is a 3- to 12-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyls; T is a C2-C6 alkenyl optionally substituted with one or more 6-membered monocyclic heterocycloalkyl; and Ar 1 is a C6 aryl 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 and R Z、 and R Za In some embodiments, Z is one or more R Z is a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Z are independently halogen, —O—(C1-C6 alkyl), C1-C6 alkyl, or 3-10 membered heterocycloalkyl, wherein —O—(C1-C6 alkyl), C1-C6 alkyl, or 3-10 membered heterocycloalkyl is optionally substituted with one or more halogens.

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

[0164] In some embodiments, Z is one or more R Z is a 3- to 12-membered heterocycloalkyl substituted with

[0165] In some embodiments, 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 the 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 selected from the group consisting of one or more R Z is optionally replaced by

[0166] In some embodiments, 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 the oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, 3-azabicyclo[3.1.0]hexanyl, 2-azaspiro[3.3]heptanyl, or 2-oxa-5-azaspiro[3.4]octanyl is selected from the group consisting of one or more R Z is optionally replaced by

[0167] In some embodiments, Z is [ka] is.

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

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

[0170] In some embodiments, Z is [ka] is.

[0171] In some embodiments, Z is [ka] is.

[0172] In some embodiments, Z is [ka] is.

[0173] In some embodiments, Z is [ka] is.

[0174] In some embodiments, Z is [ka] is.

[0175] In some embodiments, Z is [ka] is.

[0176] In some embodiments, Z is [ka] is.

[0177] In some embodiments, Z is [ka] is.

[0178] In some embodiments, Z is [ka] is.

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

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

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

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

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

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

[0185] In some embodiments, at least one R Z is -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, and is selected from the group consisting of -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, and one or more R Za is optionally replaced by

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

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

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

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

[0190] In some embodiments, at least one R Z is —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 selected from one or more R Za is optionally replaced by

[0192] In some embodiments, at least one R Z is one or more R Za is C1-C6 alkyl optionally substituted with

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

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

[0195] In some embodiments, at least one R Z is one or more R Za is a C1-C6 alkyl substituted with

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

[0197] In some embodiments, at least one R Z is C1-C6 alkyl substituted with one or more F.

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

[0199] In some embodiments, at least one R Z is a C2-C6 alkenyl or a C2-C6 alkynyl, in which the C2-C6 alkenyl or C2-C6 alkynyl is selected from the group consisting of one or more R Za is optionally replaced by

[0200] In some embodiments, at least one R Z is C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; C3-C 10 Cycloalkyl, C6-C 10 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Za is optionally replaced by

[0201] In some embodiments, at least one R Z is one or more R Za C3-C optionally substituted with 10 It is cycloalkyl.

[0202] In some embodiments, at least one R Z is one or more R Za C6-C optionally substituted with 10 It is aryl.

[0203] In some embodiments, at least one R Z is one or more R Za is a 3- to 10-membered heterocycloalkyl optionally substituted with

[0204] In some embodiments, at least one R Z is one or more R Za is a 4-membered heterocycloalkyl optionally substituted with

[0205] In some embodiments, at least one R Z is a 4-membered heterocycloalkyl.

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

[0207] In some embodiments, at least one R Z is one or more R Za is a 5-10 membered heteroaryl optionally substituted with

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

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

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

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

[0212] In some embodiments, at least one R Za is CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 It is aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[0213] Variables T and 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, wherein —O—(C1-C6 alkyl), —NH—(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R T are independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3-7 membered heterocycloalkyl, or 5-10 membered heteroaryl; and -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 An aryl, a 3- to 7-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Ta optionally replaced by, and Each R Ta are independently selected from 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 It is 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, wherein —O—(C1-C6 alkyl), —NH—(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R Tare independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3-7 membered monocyclic heterocycloalkyl, or 5-10 membered heteroaryl, and is selected from the group consisting of -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 An aryl, a 3- to 7-membered monocyclic heterocycloalkyl, or a 5- to 10-membered heteroaryl may be selected from the group consisting of one or more R Ta optionally replaced by, and Each R Ta are independently selected from 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 It is 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, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by, and Each R T are independently halogen, —OH, —O—(C1-C6 alkyl), —N(C1-C6 alkyl)2, or 3- to 7-membered heterocycloalkyl, wherein —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.

[0216] In some embodiments, T is —O—(C1-C6 alkyl), —NH—(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by, and Each R T are independently halogen, —OH, —O—(C1-C6 alkyl), or 3- to 7-membered heterocycloalkyl, wherein —O—(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more —C(═O)OH.

[0217] In some embodiments, T is —O—(C1-C6 alkyl), —NH—(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by, and Each R T are independently halogen, —OH, —O—(C1-C6 alkyl), —N(C1-C6 alkyl)2, or 3- to 7-membered monocyclic heterocycloalkyl, wherein —O—(C1-C6 alkyl), —N(C1-C6 alkyl)2, or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more —C(═O)OH.

[0218] In some embodiments, T is —O—(C1-C6 alkyl), —NH—(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by, and Each R T are independently halogen, —OH, —O—(C1-C6 alkyl), or 3- to 7-membered heterocycloalkyl, wherein —O—(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more —C(═O)OH.

[0219] In some embodiments, T is one or more R T is —O—(C1-C6 alkyl) optionally substituted with

[0220] In some embodiments, T is —O—(C 1 -C 6 alkyl).

[0221] In some embodiments, T is —OCH 3 .

[0222] In some embodiments, T is one or more R T is —NH—(C1-C6 alkyl) optionally substituted with

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

[0224] In some embodiments, T is —NHCH 3 .

[0225] In some embodiments, T is one or more R T is C1-C6 alkyl optionally substituted with

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

[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 is a C1-C6 alkyl substituted with

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

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

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

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

[0235] In some embodiments, T is —CH 2 CN.

[0236] In some embodiments, T is one or more R T is a C2-C6 alkenyl optionally substituted with

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

[0238] In some embodiments, T is ethenyl (ie, -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(CH 3 ) 2 ).

[0241] In some embodiments, T is one or more R T is a C2-C6 alkenyl substituted with

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0256] In some embodiments, T is C2-C6 alkenyl substituted with one or more 6-membered heterocycloalkyl, wherein the 6-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0257] In some embodiments, T is C2-C6 alkenyl substituted with one or more 6-membered heterocycloalkyl.

[0258] In some embodiments, T is a C2-C6 alkenyl substituted with one or more 6-membered monocyclic heterocycloalkyl, wherein the 6-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0259] In some embodiments, T is C2-C6 alkenyl substituted with one or more 6-membered monocyclic heterocycloalkyl.

[0260] In some embodiments, T is one or more R T is a C2-C6 alkynyl optionally substituted with

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

[0262] In some embodiments, T is propynyl (eg, —C≡C—CH 3 ).

[0263] In some embodiments, T is one or more R T is a C2-C6 alkynyl substituted with

[0264] In some embodiments, T is one or more R T is propynyl substituted with

[0265] In some embodiments, T is —C≡C—CH—R T is.

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

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

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

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

[0270] In some embodiments, T is [ka] is.

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

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

[0273] In some embodiments, T is [ka] is.

[0274] In some embodiments, T is [ka] is.

[0275] In some embodiments, T is [ka] is.

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

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

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

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

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

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

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

[0283] In some embodiments, at least one R T 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 -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2 is selected from the group consisting of one or more R Ta is optionally replaced by

[0285] In some embodiments, at least one R T is -O-(C1-C6 alkyl) or -N(C1-C6 alkyl)2, where O-(C1-C6 alkyl) or -N(C1-C6 alkyl)2 is selected from the group consisting of one or more R Ta is optionally replaced by

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

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

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

[0289] In some embodiments, at least one R T is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R Ta is optionally replaced by

[0290] In some embodiments, at least one R T is C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; C3-C 10 Cycloalkyl, C6-C 10 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Ta is optionally replaced by

[0291] In some embodiments, at least one R T is one or more R Ta is a 3- to 10-membered heterocycloalkyl optionally substituted with

[0292] In some embodiments, at least one R T is one or more R Ta is a 3- to 10-membered heterocycloalkyl substituted with

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

[0294] In some embodiments, at least one R T is one or more R Ta is a 3- to 7-membered heterocycloalkyl optionally substituted with

[0295] In some embodiments, at least one R T is a 3- to 7-membered heterocycloalkyl.

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

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

[0298] In some embodiments, at least one R T is one or more R Ta is a 6-membered heterocycloalkyl optionally substituted with

[0299] In some embodiments, at least one R T is a 6-membered heterocycloalkyl.

[0300] In some embodiments, at least one R T is one or more R Ta is a 6-membered heterocycloalkyl substituted with

[0301] In some embodiments, at least one R T is a 6-membered heterocycloalkyl substituted with one or more C(=O)OH.

[0302] In some embodiments, at least one R T is one or more R Ta is a 3- to 7-membered monocyclic heterocycloalkyl optionally substituted with

[0303] In some embodiments, at least one R T is a 3- to 7-membered monocyclic heterocycloalkyl.

[0304] In some embodiments, at least one R T is one or more R Ta is a 3- to 7-membered monocyclic heterocycloalkyl substituted with

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

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

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

[0308] In some embodiments, at least one R T is one or more R Ta is a 6-membered monocyclic heterocycloalkyl substituted with

[0309] In some embodiments, at least one R T is a 6-membered monocyclic heterocycloalkyl substituted with one or more C(=O)OH.

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

[0311] In some embodiments, at least one R Ta is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 It is 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 optionally substituted with 10 is aryl, Each R A1 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 selected from the group consisting of one or more R A1a optionally replaced by Each R A1a are independently halogen, CN, -OH, -NH, -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 selected from the group consisting of one or more R A1b optionally replaced by, and Each R A1b are independently halogen, CN, —OH, or —NH 2 .

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

[0314] In some embodiments, Ar 1 is one or more R A1 C6-C substituted with 10 It is aryl.

[0315] In some embodiments, Ar 1 is one or more R A1 is phenyl substituted with

[0316] In some embodiments, Ar 1 is one or more halogens, -OR A1a or phenyl substituted with —O—(C1-C6 alkyl), where —O—(C1-C6 alkyl) is selected from the group consisting of one or more R A1a and each R A1aindependently, C6-C 10 aryl or 5-10 membered heteroaryl, in which case C6-C 10 The aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogens.

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

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

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

[0320] In some embodiments, Ar 1 is phenyl optionally substituted with one or more halogens, where phenyl is —O—(C6-C 10 aryl) or -O-(5-10 membered heteroaryl), in which case -O-(C6-C 10 -O-(aryl) or -O-(5-10 membered heteroaryl) is optionally substituted with one or more halogens.

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

[0322] In some embodiments, Ar 1 is phenyl optionally substituted with one or more halogens, where the phenyl is further substituted with -O-phenyl, where the -O-phenyl is optionally substituted with one or more halogens.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0344] In some embodiments, at least one R A1 is -O-(C6-C 10 aryl) or -O-(5- to 10-membered heteroaryl), in which case -O-(C6-C 10 -aryl) or -O-(5- to 10-membered heteroaryl) may be one or more R A1b is optionally replaced by

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

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

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

[0348] In some embodiments, at least one R A1 is -O-pyridinyl 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, wherein -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R A1a is optionally replaced by

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

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

[0352] In some embodiments, at least one R A1 is one or more C6-C 10-O-(C1-C6 alkyl) substituted with aryl or 5-10 membered heteroaryl, where C6-C 10 The aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogens.

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

[0354] In some embodiments, at least one R A1 is -O-CH2-(C6-C 10 aryl) or -O-CH2-(5- to 10-membered heteroaryl), in which case -O-CH2-(C6-C 10 -aryl) or -O-CH2- (5- to 10-membered heteroaryl) is optionally substituted with one or more halogens.

[0355] In some embodiments, at least one R A1 is —O—CH 2 -phenyl or —O—CH 2 -pyridinyl, where —O—CH 2 -phenyl or —O—CH 2 -pyridinyl is optionally substituted with one or more halogens.

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

[0357] In some embodiments, at least one R A1 is —O—CH 2 -pyridinyl optionally substituted with one or more halogens.

[0358] In some embodiments, at least one R A1 is C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; C3-C 10 Cycloalkyl, C6-C 10An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R A1a is optionally replaced by

[0359] In some embodiments, at least one R A1a is 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 selected from the group consisting of one or more R A1b is optionally replaced by

[0360] In some embodiments, at least one R A1a is C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; C3-C 10 Cycloalkyl, C6-C 10 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R A1b is optionally replaced by

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

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

[0363] In some embodiments, at least one R A1a is phenyl or pyridinyl, wherein the phenyl or pyridinyl is optionally substituted with one or more halogens.

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

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

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

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

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

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

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

[0371] Exemplary Embodiments of the Compound In some embodiments, Z is [ka] When T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T and in which case the C-C alkenyl is optionally substituted with one or more R T is replaced by Each R T are independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl; and -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Ta optionally replaced by, and Each R Ta are independently selected from 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 It is aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

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

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

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

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

[0376] In some embodiments, T is [ka] isn't it.

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

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

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

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

[0381] In some aspects, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof: [ka] During the ceremony, W is CH or N, preferably CH; X 1 -O-, -S-, -NR 3 - and R a , R b are independently hydrogen or C 1-4 alkyl, or R a One of the X 1 NR 3 If so, X 1 Forms a ring with -(CH2) p - or R a One of them is R 2 Forms a ring with -(CH2) p - and R c , R d are independently hydrogen or C 1-4 is alkyl, R 1 is H or F, R 2 is hydrogen or C 1-4 alkyl or R 3 Forms a ring with R a -(CH2) forms a ring with one of the q - and R 3is hydrogen or C 1-4 alkyl, preferably hydrogen or methyl, or R 2 Forms a ring with -(CH2) p - and m is 1, 2 or 3; n is 0, 1 or 2; p is 1 or 2; q is 0, 1 or 2, and Ar 1 is unsubstituted or is 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 It is a 6-membered aryl substituted with one or more groups selected from alkoxy, or C6 aryl.

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

[0383] In some embodiments, when n is 0, R 2 is R 3 With or R a -(CH2) forms a ring with one of the q- is.

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

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

[0386] In some embodiments, n is 0 and R 2 is R 3 Forms a ring with -(CH2) q- is.

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

[0388] In some embodiments of the compound of Formula I, R b is always hydrogen, so R a may not be hydrogen. For example, R b may be hydrogen, and R a is R 2 methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl, or —(CH)— or —(CH)—, which together form a ring. Preferably, R b may be hydrogen, and R a is R 2 may be methyl, -(CH2)-, or -(CH2)2-, which together form a ring. a and R b may both be hydrogen.

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

[0390] In some embodiments of the compound of Formula I, R cis always hydrogen, so R d may not be hydrogen. For example, R c may be hydrogen, and R d may be selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. Preferably, R c may be hydrogen, and R d may be methyl. c and R d may both be hydrogen.

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

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

[0393] R a One of them is R 3 In some embodiments of compounds of Formula I that form a ring with, the ring formed 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 compounds of Formula I that form a ring with, the ring formed is a 3-, 4-, 5-, or 6-membered ring.

[0395] R 2 One of them is R 3 In some embodiments of compounds of Formula I that form a ring with, the ring formed is a 4-, 5-, or 6-membered ring, or a 5- or 6-membered ring, or a 6-membered ring. In some embodiments of the compound of Formula I, R 2 is C 1-4 alkyl or R 3 Or R a Forms a ring with -(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 is R 3 -(CH2)- or -(CH2)2- which forms a ring together with R 2 is R a and -(CH2)- or -(CH2)2-, which together form a ring. Preferably, R 2 may be selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, or i-butyl, or R 2 is R 3 -(CH2)- or -(CH2)2- which forms a ring together with R 2 is R a More preferably, R 2 may be methyl.

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

[0397] In some embodiments of compounds 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, m is 1 or 2, or n is 0, 1 or 2, m is 1, 2 or 3, or n is 1 or 2, m is 1 or 2, or n is 1 or 2, 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 is R 2 may form a heterocyclic ring with the carbon atom to which it is directly bonded. For example, X 1 may form a 4-, 5-, 6-, or 7-membered heterocycle. In some embodiments of the compounds of Formula I, X 1 may form a substituted or unsubstituted oxetanyl, thiatanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl, tetrahydropyranyl, piperidinyl, oxepanyl, thiepanyl, azepanyl, azabicyclo[2.2.1]heptane, or azabicyclo[2.2.2]octane, preferably azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, more preferably azetidinyl, pyrrolidinyl, or piperidinyl.

[0399] In some embodiments of the compound of Formula I, Ar 1 is a 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 alkoxy, or C6 aryl; R 5 , R 5’ , R 6 , R 6’ are, independently of one another, hydrogen, —CF3 or halogen, preferably F, Cl.

[0400] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of Formula i 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 Alkoxyaminocarbonyl, or C6 aryl.

[0401] Ar 1In some embodiments of the compound of Formula I, where R is a compound of Formula i 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 heteroaryl, or C6 aryl.

[0402] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of Formula i 4is generally 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, cyclophentyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl methyl, methoxymethyl, 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, pentoxybutyl, Pentoxypentyl, 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,pyridinylpropoxy, pyridinylbutoxy, pyridinylpentoxy, pyridinylhexoxy, phenyl, pyridinyl or naphthyl. Ar 1 In some embodiments of the compound of Formula I, where R is a compound of Formula i 5 and R 6 are each independently hydrogen, —CF, 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 Alkoxy, or C6 aryl.

[0403] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of Formula i 5 and R 6 are each independently hydrogen, —CF, 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 Alkoxyaminocarbonyl, or C6 aryl.

[0404] Ar 1 In some embodiments of the compound of Formula I, where is a compound of Formula i, Ar 1 contains only 1, 2 or 3 substituents that are not hydrogen. Thus, R 4 , R 5 , R 5’ , R 6 , or R 6’ At least two of may be hydrogen.

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

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

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

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

[0410] In some embodiments of the compound of Formula I, Ar 1 is a 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’ are, independently of one another, 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 0 or 1, R 5 , R 5 ', R 6 , R 6 ' are independently of each other hydrogen, -CF3 or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F.

[0412] Those skilled in the art will recognize that X 3 If represents CH, then R 7 Generally, X may also be attached to this carbon, thereby 3 is CR 7 Preferably, the corresponding aryl or heteroaryl is a single R 7 In addition, X 3 If N, then R 7 It is understood that generally cannot be attached to N.

[0413] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of Formula ii-1, ii-2, ii-3, or ii-4, 5 and R 6 are each independently hydrogen, —CF, F or Cl, and R 5’ and R 6’ is hydrogen.

[0414] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of Formula ii-1, ii-2, ii-3, or ii-4, 7 is X 3 is hydrogen when is N, and / or R 7 is X 3 is CH, then F.

[0415] Ar 1In some embodiments of the compound of Formula I, where is a compound of Formula ii-1, ii-2, ii-3, or ii-4, o is 1.

[0416] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of Formula ii-1, ii-2, ii-3, or ii-4, 5 is F and / or R 6 is F or Cl.

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

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

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

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

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

[0422] In some embodiments, X 2 is O, so that Ar 1 is a 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’ are, independently of one another, hydrogen, —CF3 or halogen, preferably F, Cl.

[0423] In some embodiments, X 2 is O, so that 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 0 or 1, R 5 , R 5 ', R 6 , R 6 ' are independently of each other hydrogen, -CF3 or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F.

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

[0425] Ar 1 In some embodiments of the compound of Formula I, where is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a, o is 1.

[0426] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a, 5 is F and / or R 6 is F or Cl.

[0427] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a, 7 is X 3 is hydrogen when is N, and / or R 7 is X 3 is CH, then F.

[0428] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a 2 is methyl or R 2 is R3 -(CH2)- or -(CH2)2- which forms a ring together with R 2 is R a It is -(CH2)- or -(CH2)2- which forms a ring together with

[0429] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a c and R d is hydrogen. Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a b , R c and R d is hydrogen.

[0430] R a One of them is R 3 Forms a ring with Ar 1 In some embodiments of compounds of Formula I, where R is a compound 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 5-membered ring.

[0431] R a One of them is R 3 Forms a ring with Ar 1 In some embodiments of compounds of Formula I, where is a compound 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 Forms a ring with Ar 1 In some embodiments of compounds of Formula I, where R is a compound 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, so that Ar 1 is a 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’ are, independently of one another, hydrogen, —CF3 or halogen, preferably F, Cl.

[0434] In some embodiments, X 3 is N, so that Ar 1 is a compound of formula ii-2b, ii-3b, ii-4b, ii-5b, or a pharmaceutically acceptable salt or stereoisomer thereof; [ka] During the ceremony, X 2 is O, NH or NMe, preferably O, o is 0 or 1, R 5 , R 5 ', R 6 , R 6 ' are independently of each other hydrogen, -CF3 or halogen, preferably F, Cl, R 7 is hydrogen or halogen, preferably F.

[0435] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, 5 and R 6 are each independently hydrogen, —CF, F or Cl, and R 5’ and R 6’ is hydrogen.

[0436] Ar 1 In some embodiments of the compound of Formula I, where is a compound of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, o is 1.

[0437] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, 5 is F and / or R 6 is F or Cl.

[0438] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, 7 is F.

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

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

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

[0442] R a One of them is R 3 Forms a ring with Ar 1 In some embodiments of compounds of Formula I, where is a compound 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 Forms a ring with Ar 1 In some embodiments of compounds of Formula I, where is a compound of Formula ii-1b, ii-2b, ii-3b, or ii-4b, the ring formed is a 4-, 5-, or 6-membered ring, or a 5- or 6-membered ring, or a 6-membered ring.

[0444] In some embodiments, X 2 is O and X 3 is N, so that Ar 1 is a 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’ are, independently of one another, hydrogen, —CF3 or halogen, preferably F, Cl.

[0445] In some embodiments, X 2 is O and X 3 is N, so that Ar 1is a compound of formula ii-2c, ii-3c, ii-4c, ii-5c, or a pharmaceutically acceptable salt or stereoisomer thereof; [ka] During the ceremony, o is 0 or 1, R 4 is hydrogen, F or Cl, R 5 , R 5 ', R 6 , R 6 ' are independently of each other hydrogen, -CF3 or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F.

[0446] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula ii-1c, ii-2c, ii-3c, ii-4c, or ii-5c, 5 and R 6 are each independently hydrogen, —CF, F or Cl, and R 5’ and R 6’ is hydrogen.

[0447] Ar 1 In some embodiments of the compound of Formula I, where is a compound of formula ii-1c, ii-2c, ii-3c, ii-4c, or ii-5c, o is 1.

[0448] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula ii-1c, ii-2c, ii-3c, ii-4c, or ii-5c, 5 is F and / or R 6 is F or Cl.

[0449] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula ii-1c, ii-2c, ii-3c, ii-4c, or ii-5c, 7 is F.

[0450] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula ii-1c, ii-2c, ii-3c, ii-4c, or ii-5c, 2 is methyl or R 2 is R 3 -(CH2)- or -(CH2)2- which forms a ring together with R 2 is R a It is -(CH2)- or -(CH2)2- which forms a ring together with

[0451] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula ii-1c, ii-2c, ii-3c, or ii-4c c and R d is hydrogen. Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula ii-1c, ii-2c, ii-3c, or ii-4c b , R c and R d is hydrogen.

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

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

[0455] In some embodiments of the compound of Formula I, Ar 1 is a 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 are, independently of one another, hydrogen, —CF 3 , 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 0 or 1, R 5 , R 6 are, independently of one another, hydrogen, —CF or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F.

[0457] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, 5 and R 6are each independently hydrogen, —CF, F or Cl, and R 5’ and R 6’ is hydrogen.

[0458] Ar 1 In some embodiments of the compound 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, o is 1.

[0459] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, 5 is F and / or R 6 is F or Cl.

[0460] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula iii-1, iii-2, iii-3, or iii-4, 7 is X 3 is hydrogen when is N, and / or R 7 is X 3 is CH, then F.

[0461] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, 2 is methyl or R 2 is R 3 -(CH2)- or -(CH2)2- which forms a ring together with R 2 is R a It is -(CH2)- or -(CH2)2- which forms a ring together with

[0462] Ar 1In some embodiments of the compound of Formula I, where R is a compound of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, c and R d is hydrogen. Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, b , R c and R d is hydrogen.

[0463] R a One of them is R 3 Forms a ring with Ar 1 In some embodiments of 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 4-, 5-, or 6-membered ring, or a 5- or 6-membered ring, or a 5-membered ring.

[0464] R a One of them is R 3 Forms a ring with Ar 1 In some embodiments of 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 Forms a ring with Ar 1 In some embodiments of 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 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, so Ar 1is a compound of formula iv-2, iv-3, or iv-4, iv-5, iv-6, or iv-7, or X 3 is C, and thus Ar 1 is a compound of formula iv-8 or iv-9. [ka] During the ceremony, o is 0 or 1, R 5 , R 6 are, independently of one another, hydrogen, —CF or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F.

[0467] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, 5 and R 6 are each independently hydrogen, —CF, F or Cl, and R 5’ and R 6’ is hydrogen.

[0468] Ar 1 In some embodiments of the compound 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, o is 1.

[0469] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, 5 is F and / or R 6 is F or Cl.

[0470] Ar 1In some embodiments of the compound of Formula I, where R is a compound of formula iiv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, 7 is F.

[0471] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, 2 is methyl or R 2 is R 3 -(CH2)- or -(CH2)2- which forms a ring together with R 2 is R a It is -(CH2)- or -(CH2)2- which forms a ring together with

[0472] Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, c and R d is hydrogen. Ar 1 In some embodiments of the compound of Formula I, where R is a compound of formula iv-1, iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, b , R c and R d is hydrogen.

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

[0474] R a One of them is R 3 Forms a ring with Ar 1In some embodiments of 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 ring formed is a 3-, 4-, 5-, or 6-membered ring.

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

[0476] In some embodiments, the disclosure provides a compound of Formula IIa or IIb, or a pharmaceutically acceptable salt or stereoisomer 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 Forms a ring with -(CH2) q - and R 3 is hydrogen or C 1-4 alkyl, preferably hydrogen or methyl, or R 2 Forms a ring with -(CH2) p - and m is 1, 2 or 3; n is 0, 1 or 2; p is 1 or 2; q is 0, 1 or 2; r is 0 or 1, s is 1 or 2, and Ar 1is unsubstituted or is 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 It is a 6-membered aryl substituted with one or more groups selected from alkoxy, or C6 aryl.

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

[0478] In some embodiments of the compound of Formula IIa or Formula IIb, R 1 is hydrogen.

[0479] In some embodiments of the compound of Formula IIa or Formula IIb, R 2 is C 1-4 alkyl or R 3 Forms a ring with -(CH2) q - For example, R 2 is R 3 R is -(CH2)- or -(CH2)2-, which is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl, and 2 Preferably, R 2 is R 3Methyl, ethyl, n-propyl, i-propyl, n-butyl, or i-butyl R, which is —(CH2)— or —(CH2)2—, forming a ring together with 2 More preferably, R 2 is R 2 R 3 It may also be methyl, which is —(CH2)— or —(CH2)2, which together form a ring.

[0480] In some embodiments of the compound of Formula IIa or Formula IIb, R 3 is R 2 is hydrogen or methyl, which together form a ring -(CH2)- or -(CH2)2-.

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

[0482] In some embodiments of compounds 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, m is 1 or 2, or n is 0, 1 or 2, m is 1, 2 or 3, or n is 1 or 2, m is 1 or 2, or n is 1 or 2, m is 1 or 3, or n is 1 or 2 and m is 2 or 3.

[0483] In some embodiments of compounds 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 is R 2 may form a heterocyclic ring with the carbon atom to which it is directly bonded. For example, X 1 may form a 4-, 5-, 6-, or 7-membered heterocyclic or heterobicyclic ring. In some embodiments of the compounds of Formula I, X 1 may form a substituted or unsubstituted oxetanyl, thiatanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl, tetrahydropyranyl, piperidinyl, oxepanyl, thiepanyl, azepanyl, azabicyclo[2.2.1]heptane, or azabicyclo[2.2.2]octane, preferably azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, more preferably azetidinyl, pyrrolidinyl, or piperidinyl.

[0485] In some embodiments of the compound of Formula IIa or Formula IIb, Ar 1 is a 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, 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 1-6alkoxy, or C6 aryl; R 5 , R 5’ , R 6 , R 6’ are, independently of one another, hydrogen, —CF3 or halogen, preferably F, Cl.

[0486] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of Formula i 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 Alkoxyaminocarbonyl, or C6 aryl.

[0487] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of Formula i 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 heteroaryl, or C6 aryl.

[0488] Ar 1In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of Formula i 4is generally 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, cyclophentyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl methyl, methoxymethyl, 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, pentoxybutyl, Pentoxypentyl, 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,pyridinylpropoxy, pyridinylbutoxy, pyridinylpentoxy, pyridinylhexoxy, phenyl, pyridinyl or naphthyl.

[0489] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of Formula i 5 and R 6 are each independently hydrogen, —CF, 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 Alkoxy, or C6 aryl.

[0490] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of Formula i 5 and R 6 are each independently hydrogen, —CF, 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 Alkoxyaminocarbonyl, or C6 aryl.

[0491] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where Ar is a compound of Formula i 1 contains only 1, 2 or 3 substituents that are not hydrogen. Thus, R 4 , R 5 , R 5’ , R 6 , or R 6’ At least two of 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 may be -(CH2)- or -(CH2)2-, which together form a ring.

[0493] In some embodiments of the compound of Formula IIa or Formula IIb, Ar 1 is a 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’ are, independently of one another, 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 0 or 1, R 5 , R 5 ', R 6 , R 6 ' are independently of each other hydrogen, -CF3 or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F.

[0495] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of Formula ii-1, ii-2, ii-3, or ii-4, 5 and R 6 are each independently hydrogen, —CF, F or Cl, and R 5’ and R 6’ is hydrogen.

[0496] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where is a compound of Formula ii-1, ii-2, ii-3, or ii-4, o is 1.

[0497] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of Formula ii-1, ii-2, ii-3, or ii-4, 5is F and / or R 6 is F or Cl.

[0498] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of Formula ii-1, ii-2, ii-3, or ii-4, 2 is methyl or R 3 It is -(CH2)- or -(CH2)2- which forms a ring together with

[0499] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of Formula ii-1, ii-2, ii-3, or ii-4, 7 is X 3 is hydrogen when is N, and / or R 7 is X 3 is CH, then F.

[0500] Ar 1 is a compound 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, m is 1 or 2, or n is 0, 1, or 2, m is 1, 2, or 3, or n is 1 or 2, m is 1 or 2, or n is 1 or 2, m is 1 or 3, or n is 1 or 2, m is 2 or 3.

[0501] Ar 1In some embodiments of compounds of Formula IIb, where r is a compound 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 r is 0 or 1 and s is 2.

[0502] In some embodiments, X 2 is O, so that Ar 1 is a 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’ are, independently of one another, hydrogen, —CF3 or halogen, preferably F, Cl.

[0503] In some embodiments, X 2 is O, so that 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 0 or 1, R 5 , R 5 ', R 6 , R 6 ' are independently of each other hydrogen, -CF3 or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F.

[0504] Ar 1In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a, 5 and R 6 are each independently hydrogen, —CF, F or Cl, and R 5’ and R 6’ is hydrogen.

[0505] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a, o is 1.

[0506] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a, 5 is F and / or R 6 is F or Cl.

[0507] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a, 7 is X 3 is hydrogen when is N, and / or R 7 is X 3 is CH, then F.

[0508] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a, 2 is methyl or R 3 It is -(CH2)- or -(CH2)2- which forms a ring together with

[0509] Ar 1is a compound 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, m is 1 or 2, or n is 0, 1 or 2, m is 1, 2 or 3, or n is 1 or 2, m is 1 or 2, or n is 1 or 2, m is 1 or 3, or n is 1 or 2 and m is 2 or 3.

[0510] Ar 1 In some embodiments of compounds of Formula IIb, where r is a compound 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 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, so that Ar 1 is a 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’ are, independently of one another, hydrogen, —CF3 or halogen, preferably F, Cl.

[0512] In some embodiments of the compound of Formula IIa or Formula IIb, X 3 is N, so that Ar 1 is a compound of formula ii-2b, ii-3b, ii-4b, ii-5b, or a pharmaceutically acceptable salt or stereoisomer thereof; [ka] During the ceremony, X 2 is O, NH or NMe, preferably O, o is 0 or 1, R 5 , R 5 ', R 6 , R 6 ' are independently of each other hydrogen, -CF3 or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F.

[0513] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, 5 and R 6 are each independently hydrogen, —CF, F or Cl, and R 5’ and R 6’ is hydrogen.

[0514] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where is a compound of Formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, o is 1.

[0515] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, 5 is F and / or R 6 is F or Cl.

[0516] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, 7 is F.

[0517] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, 2 is methyl or R 3 It is -(CH2)- or -(CH2)2- which forms a ring together with

[0518] Ar 1 In some embodiments of a compound of Formula IIa, where n is a compound 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, m is 1 or 2, or n is 0, 1, or 2, m is 1, 2, or 3, or n is 1 or 2, m is 1 or 2, or n is 1 or 2, m is 1 or 3, or n is 1 or 2, m is 2 or 3.

[0519] Ar 1 In some embodiments of compounds of Formula IIb, where r is a compound 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 r is 0 or 1 and s is 2.

[0520] In some embodiments of the compound of Formula IIa or Formula IIb, Ar1 is a 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’ are, independently of one another, 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, so that Ar 1 is a compound of formula ii-2c, ii-3c, ii-4c, ii-5c, or a pharmaceutically acceptable salt or stereoisomer thereof; [ka] During the ceremony, o is 0 or 1, R 5 , R 5 ', R 6 , R 6 ' are independently of each other hydrogen, -CF3 or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F.

[0522] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula ii-1c, ii-2c, ii-3c, ii-4c, or ii-5c, 5 and R 6 are each independently hydrogen, —CF, F or Cl, and R 5’ and R 6’ is hydrogen.

[0523] Ar 1In some embodiments of the compound of Formula IIa or Formula IIb, where is a compound of formula ii-1c, ii-2c, ii-3c, ii-4c, or ii-5c, o is 1.

[0524] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula ii-1c, ii-2c, ii-3c, ii-4c, or ii-5c, 5 is F and / or R 6 is F or Cl.

[0525] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula ii-1c, ii-2c, ii-3c, ii-4c, or ii-5c, 7 is F.

[0526] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula ii-1c, ii-2c, ii-3c, ii-4c, or ii-5c, 2 is methyl or R 3 It is -(CH2)- or -(CH2)2- which forms a ring together with

[0527] Ar 1is a compound 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, m is 1 or 2, or n is 0, 1 or 2, m is 1, 2 or 3, or n is 1 or 2, m is 1 or 2, or n is 1 or 2, m is 1 or 3, or n is 1 or 2 and m is 2 or 3.

[0528] Ar 1 In some embodiments of compounds of Formula IIb, where r is a compound 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 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 a 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 are, independently of one another, hydrogen, —CF 3 , 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 0 or 1, R 5 , R 6 are, independently of one another, hydrogen, —CF or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F.

[0531] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, 5 and R 6 are each independently hydrogen, —CF, F or Cl, and R 5’ and R 6’ is hydrogen.

[0532] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where is a compound of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, o is 1.

[0533] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, 5 is F and / or R 6 is F or Cl.

[0534] Ar 1In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula iii-1, iii-2, iii-3, or iii-4, 7 is X 3 is hydrogen when is N, and / or R 7 is X 3 is CH, then F.

[0535] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, 2 is methyl or R 3 It is -(CH2)- or -(CH2)2- which forms a ring together with

[0536] Ar 1 is a compound 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, m is 1 or 2, or n is 1, m is 1, 2, or 3, or n is 1, m is 1 or 2, or n is 2, m is 1, 2, or 3, or n is 2, m is 1 or 2, or n is 0, 1, or 2, m is 1 or 2, or n is 0, 1, or 2, m is 1, 2, or 3, or n is 1 or 2, m is 1 or 2, or n is 1 or 2, m is 1 or 3, or n is 1 or 2, m is 2 or 3.

[0537] Ar 1 In some embodiments of compounds of Formula IIb, where r is a compound 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 r is 0 or 1 and s is 2.

[0538] In some embodiments, X 3 is N, so Ar 1 is a compound of formula iv-2, iv-3, or iv-4, iv-5, iv-6, or iv-7, or X 3 is C, and thus Ar 1 is a compound of formula iv-8 or iv-9. [ka] During the ceremony, o is 0 or 1, R 5 , R 6 are, independently of one another, hydrogen, —CF or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F.

[0539] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, 5 and R 6 are each independently hydrogen, —CF, F or Cl, and R 5’ and R 6’ is hydrogen.

[0540] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where is a compound 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 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, 5 is F and / or R 6 is F or Cl.

[0542] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, 7 is F.

[0543] Ar 1 In some embodiments of the compound of Formula IIa or Formula IIb, where R is a compound of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, 2 is methyl or R 3 It is -(CH2)- or -(CH2)2- which forms a ring together with

[0544] Ar 1 is a compound 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 2, or n is 1 and m is 1, 2, or 3, or n is 1 and m is 1 or 2, or n is 2 and m is 1, 2, or 3. or n is 2 and m is 1 or 2, or n is 0, 1 or 2 and m is 1 or 2, or n is 0, 1 or 2 and m is 1, or n is 1 or 2 and m is 1, 2 or 3, or n is 1 or 2 and m is 1 or 2, or n is 1 or 2 and m is 1 or 3, or n is 1 or 2 and m is 2 or 3.

[0545] Ar 1In some embodiments of compounds of Formula IIb, where r is a compound 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 r is 0 or 1 and s is 2.

[0546] In some embodiments, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt or stereoisomer thereof: [ka] During the ceremony, R 1 is H or F, Ar 1 is an unsubstituted 6-membered aryl or is 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 alkoxy, or a 6-membered aryl substituted with one or more groups selected from C6 aryl; The compound of any one of the preceding embodiments, wherein Z is selected from: [ka]

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

[0548] In some embodiments, the present disclosure provides a compound of Formula IV, or a pharmaceutically acceptable salt or stereoisomer 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 alkoxy, or C6 aryl; R 5 , R 5 ', R 6 , R 6 ' are independently of each other hydrogen, -CF3 or halogen, preferably F or Cl, The compound of any one of the preceding embodiments, wherein Z is selected from: [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 Alkoxyaminocarbonyl, or C6 aryl.

[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 heteroaryl, or C6 aryl.

[0551] In some embodiments of the compound of Formula IV, R 4is generally 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, cyclophentyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl methyl, methoxymethyl, 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, pentoxybutyl, Pentoxypentyl, 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,pyridinylpropoxy, pyridinylbutoxy, pyridinylpentoxy, pyridinylhexoxy, phenyl, pyridinyl or naphthyl.

[0552] In some embodiments of the compound of Formula IV, R 5 and R 6 are each independently hydrogen, —CF, 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 Alkoxy, or C6 aryl.

[0553] In some embodiments of the compound of Formula IV, R 5 and R 6 are each independently hydrogen, —CF, 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 Alkoxyaminocarbonyl, or C6 aryl.

[0554] In some embodiments of the compound of Formula IV, Ar 1 contains only 1, 2 or 3 substituents that are not hydrogen. Thus, R 4 , R 5 , R 5’ , R 6 , or R 6’ At least two of may be hydrogen.

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

[0556] In some embodiments, the present disclosure provides a compound of formula V-1, or a pharmaceutically acceptable salt or stereoisomer 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 ' are independently of each other hydrogen, -CF3 or halogen, preferably F or Cl, Z is selected from: [ka]

[0557] In some embodiments, the disclosure provides a compound of formula V-2, V-3, or V-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, R 1 is H or F, R 5 , R 5 ', R 6 , R 6 ' are independently of each other hydrogen, -CF3 or halogen, preferably F or Cl, o is 0 or 1, R 7 is hydrogen or halogen, preferably F, Z is selected from: [ka]

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

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

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

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

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

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

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

[0565] In some embodiments of compounds of formula V-2, V-3, or V-4, X 2 is O, resulting in a compound of formula V-2a, V-3a, or V-4a, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, X 3 is CH or N, R 1 is H or F, R 5 , R5 ', R 6 , R 6 ' are independently of each other hydrogen, -CF3 or halogen, preferably F or Cl, o is 0 or 1, R 7 is hydrogen or halogen, preferably F, Z is selected from: [ka]

[0566] In some embodiments of the compounds of formula V-1, V-2a, V-3a, or V-4a, R 4 is 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 are each independently hydrogen, —CF, F or Cl, and R 5’ and R 6’ is hydrogen. Preferably, R 4 is 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 are each independently hydrogen, —CF, F or Cl, and R 5’ and R 6’ is hydrogen. Preferably, R 4 is hydrogen, chloro, or fluoro.

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

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

[0571] In some embodiments of 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 may be hydrogen.

[0573] In some embodiments of compounds of formula V-2, V-3, or V-4, X 3 is N, resulting in a compound of formula V-2b, V-3b, V-4b, or a pharmaceutically acceptable salt or stereoisomer thereof; or X 3 is C, resulting in a compound of formula V-5b or a pharmaceutically acceptable salt or stereoisomer thereof. [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 ' are independently of each other hydrogen, -CF3 or halogen, preferably F or Cl, o is 0 or 1, R 7 is hydrogen or halogen, preferably F, Z is selected from: [ka]

[0574] In some embodiments of the compounds of formula V-1, V-2b, V-3b, V-4b, or V-5b, R 4 is hydrogen, fluoro, or 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 are each independently hydrogen, —CF, F or Cl, and R 5’ and R 6’ is hydrogen. Preferably, R 4 is 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 are each independently hydrogen, —CF, 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 Alkoxy, Heteroaryl C 1-4 It is alkoxy, or aryl.

[0577] In some embodiments of the compounds of Formula V-1, V-2b, V-3b, V-4b, or V-5b, Ar 1 contains only 1, 2 or 3 substituents that are not hydrogen. Thus, R 4 , R5 , R 5’ , R 6 , or R 6’ At least two of 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 is F.

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

[0581] In some embodiments, the present disclosure provides a compound of formula VI-1, or a pharmaceutically acceptable salt or stereoisomer 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 are, independently of one another, hydrogen, —CF or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F, Z is selected from: [ka]

[0582] In some embodiments, the disclosure provides a compound of formula VI-2, VI-3, or VI-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, R 1 is H or F, o is 0 or 1, R 5 , R 6 are, independently of one another, hydrogen, —CF or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F, Z is selected from: [ka]

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

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

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

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

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

[0588] In some embodiments of compounds of formula VI-2, VI-3, or VI-4, X 2 is O, resulting in a compound of formula VI-2a, VI-3a, or VI-4a, or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, X 3 is CH or N, R 1 is H or F, R 5 , R 6 are, independently of one another, hydrogen, —CF or halogen, preferably F or Cl, o is 0 or 1, R 7 is hydrogen or halogen, preferably F, Z is selected from: [ka]

[0589] In some embodiments of compounds of Formula VI-1, VI-2a, VI-3a, or VI-4a, R 4 is hydrogen, fluoro, or chloro.

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

[0591] In some embodiments of compounds of Formula VI-1, VI-2a, VI-3a, or VI-4a, R 5 is F and / or R 6 is F or Cl.

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

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

[0594] In some embodiments of compounds of formula VI-2, VI-3, or VI-4, X 3 is N, resulting in a compound of formula VI-2b, VI-3b, or VI-4b, or a pharmaceutically acceptable salt or stereoisomer thereof; or X 3 is C, resulting in a compound of formula VI-5b or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] During the ceremony, X 2 is O, NH, or NMe, R 1 is H or F, R 5 , R 6 are, independently of one another, hydrogen, —CF or halogen, preferably F or Cl, o is 0 or 1, R 7 is hydrogen or halogen, preferably F, Z is selected from: [ka]

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

[0596] In some embodiments of compounds of Formula 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 is 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 is F.

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

[0600] In some embodiments, the present disclosure provides a compound of formula VII-1, or a pharmaceutically acceptable salt or stereoisomer 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 are, independently of one another, hydrogen, —CF or halogen, preferably F or Cl, Z is selected from: [ka]

[0601] In some embodiments, the present disclosure provides a compound of formula VII-2, VII-3 or VII-4, VII-5, VII-6, VII-7, VII-8 or VII-9, or a pharmaceutically acceptable salt or stereoisomer thereof: [ka] During the ceremony, R 1 is H or F, preferably H, o is 0 or 1, R 5 , R 6 are, independently of one another, hydrogen, —CF or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F, Z is selected from: [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 is hydrogen, fluoro, or chloro.

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

[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 is 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 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 may be hydrogen.

[0607] In some embodiments, the compound is selected from the compounds set forth in Tables 1 and 2, pharmaceutically acceptable salts, and stereoisomers thereof.

[0608] In some embodiments, the compound is selected from the compounds set forth in Table 1 and Table 2, and pharmaceutically acceptable salts thereof.

[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 set forth in Table 1, pharmaceutically acceptable salts, and stereoisomers thereof.

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

[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 set forth in Table 2, pharmaceutically acceptable salts, and stereoisomers thereof.

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

[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 aspects, the present disclosure provides compounds that are isotopic derivatives (eg, isotopically labeled compounds) of any one of the compounds of the formulae disclosed herein.

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

[0618] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Tables 1 and 2, and pharmaceutically acceptable salts 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 will be understood that isotopic derivatives can be made using any of a variety of art-recognized techniques. For example, isotopic derivatives can generally be made by carrying out the procedures disclosed in the schemes and / or examples described herein, and can be made by substituting isotopically labeled reagents for non-isotopically labeled reagents.

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

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

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

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

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

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

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

[0628] In some embodiments, the compound is a compound listed in Table 3. [Table 3]

[0629] The deuterium-labeled compound contains deuterium atoms with a deuterium abundance of 0.015%, which is much greater than the natural abundance of deuterium.

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

[0631] It will be understood that deuterium-labeled compounds can be made using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds can generally be made by carrying out the procedures disclosed in the schemes and / or examples described herein, and can be made by substituting a deuterium-labeled reagent for a non-deuterium-labeled reagent.

[0632] Compounds of the present invention containing the aforementioned deuterium atoms, or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present invention. 2 Substitution with H) may confer certain therapeutic benefits resulting from increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0633] The compounds of the present disclosure may contain one or more asymmetric centers in the molecule. It should be understood that compounds without a specified stereochemistry include all optical isomers (e.g., diastereomers, enantiomers, etc.) in pure or substantially pure form, as well as mixtures thereof (e.g., racemic mixtures or enantiomerically enriched mixtures). Methods for preparing such optically active forms (e.g., by resolution of racemic forms by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, by chromatographic separation using chiral stationary phases, and other methods) are well known in the art.

[0634] The compounds may be isotopically labeled compounds, for example, compounds containing various isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine, or chlorine. The compounds of the present disclosure may exist in tautomeric forms, and mixtures and separate individual tautomers are contemplated. In addition, some compounds may exhibit polymorphism.

[0635] The compounds of the present disclosure include free forms and their pharmaceutically acceptable salts and stereoisomers. Pharmaceutically acceptable salts include all typical pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the present compounds can be synthesized from the compounds of the present disclosure that contain a basic or acidic moiety 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, and the like, 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-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like. Conventional pharmaceutically acceptable salts of acidic compounds include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like, including those derived from inorganic bases. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0637] The compounds of the present disclosure can exist in solid, i.e., crystalline or amorphous form (optionally as a solvate), or liquid form. In the solid state, they can exist in or as a mixture. In crystalline solvates, solvent molecules are incorporated into the crystalline lattice during crystallization. Solvate formation can include, but is 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 generally known that crystalline forms (and their solvates) can exhibit polymorphism, i.e., exist in different crystalline structures known as "polymorphs," which have the same chemical composition but differ in packing, geometric arrangement, and other descriptive properties of the crystalline solid state. Thus, polymorphs can have different physical properties such as shape, density, hardness, morphology, stability, and dissolution properties, and can exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which can be used for identification. Such different polymorphs may be produced during the preparation of the compounds of the present disclosure by, for example, changing or adjusting the reaction conditions or reagents.

[0638] In some aspects, the present disclosure also provides methods of making the disclosed compounds. Typically, the disclosed compounds are made according to the syntheses set forth in the Experimental Section.

[0639] It will be appreciated that the synthetic processes of the present disclosure can tolerate a wide range of functional groups and, therefore, can employ a variety of substituted starting materials. While the processes generally provide the desired final compound at or near the completion of the overall process, in certain instances it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0640] It will be understood that the compounds of the present disclosure can be made in a variety of ways using commercially available starting materials, compounds known in the literature, or readily made intermediates by employing standard synthetic methods and procedures that are known to those of skill in the art or that will be apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. See, for example, but not limited to, any one or more sources, 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 edition, 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, such as the introduction and removal of protecting groups, may be varied during the reaction sequences and synthetic schemes described herein. Those skilled in the art will 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 edition, John Wiley & Sons: New York, 1999.

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

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

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

[0645] Pharmaceutical Composition In some embodiments, the present disclosure further provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of the present disclosure, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers and / or excipients (also referred to as diluents). An excipient is acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient (i.e., patient) thereof. As used herein, the term "therapeutically effective amount" refers to an amount of a compound of the present disclosure (per se or in the form of a pharmaceutical composition) that is effective to produce some desired therapeutic effect.

[0646] Pharmaceutical compositions can be in unit dosage form, each unit dosage contains a predetermined amount of the compound of the present disclosure.Such unit can contain a therapeutically effective amount of the compound of the present disclosure or its salt, or a fraction thereof, so that multiple unit dosage forms can be administered at a given time to achieve a desired therapeutically effective amount.Preferred unit dosage formulations are those that contain a daily dose or sub-dose of the compound of the present disclosure or its salt, or an appropriate fraction thereof.

[0647] The compounds of the present 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., buccal, sublingual, and targeted boluses for systemic absorption, powders, granules, pastes for application to the tongue; (2) parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or sustained release formulation; (3) topical application, e.g., as a cream, ointment, or controlled release patch or spray applied to the skin; (4) vaginally or rectally, e.g., as a pessary, cream, or foam; (5) sublingually; (6) ophthalmically; (7) transdermally; (8) nasally; (9) pulmonary; or (10) intrathecally.

[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 encapsulating material that is involved in carrying or transporting a compound of interest from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious 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, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, e.g., cocoa butter and suppository wax; (9) oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, e.g., cereals such as cereals containing gluten; For example, propylene glycol, (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) esters, such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers, such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) pH buffers, (21) polyesters, polycarbonates, and / or polyanhydrides, and (22) other non-toxic, compatible 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 coloring agents, release agents, coating agents, sweeteners, flavors and perfuming agents, preservatives and antioxidants, pH adjusters, bulking agents, and additional active agents. Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; (2) fat-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 can be prepared by any method known in the art, for example, by combining the active ingredient 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, in Remington: The Science and Practice of Pharmacy. Pharmaceutical Press, 2013; Rowe, Sheskey, Quinn: Handbook of Pharmaceutical Excipients. Pharmaceutical Press, 2009. Excipients that can be used to prepare pharmaceutical compositions can include buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, flavors, flavorings, diluents, and other known additives to provide a composition suitable for the selected administration.

[0651] As noted above, the compounds of the present disclosure may be in solid or liquid form and may be administered by a variety of routes in any conventional dosage form, e.g., tablet, powder, capsule, solution, dispersion, suspension, syrup, spray, suppository, gel, emulsion, patch, etc.

[0652] In solid dosage forms of the present disclosure for oral administration (capsules, tablets, pills, dragees, powders, granules, lozenges, etc.), the compound is mixed with one or more pharmaceutically acceptable carriers, such as, for example, sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, 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, for example, glycerol; (4) sorbents, such as, for example, agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) disintegrating agents such as thorium; (6) solution retardants such as paraffin; (7) absorption enhancers such as quaternary ammonium compounds, and surfactants such as poloxamers 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) controlled-release agents such as crospovidone or ethylcellulose. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Similar types of solid compositions may also be used as fillers in soft- and hard-shell gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, etc. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersing agents.Molded tablets can be produced by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets and other solid formulations of the pharmaceutical compositions of the present disclosure, such as sugar-coated tablets, capsules, pills, and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation field. They can also be formulated to provide a slow or controlled release of the active ingredient therein, for example, using hydroxypropylmethylcellulose in various proportions to provide a desired release profile, other polymer matrices, liposomes, and / or microspheres. They can be formulated for immediate release, for example, lyophilized. They can be sterilized, for example, by filtration through a bacteria-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 injectable medium immediately before use. The composition may optionally contain an opacifying agent and may be a composition that releases the active ingredient only, or preferably, releases the active ingredient only in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0653] The liquid formulation for oral administration of the compounds of the present disclosure includes pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active ingredients, liquid formulations can 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 (especially 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, and mixtures thereof.Oral compositions can also contain auxiliary agents, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, flavoring agents and preservatives.

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

[0655] Dosage forms for rectal or vaginal administration of the compounds of the present disclosure include suppositories, which can be prepared by mixing one or more compounds of the present disclosure with one or more suitable non-irritating excipients or carriers, such as 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 in the art to be appropriate.

[0656] The dosage forms for topical or transdermal administration of the compound of the present disclosure include powder, spray, ointment, paste, cream, lotion, gel, solution, patch and inhalant.The active compound can be mixed with a pharmaceutically acceptable carrier under sterile conditions and any preservative, buffer or propellant that may be required.Such ointment, paste, cream and gel can contain, in addition to the compound of the present disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide or their mixtures.

[0657] Dosage forms such as powders and sprays for administering the compounds of the present disclosure may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances.Sprays may additionally contain customary propellants such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons such as butane and propane.

[0658] Dosage forms such as transdermal patches for administering the compounds of the present disclosure can contain absorption enhancers or retardants to increase or decrease the flux of the compound across the skin. Such flux rate can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel. Other contemplated dosage forms include eye drops, eye ointments, powders, solutions, etc. It is understood that all contemplated compositions must be stable under the conditions of manufacture and storage and preserved against the contaminating action of microorganisms such as bacteria and fungi.

[0659] The dosage level of the compound of the present disclosure in the pharmaceutical composition of the present disclosure can be adjusted to obtain an amount of the compound of the present disclosure that is effective to achieve the desired therapeutic response for a particular patient, compound, and administration mode without causing harm to the patient. The selected dosage will depend on various factors, including the nature of the particular compound of the present disclosure used, the route of administration, the time of administration, the excretion or metabolic rate of the particular compound used, the rate and extent of absorption, the duration of treatment or prophylaxis, other drugs, compounds, and / or materials used in combination with the particular compound, the age, sex, weight, condition, overall health, and previous medical history of the patient being treated, as well as similar factors well known in the medical field. A physician skilled in the art can easily determine and prescribe the effective amount of the pharmaceutical composition required.

[0660] Typically, a suitable daily dose of a compound of the present disclosure is that amount of compound that is the lowest dose effective to produce a therapeutic effect. Such an effective amount generally depends on the factors described above. Generally, oral, intravenous, intracerebroventricular, and subcutaneous doses of a compound of the present disclosure for a patient, when used for the indicated analgesic effect, range from about 0.0001 to about 100 mg per kilogram of recipient (patient, mammal) body weight per day, more usually 0.1 to 100 mg / kg. Acceptable daily dosages can be from about 1 to about 1000 mg / day, e.g., from about 1 to about 100 mg / day.

[0661] An effective amount of a compound of the present disclosure can be administered as two, three, four, five, six or more sub-doses, optionally in unit dosage form, administered separately at appropriate intervals (daily, weekly, or monthly) throughout a specified period of time. The preferred dosage will depend on factors such as administration as set forth above, and can be readily determined by one skilled in the medicinal or pharmaceutical arts.

[0662] Uses of the Compounds and Compositions The compounds of the present disclosure inhibit or modulate the activity of receptor tyrosine kinases, particularly ErbB-receptors, such as, but not limited to, extracellular mutants of EGFR-VIII, EGFR-Vii, EGFR-Vvi, EGFR-A289V, and EGFR-G598V, as well as HER2-S310F. Thus, the compounds and compositions of the present disclosure can be useful as pharmaceuticals, i.e., in therapeutic methods for the prevention or treatment of cancer, more particularly as described in detail below. Thus, in a further aspect, the present disclosure provides methods for the prevention or treatment of mammals, e.g., humans, suffering from cancer, as described in detail below.

[0663] The terms "prevention" or "preventing" refer to reducing or eliminating the onset of symptoms or complications of a disease (e.g., cancer). Such prevention includes administering a therapeutically effective amount of a compound of Formula I or a salt thereof (or a pharmaceutical composition containing a compound of Formula I or a salt thereof) to the mammal, e.g., a human.

[0664] The terms "treatment" or "treating" are intended to encompass therapy and cure. Such treatment comprises administering a therapeutically effective amount of a compound of Formula I or a salt thereof (or a pharmaceutical composition containing a compound of Formula I or a salt thereof) to the mammal, e.g., a human.

[0665] Accordingly, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, for the treatment of cancer, as detailed below, in a mammal, e.g., a human.

[0666] In some aspects, the present disclosure is directed to a method of inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of EGFR), comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0667] In some aspects, the present disclosure is directed to a method of inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of EGFR), comprising administering to a subject in need thereof a composition described herein.

[0668] In some aspects, the present disclosure is directed to a method of preventing or treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0669] In some aspects, the present disclosure is directed to methods of preventing or treating cancer, comprising administering to a subject in need thereof a composition described herein.

[0670] In some aspects, the present disclosure is directed to compounds described herein for use in inhibiting oncogenic variants of ErbB receptors (eg, oncogenic variants of EGFR).

[0671] In some aspects, the present disclosure is directed to a compound described herein for use in the prevention or treatment of cancer.

[0672] In some aspects, the present disclosure is directed to a composition described herein for use in inhibiting an oncogenic variant of an ErbB receptor (eg, an oncogenic variant of EGFR).

[0673] In some aspects, the present disclosure is directed to a composition described herein for use in the prevention or treatment of cancer.

[0674] In some aspects, the present disclosure is directed to the use of a compound described herein in the manufacture of a medicament for inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of EGFR).

[0675] In some aspects, the present disclosure is directed to the use of a compound described herein in the manufacture of a medicament for preventing or treating cancer.

[0676] In some embodiments, the compound is selected from the compounds set forth in Tables 1 and 2, pharmaceutically acceptable salts, and stereoisomers thereof.

[0677] In some embodiments, the compound is selected from the compounds set forth in Table 1 and Table 2, and pharmaceutically acceptable salts thereof.

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

[0679] In some embodiments, the cancer comprises a solid tumor.

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

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

[0682] In some embodiments, the cancer is glioblastoma.

[0683] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of an ErbB receptor.

[0684] In some embodiments, the oncogenic variant of an ErbB receptor comprises an allosteric mutation.

[0685] In some embodiments, the oncogenic variant of an ErbB receptor is an allosteric variant of an 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 epidermal growth factor receptor (EGFR).

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

[0689] In some embodiments, the cancer, or tumor, or cells thereof, express an oncogenic variant 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, the oncogenic variant of EGFR comprises an allosteric mutation.

[0692] In some embodiments, the cancer, or tumor, or cells thereof, express an oncogenic variant 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, the oncogenic variant of the HER2 receptor comprises an allosteric mutation.

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

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

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

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

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

[0700] In some embodiments, the cancer, tumor, or cells thereof express an oncogenic variant of EGFR, wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, and the oncogenic variant of EGFR comprises a structural modification of EGFR, wherein the oncogenic variant of EGFR can form a covalently linked dimer, wherein the covalently linked dimer is structurally active, and wherein the covalently linked dimer enhances the activity of EGFR when contacted with 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 a mutation, a splicing event, a post-translational process, a conformational change, or any combination thereof. In some embodiments, the structural modification of EGFR occurs within the first cysteine-rich (CR1) and / or second cysteine-rich (CR2) regions of EGFR. In some embodiments, the first cysteine-rich (CR1) and / or second cysteine-rich (CR2) regions of EGFR comprise amino acid residues T211 to R334 and / or C526 to S645 of SEQ ID NO: 1, respectively. In some embodiments, the oncogenic variant of EGFR creates a physical barrier to disulfide bond formation within the CR1 and / or CR2 regions. In some embodiments, the oncogenic variant of EGFR removes the physical barrier to disulfide bond formation within the CR1 and / or CR2 regions. In some embodiments, the oncogenic variant of EGFR comprises one or more free or unpaired cysteine ​​(C) residues located at the dimer interface of EGFR.In some embodiments, the oncogenic variant of EGFR is 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. , C506 to C515, C510 to C523, C526 to C535, C539 to C555, C558 to C571, C562 to C579, C582 to C591, C595 to C617, C620 to C628, and C624 to C636. In some embodiments, the modification occurs at an intramolecular disulfide bond within 10 angstroms or less of a site 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 according to SEQ ID NO:1.

[0701] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of EGFR, the oncogenic variant of EGFR is a mutation of EGFR, and the nucleotide sequence encoding the oncogenic variant of EGFR comprises a deletion or substitution comprising one or more amino acids encoding an adenosine triphosphate (ATP) binding site. In some embodiments, the ATP binding site comprises amino acids E746-A750 of SEQ ID NO: 1. In some embodiments, the ATP binding site or deletion or substitution thereof comprises K858 of SEQ ID NO: 1. In some embodiments, the deletion comprises K858 of SEQ ID NO: 1. In some embodiments, at position 858 of SEQ ID NO: 1, a lysine (K) is substituted with arginine (R) (K858R).

[0702] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of EGFR, wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, and the nucleotide sequence encoding the oncogenic variant of EGFR comprises an insertion within a sequence encoding exon 20, or a portion thereof. In some embodiments, the sequence encoding exon 20, or a portion thereof, comprises a sequence encoding KEILDEAYVMASVDNPHVCAR (SEQ ID NO: 7). In some embodiments, the sequence encoding exon 20, or a portion thereof, comprises a sequence encoding the C-helix, the end of the C-helix, or the post-C-helix loop. In some embodiments, the insertion comprises the amino acid sequence of ASV, SVD, NPH, or FQEA. In some embodiments, the sequence encoding exon 20, or a portion thereof, comprises one or more of the following: (a) an insertion of the amino acid sequence ASV between positions V769 and D770 of SEQ ID NO:1; (b) an insertion of the amino acid sequence SVD between positions D770 and N771 of SEQ ID NO:1; (c) an insertion of the amino acid sequence NPH between positions H773 and V774 of SEQ ID NO:1; (d) an insertion of the amino acid sequence FQEA between positions A763 and Y764 of SEQ ID NO:1; (e) an insertion of the amino acid sequence PH between positions H773 and V774 of SEQ ID NO:1; (f) an insertion of the amino acid G between positions D770 and N771 of SEQ ID NO:1; (g) an insertion of the amino acid H between positions H773 and V774 of SEQ ID NO:1; (h) an insertion of the amino acid sequence HV between positions V774 and C775 of SEQ ID NO:1; (j) insertion of amino acid sequence SVA between positions A767 and S768 of SEQ ID NO: 1; (k) insertion of amino acid sequence GYN between positions 770 and 771 of SEQ ID NO: 1; (l) insertion of amino acid H between positions N771 and P772 of SEQ ID NO: 1; (m) insertion of amino acid Y between positions H773 and V774 of SEQ ID NO: 1; (n) insertion of amino acid sequence PHVC between positions C775 and 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 and H773 of SEQ ID NO: 1; (q) insertion of amino acid sequence VDS between positions S768 and V769 of SEQ ID NO: 1; (r) insertion of amino acid H between positions D770 and 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 amino acid sequence GSVDN for DN between positions 770 and 771 of SEQ ID NO: 1; (v) substitution of amino acid sequence GYP for NP between positions 771 and 772 of SEQ ID NO: 1; (w) insertion of amino acid G between positions N771 and P772 of SEQ ID NO: 1; (x) insertion of amino acid G between positions P772 and H773 of SEQ ID NO: 1 (y) insertion of the amino acid sequence GNP between positions V769 and D770 of SEQ ID NO: 1; (z) substitution of the amino acid sequence GNPHVC for VC between positions 774 and 775 of SEQ ID NO: 1; (aa) insertion of the amino acid sequence LQEA between positions A763 and Y764 of SEQ ID NO: 1; (bb) insertion of the amino acid sequence GL between positions D770 and N771 of SEQ ID NO: 1; (cc) insertion of the amino acid Y between positions D770 and N771 of SEQ ID NO: 1; (dd) insertion of the amino acid sequence NPY between positions H773 and V774 of SEQ ID NO: 1. (ee) insertion of the amino acid sequence TH between positions H773 and V774 of SEQ ID NO: 1; (ff) substitution of the amino acid sequence KGP with NP between positions 771 and 772 of SEQ ID NO: 1; (gg) substitution of the amino acid sequence SVDNP with NP between positions 771 and 772 of SEQ ID NO: 1; (hh) insertion of the amino acid sequence NN between positions N771 and P772 of SEQ ID NO: 1; (ii) insertion of the amino acid T between positions N771 and P772 of SEQ ID NO: 1; and (jj) substitution of the amino acid sequence STLASV with SV between positions 768 and 769 of SEQ ID NO: 1.

[0703] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of EGFR, wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, and the oncogenic variant of EGFR includes EGFR-Vii, EGFR-Vvi, EGFR-R222C, EGFR-R252C, EGFR-R252P, EGFR-R256Y, EGFR-T263P, EGFR-Y270C, EGFR-A289T ... EGFR-A289V, EGFR-A289D, EGFR-H304Y, EGFR-G331R, EGFR-P596S, EGFR-P596L, EGFR-P596R, EGFR-G598V, EGFR-G598A, EGFR-G614D, EGFR-C620Y, EGFR-C614W, EGFR-C628F, EGFR-C628Y, EGFR-C636Y, EGFR-G645C, EGFR-Δ660, EGFR-Δ768, or any combination thereof.

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

[0705] In some embodiments, the cancer or tumor, or cells thereof, expresses a wild-type HER-2 receptor, wherein the wild-type HER2 receptor comprises the amino acid sequence of SEQ ID NO: 2, 3, 4, 5, or 6.

[0706] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of the HER-2 receptor, and the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor.

[0707] In some embodiments, the cancer, or tumor, or cells thereof, express an oncogenic variant of the HER2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises a substitution of serine (S) with phenylalanine (F) at position 310 of SEQ ID NO: 2 or 5.

[0708] In some embodiments, the cancer, or tumor, or cells thereof, express an oncogenic variant of the HER2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises a substitution of serine (S) with tyrosine (Y) at position 310 of SEQ ID NO: 2 or 5.

[0709] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of the HER2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises a substitution of arginine (R) with glutamine (Q) at position 678 of SEQ ID NO: 2 or 5.

[0710] In some embodiments, the cancer, or tumor, or cells thereof, express an oncogenic variant of the HER2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises a substitution of valine (V) with leucine (L) at position 777 of SEQ ID NO: 2 or 5.

[0711] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of the HER2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises a substitution of valine (V) with methionine (M) at position 777 of SEQ ID NO: 2 or 5.

[0712] In some embodiments, the cancer, or tumor, or cells thereof, express an oncogenic variant of the HER2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises a substitution of valine (V) with isoleucine (I) at position 842 of SEQ ID NO: 2 or 5.

[0713] In some embodiments, the cancer, or tumor, or cells thereof, express an oncogenic variant of the HER2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises a substitution of leucine (L) with alanine (A) at position 755 of SEQ ID NO: 2 or 5.

[0714] In some embodiments, the cancer, or tumor, or cells thereof, express an oncogenic variant of the HER2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises a substitution of leucine (L) with proline (P) at position 755 of SEQ ID NO: 2 or 5.

[0715] In some embodiments, the cancer, or tumor, or cells thereof, express an oncogenic variant of the HER2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises a substitution of leucine (L) with serine (S) at position 755 of SEQ ID NO: 2 or 5.

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

[0717] In some embodiments, the cancer, or tumor, or cells thereof, express an oncogenic variant of the HER2 receptor, wherein 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, the cancer or tumor, or cells thereof, express an oncogenic variant of the HER-4 receptor. In some embodiments, the oncogenic variant of the HER-4 receptor is an allosteric variant of the HER4 receptor. In some embodiments, the oncogenic variant of the HER4 receptor comprises a deletion of exon 16 (HER4-Δ16).

[0719] In some embodiments, the cancer, tumor, or cells thereof express an oncogenic variant of EGFR, wherein the sequence encoding the oncogenic variant of EGFR comprises a deletion of exon 20 or a portion thereof, and wherein the cancer, tumor, or cells thereof does not comprise a second oncogenic variation in a sequence of EGFR outside of exon 20. In some embodiments, the second oncogenic variation comprises a sequence encoding one or more of the EGFR kinase domain (KD), BRAF, NTRK, and KRAS.

[0720] In some embodiments, the cancer, tumor, or cells thereof express an oncogenic variant of EGFR, wherein the sequence encoding the oncogenic variant of EGFR comprises a deletion of exon 20 or a portion thereof, and wherein the cancer, tumor, or cells thereof do not comprise a marker indicative of responsiveness to immunotherapy.

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

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

[0723] In some embodiments, the cancer or tumor, or cells thereof, are insensitive or resistant to treatment with a therapeutic agent other than the compound of the present disclosure. In some embodiments, the cancer or tumor, or cells thereof, are insensitive or resistant to treatment with a type I inhibitor. In some embodiments, the cancer or tumor, or cells thereof, are insensitive or resistant to treatment with one or more of gefinitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686, and AZD9291.

[0724] In some embodiments, the subject has an adverse reaction to treatment with a therapeutic agent other than the compound of the present disclosure. In some embodiments, the subject has an adverse reaction to treatment with a type I inhibitor. In some embodiments, the subject has an adverse reaction to treatment with one or more of gefinitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686, and AZD9291. In some embodiments, the adverse reaction is activation of an oncogenic variant of EGFR, the oncogenic variant comprising a mutation in the extracellular domain of the receptor. In some embodiments, the adverse reaction is activation of an oncogenic variant of the HER-2 receptor, where the oncogenic variant comprises a mutation in the extracellular domain of the receptor.

[0725] In some embodiments, the method further comprises administering to a subject in need thereof a therapeutically effective amount of a non-type I inhibitor, hi some embodiments, the non-type I inhibitor comprises a small molecule type II inhibitor.

[0726] In some embodiments, the method further comprises administering to a subject in need thereof a therapeutically effective amount of a non-type I inhibitor, hi some embodiments, the non-type I inhibitor comprises a small molecule type II inhibitor.

[0727] In some embodiments, the compound is used in combination with a therapeutically effective amount of a non-type I inhibitor. In some embodiments, the non-type I inhibitor comprises 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 amount reduces the severity of a sign or symptom of cancer.

[0730] In some embodiments, the symptoms of cancer include tumor grade, and reducing the severity of the symptoms includes reducing tumor grade.

[0731] In some embodiments, the symptom of cancer comprises tumor metastasis, and reducing the severity of the symptom comprises eliminating metastasis or reducing the rate or extent of metastasis.

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

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

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

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

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

[0737] The present disclosure relates to the administration of the compounds of the present disclosure alone or in combination with one or more additional therapeutic agents, such as 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, described in U.S. Pat. No. 6,780,996), dasatinib (e.g., Bristol-Myers Squibb), 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 AG013736, described in WO01 / 002369), brivanib alaninate (or BMS-582664), motesanib (or AMG-706, PCTWO02 / 066470), pasireotide (e.g. SOM230, described in WO02 / 010192), sorafenib (e.g. Nexavar®); HER2 receptor inhibitors: trastuzumab (e.g. Herceptin® by Genentech / Roche), neratinib (or HKI-272, described in WO05 / 028443), lapatinib or lapatinib ditosylate (e.g. Tykerb® by GlaxoSmithKline); CD20 antibodies: rituximab (e.g. G Riuxan® and MabThera® by Enentech / Roche), tositumomab (e.g. Bexxar® by GlaxoSmithKline), ofatumumab (e.g. Arzerra®) by GlaxoSmithKline); Bcr / Abl kinase inhibitors: nilotinib hydrochloride (e.g. Tasigna® by Novartis); DNA synthesis inhibitors: capecitabine (e.g. Xeloda® by Roche), gemcitabine hydrochloride (e.g. Eli antitumor agents: oxaliplatin (e.g., Eloxatin (R) by Sanofi-Aventis, as described in US 4,169,846); epidermal growth factor receptor (EGFR) inhibitors: gefitinib (or Iressa (R), afatinib (or Tovok (R) by Boehringer Ingelheim), cetuximab (e.g., Bristol-Myers Squibb), rifabutinib (or rifabutinib ...Erbitux® by Squibb), panitumumab (e.g., Vectibix® by Amgen); HER dimerization inhibitors: pertuzumab (e.g., Omnitarg® by Genentech); human granulocyte colony-stimulating factor (G-CSF) modifiers: filgrastim (e.g., Neupogen® by Amgen); immunomodulators: afutuzumab (® by Roche), pegfilgrastim (e.g., Neulasta® by Amgen), lenalidomide (e.g., CC-5013, e.g., Revlimid®), thalidomide (e.g., Thalomid®); (m) CD40 inhibitors: dacetuzumab (e.g., Seattle SGN-40 or huS2C6 by Genetics, Inc; pro-apoptotic receptor agonists (PARA): dulanermin (e.g., AMG-951 by Amgen / Genentech); hedgehog antagonists: vismodegib (or GDC-0449, described in WO06 / 028958); PI3K inhibitors: pictilisib (or GDC-0941, described in WO09 / 036082 and WO09 / 055730), dactolisib (or BEZ 235 or NVP-BEZ 235, described in WO06 / 122806); phospholipase A2 inhibitors: anagrelide (e.g., Agrylin®); BCL-2 inhibitors: navitoclax (or ABT-263, described in WO09 / 155386); mitogen-activated protein kinase kinase (MEK) inhibitors: XL-518 (ACCCorp. Cas number 1029872-29-4; 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®); topoisomerase II inhibitors: etoposide (e.g., VP-16 and etoposide phosphate, e.g., Toposar®, VePesid®, and Etopophos®), teniposide (e.g., VM-26, e.g., Vumon®), mTOR inhibitors: temsirolimus (e.g., Torisel®, Pfizer), ridafolium (formerly known as deferolimus, (or AP23573 and MK8669, WO 03 / 064383), everolimus (e.g., Afinitor®, Novartis), osteoclast bone resorption inhibitor: 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 analogues: octreotide (e.g., octreotide acetate, e.g., Sandostatin® and SandostatinLAR®), synthetic interleukin-11 (IL-11): oprelvekin (e.g., Neumega®, Pfizer / Wyeth), synthetic erythropoietin: darbepoetin alfa (e.g., Aranesp®, Amgen), receptor activator of nuclear factor kappa B (RANK) inhibitor: denosumab (e.g., Prolia®, Amgen), thrombopoietin mimetic peptibody: romiplostim (e.g., Nplate®, Amgen), cell proliferation stimulator: palifermin (e.g., Kepivance®, Amgen), anti-insulin-like growth factor 1 receptor (IGF-1R) antibody: figitumumab (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 ticilimumab, 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 Temodal®, Schering-Plough / Merck), dactinomycin (e.g., actinomycin D and e.g., Cosmegen®), melphalan (e.g., L-PAM, L-sarcolysin, and phenylalanine mustard, e.g., Alkeran®), altretamine (e.g., hexamethylmelamine (HMM), e.g., Hexalen®), carmustine (e.g., BiCNU®), bendamustine (e.g., Treanda®), busulfan (e.g., Busulfex® and Myleran®), carboplatin (e.g., Paraplain®), atin®), lomustine (e.g., CCNU, e.g., CeeNU®), cisplatin (e.g., CDDP, e.g., Platinol® and Platinol®-AQ), chlorambucil (e.g., Leukeran®), cyclophosphamide (e.g., Cytoxan® and Neosar®), decarbazine (e.g., DTIC, DIC, and imidazole-carboxamide, e.g., DTIC-Dome®), altretamine (e.g., hexamethylmelamine (HMM), e.g., Hexalen®), ifosfamide (e.g., Ifex®), procarbazine (e.g., Matulane®), mechlorethamine (e.g., nitrogen mustard, mustine, and mechloroethamine hydrochloride) hydrochloride), e.g., Mustargen®), streptozocin (e.g., Zanosar®), thiotepa (e.g., thiophosphoamide, TESPA and TSPA, e.g., Thioplex®), biological response modifiers: bacillus Calmette-Guerin (e.g., theraCys® and TICE® BCG), denileukinDiftitox (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®), mitomycin C (e.g., Mutamycin®), anti-microtubule agent: estramustine (e.g., Emcyl®), cathepsin K inhibitor: odanacatib (or MK-0822, Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, described in WO 03 / 075836), epothilone B analogue: ixabepilone (e.g., Lxempra®, Bristol-Myers Squibb), heat shock protein (HSP) inhibitor: tanespimycin (17-allylamino-17-demethoxygeldanamycin, e.g., KOS-953 and 17-AAG, SIGMA, US), 4,261,989), TpoR agonists: eltrombopag (e.g., Promacta® and Revolade®, GlaxoSmithKline), anti-cancer drugs: Mitotic 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: alvocidib (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 agonists: xaliproden (or SR57746, US 5,266,573), HPC vaccines: Cervarix®, sold by GlaxoSmithKline, Gardasil®, sold by Merck, iron chelators: Deferasinox (e.g., Exjade®, sold 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., LiposomalAra-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., amethopterin, methotrexate sodium (MTX), e.g., Rheumatrex® and Trexall™), pentostatin (e.g., Nipent®), ), bisphosphonates: pamidronate (e.g., Aredia®), zoledronic acid (e.g., Zometa®), demethylating agents: 5-azacytidine (e.g., Vidaza®), decitabine (e.g., Dacogen®), plant alkaloids: paclitaxel protein-bound (e.g., Abraxane®), vinblastine (e.g., vinblastine sulfate, vincaleukoblastine, and VLB, e.g., Alkaban-AQ® and Velban®), vincristine (e.g., vincristine sulfate, LCR, and VCR, e.g., Oncovin® and Vincasar®),Pfs®), vinorelbine (e.g., Navelbine®), paclitaxel (e.g., Taxol and Onxal®), retinoids: alitretinoin (e.g., Panretin®), tretinoin (all-trans retinoic acid, e.g., ATRA, e.g., Vesanoid®), isotretinoin (13-cis-retinoic acid, e.g., Accutane®, Amnesteem®, Claravis®, Clarus®, De cutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), bexarotene (e.g., Targretin®), glucocorticosteroids: hydrocortisone (e.g., cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and e.g., Ala-Cort®, hydrocortisone phosphate, Solu-Cortef®, Hydrocort Acetate®, and Lanacort®), dexamethasone, prednisolone (e.g., Delta-Cortel®, Orapred®, Pediapred®, and Prelone®), prednisone (e.g., Deltasone®, LiquidRed®, Meticorten® and Orasone®), methylprednisolone (e.g., 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, e.g., Duralone®, Medralone®, Medrol®, M-Prednisol® and Solu-Medrol®), cytokines: interleukin-2 (e.g., aldesleukin and IL-2, e.g., Proleukin®), interleukin-11 ( For example, oprelvekin, 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, Erwinia Administration in combination with L-asparaginase (e.g., Elspar® and Kidrolase®), anti-nausea: NK-1 receptor antagonist: casopitant (e.g., Rezonic® and Zunrisa®, GlaxoSmithKline), and cytoprotective agents: amifostine (e.g., Ethyol®), leucovorin (e.g., leucovorin calcium, citrovorum factor, and folinic acid) is contemplated. [Embodiment] Exemplary Embodiments Embodiment 1: A compound of formula (I'): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, W is CH or N; Z is one or more RZ is a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Z are independently selected from 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 3- C 10 Cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, and is selected from the group consisting of -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 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Za optionally replaced by Each R Za are independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R T are independently selected from 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 3- C10 Cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, and is selected from the group consisting of -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 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Ta optionally replaced by Each R Ta are independently selected from halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; Ar 1 is one or more R A1 C6-C optionally substituted with 10 is aryl, Each R A1 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 Aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, and is selected from the group consisting of -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 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R A1a optionally replaced by Each R A1a are independently selected from 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 3- C 10 Cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, and is selected from the group consisting of -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 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R A1b optionally replaced by, and Each R A1b are independently halogen, CN, —OH, or —NH 2 . Embodiment 2: The compound according to any one of the preceding embodiments, wherein the compound is a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH or N; Z is one or more R Z is a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Z are independently selected from 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 3- C 10 Cycloalkyl, C6-C 10 Aryl, or 5-10 membered heteroaryl, and is selected from the group consisting of -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C 10 Cycloalkyl, C6-C10 Aryl, 3- or 5- to 10-membered heteroaryl may be one or more R Za optionally replaced by Each R Za are independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R T are independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3-7 membered heterocycloalkyl, or 5-10 membered heteroaryl; and -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 An aryl, a 3- to 7-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Ta optionally replaced by Each R Ta are independently selected from halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; Ar1 is one or more R A1 C6-C optionally substituted with 10 is aryl, Each R A1 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 selected from the group consisting of one or more R A1a optionally replaced by, and Each R A1a are independently halogen, CN, -OH, -NH, -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 selected from the group consisting of one or more R A1b optionally replaced by, and Each R A1b are independently halogen, CN, -OH, or -NH; However, Z is [ka] When Ar 1 is a C6-C optionally substituted with one or more halogens 10 It is aryl. Embodiment 3: The compound according to any one of the preceding embodiments, wherein the compound is a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH or N; Z is one or more R Z is a 3- to 12-membered heterocycloalkyl optionally substituted with Each RZ are independently selected from 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 3- C 10 Cycloalkyl, C6-C 10 Aryl, or 5-10 membered heteroaryl, and is selected from the group consisting of -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C 10 Cycloalkyl, C6-C 10 Aryl, 3- or 5- to 10-membered heteroaryl may be one or more R Za optionally replaced by Each R Za are independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R T are independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3-7 membered monocyclic heterocycloalkyl, or 5-10 membered heteroaryl, and is selected from the group consisting of -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 Cycloalkyl, C6-C 10 An aryl, a 3- to 7-membered monocyclic heterocycloalkyl, or a 5- to 10-membered heteroaryl may be selected from the group consisting of one or more R Ta optionally replaced by Each R Ta are independently selected from halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; Ar 1 is one or more R A1 C6-C optionally substituted with 10 is aryl, Each R A1 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 selected from the group consisting of one or more R A1a optionally replaced by, and Each R A1a are independently halogen, CN, -OH, -NH, -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 selected from the group consisting of one or more R A1b optionally replaced by, and Each R A1b are independently halogen, CN, -OH, or -NH; However, Z is [ka] When Ar 1 is a C6-C optionally substituted with one or more halogens 10 It is aryl. Embodiment 4: The compound according to any one of the preceding embodiments, wherein the compound is a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is one or more R Z is a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Z are independently halogen, —O—(C1-C6 alkyl), C1-C6 alkyl, or 3-10 membered heterocycloalkyl, wherein —O—(C1-C6 alkyl), C1-C6 alkyl, or 3-10 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 the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R T are independently halogen, —OH, —O—(C1-C6 alkyl), —N(C1-C6 alkyl)2, or 3- to 7-membered heterocycloalkyl, wherein —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; Ar 1 is one or more R A1 C6-C optionally substituted with 10 is aryl, Each R A1 are independently halogen, -OR A1a , or one or more R A1a is —O—(C1-C6 alkyl) optionally substituted with Each R A1a independently, C6-C 10aryl or 5- to 10-membered heteroaryl, C6-C 10 The aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogens. Embodiment 5: The compound according to any one of the preceding embodiments, wherein the compound is a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is one or more R Z is a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Z are independently halogen, —O—(C1-C6 alkyl), C1-C6 alkyl, or 3-10 membered heterocycloalkyl, wherein —O—(C1-C6 alkyl), C1-C6 alkyl, or 3-10 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 the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R T are independently halogen, —OH, —O—(C1-C6 alkyl), —N(C1-C6 alkyl)2, or 3- to 7-membered monocyclic heterocycloalkyl, wherein —O—(C1-C6 alkyl), —N(C1-C6 alkyl)2, or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more —C(═O)OH; Ar 1 is one or more R A1 C6-C optionally substituted with 10 is aryl, Each R A1 are independently halogen, -OR A1a , or one or more R A1a is —O—(C1-C6 alkyl) optionally substituted with Each R A1a independently, C6-C 10aryl or 5- to 10-membered heteroaryl, C6-C 10 The aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogens. Embodiment 6: The compound according to any one of the preceding embodiments, wherein the compound is a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is one or more R Z is a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Z are independently halogen, —O—(C1-C6 alkyl), or C1-C6 alkyl, wherein —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 the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R T are independently halogen, —OH, —O—(C1-C6 alkyl), or 3- to 7-membered heterocycloalkyl, wherein —O—(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more —C(═O)OH; Ar 1 is one or more R A1 C6-C optionally substituted with 10 is aryl, Each R A1 are independently halogen, -OR A1a , or one or more R A1a is —O—(C1-C6 alkyl) optionally substituted with Each R A1a independently, C6-C 10 aryl or 5- to 10-membered heteroaryl, C6-C 10 the aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogens; However, Z is [ka] When Ar 1 is a C6-C optionally substituted with one or more halogens 10 It is aryl. Embodiment 7: The compound according to any one of the preceding embodiments, wherein the compound is a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is one or more R Z is a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Z are independently halogen, —O—(C1-C6 alkyl), or C1-C6 alkyl, wherein —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 the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R T are independently halogen, —OH, —O—(C1-C6 alkyl), or 3- to 7-membered monocyclic heterocycloalkyl, wherein —O—(C1-C6 alkyl) or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more —C(═O)OH; Ar 1 is one or more R A1 C6-C optionally substituted with 10 is aryl, Each R A1 are independently halogen, -OR A1a , or one or more R A1a is —O—(C1-C6 alkyl) optionally substituted with Each R A1a independently, C6-C 10aryl or 5- to 10-membered heteroaryl, C6-C 10 the aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogens; However, Z is [ka] When Ar 1 is a C6-C optionally substituted with one or more halogens 10 It is aryl. Embodiment 8: The compound according to any one of the preceding embodiments, wherein the compound is a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is one or more R Z is a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Z are independently halogen, —O—(C1-C6 alkyl), or C1-C6 alkyl, wherein —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 the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R T are independently halogen, —OH, —O—(C1-C6 alkyl), or 3- to 7-membered heterocycloalkyl, wherein —O—(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more —C(═O)OH; Ar 1 is a C6-C optionally substituted with one or more halogens 10 It is aryl. Embodiment 9: The compound according to any one of the preceding embodiments, wherein the compound is a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is one or more R Z is a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Z are independently halogen, —O—(C1-C6 alkyl), or C1-C6 alkyl, wherein —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 the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by Each R T are independently halogen, —OH, —O—(C1-C6 alkyl), or 3- to 7-membered monocyclic heterocycloalkyl, wherein —O—(C1-C6 alkyl) or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more —C(═O)OH; Ar 1 is a C6-C optionally substituted with one or more halogens 10 It is aryl. Embodiment 10: The compound according to any one of the preceding embodiments, wherein the compound is a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is a 3- to 12-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyls; T is a C2-C6 alkenyl optionally substituted with one or more 6-membered heterocycloalkyl; and Ar 1 is a C6 aryl optionally substituted with one or more halogens. Embodiment 11: The compound according to any one of the preceding embodiments, wherein the compound is a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is a 3- to 12-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyls; T is a C2-C6 alkenyl optionally substituted with one or more 6-membered monocyclic heterocycloalkyl; and Ar 1 is a C6 aryl optionally substituted with one or more halogens. Embodiment 12: The compound according to any one of the preceding embodiments, wherein W is CH. Embodiment 13: The compound according to any one of the preceding embodiments, wherein W is N. Embodiment 14: Z is one or more R Z is a 3- to 12-membered heterocycloalkyl optionally substituted with Each R Z are independently halogen, —O—(C1-C6 alkyl), C1-C6 alkyl, or 3-10 membered heterocycloalkyl, wherein —O—(C1-C6 alkyl), C1-C6 alkyl, or 3-10 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 the 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 selected from the group consisting of one or more R Z The compound according to any one of the preceding embodiments, optionally substituted with Embodiment 16: 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 the oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, 3-azabicyclo[3.1.0]hexanyl, 2-azaspiro[3.3]heptanyl, or 2-oxa-5-azaspiro[3.4]octanyl is selected from the group consisting of one or more R Z The compound according to any one of the preceding embodiments, optionally substituted with Embodiment 17: Z, [ka] The compound of any one of the preceding embodiments, wherein Embodiment 18: Z, [ka] The compound of any one of the preceding embodiments, wherein Embodiment 19: At least one R Z The compound of any one of the preceding embodiments, wherein is halogen. Embodiment 20: At least one R Z The compound according to any one of the preceding embodiments, wherein is F or Cl. Embodiment 21: At least one R Z The compound of any one of the preceding embodiments, wherein is CN, —OH, or —NH 2 . Embodiment 22: At least one R Z is -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C10 Aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, and is selected from the group consisting of -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, and one or more R Za The compound according to any one of the preceding embodiments, optionally substituted with Embodiment 23: At least one R Z is one or more R Za The compound according to any one of the preceding embodiments, wherein the alkyl group is -O-(C1-C6 alkyl) optionally substituted with Embodiment 24: At least one R Z The compound of any one of the preceding embodiments, wherein is —OCH 3 . Embodiment 25: At least one R Z The compound according to any one of the preceding embodiments, wherein is —O—(C 1 -C 6 alkyl) substituted with one or more halogens. Embodiment 26: At least one R Z The compound according to any one of the preceding embodiments, wherein is C1-C6 alkyl. Embodiment 27: At least one R Z The compound according to any one of the preceding embodiments, wherein is methyl, ethyl or propyl. Embodiment 28: At least one R Z The compound according to any one of the preceding embodiments, wherein is C1-C6 alkyl substituted with one or more halogens. Embodiment 29: At least one R Z is CF3. Embodiment 30: At least one R Z is C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; C3-C 10 Cycloalkyl, C6-C 10 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Za The compound according to any one of the preceding embodiments, optionally substituted with Embodiment 31: At least one R Z is one or more R Za The compound of any one of the preceding embodiments, wherein R is a 3- to 10-membered heterocycloalkyl optionally substituted with R. Embodiment 32: At least one R Z is one or more R Za The compound according to any one of the preceding embodiments, wherein R is a 4-membered heterocycloalkyl optionally substituted with R. Embodiment 33: At least one R Z The compound according to any one of the preceding embodiments, wherein is oxetanyl. Embodiment 34: At least one R Za The compound of any one of the preceding embodiments, wherein is halogen. Embodiment 35: At least one R Za The compound according to any one of the preceding embodiments, wherein is F or Cl. Embodiment 36: At least one R Za is CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10The compound according to any one of the preceding embodiments, wherein the heterocycloalkyl is aryl, 3-10 membered heterocycloalkyl, or 5-10 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 selected from the group consisting of one or more R T optionally replaced by Each R T are independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3-7 membered heterocycloalkyl, or 5-10 membered heteroaryl; and -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 An aryl, a 3- to 7-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Ta optionally replaced by, and Each R Ta are independently selected from 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 preceding embodiments, wherein the heterocycloalkyl is aryl, 3-10 membered heterocycloalkyl, or 5-10 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 selected from the group consisting of one or more RT optionally replaced by Each R T are independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3-7 membered monocyclic heterocycloalkyl, or 5-10 membered heteroaryl, and is selected from the group consisting of -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 An aryl, a 3- to 7-membered monocyclic heterocycloalkyl, or a 5- to 10-membered heteroaryl may be selected from the group consisting of one or more R Ta optionally replaced by, and Each R Ta are independently selected from 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 It is 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 the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by, and Each R T are independently halogen, —OH, —O—(C1-C6 alkyl), —N(C1-C6 alkyl)2, or 3- to 7-membered heterocycloalkyl, wherein —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. Embodiment 40: T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by, and Each R T are independently halogen, —OH, —O—(C1-C6 alkyl), —N(C1-C6 alkyl)2, or 3- to 7-membered monocyclic heterocycloalkyl, wherein —O—(C1-C6 alkyl), —N(C1-C6 alkyl)2, or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more —C(═O)OH. Embodiment 41: T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by, and Each R T are independently halogen, —OH, —O—(C1-C6 alkyl), or 3- to 7-membered heterocycloalkyl, wherein —O—(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more —C(═O)OH. Embodiment 42: T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T optionally replaced by, and Each R T are independently halogen, —OH, —O—(C1-C6 alkyl), or 3- to 7-membered monocyclic heterocycloalkyl, wherein —O—(C1-C6 alkyl), or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more —C(═O)OH. Embodiment 43: T is one or more R T The compound according to any one of the preceding embodiments, wherein the alkyl group is -O-(C1-C6 alkyl) optionally substituted with Embodiment 44: The compound according to any one of the preceding embodiments, wherein T is —OCH 3 . Embodiment 45: T is one or more R T The compound according to any one of the preceding embodiments, wherein the alkyl group is -NH-(C1-C6 alkyl) optionally substituted with Embodiment 46: The compound according to any one of the preceding embodiments, wherein T is -NHCH3. Embodiment 47: T is one or more R T The compound according to any one of the preceding embodiments, wherein R is C1-C6 alkyl optionally substituted with Embodiment 48: The compound according to any one of the preceding embodiments, wherein T is C1-C6 alkyl. Embodiment 49: The compound according to any one of the preceding embodiments, wherein T is methyl or ethyl. Embodiment 50: The compound according to any one of the preceding embodiments, wherein T is C1-C6 alkyl substituted with one or more halogens. Embodiment 51: The compound according to any one of the preceding embodiments, wherein T is -CHFCl. Embodiment 52: T is one or more R T The compound according to any one of the preceding embodiments, wherein the alkyl group is C2-C6 alkenyl optionally substituted with Embodiment 53: The compound according to any one of the preceding embodiments, wherein T is C2-C6 alkenyl. Embodiment 54: The compound according to any one of the preceding embodiments, wherein T is ethenyl. Embodiment 55: The compound according to any one of the preceding embodiments, wherein T is propenyl. Embodiment 56: The compound according to any one of the preceding embodiments, wherein T is pentenyl. Embodiment 57: T is one or more R T The compound according to any one of the preceding embodiments, wherein the compound is C2-C6 alkenyl substituted with Embodiment 58: The compound of any one of the preceding embodiments, wherein T is C2-C6 alkenyl substituted with one or more -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or 3-10 membered heterocycloalkyl, wherein the 3-10 membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH. Embodiment 59: The compound according to any one of the preceding embodiments, wherein T is C2-C6 alkynyl. Embodiment 60: The compound according to any one of the preceding embodiments, wherein T is propynyl. Embodiment 61: T is one or more R T The compound according to any one of the preceding embodiments, wherein the compound is C2-C6 alkynyl substituted with Embodiment 62: T is one or more R T The compound according to any one of the preceding embodiments, wherein the compound is propynyl substituted with Embodiment 63: The compound according to any one of the previous embodiments, wherein T is propynyl substituted with one or more 3-10 membered heterocycloalkyl. Embodiment 64: T is [ka] The compound of any one of the preceding embodiments, wherein Embodiment 65: T is [ka] The compound of any one of the preceding embodiments, wherein Embodiment 66: At least one R T The compound of any one of the preceding embodiments, wherein is halogen. Embodiment 67: At least one R T The compound of any one of the preceding embodiments, wherein is CN, —OH, or —NH 2 . Embodiment 68: At least one R T is -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2, in which -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2 is selected from the group consisting of one or more R Ta The compound according to any one of the preceding embodiments, optionally substituted with Embodiment 69: At least one R T The compound according to any one of the preceding embodiments, wherein is —O—(C1-C6 alkyl) or —N(C1-C6 alkyl)2. Embodiment 70: At least one R T is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R Ta The compound according to any one of the preceding embodiments, optionally substituted with Embodiment 71: At least one R T is C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; C3-C 10 Cycloalkyl, C6-C 10 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more RTa The compound according to any one of the preceding embodiments, optionally substituted with Embodiment 72: At least one R T The compound of any one of the preceding embodiments, wherein is a 3- to 10-membered heterocycloalkyl substituted with one or more C(=O)OH. Embodiment 73: At least one R Ta The compound of any one of the preceding embodiments, wherein is C(=O)OH. Embodiment 74: At least one R Ta is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The compound according to any one of the preceding embodiments, wherein the heterocycloalkyl is aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl. Embodiment 75: Ar 1 is one or more R A1 C6-C optionally substituted with 10 is aryl, Each R A1 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 selected from the group consisting of one or more R A1a optionally replaced by Each R A1aare independently halogen, CN, -OH, -NH, -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 selected from the group consisting of one or more R A1b optionally replaced by, and Each R A1b is independently halogen, CN, —OH, or —NH 2 . Embodiment 76: Ar 1 But C6-C 10 The compound according to any one of the preceding embodiments, which is aryl. Embodiment 77: Ar 1 But there is one or more R A1 C6-C substituted with 10 The compound according to any one of the preceding embodiments, which is aryl. Embodiment 78: Ar 1 is one or more halogens, -OR A1a or phenyl substituted with —O—(C1-C6 alkyl), where —O—(C1-C6 alkyl) is selected from the group consisting of one or more R A1a and each R A1a independently, C6-C 10 aryl or 5-10 membered heteroaryl, in which case C6-C 10 The compound according to any one of the preceding embodiments, wherein the aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogens. Embodiment 79: Ar 1 The compound of any one of the preceding embodiments, wherein is phenyl substituted with one or more halogens. Embodiment 80: Ar 1The compound according to any one of the preceding embodiments, wherein is phenyl substituted with one F and one Cl. Embodiment 81: Ar 1 is phenyl optionally substituted with one or more halogens, where phenyl is —O—(C6-C 10 aryl) or -O-(5-10 membered heteroaryl), in which case -O-(C6-C 10 The compound of any one of the preceding embodiments, wherein -O-(aryl) or -O-(5-10 membered heteroaryl) is optionally substituted with one or more halogens. Embodiment 82: Ar 1 is phenyl optionally substituted with one or more halogens, wherein phenyl is further substituted with -O-phenyl or -O-pyridinyl, wherein -O-phenyl or -O-pyridinyl is optionally substituted with one or more halogens. Embodiment 83: Ar 1 teeth, [ka] The compound of any one of the preceding embodiments, wherein Embodiment 84: Ar 1 teeth, [ka] The compound of any one of the preceding embodiments, wherein Embodiment 85: Ar 1 teeth, [ka] The compound of any one of the preceding embodiments, wherein Embodiment 86: Ar 1 teeth, [ka] The compound of any one of the preceding embodiments, wherein Embodiment 87: At least one R A1 The compound of any one of the preceding embodiments, wherein is halogen. Embodiment 88: At least one R A1 is F and at least one R A1 The compound according to any one of the preceding embodiments, wherein is Cl. Embodiment 89: At least one R A1 The compound of any one of the preceding embodiments, wherein is CN, —OH, or —NH 2 . Embodiment 90: At least one R A1 But, -OR A1a The compound of any one of the preceding embodiments, wherein Embodiment 91 At least one R A1 is -O-(C6-C 10 aryl) or -O-(5- to 10-membered heteroaryl), in which case -O-(C6-C 10 -aryl) or -O-(5- to 10-membered heteroaryl) may be one or more R A1b The compound according to any one of the preceding embodiments, optionally substituted with Embodiment 92: At least one R A1 is -O-(C6-C 10 aryl) or -O-(5- to 10-membered heteroaryl), in which case -O-(C6-C 10 The compound of any one of the preceding embodiments, wherein -O-(aryl) or -O-(5-10 membered heteroaryl) is optionally substituted with one or more halogens. Embodiment 93: At least one R A1The compound according to any one of the previous embodiments, wherein is -O-phenyl or -O-pyridinyl, wherein -O-phenyl or -O-pyridinyl is optionally substituted with one or more halogens. EMBODIMENT 94: 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, wherein -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R A1a The compound according to any one of the preceding embodiments, optionally substituted with EMBODIMENT 95 At least one R A1 is one or more C6-C 10 -O-(C1-C6 alkyl) substituted with aryl or 5-10 membered heteroaryl, where C6-C 10 The compound according to any one of the preceding embodiments, wherein the aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogens. EMBODIMENT 96 At least one R A1 is -O-CH2-(C6-C 10 aryl) or -O-CH2-(5- to 10-membered heteroaryl), in which case -O-CH2-(C6-C 10 The compound of any one of the preceding embodiments, wherein -O-CH2- (aryl) or -O-CH2- (5-10 membered heteroaryl) is optionally substituted with one or more halogens. EMBODIMENT 97 At least one R A1 The compound of any one of the preceding embodiments, wherein is -O-CH2-phenyl or -O-CH2-pyridinyl, wherein -O-CH2-phenyl or -O-CH2-pyridinyl is optionally substituted with one or more halogens. EMBODIMENT 98: At least one R A1 is C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; C3-C 10 Cycloalkyl, C6-C 10 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R A1a The compound according to any one of the preceding embodiments, optionally substituted with EMBODIMENT 99: At least one R A1a is 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 selected from the group consisting of one or more R A1b The compound according to any one of the preceding embodiments, optionally substituted with EMBODIMENT 100: At least one R A1a is C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; C3-C 10 Cycloalkyl, C6-C 10 An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R A1b The compound according to any one of the preceding embodiments, optionally substituted with Embodiment 101: At least one R A1a is C6-C 10 aryl or 5- to 10-membered heteroaryl, C6-C 10 The compound according to any one of the preceding embodiments, wherein the aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogens. Embodiment 102: At least one R A1a The compound according to any one of the preceding embodiments, wherein is phenyl or pyridinyl, wherein phenyl or pyridinyl is optionally substituted with one or more halogens. Embodiment 103: At least one R A1b The compound of any one of the preceding embodiments, wherein is halogen. Embodiment 104: At least one R A1b is F and at least one R A1b The compound according to any one of the preceding embodiments, wherein is Cl. Embodiment 105: At least one R A1b The compound of any one of the preceding embodiments, wherein is CN, —OH, or —NH 2 . EMBODIMENT 106: Z, [ka] and T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, or C2-C6 alkynyl is selected from the group consisting of one or more R T and in which case the C-C alkenyl is optionally substituted with one or more R T is replaced by Each R T are independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3-7 membered heterocycloalkyl, or 5-10 membered heteroaryl; and -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 Cycloalkyl, C6-C 10 An aryl, a 3- to 7-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Ta optionally replaced by, and Each R Ta are independently selected from 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 preceding embodiments, wherein the heterocycloalkyl is aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl. EMBODIMENT 107: Z, [ka] When T is [ka] Th...

Claims

1. A compound of the following formula (II'): 【Chemistry 1】 or a pharmaceutically acceptable salt or stereoisomer thereof, Z is a 3- to 12-membered heterocycloalkyl optionally substituted with one or more R Z ; 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; —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 the cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Za ; each R Za 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; 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 alkynyl, wherein —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 alkynyl is optionally substituted with one or more R T ; 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 -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; the cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Ta ; each R Ta is independently halogen, CN, —OH, —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 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; Ar 1 is of the following formula iii-1: 【Chemistry 2】 During the ceremony, R 4 is hydrogen or halogen; A compound, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 , R 6 are, independently of each other, F or Cl.

2. The compound, pharmaceutically acceptable salt or stereoisomer of claim 1, wherein R 4 is hydrogen.

3. The compound, pharmaceutically acceptable salt or stereoisomer of claim 1 or 2, wherein R 5 is F.

4. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein 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, wherein said 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 optionally substituted with one or more R Z .

5. Z is 【Transformation 3】 5. The compound, pharmaceutically acceptable salt or stereoisomer according to any one of claims 1 to 4, wherein:

6. Z is 【Chemistry 4】 6. The compound, pharmaceutically acceptable salt or stereoisomer according to any one of claims 1 to 5, wherein:

7. Z is 【Transformation 5】 7. The compound, pharmaceutically acceptable salt or stereoisomer of any one of claims 1 to 6, wherein:

8. The compound, pharmaceutically acceptable salt or stereoisomer according to any one of claims 1 to 7, wherein at least one R Z is C 1 -C 6 alkyl.

9. The compound, pharmaceutically acceptable salt or stereoisomer according to any one of claims 1 to 8, wherein at least one R Z is methyl, ethyl or propyl.

10. The compound, pharmaceutically acceptable salt, or stereoisomer of any one of claims 1 to 9, wherein T is C 2 -C 6 alkenyl substituted with one or more R T .

11. The compound, pharmaceutically acceptable salt or stereoisomer of any one of claims 1 to 10, wherein each R T is independently halogen, -OH, -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 7-membered heterocycloalkyl, wherein the -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

12. The compound, pharmaceutically acceptable salt, or stereoisomer of any one of claims 1 to 11, wherein T is C 2 -C 6 alkenyl substituted with one or more 3- to 10-membered heterocycloalkyl.

13. T is 【Transformation 6】 13. The compound, pharmaceutically acceptable salt or stereoisomer of any one of claims 1 to 12, wherein:

14. The compound of formula (II') is a compound of the following formula (IV'): 【Transformation 7】 (IV′) 14. The compound, pharmaceutically acceptable salt or stereoisomer of any one of claims 1 to 13, wherein:

15. The compound of formula (II′) 【Chemistry 8-1】 【Chemistry 8-2】 【Chemistry 8-3】 【Chemistry 8-4】 【Chemistry 8-5】 【Chemistry 8-6】 【Chemistry 8-7】 【Chemistry 8-8】 [Chemistry 8-9] 【Chemistry 8-10】 【Chemistry 8-11】 【Chemistry 8-12】 【Chemistry 8-13】 【Chemistry 8-14】 【Chemistry 8-15】 【Chemistry 8-16】 15. The compound, pharmaceutically acceptable salt or stereoisomer of any one of claims 1 to 14, selected from: and pharmaceutically acceptable salts thereof.

16. The following compound: 【Chemistry 9-1】 【Chemistry 9-2】 【Chemistry 9-3】 【Chemistry 9-4】 or a pharmaceutically acceptable salt thereof.

17. A composition comprising a compound according to any one of claims 1 to 16, a pharmaceutically acceptable salt or stereoisomer, and a pharmaceutically acceptable carrier.

18. A compound, a pharmaceutically acceptable salt or stereoisomer according to any one of claims 1 to 16, or a composition according to claim 17, for use in the prevention or treatment of cancer.

19. 19. The compound, pharmaceutically acceptable salt, stereoisomer, or composition for use according to claim 18, wherein the cancer is a solid tumor.

20. 20. The compound, pharmaceutically acceptable salt, stereoisomer, or composition for use according to claim 18 or 19, wherein the cancer is bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma, head and neck cancer, lung cancer, or non-small cell lung cancer, or any subtype thereof.

21. 21. The compound, pharmaceutically acceptable salt, stereoisomer, or composition for use according to any one of claims 18 to 20, wherein the cancer is glioblastoma or non-small cell lung cancer, or any subtype thereof.

22. 22. The compound, pharmaceutically acceptable salt, stereoisomer, or composition for use according to any one of claims 18 to 21, wherein the cancer is glioblastoma.

23. A compound, pharmaceutically acceptable salt, stereoisomer, or composition for use according to any one of claims 18 to 21, wherein the cancer is non-small cell lung cancer.

24. 24. The compound, pharmaceutically acceptable salt, stereoisomer, or composition for use according to any one of claims 18 to 23, wherein the cancer or tumor, or cells thereof, express an oncogenic variant of an ErbB receptor.

25. 25. The compound, pharmaceutically acceptable salt, stereoisomer, or composition for use according to claim 24, wherein the oncogenic variant of the ErbB receptor comprises an allosteric mutation.

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