Alkynyl quinazoline 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 and the benefit thereof to U.S. Application No. 63 / 065,028, filed on August 13, 2020, and U.S. Application No. 62 / 887,392, filed on August 15, 2019, the entire contents of each of which are incorporated herein by reference.

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

Background Art

[0003] Mutations that affect either the intracellular catalytic domain or the extracellular ligand-binding domain of the ErbB receptor can give rise to oncogenic activity (the ErbB protein family consists of four members including ErbB-1, also known as epidermal growth factor receptor (EGFR) in humans, and Erb-2, also known as HER2). ErbB inhibitors are known treatments for some cancers. However, not all patients respond well to this treatment. Thus, there has long been a 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 having these oncogenic mutations without the variability in responsiveness observed when patients having these ErbB variants are treated using existing standard treatments.

Summary of the Invention

[0004] In some aspects, the present disclosure provides a compound of formula (I’),

Chemical Formula

[0005] In some embodiments, the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof:

Chemical formula

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

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

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

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

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

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

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

[0013] R a One of 3 forms a ring with R

[0014] In some embodiments where one of R a forms a ring with R 3 the formed ring is a 4-, 5- or 6-membered ring, or a 5- or 6-membered ring, or a 5-membered ring.

[0015] R 2 One of 3 forms a ring with R

[0016] In some embodiments, Ar 1 is a compound of formula i, or a pharmaceutically acceptable salt or stereoisomer thereof,

Chemical formula

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

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

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

[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,

Chemical formula

[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 -(CH2)- or -(CH2)2- that forms a ring together with R 3 , or R 2 is -(CH2)- or -(CH2)2- that forms a ring together with one of R a .

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

[0025] In some embodiments, Ar 1is 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, [Chemical formula] wherein, X 3 is CH or N, o is 0 or 1, R 4 is hydrogen or halogen, preferably F or Cl, R 5 and R 6 are each independently hydrogen, -CF3, 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 are hydrogen. In some embodiments, R b and R c and R d are hydrogen.

[0029] In some embodiments, R 2 is methyl, or R 2 is -(CH2)- or -(CH2)2- that forms a ring with R 3 , or R 2 is -(CH2)- or -(CH2)2- that forms a ring with one of R a s.

[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, [Chemical formula] wherein, 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 and R 6 are independently of each other hydrogen, -CF3, or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F.

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

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

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

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

[0035] In some embodiments, Ar​1 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,

Chemical formula

[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 are hydrogen. In some embodiments, R b , R c and R d are hydrogen.

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

[0040] In some embodiments, the present disclosure provides a compound of Formula IIa or IIb below, or a pharmaceutically acceptable salt or stereoisomer thereof:

Chemical formula

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

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

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

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

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

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

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

[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: [Chemical formula] Wherein, R 1is H or F, and 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, and R 5 , R 5 ’, R 6 ’, R 6 ’ are each independently hydrogen, -CF3 or halogen, preferably F or Cl, and Z is selected from:

Chemical formula

[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 formula V-1, V-2, V-3, or V-4 below or a pharmaceutically acceptable salt or stereoisomer thereof:

Chemical formula

Chemical formula

[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 present disclosure provides a compound of formula VI-1, VI-2, VI-3, or VI-4 below or a pharmaceutically acceptable salt or stereoisomer thereof:

Chemical formula

Chemical formula

[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 below, or a pharmaceutically acceptable salt or stereoisomer thereof:

Chemical formula

Chemical formula

[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 a composition comprising a compound described in any of the embodiments described herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

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

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

[0064] In some aspects, the present disclosure is directed to a method of inhibiting an oncogenic variant of the ErbB receptor (e.g., an oncogenic variant of EGFR), which comprises 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 the ErbB receptor (e.g., an oncogenic variant of EGFR), which comprises 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, which comprises 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 a method of preventing or treating cancer, which comprises administering to a subject in need thereof a composition described herein.

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

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

[0070] In some embodiments, the present disclosure is directed to the compositions described herein for use in inhibiting oncogenic variants of ErbB receptors (e.g., oncogenic variants of EGFR).

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

[0072] In some embodiments, the present disclosure is directed to the use of the compounds described herein in the manufacture of a medicament for inhibiting oncogenic variants of ErbB receptors (e.g., oncogenic variants of EGFR).

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

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

[0075] In some embodiments, the present disclosure is directed to a method for 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 embodiments, the present disclosure is directed to the compounds described in any of the embodiments described herein for use in the prevention or treatment of glioblastoma.

[0077] In some embodiments, 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 embodiments, the present disclosure is directed to a composition described in any of the embodiments described herein for use in preventing or treating glioblastoma.

DETAILED DESCRIPTION OF THE INVENTION

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

[0080] Mutations that affect either the intracellular catalytic domain or the extracellular ligand-binding domain of the ErbB receptor can give rise to oncogenic activity (the ErbB protein family consists of four members including ErbB-1, also known as epidermal growth factor receptor (EGFR) in humans, and Erb-2, also known as HER2). Extracellular variants of the ErbB receptor in cancers 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). The expression of EGFR-VIII in GBM tends to be mutually exclusive with the expression of other RTK oncogenes that are co-expressed with EGFR variants in only 7% of GBM tumors (Furnari, Cloughesy et al. 2015). These data indicate how EGFR-VIII has a major and mutually exclusive expression pattern in GBM compared to other cancer 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 it is only one of several abnormally spliced variants of EGFR expressed in GBM tumors. The other two resulted in exon 12-13 (EGFR-VVI) and exon 14-15 truncation (EGFR-VII). Similar to 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 that are transforming and tumorigenic.

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

[0084] Short insertions within exon 20 of EGFR and HER2 are expressed by lung adenocarcinoma tumors and other tumor groups. ErbB exon 20 insertion 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, transform BaF3 cells into IL-3 independence, and promote tumor growth in vivo.

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

[0086] Paradoxical ErbB receptor activation The mechanisms described herein apply to any form of cancer in which these EGFR variants of the present disclosure are expressed, and the spread of these variants in glioblastoma (GBM) is provided as an example. Other cancers expressing the EGFR variants of the present disclosure include, but are not limited to, solid cancers, epithelial cancers, and / or cancers derived from epithelium, 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 often 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. The present disclosure provides the mechanisms of activation of the most commonly occurring variants, EGFR-VIII, EGFR-VII, EGFR-VVI, EGFR-G598V, and EGFR-A289V. Each isoform / point mutation is the result of unique external domain changes, 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-activated variants. Rindopepimut (Celldex) is a vaccine that selectively elicits an immunological response against tumor cells that express EGFR-VIII but do not express wild-type EGFR or other splice-activated isoforms. Other EGFR isoforms expressed in GBM tumors (EGFR-VII and EGFR-VVI) are constitutively active covalent receptors, and their expression can limit the breadth and duration of the therapeutic benefit of ErbB inhibitors that are selective only for EGFR-VIII. Thus, it may be useful to exclude patients whose tumors express EGFR-VII, EGFR-VVI, or EGFR external domain point mutants from treatment with EGFR-VIII-selective therapies.

[0089] The heterogeneous genotype expression patterns of multiple extracellular domain variants of the ErbB receptor in tumors indicate that small molecule inhibitors that inhibit all variants are preferred. The family of covalently activated EGFR isoforms responds very differently to small molecule ErbB inhibitors compared to the EGFR catalytic domain mutations observed in NSCLC. Importantly, all type I inhibitors, including erlotinib, induce the formation of covalent EGFR dimers and increase EGFR phosphorylation at sub-saturating concentrations, an activity that is further enhanced when the ErbB inhibitor is washed out. This appears as a paradoxical activation of proliferation at sub-saturating concentrations.

[0090] The discovery of the paradoxical activation of proliferation by type I ErbB inhibitors at sub-saturating concentrations has been further demonstrated for a series of extracellular variants of HER2 that are widespread in several cancers, including breast and bladder. The levels of all variants present as covalently activated receptors, and of covalent dimers, increased after treatment with type I inhibitors, including sapitinib and afatinib. Similar to the covalently activated EGFR variants, sub-saturating doses of type I inhibitors paradoxically increased the phosphorylation of HER2 variants and increased the proliferation of cells expressing them.

[0091] In contrast to type I inhibitors, the present disclosure shows that non-type I (e.g., type II) inhibitors, including neratinib, do not have paradoxical activation against cells expressing ErbB extracellular domain variants. Neratinib has been found to be a typical example of a preferred molecule that is both potent and selective for each member of the covalently activated EGFR family compared to wild-type EGFR.

[0092] In summary, the present disclosure provides a structure / function relationship for predicting how structural variations that affect receptor regions distal to the active site can confer dramatically different responses to small molecule active site inhibitors. The discoveries described herein regarding the paradoxical activation of ErbB receptor variants activated by covalent binding with type I inhibitors have important clinical implications. The data of the present disclosure provide a mechanistic explanation for the failed clinical studies of type I inhibitors in tumor types where the expression of covalent-bond-activated ErbB receptors is widespread. This includes erlotinib and gefitinib in GBM tumors, erlotinib in SCCHN tumors, and sapitinib in breast tumors.

[0093] Glioblastoma Glioblastoma (GBM), grade IV astrocytoma, is the most common form of brain cancer. The prognosis of this disease is poor. The treatment regimen of radiation and temozolomide following surgery is the standard treatment, but the median overall survival (OS) by this is only 14.6 months, and most patients do not survive for 5 years. Over the past 10 years, there has been little progress in extending the survival of GBM patients. In the recurrent setting, bevacizumab showed an improvement in progression-free survival benefit, but the addition of bevacizumab to the standard treatment therapy in the front-line setting did not result in an OS benefit.

[0094] EGFR is the most frequently altered oncogene in GBM. In addition to EGFR gene amplification, many tumors express variants generated by abnormal splicing or genomic mutations. The first recognized variant is EGFR-VIII, which results from the 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. The expression of EGFR-VIII is associated with poor long-term overall survival in GBM.

[0095] RNA sequencing data revealed that it is only one of several abnormally spliced variants of EGFR expressed in GBM tumors. The other two result in exon 12-13 (EGFR-Vvi) and truncation of 14-15 (EGFR-Vii). Similar to 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 that are transforming and tumorigenic. The complex situation of EGFR changes in GBM is further complicated by the finding that many tumors express more than one receptor variant.

[0096] Because the expression of multiple EGFR variants in GBM gives rise to transformation and tumorigenic activity, and because EGFR is the most frequently altered oncogene present in GBM tumors, EGFR is a particularly attractive target for small molecule ErbB inhibitors. After the success of small molecule EGFR therapeutics (erlotinib, gefitinib, and afatinib) against NSCLC tumors bearing 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, they were unable to confer any benefit, even to those tumors expressing EGFR-VIII. Surprisingly, some evidence suggests that erlotinib promoted disease progression. A phase II trial evaluating erlotinib in combination with radiation and temozolomide showed median progression-free survival (mPFS) and overall survival (mOS) of 2.8 months and 8.6 months, compared with 6.9 months and 14.6 months for patients receiving radiation and temozolomide alone. Another randomized phase II trial using erlotinib showed that patients receiving erlotinib, including those with tumors expressing EGFR-VIII, had less progression compared to patients receiving standard therapy. The clinical failure of ErbB inhibitors such as erlotinib in GBM tumors has called into question the role of EGFR as a driver of tumor growth in GBM, leading to an inquiry into why ErbB inhibitors, which were highly effective in treating EGFR mutations in lung cancer, were so ineffective in treating EGFR variants in GBM.

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

[0098] Several recent preclinical studies have suggested that EGFR kinase inhibitors such as erlotinib are not very effective in inhibiting EGFR-VIII, but no mechanism has been proposed for this effect. There is also a lack of current understanding of the mechanisms involved in the activation of other extracellular domain variants in GBM, including EGFR-VII and EGFR-A289V. The present disclosure provides the mechanisms of receptor activation and the effects on ErbB inhibitor activity of four groups of the most common extracellular domain variants in GBM, EGFR-VIII, EGFR-VII, EGFR-VVI, EGFR-G598V, and EGFR-A289V.

[0099] Similar to EGFR-VIII, all additional groups of EGFR variants commonly occurring in GBM (EGFR-VII, EGFR-VVI, EGFR-G598V, and EGFR-A289V) exist as constitutively active covalent dimers and together form a family of EGFR isoforms activated by this common mechanism. Furthermore, the present disclosure shows that the tendency of these variants to dimerize covalently is related to the three-dimensional structure of the intracellular catalytic site and confers unique activity against a class of small molecule inhibitors that bind to this distal site. Inhibitors that stabilize the active three-dimensional structure of kinases (including type I inhibitors, erlotinib) induce the formation of covalent dimers for all covalently activated EGFR isoforms. This is related to the tendency of type I inhibitors to increase EGFR phosphorylation at sub-saturating concentrations and paradoxically stimulate the growth of cells expressing covalently activated EGFR isoforms.

[0100] Neither enhanced dimerization or paradoxical activation of EGFR is seen with small molecule inhibitors (including type II inhibitors, lapatinib and neratinib) that stabilize the inactive kinase three-dimensional structure. Examples of type II inhibitors that are potent inhibitors of covalently activated EGFR isoforms and are selective for this family compared to WT-EGFR have been identified.

[0101] Similar to the mutations identified for EGFR, the present disclosure identifies a group of splice events and mutations that affect the CR domains of HER2 and HER4. The present disclosure shows that this group of splice events and mutations that affect the CR domains of HER2 and HER4 exist as covalent dimers and are paradoxically activated by agents in the type I binding mode. These data provide a mechanistic explanation for the failure of multiple clinical trials with type I inhibitors, including >30 clinical trials of type I ErbB inhibitors in GBM. Collectively, these data indicate that tumors expressing EGFR isoforms activated by covalent bonding 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 for the ErbB family activated by covalent bonding.

[0102] Definitions Unless otherwise specified, the following general definitions apply to the compounds of the present disclosure by description.

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

[0104] However, it is understood that the compounds disclosed herein can be represented by one specific structure. Such a specific structure should not be construed as being limited to one or another isomer, tautomer, positional isomer, or stereoisomer, nor does it exclude a mixture of isomers, tautomers, positional isomers, or stereoisomers. In some embodiments, the representation of the compounds herein in a specific structure is intended to include and refer to each of the available isomers, tautomers, positional isomers, and stereoisomers of the compound, or any mixture thereof, while the representation is also intended to refer to the specific structure of the compound.

[0105] Furthermore, it is understood that the compounds disclosed herein can be represented without a particular structure (e.g., without a particular stereochemistry). Such representations are intended to encompass all available isomers, tautomers, positional isomers, and stereoisomers of the compound. In some embodiments, the representation of the compounds herein without a particular 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 the same molecular formula but differ in the order of bonding of their atoms or in the spatial arrangement of their atoms. Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereoisomers", and stereoisomers that are mirror images that cannot be superimposed on each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of the 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 "mixture of diastereomers". When there is one chiral center, the absolute configuration (R or S) of that chiral center can be used to characterize the stereoisomer. The 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" means a diastereomer whose existence is hindered by rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are named differently by the prefixes cis and trans, or Z and E, which indicate whether 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 one another" is understood to mean that when a group occurs two or more times in any compound, its definition for each occurrence is independent of any other occurrence.

[0111] It is further understood that the dashed line (or a wave perpendicular to the bond) indicates the binding site of the residue (i.e., the partial formula).

[0112] As used herein, the terms "halogen" or "hal" can 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 groups of straight-chain (linear) saturated aliphatic hydrocarbons of C1, C2, C3, C4, C5 or C6, and branched-chain saturated aliphatic hydrocarbon groups of C3, C4, C5 or C6. For example, C1-C6 alkyl is intended to include alkyl groups of C1, C2, C3, C4, C5, and C6. Examples of 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, the straight-chain or branched-chain alkyl has 6 or fewer carbon atoms (e.g., C 1- C6 for straight-chain and C 3- C6 for branched-chain), and in another embodiment, the straight-chain 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. The term "C 1-4 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, tert-butyl.

[0114] As used herein, the term "optionally substituted alkyl" refers to unsubstituted alkyl or alkyl in which the 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, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0115] As used herein, the term "alkenyl" includes an unsaturated aliphatic group that is similar to the above-described alkyl in length and substitution possibilities but contains 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, the straight-chain or branched-chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-C6 for straight-chain and 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 the 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, sulfonamide, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic moiety or heteroaromatic moiety.

[0117] As used herein, the term "alkynyl" includes an unsaturated aliphatic group that is similar to the above-described alkyl in length and substitution possibilities, but contains at least one triple bond. For example, the term "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and branched-chain alkynyl groups. In certain embodiments, the straight-chain or branched-chain alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-C6 for straight-chain and 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, the term "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to include a divalent unsaturated aliphatic hydrocarbon group of a C2, C3, C4, C5, or C6 chain (straight-chain or branched-chain). For example, the C2-C6 alkenylene linker is intended to include C2, C3, C4, C5, or C6 alkenylene linker groups.

[0118] As used herein, the term "optionally substituted alkynyl" refers to unsubstituted alkynyl or alkynyl in which the 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, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0119] Other optionally substituted moieties (e.g., optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, etc.) include both unsubstituted moieties and moieties having 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 term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl groups covalently bonded to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy group, ethoxy group, isopropyloxy group, propoxy group, butoxy group, and pentoxy group.

[0121] As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) system of saturated or partially unsaturated hydrocarbons having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, adamantyl, hexahydroindacenyl. It is understood that for polycyclic (e.g., fused, bridged, or spirocyclic) systems, only one of the rings therein needs to be non-aromatic.

[0122] As used herein, the term "aryl" refers to an aromatic group that includes a "conjugated" or polycyclic system 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, etc. In some embodiments, aryl is phenyl.

[0123] As used herein, the term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic ring system having from 3 to 8 members, bicyclic ring system having from 7 to 12 members (fused, bridged or spiro), or tricyclic ring system having from 11 to 14 members (fused, bridged or spiro), 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, unless otherwise specified.Examples of the heterocycloalkyl group 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-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-azaspiro[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’-isobenzofuran]-yl, 7’H-spiro[cyclohexane-1,5’-furo[3,4-b]pyridine]-yl, 3’H-spiro[cyclohexane-1,1’-furo[3,4-c]pyridine]-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 heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic.In some embodiments, the heterocycloalkyl is oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 2-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 stable 5-membered, 6-membered or 7-membered monocyclic, or 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered bicyclic aromatic heterocycles consisting of carbon atoms and one or more heteroatoms independently selected from the group consisting of, for example, nitrogen, oxygen and sulfur, for example 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or for example 1, 2, 3, 4, 5, or 6 heteroatoms. The nitrogen atom may be substituted or unsubstituted (i.e., it may be N or NR, where R is H or another defined substituent). The nitrogen heteroatom and the sulfur heteroatom may optionally be oxidized (i.e., N→O, and S(O) p, where p = 1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocycle is 1 or less. In some embodiments, the term "heteroaryl" has 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, and the number of N atoms is preferably 0, 1, 2, or 3, and the number of O and S atoms is each 0, 1, or 2 (a fully aromatic ring system). 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, a cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted at one or more ring positions (e.g., a ring-forming carbon or a heteroatom such as N) with the substituents described above, e.g., alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or a substituted aromatic or heteroaromatic moiety. In some embodiments, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with a halogen (e.g., F or Cl).

[0126] As used herein, the term “substituted” means that any one or more hydrogen atoms on the designated atom are replaced with a selected group from the designated groups, provided that the normal valency of the designated atom is not exceeded and that a stable compound results from the substitution. When a substituent is oxo or keto (i.e., =O), two hydrogen atoms on the atom are replaced. A keto substituent is not present on an aromatic moiety. 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-stranded or double-stranded RNA, DNA, or hybrid polymers. Polynucleotides can include genomic sequences, extra-genomic and plasmid sequences that express or are adapted to express polypeptides, and smaller engineered gene segments.

[0128] An "isolated nucleic acid" is a nucleic acid substantially separated from other genomic DNA sequences that naturally accompany its native sequence, as well as proteins or complexes such as ribosomes and polymerases. The term encompasses nucleic acid sequences removed from their native environment, including recombinant or cloned DNA isolates, and chemically synthesized analogs or biologically synthesized analogs by heterologous systems. Substantially pure nucleic acids include isolated forms of the nucleic acid. Of course, this refers to the originally isolated nucleic acid, but does not exclude genes or sequences subsequently added by human hand to the isolated nucleic acid.

[0129] The term "polypeptide" is used in its conventional sense, i.e., as a sequence of amino acids. Polypeptides are not limited to a particular 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 polypeptides, 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 the whole protein or a portion thereof.

[0130] "Isolated polypeptide" refers to a polypeptide that has been identified, separated from, and / or recovered from the components of its natural environment. In preferred embodiments, the isolated polypeptide is (1) greater than 95% by weight, 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 the N-terminal or internal amino acid sequence by use of a spinning cup sequencer, or (3) purified to homogeneity by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or preferably silver staining. An isolated polypeptide includes a polypeptide in situ within a recombinant cell because at least one component of the polypeptide's natural environment is not present. However, usually an isolated polypeptide is prepared by at least one purification step.

[0131] A polynucleotide of "native sequence" has the same nucleotide sequence as a polynucleotide that occurs in nature. A polypeptide of "native sequence" has the same amino acid sequence as a polypeptide that occurs in nature (e.g., EGFR). 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 the 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 the term is used herein, is a polypeptide that typically differs from the polypeptides specifically disclosed herein in one or more substitutions, deletions, additions, insertions, or inversions. Such variants can occur naturally, non-naturally, or be generated synthetically.

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

[0135] When comparing polynucleotide and polypeptide sequences, two sequences are said to be "identical" if the sequences of nucleotides or amino acids in the two sequences are the same when the two sequences are aligned for maximum correspondence, as described below. Comparisons between two sequences are typically performed by comparing sequences over a comparison window to identify and compare local regions of sequence similarity. As used herein, a "comparison window" refers to a segment of at least about 20 contiguous positions, usually 30 to about 75, 40 to about 50 contiguous positions, in which the sequences, after optimal alignment, can be compared to a reference sequence of the same number of contiguous positions.

[0136] Optimal alignment of arrays for comparison can be performed using the Megalign program of the Lasergene suite of bioinformatics software (DNASTAR, Inc., Madison, WI) using default parameters. This program embodies several alignment schemes described in the following references. Dayhoff, M.O. (1978) A model of evolutionary change in proteins-Matrices for detecting distant relationships. In Dayhoff, M.O. (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, D.G. and Sharp, P.M. (1989) CABIOS 5:151-153; Myers, E.W. and Muller W. (1988) CABIOS 4:11-17; Robinson, E.D. (1971) Comb. Theor 11:105; Santou, N. Nes, M. (1987) Mol. Biol. Evol. 4:406-425; Sneath, P.H.A. and Sokal, R.R. (1973) Numerical Taxonomy-the Principles and Practice of Numerical Taxonomy, Freeman Press, San Francisco, CA; Wilbur, W.J. and Lipman, D.J. (1983) Proc. Natl. Acad., Sci. USA 80:726-730。

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

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

[0139] In one example, for nucleotide sequences, the cumulative score can be calculated using parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for a pair of mismatched residues; always <0). Extension of a word hit in each direction stops when the cumulative alignment score drops by amount X from its maximum achieved value, when the cumulative score becomes zero or less due to the accumulation of one or more negative-score 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. The BLASTN program (for nucleotide sequences) uses a word length (W) of 11, an expectation value (E) of 10, and the BLOSUM62 score matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89:10915). The algorithm uses (B) 50, expectation value (E) 10, M = 5, N = -4, and comparison of both strands as default.

[0140] For amino acid sequences, a score matrix can be used to calculate the cumulative score. Extension of a word hit in each direction stops when the cumulative alignment score drops by amount X from its maximum achieved value, when the cumulative score becomes zero or less due to the accumulation of one or more negative-score 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, the "percent sequence identity" is determined by comparing two optimally aligned sequences over a comparison window of at least 20 positions, where a portion of the polynucleotide sequence or polypeptide sequence in the comparison window may include from 20% or less, usually 5 - 15%, or 10 - 12% additions or deletions (i.e., gaps) as compared to the reference sequence (excluding additions or deletions) for optimal alignment of the two sequences. The number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences is determined to obtain the number of matched positions, the number of matched positions is divided by the total number of positions in the reference sequence (i.e., window size), and the result is multiplied 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, corresponding to epidermal growth factor receptor [Homo sapiens] and Genbank accession number CAA25240).

[0143] The wild - type HER2 receptor sequence of the present disclosure can include 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 dcqsltrtvc aggcarckgp lptdccheqc 241 aagctgpkhs dclaclhfnh sgicelhcpa lvtyntdtfe smpnpegryt fgascvtacp 301 ynylstdvgs ctlvcplhnq evtaedgtqr cekcskpcar vcyglgmehl revravtsan 361 iqefagckki fgslaflpes fdgdpasnta plqpeqlqvf etleeitgyl yisawpdslp 421 dlsvfqnlqv irgrilhnga ysltlqglgi swlglrslre lgsglalihh nthlcfvhtv 481 pwdqlfrnph qallhtanrp edecvgegla chqlcarghc wgpgptqcvn csqflrgqec 541 veecrvlqgl preyvnarhc lpchpecqpq ngsvtcfgpe adqcvacahy kdppfcvarc 601 psgvkpdlsy mpiwkfpdee gacqpcpinc thscvdlddk gcpaeqrasp ltsiisavvg 661 illvvvlgvv fgilikrrqq kirkytmrrl lqetelvepl tpsgampnqa qmrilketel 721 rkvkvlgsga fgtvykgiwi pdgenvkipv aikvlrents pkankeilde ayvmagvgsp 781 yvsrllgicl tstvqlvtql mpygclldhv renrgrlgsq dllnwcmqia kgmsyledvr 841 lvhrdlaarn vlvkspnhvk itdfglarll dideteyhad ggkvpikwma lesilrrrft 901 hqsdvwsygv tvwelmtfga kpydgipare ipdllekger lpqppictid vymimvkcwm 961 idsecrprfr elvsefsrma rdpqrfvviq nedlgpaspl dstfyrslle dddmgdlvda 1021 eeylvpqqgf fcpdpapgag gmvhhrhrss strsgggdlt lglepseeea prsplapseg 1081 agsdvfdgdl gmgaakglqs lpthdpsplq rysedptvpl psetdgyvap ltcspqpeyv 1141 nqpdvrpqpp spregplpaa rpagatlerp ktlspgkngv vkdvfafgga venpeyltpq 1201 ggaapqphpp pafspafdnl yywdqdpper gappstfkgt ptaenpeylg ldvpv (corresponding to SEQ ID NO: 2, precursor of receptor tyrosine-protein kinase erbB-2 isoform a [Homo sapiens] and GenBank accession number NP_004439).

[0144] The wild-type HER2 receptor sequence of the present disclosure can include 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 dcqsltrtvc aggcarckgp lptdccheqc aagctgpkhs dclaclhfnh sgicelhcpa 241 lvtyntdtfe smpnpegryt fgascvtacp ynylstdvgs ctlvcplhnq evtaedgtqr 301 cekcskpcar vcyglgmehl revravtsan iqefagckki fgslaflpes fdgdpasnta 361 plqpeqlqvf etleeitgyl yisawpdslp dlsvfqnlqv irgrilhnga ysltlqglgi 421 swlglrslre lgsglalihh nthlcfvhtv pwdqlfrnph qallhtanrp edecvgegla 481 chqlcarghc wgpgptqcvn csqflrgqec veecrvlqgl preyvnarhc lpchpecqpq 541 ngsvtcfgpe adqcvacahy kdppfcvarc psgvkpdlsy mpiwkfpdee gacqpcpinc 601 thscvdlddk gcpaeqrasp ltsiisavvg illvvvlgvv fgilikrrqq kirkytmrrl 661 lqetelvepl tpsgampnqa qmrilketel rkvkvlgsga fgtvykgiwi pdgenvkipv 721 aikvlrents pkankeilde ayvmagvgsp yvsrllgicl tstvqlvtql mpygclldhv 781 renrgrlgsq dllnwcmqia kgmsyledvr lvhrdlaarn vlvkspnhvk itdfglarll 841 dideteyhad ggkvpikwma lesilrrrft hqsdvwsygv tvwelmtfga kpydgipare 901 ipdllekger lpqppictid vymimvkcwm idsecrprfr elvsefsrma rdpqrfvviq 961 nedlgpaspl dstfyrslle dddmgdlvda eeylvpqqgf fcpdpapgag gmvhhrhrss 1021 strsgggdlt lglepseeea prsplapseg agsdvfdgdl gmgaakglqs lpthdpsplq 1081 rysedptvpl psetdgyvap ltcspqpeyv nqpdvrpqpp spregplpaa rpagatlerp 1141 ktlspgkngv vkdvfafgga venpeyltpq ggaapqphpp pafspafdnl yywdqdpper 1201 gappstfkgt ptaenpeylg ldvpv (corresponding to SEQ ID NO: 3, 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 ekgerlpqpp ictidvymim vkcwmidsec rprfrelvse 961 fsrmardpqr fvviqnedlg paspldstfy rslledddmg dlvdaeeylv pqqgffcpdp 1021 apgaggmvhh rhrssstrsg ggdltlglep seeeaprspl apsegagsdv fdgdlgmgaa 1081 kglqslpthd psplqrysed ptvplpsetd gyvapltcsp qpeyvnqpdv rpqppspreg 1141 plpaarpaga tlerpktlsp gkngvvkdvf afggavenpe yltpqggaap qphpppafsp 1201 afdnlyywdq dppergapps tfkgtptaen peylgldvpv (corresponding to SEQ ID NO: 4, 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 can include 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 dcqsltrtvc aggcarckgp lptdccheqc 241 aagctgpkhs dclaclhfnh sgicelhcpa lvtyntdtfe smpnpegryt fgascvtacp 301 ynylstdvgs ctlvcplhnq evtaedgtqr cekcskpcar vcyglgmehl revravtsan 361 iqefagckki fgslaflpes fdgdpasnta plqpeqlqvf etleeitgyl yisawpdslp 421 dlsvfqnlqv irgrilhnga ysltlqglgi swlglrslre lgsglalihh nthlcfvhtv 481 pwdqlfrnph qallhtanrp edecvgegla chqlcarghc wgpgptqcvn csqflrgqec 541 veecrvlqgl preyvnarhc lpchpecqpq ngsvtcfgpe adqcvacahy kdppfcvarc 601 psgvkpdlsy mpiwkfpdee gacqpcpinc thscvdlddk gcpaeqrasp ltsiisavvg 661 illvvvlgvv fgilikrrqq kirkytmrrl lqetelvepl tpsgampnqa qmrilketel 721 rkvkvlgsga fgtvykgiwi pdgenvkipv aikvlrents pkankeilde ayvmagvgsp 781 yvsrllgicl tstvqlvtql mpygclldhv renrgrlgsq dllnwcmqia kgmsyledvr 841 lvhrdlaarn vlvkspnhvk itdfglarll dideteyhad ggkvpikwma lesilrrrft 901 hqsdvwsygv tvwelmtfga kpydgipare ipdllekger lpqppictid vymimvkcwm 961 idsecrprfr elvsefsrma rdpqrfvviq nedlgpaspl dstfyrslle dddmgdlvda 1021 eeylvpqqgf fcpdpapgag gmvhhrhrss strnm (corresponding to SEQ ID NO: 5, 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 include 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 dcqsltrtvc aggcarckgp lptdccheqc aagctgpkhs dclaclhfnh sgicelhcpa 241 lvtyntdtfe smpnpegryt fgascvtacp ynylstdvgs ctlvcplhnq evtaedgtqr 301 cekcskpcar vcyglgmehl revravtsan iqefagckki fgslaflpes fdgdpasnta 361 plqpeqlqvf etleeitgyl yisawpdslp dlsvfqnlqv irgrilhnga ysltlqglgi 421 swlglrslre lgsglalihh nthlcfvhtv pwdqlfrnph qallhtanrp edecvgegla 481 chqlcarghc wgpgptqcvn csqflrgqec veecrvlqgl preyvnarhc lpchpecqpq 541 ngsvtcfgpe adqcvacahy kdppfcvarc psgvkpdlsy mpiwkfpdee gacqpcpinc 601 ths (corresponding to SEQ ID NO: 6, receptor tyrosine-protein kinase erbB-2 isoform e [Homo sapiens] and GenBank accession number NP_001276867).

[0148] Based on the definitions provided through this application, one of ordinary skill in the art will recognize which combinations are synthetically feasible and realistic. For example, typical combinations of groups that result in heteroatoms directly linked to each other are not contemplated.

[0149] The compounds of the present disclosure In some embodiments, the present disclosure provides a compound of formula (I’),

Chemical formula

[0150] In some embodiments, 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 Zis a 3- to 12-membered heterocycloalkyl optionally substituted with, each R Z independently 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, C 3- C 10 cycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl, and -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C 10 cycloalkyl, C6-C 10 aryl, 3- or 5- to 10-membered heteroaryl is optionally substituted with one or more R Za and, each R Za independently 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 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 optionally substituted with one or more R T and, each R T independently is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10Aryl, 3- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Ta s. Each R Ta is independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, Ar 1 is optionally substituted with one or more R A1 s and is C6-C 10 aryl, Each R A1 is 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 optionally substituted with one or more R A1a s, and Each R A1a is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, 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 optionally substituted with one or more R A1b s, and Each RA1b is independently halogen, CN, -OH, or -NH2, provided that Z is

Chemical formula

[0151] In some embodiments, the compound is a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH or N, Z is 3- to 12-membered heterocycloalkyl optionally substituted with one or more R Z each R is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C each R Z is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C 10 cycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl, -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 or 5- to 10-membered heteroaryl is optionally substituted with one or more R Za each R is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C Za cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, 10 and is T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more R T and is optionally substituted with each R T is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 7-membered monocyclic heterocycloalkyl, or 5- to 10-membered heteroaryl, and -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Ta and is optionally substituted with each R Ta is independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, and Ar 1 is aryl C6-C optionally substituted with one or more R A1 and is optionally substituted with 10 and each R A1 is 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 optionally substituted with one or more R A1a and each R A1a is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, 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 optionally substituted with one or more R A1b and each R A1b is independently halogen, CN, -OH, or -NH2, provided that when Z is

Chemical formula

[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 a 3- to 12-membered heterocycloalkyl optionally substituted with one or more R Z and each R is independently halogen, -O-(C1-C6 alkyl), C1-C6 alkyl, or 3- to 10-membered heterocycloalkyl, and -O-(C1-C6 alkyl), C1-C6 alkyl, or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogens, Z and T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more R T and is optionally substituted with each R T is independently halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or 3- to 7-membered heterocycloalkyl, and -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 C6-C A1 aryl optionally substituted with one or more R 10 and each R A1 is independently halogen, -OR A1a , or -O-(C1-C6 alkyl) optionally substituted with one or more R A1a and each R A1a is independently C6-C 10 aryl or 5- to 10-membered heteroaryl, and C6-C 10 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 3- to 12-membered heterocycloalkyl optionally substituted with one or more R Z and each R Z is independently halogen, -O-(C1-C6 alkyl), C1-C6 alkyl, or 3- to 10-membered heterocycloalkyl, and -O-(C1-C6 alkyl), C1-C6 alkyl, or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogens T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more R T and is optionally substituted with each R T is independently halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or 3- to 7-membered monocyclic heterocycloalkyl, and -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 C6-C A1 aryl optionally substituted with one or more R 10 and each R A1 is independently halogen, -OR A1a , or -O-(C1-C6 alkyl optionally substituted with one or more R A1a and each R A1a is independently C6-C 10 aryl or 5- to 10-membered heteroaryl, and C6-C 10 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 3- to 12-membered heterocycloalkyl optionally substituted with one or more R Z and each R Z is independently halogen, -O-(C1-C6 alkyl), or C1-C6 alkyl, and -O-(C1-C6 alkyl) or C1-C6 alkyl is optionally substituted with one or more halogens T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more R T and is optionally substituted with each R T is independently halogen, -OH, -O-(C1-C6 alkyl), or 3- to 7-membered heterocycloalkyl, and -O-(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH Ar 1 is C6-C A1 aryl optionally substituted with one or more R 10 and each R A1 is independently halogen, -OR A1a or -O-(C1-C6 alkyl) optionally substituted with one or more R A1a and each R A1a is independently C6-C 10 aryl or 5- to 10-membered heteroaryl, and C6-C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogens provided that when Z is

Chemical formula

[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 3- to 12-membered heterocycloalkyl optionally substituted with one or more R Z and each R Zis independently halogen, -O-(C1-C6 alkyl), or C1-C6 alkyl, and -O-(C1-C6 alkyl) or C1-C6 alkyl is optionally substituted with one or more halogens, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more R T and each R T is independently halogen, -OH, -O-(C1-C6 alkyl), or 3- to 7-membered monocyclic heterocycloalkyl, and -O-(C1-C6 alkyl) or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH, Ar 1 is optionally substituted with one or more R A1 and is C6-C 10 aryl, each R A1 is independently halogen, -OR A1a or -O-(C1-C6 alkyl) optionally substituted with one or more R A1a and each R A1a is independently C6-C 10 aryl or 5- to 10-membered heteroaryl, and C6-C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogens, provided that when Z is

Chemical formula

[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 an optionally substituted 3- to 12-membered heterocycloalkyl, each R Z is independently halogen, -O-(C1-C6 alkyl), or C1-C6 alkyl, and -O-(C1-C6 alkyl) or C1-C6 alkyl is optionally substituted with one or more halogens, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more R T and each R T is independently halogen, -OH, -O-(C1-C6 alkyl), or 3- to 7-membered heterocycloalkyl, and -O-(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH, Ar 1 is C6-C 10 aryl optionally substituted with one or more halogens.

[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 an optionally substituted 3- to 12-membered heterocycloalkyl with one or more R Z and each R Z is independently halogen, -O-(C1-C6 alkyl), or C1-C6 alkyl, and -O-(C1-C6 alkyl) or C1-C6 alkyl is optionally substituted with one or more halogens, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more R T and each R Tis independently halogen, -OH, -O-(C1-C6 alkyl), or 3- to 7-membered monocyclic heterocycloalkyl, and -O-(C1-C6 alkyl) or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH, Ar 1 is C6-C optionally substituted with one or more halogens 10 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 3- to 12-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyls, T is C2-C6 alkenyl optionally substituted with one or more 6-membered heterocycloalkyls, and Ar 1 is 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 3- to 12-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyls, T is C2-C6 alkenyl optionally substituted with one or more 6-membered monocyclic heterocycloalkyls, and Ar 1 is C6 aryl optionally substituted with one or more halogens.

[0160] The variable W In some embodiments, W is CH.

[0161] In some embodiments, W is N.

[0162] The variables Z, R Z、 and R Za In some embodiments, Z is a 3- to 12-membered heterocycloalkyl optionally substituted with one or more R Z and each R is independently halogen, -O-(C1-C6 alkyl), C1-C6 alkyl, or 3- to 10-membered heterocycloalkyl, and -O-(C1-C6 alkyl), C1-C6 alkyl, or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogen. Z

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

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

[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, 2-oxa-5-azaspiro[3.4]octanyl, and oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azaspiro[3.3]heptanyl, or 2-oxa-5-azaspiro[3.4]octanyl is optionally substituted with one or more R Z .

[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, 2-oxa-5-azaspiro[3.4]octanyl, and 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 optionally substituted with one or more R Z groups.

[0167] In some embodiments, Z is

Chemical formula

[0168] In some embodiments, Z is

Chemical formula

[0169] In some embodiments, Z is

Chemical formula

[0170] In some embodiments, Z is

Chemical formula

[0171] In some embodiments, Z is

Chemical formula

[0172] In some embodiments, Z is

Chemical formula

[0173] In some embodiments, Z is

Chemical formula

[0174] In some embodiments, Z is

Chemical formula

[0175] In some embodiments, Z is

Chemical formula

[0176] In some embodiments, Z is

Chemical formula

[0177] In some embodiments, Z is

Chemical formula

[0178] In some embodiments, Z is

Chemical formula

[0179] In some embodiments, at least one R Z is 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 -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 substituted therewith.

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

[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 -O-(C1-C6 alkyl) substituted with one or more R Za .

[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 optionally substituted with one or more R Za .

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

[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 C1-C6 alkyl substituted with one or more R Za .

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

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

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

[0199] In some embodiments, at least one R Z is C2-C6 alkenyl or C2-C6 alkynyl, where the C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more Rs Za in this case.

[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, and the C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more Rs Za in this case.

[0201] In some embodiments, at least one R Z is a C3-C Za cycloalkyl that is optionally substituted with one or more Rs 10 in this case.

[0202] In some embodiments, at least one R Z is a C6-C Za aryl that is optionally substituted with one or more Rs 10 in this case.

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

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

[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 a 5- to 10-membered heteroaryl optionally substituted with one or more R Za .

[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 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[0213] The variables T, R T , and RTa In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more R T and each R T is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, and -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Ta and each R Ta is independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[0214] In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more R T and each R Tis independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 7-membered monocyclic heterocycloalkyl, or 5- to 10-membered heteroaryl, and -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 7-membered monocyclic heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Ta and each R Ta is independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[0215] In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more R T and each R T is independently halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or 3- to 7-membered heterocycloalkyl, and -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, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more R T and each R T is independently halogen, -OH, -O-(C1-C6 alkyl), or 3- to 7-membered heterocycloalkyl, and -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, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more R T and each R T is independently halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or 3- to 7-membered monocyclic heterocycloalkyl, and -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, and C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more R T and each R T is independently halogen, -OH, -O-(C1-C6 alkyl), or 3- to 7-membered heterocycloalkyl, and -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 optionally substituted -O-(C1-C6 alkyl).

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

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

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

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

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

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

[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 substituted C1-C6 alkyl.

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

[0232] In some embodiments, T is methyl substituted with one or more halogens (e.g., 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 -CH2CN.

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

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

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

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

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

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

[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- to 10-membered heterocycloalkyl, where the 3- to 10-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

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

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

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

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

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

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

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

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

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

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

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

[0254] In some embodiments, T is C2-C6 alkenyl substituted with one or more 3- to 7-membered monocyclic heterocycloalkyls, where the 3- to 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- to 7-membered monocyclic heterocycloalkyls.

[0256] In some embodiments, T is C2-C6 alkenyl substituted with one or more 6-membered heterocycloalkyls, where 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 heterocycloalkyls.

[0258] In some embodiments, T is C2-C6 alkenyl substituted with one or more 6-membered monocyclic heterocycloalkyls, where 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 heterocycloalkyls.

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

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

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

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

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

[0265] In some embodiments, T is -C≡C-CH2-R T and is -C≡C-CH2-R

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

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

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

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

[0270] In some embodiments, T is

Chemical formula

[0271] In some embodiments, T is

Chemical formula

[0272] In some embodiments, T is

Chemical formula

[0273] In some embodiments, T is

Chemical formula

[0274] In some embodiments, T is

Chemical formula

[0275] In some embodiments, T is

Chemical formula

[0276] In some embodiments, T is

Chemical formula

[0277] In some embodiments, T is

Chemical formula

[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, where -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2 is optionally substituted with one or more R Ta s.

[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 optionally substituted with one or more R Ta s.

[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, where C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more R Ta s.

[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, and C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Ta .

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

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

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

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

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

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

[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 a 6-membered heterocycloalkyl optionally substituted with one or more R Ta s.

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

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

[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 a 3- to 7-membered monocyclic heterocycloalkyl optionally substituted with one or more R Ta s.

[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 a 3- to 7-membered monocyclic heterocycloalkyl substituted with one or more R Ta s.

[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 a 6-membered monocyclic heterocycloalkyl optionally substituted with one or more R Ta s.

[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 a 6-membered monocyclic heterocycloalkyl substituted with one or more R Ta s.

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

[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 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[0312] The variable Ar 1 , R A1 , R A1a , and R A1b In some embodiments, Ar 1 is a C6-C A1 aryl optionally substituted with one or more R 10 s, each R A1 is 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 optionally substituted with one or more R A1a and is optionally substituted with each R A1a is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, 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 optionally substituted with one or more R A1b and each R A1b is independently halogen, CN, -OH, or -NH2.

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

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

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

[0316] In some embodiments, Ar 1 is phenyl substituted with one or more halogen, -OR A1a , or -O-(C1-C6 alkyl), where -O-(C1-C6 alkyl) is optionally substituted with one or more R A1a and each R A1ais independently C6-C 10 aryl or 5- to 10-membered heteroaryl, where in this case C6-C 10 aryl or 5- to 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 in this case phenyl is further substituted with -O-(C6-C 10 aryl) or -O-(5- to 10-membered heteroaryl), where in this case -O-(C6-C 10 aryl) or -O-(5- to 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 in this case phenyl is further substituted with -O-phenyl or -O-pyridinyl, where in this case -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 in this case phenyl is further substituted with -O-phenyl, where in this case -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, and where the -O-pyridinyl is optionally substituted with one or more halogens.

[0324] In some embodiments, Ar 1 is

Chemical formula

[0325] In some embodiments, Ar 1 is

Chemical formula

[0326] In some embodiments, Ar 1 is

Chemical formula

[0327] In some embodiments, Ar 1 is

Chemical formula

[0328] In some embodiments, Ar 1 is

Chemical formula

[0329] In some embodiments, Ar 1 is

Chemical formula

[0330] In some embodiments, Ar1 is [Chemical formula] .

[0331] In some embodiments, Ar 1 is [Chemical formula] .

[0332] In some embodiments, Ar 1 is [Chemical formula] .

[0333] In some embodiments, Ar 1 is [Chemical formula] .

[0334] In some embodiments, Ar 1 is [Chemical formula] .

[0335] In some embodiments, Ar 1 is [Chemical formula] .

[0336] In some embodiments, Ar 1 is [Chemical formula] .

[0337] In some embodiments, Ar 1 is [Chem.] is as follows.

[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 is -OR A1a as follows.

[0344] In some embodiments, at least one R A1 is -O-(C6-C 10 aryl) or -O-(5- to 10-membered heteroaryl), where -O-(C6-C 10 aryl) or -O-(5- to 10-membered heteroaryl) is optionally substituted with one or more R A1b as follows.

[0345] In some embodiments, at least one R A1 is -O-(C6-C 10 aryl) or -O-(5- to 10-membered heteroaryl), where -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, where -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, where -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more R A1a s.

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

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

[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- to 10-membered heteroaryl, where C6-C 10 The aryl or 5- to 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 wherein.

[0354] In some embodiments, at least one R A1 is -O-CH2-(C6-C 10 aryl) or -O-CH2-(5- to 10-membered heteroaryl), where -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-CH2-phenyl or -O-CH2-pyridinyl, where -O-CH2-phenyl or -O-CH2-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-CH2-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, where C3-C 10 cycloalkyl, C6-C 10Aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R A1a s.

[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 optionally substituted with one or more R A1b s.

[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, and C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R A1b s.

[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, and C3-C 10 cycloalkyl, C6-C 10 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, and C6-C10 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, in which case 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 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, when Z is

Chemical formula

[0372] In some embodiments, when Z is

Chemical formula

Chemical formula

[0373] ​ [Chemical formula] when it is, Ar 1 is a C6-C optionally substituted with one or more halogens 10 aryl.

[0374] In some embodiments, Z is [Chemical formula] not.

[0375] In some embodiments, Z is [Chemical formula] not.

[0376] In some embodiments, T is [Chemical formula] not.

[0377] In some embodiments, the compound is a compound of formula (II’) below [Chemical formula] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0378] In some embodiments, the compound is a compound of formula (II’) below [Chemical formula] or a pharmaceutically acceptable salt or stereoisomer thereof.

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

[0380] In some embodiments, the compound is a compound of formula (IV’) or (IV’-a) below

Chemical formula

[0381] In some aspects, the present disclosure provides a compound of formula I below or a pharmaceutically acceptable salt or stereoisomer thereof:

Chemical formula

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

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

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

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

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

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

[0388] In some embodiments of the compound of formula I, R b is always hydrogen, so R a alone 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 which forms a ring together with, or - (CH2) - or - (CH2)2 - may be selected. Preferably, R b may be hydrogen, and R a is, R 2 methyl or - (CH2) - or - (CH2)2 - which forms a ring together with may be. Further, both R a and R b may be hydrogen.

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

[0390] In some embodiments of the compound of formula I, R cis always hydrogen, so R d alone 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. Further, both R c and R d may 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 are hydrogen. In some embodiments of the compound of formula I, R b , R c , and R d are hydrogen. In some embodiments of the compound of formula I, R 1 , R b , R c and R d are hydrogen.

[0393] R a In some embodiments of the compound of formula I in which one of R 3 forms a ring with R

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

[0395] the ring formed is a 3-, 4-, 5-, or 6-membered ring. 2 In some embodiments of the compound of formula I in which one of R 3 forms a ring with R In some embodiments of the compound of formula I, R 2 is C 1-4 alkyl, or R 3 or R a together with -(CH2) q forms a ring. 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 -(CH2)- or -(CH2)2- which forms a ring together with R 3 , or R 2 is -(CH2)- or -(CH2)2- which forms a ring together with R a . Preferably, R 2 may be selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, or i-butyl, or R 2 is -(CH2)- or -(CH2)2- which forms a ring together with R 3 , or R 2 is -(CH2)- or -(CH2)2- which forms a ring together with 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 -(CH2)- or -(CH2)2- which forms a ring together with R 2 .

[0397] In some embodiments of the compound of formula I, n is 0 and m is 1, 2 or 3, or n is 0 and m is 1 or 2, or n is 1 and m is 1, 2 or 3, or n is 1 and m is 1 or 2, or n is 2 and m is 1, 2 or 3, or n is 2 and m is 1 or 2, or n is 0, 1 or 2 and m is 1 or 2, or n is 0, 1 or 2 and m is 1, 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.

[0398] In some embodiments of the compound of formula I, X 1 may form a heterocycle with the carbon to which R 2 is directly attached. For example, X 1 may form a 4-, 5-, 6- or 7-membered heterocycle. In some embodiments of the compound 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,

Chemical formula

[0400] Ar 1 In some embodiments of the compound of formula I, where the compound of formula i is, R 4 is hydrogen, fluoro, chloro, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy-C6 aryl, C 1-4 Alkoxy-C 5-6 Heteroaryl, amino C 1-4 Alkyl, C 1-4 Alkylamino, C 1-4 Aminoalkyl-C6 aryl, C 1-4 Aminoalkyl-C6 heteroaryl, C 1-4 Alkoxycarbonyl, C 1-4 Is alkoxyaminocarbonyl, or C6 aryl.

[0401] Ar 1In some embodiments of the compound of formula I which is a compound of formula i, R 4 is hydrogen, fluoro, chloro, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy-C6 aryl, C 1-4 alkoxy-C 5-6 heteroaryl, or C6 aryl.

[0402] Ar 1 In some embodiments of the compound of formula I which is a compound of formula i, R 4Generally, it is 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, cycloheptyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, 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, ethoxyaminocarbonyl, propoxyaminocarbonyl, butoxyaminocarbonyl, pentoxyaminocarbonyl, hexoxyaminocarbonyl, phenylmethoxy, phenylethoxy, phenylpropyl, phenylbutoxy, phenylpentoxy, phenylhexoxy, m-fluorophenylmethoxy, m-fluorophenylethoxy, m-fluorophenylpropyl, m-fluorophenylbutoxy, m-fluorophenylpentoxy, m-fluorophenylhexoxy, pyridinylmethoxy, pyridinylethoxy,It is pyridinylpropoxy, pyridinylbutoxy, pyridinylpentyloxy, pyridinylhexyloxy, phenyl, pyridinyl or naphthyl., Ar 1 In some embodiments of the compound of formula I where Ar is a compound of formula i, R 5 and R 6 are, independently of each other, hydrogen, -CF3, F or Cl, and R 5’ and R 6’ are hydrogen. Preferably, R 4 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, hydroxyC 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, aminoC 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, arylC 1-6 alkoxy, or C6 aryl.

[0403] Ar 1 In some embodiments of the compound of formula I where Ar is a compound of formula i, R 5 and R 6 are, independently of each other, hydrogen, -CF3, F or Cl, and R 5’ and R 6’ are hydrogen. Preferably, R 4 is hydrogen, fluoro, chloro, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, hydroxyC 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 Is alkoxyaminocarbonyl, or C6 aryl.

[0404] Ar 1 In some embodiments of the compound of formula I where Ar 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’ Of which at least two may be hydrogen.

[0405] Ar 1 In some embodiments of the compound of formula I where Ar is a compound of formula i, R 1 May be hydrogen, and / or R 2 May be methyl, or R 2 Is -(CH2)- or -(CH2)2- forming a ring with R 3 , or R 2 Is -(CH2)- or -(CH2)2- forming a ring with R a .

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

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

[0409] R 2 One of which is R 3 which forms a ring with Ar 1 In some embodiments of the compound of formula I where Ar 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,

Chemical formula

[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,

Chemical formula

[0412] One of ordinary skill in the art will understand that when X 3 represents CH, R 7 may generally also be attached to this carbon, whereby X 3 can be CR 7 . Preferably, the corresponding aryl or heteroaryl is substituted only with a single R 7 . Further, it is understood that when X 3 is N, R 7 generally cannot be attached to N.

[0413] Ar 1 In some embodiments of the compound of formula I where Ar 5 is a compound of formula ii-1, ii-2, ii-3, or ii-4, R 6 and R 5’ and R 6’ are each independently hydrogen, -CF3, F or Cl, and R

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

[0415] Ar 1In some embodiments of the compound of formula I that 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 that is a compound of formula ii-1, ii-2, ii-3, or ii-4, R 5 is F, and / or R 6 is F or Cl.

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

[0418] R a One of which forms a ring with R 3 Ar 1 In some embodiments of the compound of formula I that 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 which forms a ring with R 3 Ar 1 In some embodiments of the compound of formula I that 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 which forms a ring with R 3 Ar 1In some embodiments of the compound of formula I that 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 that is a compound of formula ii-1, ii-2, ii-3, or ii-4, R 2 is methyl, or R 2 is R 3 that forms a ring with -(CH2)- or -(CH2)2-, or R 2 is R a that forms a ring with -(CH2)- or -(CH2)2-.

[0422] In some embodiments, X 2 is O, whereby Ar 1 is a compound of formula ii-1a, or a pharmaceutically acceptable salt or stereoisomer thereof,

Chemical formula

[0423] In some embodiments, X 2 is O, whereby Ar 1 is a compound of formula ii-2a, ii-3a, or ii-4a, or a pharmaceutically acceptable salt or stereoisomer thereof,

Chemical formula

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

[0425] Ar 1 In some embodiments of the compound of formula I wherein Ar 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 wherein Ar is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a, R 5 is F, and / or 6 R is F or Cl.

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

[0428] Ar 1 In some embodiments of the compound of formula I wherein Ar is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a, R 2 is methyl, or 2 R is3 is -(CH2)- or -(CH2)2- which forms a ring together with, or R 2 is R a is -(CH2)- or -(CH2)2- which forms a ring together with.

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

[0430] R a One of is R 3 which forms a ring together with, Ar 1 In some embodiments of the compound of formula I wherein Ar is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a, the formed ring 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 is R 3 which forms a ring together with, Ar 1 In some embodiments of the compound of formula I wherein Ar is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a, the formed ring is a 3-, 4-, 5-, or 6-membered ring.

[0432] R 2 One of is R 3 which forms a ring together with, Ar 1 In some embodiments of the compound of formula I wherein Ar is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a, the formed ring 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, whereby Ar 1 is a compound of formula ii-1b, or a pharmaceutically acceptable salt or stereoisomer thereof, [Chemical formula] wherein, 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, whereby Ar 1 is a compound of formula ii-2b, ii-3b, ii-4b, ii-5b, or a pharmaceutically acceptable salt or stereoisomer thereof, [Chemical formula] wherein, 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 one another, hydrogen, -CF3 or halogen, preferably F, Cl, R 7 is hydrogen or halogen, preferably F.

[0435] Ar 1 is a compound of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, in some embodiments of the compound of formula I, R 5 and R 6 are, independently of one another, hydrogen, -CF3, F or Cl, and R 5’ and R 6’ are hydrogen.

[0436] Ar 1 In some embodiments of the compound of formula I where Ar 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 Ar is a compound of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, R 5 is F, and / or R 6 is F or Cl.

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

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

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

[0441] R a where one of them forms a ring with R 3 and Ar1 In some embodiments of the compound of formula I, which 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 3 forms a ring with 1 Ar

[0443] R 2 One of 3 forms a ring with 1 Ar

[0444] In some embodiments, X 2 is O, and X 3 is N, whereby Ar 1 is a compound of formula ii-1c, or a pharmaceutically acceptable salt or stereoisomer thereof,

Chemical formula

[0445] In some embodiments, X 2 is O, and X 3 is N, whereby Ar 1is a compound of formula ii-2c, ii-3c, ii-4c, ii-5c, or a pharmaceutically acceptable salt or stereoisomer thereof, [Chemical formula] wherein, 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 Ar is a compound of formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 5 and R 6 are independently of each other hydrogen, -CF3, F or Cl, and R 5’ and R 6’ are hydrogen.

[0447] Ar 1 In some embodiments of the compound of formula I where Ar 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 Ar is a compound of formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 5 is F, and / or R 6 is F or Cl.

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

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

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

[0452] R a One of 3 forms a ring with R 1 In some embodiments of the compound of formula I, wherein Ar is a compound of formula ii-1c, ii-2c, ii-3c or ii-4c, the formed ring is a 4-, 5- or 6-membered ring, or a 5- or 6-membered ring, or a 5-membered ring.

[0453] R a One of 3 forms a ring with R 1 In some embodiments of the compound of formula I, wherein Ar is a compound of formula ii-1c, ii-2c, ii-3c or ii-4c, the formed ring is a 3-, 4-, 5- or 6-membered ring.

[0454] R 2 One of 3 forms a ring with R 1In some embodiments of the compound of formula I which 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,

Chemical formula

[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,

Chemical formula

[0457] Ar 1 In some embodiments of the compound of formula I which is a compound of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, R 5 and R 6are, independently of one another, hydrogen, -CF3, F or Cl, and R 5’ and R 6’ is hydrogen.

[0458] Ar 1 In some embodiments of the compound of formula I, wherein Ar 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, wherein Ar is a compound of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, R 5 is F, and / or R 6 is F or Cl.

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

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

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

[0463] One of R a forms a ring with R 3 . In some embodiments of the compound of formula I where Ar 1 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] One of R a forms a ring with R 3 . In some embodiments of the compound of formula I where Ar 1 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] One of R 2 forms a ring with R 3 . In some embodiments of the compound of formula I where Ar 1 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, whereby 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, whereby Ar 1 is a compound of formula iv-8 or iv-9. [Chemical formula] In the formula, o is 0 or 1, R 5 , R 6 are, independently of each other, hydrogen, -CF3, 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 Ar is a compound of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, R 5 and R 6 are, independently of each other, hydrogen, -CF3, F or Cl, and R 5’ and R 6’ are hydrogen.

[0468] Ar 1 In some embodiments of the compound of formula I where Ar 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 Ar is a compound of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, R 5 is F, and / or R 6 is F or Cl.

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

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

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

[0473] R a One of 3 forms a ring with R 1 In some embodiments of the compound of formula I in which Ar 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 3 forms a ring with R 1In some embodiments of the compound of Formula I that 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 which is R 3 Together with Ar to form a ring 1 In some embodiments of the compound of Formula I that 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 present disclosure provides a compound of Formula IIa or IIb below or a pharmaceutically acceptable salt or stereoisomer thereof:

Chemical formula

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

[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 -(CH2) 3 which forms a ring with R q -. For example, R 2 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl which is -(CH2)- or -(CH2)2- that forms a ring with R 3 and may be selected from R 2 . Preferably, R 2 is R 3Methyl, ethyl, n-propyl, i-propyl, n-butyl, or i-butyl R which forms a ring together with -(CH2)- or -(CH2)2 2 may be selected from. More preferably, R 2 is such that R 2 forms a ring with R 3 and may be methyl which is -(CH2)- or -(CH2)2.

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

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

[0482] In some embodiments of the compound of formula IIa, n is 0, 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, or n is 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.

[0483] In some embodiments of the compound of formula IIb, r is 0, s is 1 or 2, or r is 1, s is 1 or 2, or r is 0 or 1, s is 1, or r is 0 or 1, s is 2.

[0484] In some embodiments of the compounds of formula IIa or formula IIb, X 1 may form a heterocycle with the carbon to which R 2 is directly attached. For example, X 1 may form a 4-, 5-, 6- or 7-membered heterocycle or heterobicycle. 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 compounds of formula IIa or formula IIb, Ar 1 is a compound of formula i, or a pharmaceutically acceptable salt or stereoisomer thereof,

Chemical formula

[0486] Ar 1 In some embodiments of the compound of formula IIa or formula IIb, where Ar is a compound of formula i, R 4 is hydrogen, fluoro, chloro, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, hydroxy C 1-5 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy-C6 aryl, C 1-4 alkoxy-C 5-6 heteroaryl, amino C 1-4 alkyl, C 1-4 alkylamino, C 1-4 aminoalkyl-C6 aryl, C 1-4 aminoalkyl-C6 heteroaryl, C 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 Ar is a compound of formula i, R 4 is hydrogen, fluoro, chloro, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy-C6 aryl, C 1-4 alkoxy-C 5-6 heteroaryl, or C6 aryl.

[0488] Ar 1In some embodiments of the compound of formula IIa or formula IIb that is a compound of formula i, 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, cyclopheptyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, 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, ethoxyaminocarbonyl, propoxyaminocarbonyl, butoxyaminocarbonyl, pentoxyaminocarbonyl, hexoxyaminocarbonyl, phenylmethoxy, phenylethoxy, phenylpropyl, phenylbutoxy, phenylpentoxy, phenylhexoxy, m-fluorophenylmethoxy, m-fluorophenylethoxy, m-fluorophenylpropyl, m-fluorophenylbutoxy, m-fluorophenylpentoxy, m-fluorophenylhexoxy, pyridinylmethoxy, pyridinylethoxy,It is pyridinylpropoxy, pyridinylbutoxy, pyridinylpentyloxy, pyridinylhexyloxy, phenyl, pyridinyl or naphthyl.,

[0489] Ar 1 In some embodiments of the compound of formula IIa or formula IIb, where Ar is a compound of formula i, R 5 and R 6 are, independently of one another, hydrogen, -CF3, F or Cl, and R 5’ and R 6’ are hydrogen. Preferably, R 4 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, hydroxyC 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, aminoC 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, arylC 1-6 alkoxy, or C6 aryl.

[0490] Ar 1 In some embodiments of the compound of formula IIa or formula IIb, where Ar is a compound of formula i, R 5 and R 6 are, independently of one another, hydrogen, -CF3, F or Cl, and R 5’ and R 6’ are hydrogen. Preferably, R 4 is hydrogen, fluoro, chloro, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, hydroxyC 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 Is 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, 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.

[0492] In some embodiments of the compound of formula IIa or formula IIb, Ar 1 Is a compound of formula i, R 1 May be hydrogen, and / or R 2 May be methyl, or may be -(CH2)- or -(CH2)2- that forms a ring with R 3 .

[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,

Chemical formula

[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, [Chemical formula] wherein 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 one another, 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 Ar is a compound of formula ii-1, ii-2, ii-3, or ii-4, R 5 and R 6 are, independently of one another, hydrogen, -CF3, F or Cl, and R 5’ and R 6’ are hydrogen.

[0496] Ar 1 In some embodiments of the compound of formula IIa or formula IIb where Ar 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 Ar is a compound of formula ii-1, ii-2, ii-3, or ii-4, R 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, wherein Ar is a compound of formula ii-1, ii-2, ii-3, or ii-4, R 2 is methyl or R 3 together with forms a ring and is -(CH2)- or -(CH2)2-.

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

[0500] Ar 1 In some embodiments of the compound of formula IIa, wherein Ar is a compound of formula ii-1, ii-2, ii-3, or ii-4, n is 0, 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, or n is 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 the compound of formula IIb that is a compound of formula ii-1, ii-2, ii-3, or ii-4, r is 0, s is 1 or 2, or r is 1, s is 1 or 2, or r is 0 or 1, s is 1, or r is 0 or 1, s is 2.

[0502] In some embodiments, X 2 is O, whereby Ar 1 is a compound of formula ii-1a, or a pharmaceutically acceptable salt or stereoisomer thereof,

Chemical formula

[0503] In some embodiments, X 2 is O, whereby Ar 1 is a compound of formula ii-2a, ii-3a, or ii-4a, or a pharmaceutically acceptable salt or stereoisomer thereof,

Chemical formula

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

[0505] Ar 1 In some embodiments of the compound of formula IIa or formula IIb which 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 which is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a, R 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 which is a compound of formula ii-1a, ii-2a, ii-3a, or ii-4a, R 7 is hydrogen when X 3 is N, and / or R 7 is F when X 3 is CH.

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

[0509] Ar 1In some embodiments of the compound of formula IIa which is 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 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.

[0510] Ar 1 In some embodiments of the compound of formula IIb which 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 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0511] In some embodiments of the compound of formula IIa or formula IIb, X 3 is N, whereby Ar 1 is a compound of formula ii-1b, or a pharmaceutically acceptable salt or stereoisomer thereof,

Chemical formula

[0512] In some embodiments of the compounds of formula IIa or formula IIb, X 3 is N, whereby Ar 1 is a compound of formula ii-2b, ii-3b, ii-4b, ii-5b, or a pharmaceutically acceptable salt or stereoisomer thereof,

Chemical formula

[0513] Ar 1 In some embodiments of the compounds of formula IIa or formula IIb where Ar is a compound of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, R 5 and R 6 are each independently hydrogen, -CF3, F or Cl, and R 5’ and R 6’ are hydrogen.

[0514] Ar 1 In some embodiments of the compounds of formula IIa or formula IIb where Ar 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 compounds of formula IIa or formula IIb where Ar is a compound of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, R 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 that is a compound of formula ii-1b, ii-2b, ii-3b, ii-4b, or ii-5b, R 7 is F.

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

[0518] Ar 1 In some embodiments of the compound of formula IIa where Ar 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 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.

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

[0520] In some embodiments of the compound of formula IIa or formula IIb, Ar1 is a compound of formula ii-1c, or a pharmaceutically acceptable salt or stereoisomer thereof,

Chemical formula

[0521] In some embodiments of the compound of formula IIa or formula IIb, X 2 is O, X 3 is N, whereby Ar 1 is a compound of formula ii-2c, ii-3c, ii-4c, ii-5c, or a pharmaceutically acceptable salt or stereoisomer thereof,

Chemical formula

[0522] Ar 1 In some embodiments of the compound of formula IIa or formula IIb wherein Ar is a compound of formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 5 and R 6 are, independently of one another, hydrogen, -CF3, F or Cl, and R 5’ and R 6’ are hydrogen.

[0523] Ar 1In some embodiments of the compound of formula IIa or formula IIb that 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 that is a compound of formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 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 that is a compound of formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 7 is F.

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

[0527] Ar 1In some embodiments of the compound of formula IIa that is a compound of formula ii-1c, ii-2c, ii-3c, or ii-4c, n is 0, 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, or n is 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.

[0528] Ar 1 In some embodiments of the compound of formula IIb that is a compound of formula ii-1c, ii-2c, ii-3c, or ii-4c, r is 0, s is 1 or 2, or r is 1, s is 1 or 2, or r is 0 or 1, s is 1, or r is 0 or 1, 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,

Chemical formula

[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, [Chemical formula] wherein, X 3 is CH or N, preferably N, o is 0 or 1, R 5 , R 6 are independently of each other hydrogen, -CF3, 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 Ar is a compound of formula iii-1, iii-2, iii-3, or iii-4, iii-5, iii-6, or iii-7, R 5 and R 6 are independently of each other hydrogen, -CF3, F or Cl, and R 5’ and R 6’ are hydrogen.

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

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

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

[0536] Ar 1 In some embodiments of the compound of formula IIa where Ar is a compound of formula iii-1, iii-2, iii-3, or iii-4, n is 0, 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, or n is 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 the compound of formula IIb where Ar is a compound of formula iii-1, iii-2, iii-3, or iii-4, r is 0, s is 1 or 2, or r is 1, s is 1 or 2, or r is 0 or 1, s is 1, or r is 0 or 1, s is 2.

[0538] In some embodiments, X 3 is N, whereby 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, whereby Ar 1 is a compound of formula iv-8 or iv-9.

Chemical formula

[0539] Ar 1 In some embodiments of the compound of formula IIa or formula IIb, where Ar is a compound of formula iv-2, iv-3, or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, R 5 and R 6 are, independently of one another, hydrogen, -CF3, F or Cl, and R 5’ and R 6’ are hydrogen.

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

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

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

[0544] Ar 1 In some embodiments of the compound of formula IIa, where Ar 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 the compound of formula IIb that 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, s is 1 or 2, or r is 1, s is 1 or 2, or r is 0 or 1, s is 1, or r is 0 or 1, s is 2.

[0546] In some embodiments, the present disclosure provides a compound of formula III below or a pharmaceutically acceptable salt or stereoisomer thereof:

Chemical formula

Chemical formula

[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 below or a pharmaceutically acceptable salt or stereoisomer thereof:

Chemical formula

Chemical formula

[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, hydroxyC 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, aminoC 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 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, cycloheptyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, 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, ethoxyaminocarbonyl, propoxyaminocarbonyl, butoxyaminocarbonyl, pentoxyaminocarbonyl, hexoxyaminocarbonyl, phenylmethoxy, phenylethoxy, phenylpropyl, phenylbutoxy, phenylpentoxy, phenylhexoxy, m-fluorophenylmethoxy, m-fluorophenylethoxy, m-fluorophenylpropyl, m-fluorophenylbutoxy, m-fluorophenylpentoxy, m-fluorophenylhexoxy, pyridinylmethoxy, pyridinylethoxy,It is pyridinylpropoxy, pyridinylbutoxy, pyridinylpentyloxy, pyridinylhexyloxy, phenyl, pyridinyl or naphthyl.,

[0552] In some embodiments of the compound of formula IV, R 5 and R 6 are each independently of the other hydrogen, -CF3, F or Cl, and R 5’ and R 6’ are hydrogen. Preferably, R 4 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, hydroxyC 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, aminoC 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, arylC 1-6 alkoxy, or C6 aryl.

[0553] In some embodiments of the compound of formula IV, R 5 and R 6 are each independently of the other hydrogen, -CF3, F or Cl, and R 5’ and R 6’ are hydrogen. Preferably, R 4 is hydrogen, fluoro, chloro, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, hydroxyC 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’ of at least two of which 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 below or a pharmaceutically acceptable salt or stereoisomer thereof:

Chemical formula

Chemical formula

[0557] In some embodiments, the present disclosure provides a compound of formula V-2, V-3, or V-4, or a pharmaceutically acceptable salt or stereoisomer thereof:

Chemical formula

Chemical formula

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

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

[0560] In some embodiments of the compound of formula V-1, V-2, V-3 or V-4, R 5 and R 6are, independently of each other, hydrogen, -CF3, 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’ of at least two of them may be hydrogen.

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

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

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

[0565] In some embodiments of the compounds of formula V-2, V-3, or V-4, X 2 is O, giving rise to a compound of formula V-2a, V-3a, or V-4a or a pharmaceutically acceptable salt or stereoisomer thereof.

Chemical formula

Chemical formula

[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, -CF3, F or Cl, and R 5’ and R 6’ are 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, -CF3, F or Cl, and R 5’ and R 6’ are 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 them may be hydrogen.

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

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

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

[0573] In some embodiments of the compound of formula V-2, V-3, or V-4, X 3 is N, resulting in the compound of formula V-2b, V-3b, V-4b or a pharmaceutically acceptable salt or stereoisomer thereof, or X 3 is C, resulting in the compound of formula V-5b or a pharmaceutically acceptable salt or stereoisomer thereof.

Chemical formula

Chemical formula

[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, 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 independently of each other hydrogen, -CF3, F or Cl, and R 5’ and R 6’ are 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 independently of each other hydrogen, -CF3, F or Cl, and R 5’ and R 6’ are hydrogen. Preferably, R 4 is hydrogen, fluoro, chloro, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, hydroxyC 1-5 alkyl, C 1-4 alkoxy-C 1-4 alkyl, aminoC 1-4 alkyl, C 1-4 alkylamino, C 1-4 alkoxycarbonyl, C 1-4 alkoxyaminocarbonyl, arylC 1-4 alkoxy, heteroarylC 1-4 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’ of at least two of them 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 below or a pharmaceutically acceptable salt or stereoisomer thereof:

Chemical formula

Chemical formula

[0582] In some embodiments, the present disclosure provides a compound of formula VI-2, VI-3, or VI-4 below or a pharmaceutically acceptable salt or stereoisomer thereof: [Chemistry] In the formula, X 2 is O, NH, or NMe, and X 3 is CH or N, and R 1 is H or F, and o is 0 or 1, and R 5 and R 6 are, independently of each other, hydrogen, -CF3, or halogen, preferably F or Cl, R 7 is hydrogen or halogen, preferably F, Z is selected from the following: [Chemistry]

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

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

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

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

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

[0588] In some embodiments of the 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.

Chemical formula

Chemical formula

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

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

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

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

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

[0594] In some embodiments of the 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

Chemical formula

Chemical formula

[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 the compound of formula VI-1, VI-2b, VI-3b, VI-4b or VI-5b, o is 1.

[0597] In some embodiments of the compound 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 compound of formula VI-1, VI-2b, VI-3b, VI-4b or VI-5b, R 7 is F.

[0599] In some embodiments of the compound 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 below or a pharmaceutically acceptable salt or stereoisomer thereof:

Chemical formula

Chemical formula

[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:

Chemical formula

Chemical formula

[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 the 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 in this case R 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 described in Tables 1 and 2, their pharmaceutically acceptable salts, and stereoisomers.

[0608] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2, and their pharmaceutically acceptable salts.

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

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

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

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

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

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

[0615] In some embodiments, the compound is selected from the compounds set forth in Table 2. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13]

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

[0616] In some embodiments, the disclosure provides a compound that is an isotope derivative (e.g., an isotope-labeled compound) of any one of the compounds of the formulas disclosed herein.

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

[0618] In some embodiments, the compound is an isotope derivative of any one of the compounds described in Tables 1 and 2 and their pharmaceutically acceptable salts.

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

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

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

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

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

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

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

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

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

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

Table 3

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

[0630] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor of at least 3500 (52.5% deuterium 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) for each deuterium atom. As used herein, the term "deuterium enrichment factor" means the ratio between the abundance of deuterium and the natural abundance of deuterium.

[0631] It is understood that the deuterium-labeled compound can be prepared using any of a variety of techniques recognized in the art. For example, the deuterium-labeled compound can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein, and can be prepared by substituting non-deuterium-labeled reagents with deuterium-labeled reagents.

[0632] The compounds of the invention containing the aforementioned deuterium atoms, or pharmaceutically acceptable salts or solvates thereof, are within the scope of the invention. Further, substitution with deuterium (i.e., 2 H) can result in certain therapeutic benefits arising from increased metabolic stability, such as an extended in vivo half-life or a reduced required dose.

[0633] The compounds of the present disclosure may contain one or more asymmetric centers in the molecule. It should be understood that compounds not designated as to 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 the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, by chromatographic separation using a chiral stationary phase, and other methods) are well known in the art.

[0634] The compounds may be isotopically labeled compounds, e.g., compounds that contain 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 individual distinct tautomers are contemplated. In addition, some compounds may exhibit polymorphism.

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

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

[0637] The compounds of the present disclosure can exist in solid form, i.e., crystalline or amorphous form (optionally as a solvate), or in liquid form. In the solid state, it can exist in or as a mixture thereof. In a crystalline solvate, solvent molecules are incorporated into the crystal lattice during crystallization. The formation of solvates 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 referred to as a "hydrate"). It is common knowledge that the crystalline form (and its solvates) can exhibit polymorphism, i.e., exist in different crystal structures known as "polymorphs" that have the same chemical composition but different packing, geometric arrangements, and other descriptive properties of the solid state of the crystal. Thus, polymorphs can have different physical properties such as shape, density, hardness, deformability, stability, and dissolution characteristics, and can exhibit different melting points, IR spectra, and X-ray powder diffraction patterns that can be used for specific purposes. Such different polymorphs can be produced during the preparation of the compounds of the present disclosure, for example, by changing or adjusting the reaction conditions or reagents.

[0638] In some embodiments, the present disclosure also provides methods of making the compounds of the present disclosure. Typically, the compounds of the present disclosure are made according to the syntheses shown in the experimental section.

[0639] It is understood that the synthetic processes of the present disclosure can tolerate a wide range of functional groups and thus can use various starting materials with substitutions. The process generally provides the desired final compound at or near the end of the overall process, but in certain instances, it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0640] The compounds of the present disclosure can be prepared in various ways by employing standard synthetic methods and procedures that are known to those skilled in the art or would be apparent to those skilled in the art in light of the teachings herein, using commercially available starting materials, compounds known in the literature, or readily prepared intermediates. Standard synthetic methods and procedures for the preparation of organic molecules and the transformation, manipulation of functional groups can be obtained from relevant scientific literature or standard textbooks in the field. Without limitation to any one or more sources, for example, Smith, M.B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G.M., 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 classical texts such as L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) are useful and widely recognized references for organic synthesis known to those skilled in the art, and they are hereby incorporated by reference into this specification.

[0641] One of ordinary skill in the art will note that, among the reaction sequences and synthetic schemes described herein, the order of certain steps, such as the introduction and removal of protecting groups, may vary. One of ordinary skill in the art will recognize that certain groups may need to be protected from reaction conditions via 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 their introduction and removal, can be found in Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999.

[0642] Biological assays Compounds designed, selected, and / or optimized by the methods described herein, upon generation, can be characterized using a variety of assays known to one of ordinary skill in the art to determine whether the compound has 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] A variety of in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure. These in vitro or in vivo biological assays may include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0645] Pharmaceutical composition In some aspects, the present disclosure further provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds of the present disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients (also referred to as diluents). An excipient is acceptable in the sense that it is compatible with the other ingredients of the formulation and not harmful to its recipient (i.e., the patient). As used herein, the term "therapeutically effective amount" refers to the amount of a compound of the present disclosure (either by itself or in the form of a pharmaceutical composition) that is effective to produce a desired therapeutic effect.

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

[0647] The compounds of the present disclosure can 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., those targeted for buccal, sublingual, and 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 a sustained release formulation, (3) topical application, e.g., as creams, ointments, or controlled release patches or sprays applied to the skin, (4) intravaginal or intrarectal, e.g., as pessaries, creams, or foams, (5) sublingual, (6) ocular, (7) transdermal, (8) nasal, (9) pulmonary, or (10) intrathecal.

[0648] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricants, magnesium stearate, calcium stearate or zinc stearate, or stearic acid), or a solvent encapsulating material involved in carrying or transporting a subject compound 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, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffering solutions; (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, emulsifying agents, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents and fragrances, preservatives and antioxidants, pH adjusters, bulking agents, and further active agents. Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, etc., (2) fat-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc., and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0650] Such compositions can be prepared by any method known in the art, for example, by bringing the active ingredient into association with one or more carriers and / or excipients. Examples of different compositions as well as 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 in the preparation of pharmaceutical compositions can include buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifying agents, suspending agents, preservatives, antioxidants, opaquing agents, flow promoters, processing aids, coloring agents, sweetening agents, flavoring agents, fragrances, diluents, and other known additives in order to provide a composition suitable for the selected route of administration.

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

[0652] In the solid dosage forms of the present disclosure for oral administration (capsules, tablets, pills, dragees, powders, granules, troches, 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 bulking agents such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; (3) humectants such as, for example, glycerol; (4) disintegrants such as, for example, agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retardants such as, for example, paraffin; (6) absorption promoters such as, for example, quaternary ammonium compounds, and surfactants such as, for example, poloxamers and sodium lauryl sulfate; (7) wetting agents such as, for example, cetyl alcohol, glycerol monostearate, and nonionic surfactants; (8) absorbents such as, for example, kaolin and bentonite clay; (9) lubricants such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents, and; (11) controlled release agents such as, for example, crospovidone or ethyl cellulose. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain a buffering agent. Similar types of solid compositions can also be used as excipients such as lactose or milk sugar, and as fillers in soft shell and hard shell gelatin capsules using high molecular weight polyethylene glycol and the like. Tablets can optionally be made by compression or molding with one or more auxiliary components. Compressed tablets can be prepared using binders (such as, for example, gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (such as, for example, sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersing agents.The shaped tablets can be produced by shaping a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms of the pharmaceutical compositions of the present disclosure, such as dragees, capsules, pills, and granules, can optionally be prepared using coatings and shells such as scored, enteric coatings, and other coatings well known in the pharmaceutical formulation art. They can also be formulated, for example, using hydroxypropylmethylcellulose in various ratios to provide sustained or controlled release of the active ingredient therein, to provide a desired release profile, other polymer matrices, liposomes, and / or microspheres. They can be formulated for immediate release and, for example, lyophilized. They can be sterilized, for example, by filtration through a bacteria-retaining filter or, in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use, by incorporating a sterilizing agent. The composition may optionally contain an opacifying agent and may be a composition that releases only the active ingredient, or preferably, may be a composition that releases only the active ingredient in a particular portion of the digestive tract, optionally in a delayed manner. Examples of implantable compositions that can be used include polymeric substances and waxes. The active ingredient can also, where appropriate, be in microencapsulated form, together with one or more of the excipients described above.

[0653] Oral dosage forms of the compounds of the present disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, 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, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof. Oral compositions may also contain adjuncts such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, coloring agents, perfuming agents, and preservatives.

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

[0655] Rectal or vaginal dosage forms of the compounds of the present disclosure include suppositories 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 salicylates, which are solid at room temperature but liquid at body temperature and thus melt in the rectal or vaginal cavity to release the active compound. Other suitable forms include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing carriers known in the art to be appropriate.

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

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

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

[0659] The dosage levels of the compounds of the present disclosure in the pharmaceutical compositions of the present disclosure can be adjusted to obtain an amount of the compounds of the present disclosure that is effective to achieve the desired therapeutic response for a particular patient, compound, and mode of administration without being harmful to the patient. The selected dosage depends on the nature of the particular compound of the present disclosure being used, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being used, the rate and extent of absorption, the period of treatment or prophylaxis, other drugs, compounds, and / or materials used in combination with the particular compound, the age, sex, weight, condition, general health, and previous medical history of the patient being treated, as well as various factors including similar factors well known in the medical arts. Physicians in the relevant art can readily determine and prescribe the effective amount of the pharmaceutical composition required.

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

[0661] The effective amount of the compounds of the present disclosure can optionally be administered as two, three, four, five, six or more sub-dosages, in unit dosage forms, at appropriate intervals (per day, or per week, or per month) over a specified period. The preferred dosage also depends on the factors indicated above, for example, the route of administration, and can be readily achieved by those skilled in the pharmaceutical or pharmaceutic arts.

[0662] Use of Compounds and Compositions The compounds of the present disclosure inhibit or modulate the activity of receptor tyrosine kinases, particularly extracellular variants of ErbB-receptors such as, but not limited to, EGFR-Viii, EGFR-Vii, EGFR-Vvi, EGFR-A289V and EGFR-G598V as well as HER2-S310F. Accordingly, the compounds and compositions of the present disclosure may be useful as pharmaceuticals, i.e., as pharmaceuticals in a method of treatment, more specifically for the prevention or treatment of cancer, as detailed below. Accordingly, in a further aspect, the present disclosure provides a method of prevention or treatment of a mammal, such as a human, suffering from cancer, as detailed below.

[0663] The term "prevention" or "preventing" refers to reducing or eliminating the onset of symptoms or complications of a disease (such as cancer). Such prevention includes administering to the mammal, such as a human, a therapeutically effective amount of a compound of formula I or a salt thereof (or a pharmaceutical composition containing a compound of formula I or a salt thereof).

[0664] The term "treatment" or "treating" is intended to encompass therapy and cure. Such treatment includes administering to the mammal, such as a human, a therapeutically effective amount of a compound of formula I or a salt thereof (or a pharmaceutical composition containing a compound of formula I or a salt thereof).

[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 in a mammal, such as a human, as detailed below.

[0666] In some aspects, the present disclosure is directed to a method of inhibiting an oncogenic variant of an ErbB receptor (such as an oncogenic variant of EGFR), which includes 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 methods of inhibiting oncogenic variants of ErbB receptors (e.g., oncogenic variants of EGFR), which include administering to a subject in need thereof a composition described herein.

[0668] In some aspects, the present disclosure is directed to methods of preventing or treating cancer, which include 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, which include administering to a subject in need thereof a composition described herein.

[0670] In some aspects, the present disclosure is directed to a compound described herein for use in inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant 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 (e.g., 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, their pharmaceutically acceptable salts, and stereoisomers.

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

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

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

[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 the ErbB receptor.

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

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

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

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

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

[0689] In some embodiments, 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 contains 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 contains an allosteric mutation.

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

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

[0697] In some embodiments, the oncogenic variant of EGFR contains the 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, cancer, or a 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 modification of the structure of EGFR, wherein, in this case, 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 modification of the structure of EGFR comprises one or more modifications of a nucleic acid sequence, an amino acid sequence, a secondary structure, a tertiary structure, and a 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 modification of the structure 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 each comprise amino acid residues T211-R334 and / or C526-S645 of SEQ ID NO: 1. In some embodiments, the oncogenic variant of EGFR creates a physical barrier to the formation of disulfide bonds within the CR1 and / or CR2 regions. In some embodiments, the oncogenic variant of EGFR removes a physical barrier to the formation of disulfide bonds 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 comprises one or more free or unpaired cysteine (C) residues at 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. In some embodiments, the modification results from 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 its deletion or substitution 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, lysine (K) is substituted with arginine (R) (K858R).

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

[0703] In some embodiments, cancer, or a tumor, or cells thereof express an oncogenic variant of EGFR, in which case the oncogenic variant of EGFR is an allosteric variant of EGFR, and the oncogenic variant of EGFR 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, cancer, or a tumor, or cells thereof express one or more of the following: (a) the wild-type human epidermal growth factor receptor 2 (HER2) receptor or an oncogenic variant of the HER-2 receptor.

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

[0706] In some embodiments, cancer, or a 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, cancer, or a tumor, or cells thereof, express an oncogenic variant of the HER-2 receptor, in which case the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises a substitution of serine (S) for phenylalanine (F) at position 310 of SEQ ID NO: 2 or 5.

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

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

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

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

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

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

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

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

[0716] In some embodiments, cancer, or a tumor, or cells thereof, express an oncogenic variant of the HER-2 receptor, in which case the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the nucleotide sequence encoding the oncogenic variant of the HER2 receptor contains an insertion within the sequence encoding exon 20 or a part thereof. In some embodiments, the sequence encoding exon 20 or a part thereof contains a sequence encoding KEILDEAYVMAGVGSPYVSR (SEQ ID NO: 8). In some embodiments, the sequence encoding exon 20 or a part thereof contains a sequence encoding a C-helix, the end of the C-helix, or a loop after the C-helix. In some embodiments, the insertion contains the amino acid sequence of GSP or YVMA. In some embodiments, the sequence encoding exon 20 or a part thereof contains one or more of the following: (a) insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (b) insertion of the amino acid sequence GSP between positions P780 and Y781 of SEQ ID NO: 2; (c) insertion of the amino acid sequence YVMA between positions A771 and Y772 of SEQ ID NO: 2; (d) insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (e) insertion of amino acid V between positions V777 and G778 of SEQ ID NO: 2; (f) insertion of amino acid V between positions V777 and G778 of SEQ ID NO: 2; (g) substitution of GV between positions 776 and 777 of SEQ ID NO: 2 with the amino acid sequence AVGCV; (h) substitution of G at position 776 of SEQ ID NO: 2 with the amino acid sequence LC; (i) substitution of G at position 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 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 amino acid G between positions G778 and S779 of SEQ ID NO: 2, (s) Insertion of LRE between positions 755 and 757 of SEQ ID NO: 2 and insertion of amino acid sequence PK, (t) Insertion of amino acid V between positions A775 and G776 of SEQ ID NO: 2, (u) Insertion of amino acid sequence YAMA between positions A775 and G776 of SEQ ID NO: 2, (v) Substitution of G at position 776 of SEQ ID NO: 2 with amino acid sequence CV, (w) Substitution of GVG between positions 776 and 778 of SEQ ID NO: 2 with amino acid sequence AVCGG, (x) Substitution of GVG between positions 776 and 778 of SEQ ID NO: 2 with amino acid sequence CVCG, (y) Substitution of GVG between positions 776 and 778 of SEQ ID NO: 2 with amino acid sequence VVVG, (z) Substitution of GVGS between positions 776 and 779 of SEQ ID NO: 2 with amino acid sequence SVGG, (aa) Substitution of GVGS between positions 776 and 779 of SEQ ID NO: 2 with amino acid sequence VVGES, (bb) Substitution of GV between positions 776 and 777 of SEQ ID NO: 2 with amino acid sequence AVGSGV, (cc) Substitution of GV between positions 776 and 777 of SEQ ID NO: 2 with amino acid sequence CVC, (dd) Substitution of GV between positions 776 and 777 of SEQ ID NO: 2 with amino acid sequence HVC, (ee) Substitution of GV between positions 776 and 777 of SEQ ID NO: 2 with amino acid sequence VAAGV, (ff) Substitution of GV between positions 776 and 777 of SEQ ID NO: 2 with amino acid sequence VAGV, (gg) Substitution of GV between positions 776 and 777 of SEQ ID NO: 2 with amino acid sequence VVV, (hh) Insertion of amino acid sequence FPG between positions G778 and S779 of SEQ ID NO: 2, (ii) Insertion of amino acid sequence GS between positions S779 and P780 of SEQ ID NO: 2, (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, cancer, or a tumor, or cells thereof express an oncogenic variant of the HER-2 receptor, in which case the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes HER2-Δ16, HER2-C311R, HER2-S310F, p95-HER2-M611, or any combination thereof.

[0718] In some embodiments, cancer, or a 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 includes a deletion of exon 16 (HER4-Δ16).

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

[0720] In some embodiments, cancer, or a tumor, or cells thereof express an oncogenic variant of EGFR, in which case the sequence encoding the oncogenic variant of EGFR includes a deletion of exon 20 or a portion thereof, and in this case, cancer, a tumor, or cells thereof do not include a marker suggesting responsiveness to immunotherapy.

[0721] In some embodiments, an oncogenic variant (e.g., an allosteric variant) or an oncogenic mutation (e.g., an allosteric mutation) is detected by a diagnostic method approved by the Food and Drug Administration (FDA).

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

[0723] In some embodiments, the cancer, or tumor, or their cells are insensitive or resistant to treatment with a therapeutic agent different from the compound of the present disclosure. In some embodiments, the cancer, or tumor, or their cells are insensitive or resistant to treatment with a type I inhibitor. In some embodiments, the cancer, or tumor, or their cells are insensitive or resistant to treatment with one or more of gefitinib, 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 different from 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 gefitinib, 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, and the oncogenic variant contains 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, and the oncogenic variant contains 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. In 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. In 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 cancer signs or symptoms.

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

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

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

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

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

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

[0736] Such use (or method of treatment or prophylaxis) of the subject comprises administering to a subject in need of such prophylaxis 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 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 US 6,780,996), dasatinib (e.g., Sprycel® by Bristol-Myers Squibb), armala (e.g., pazopanib, e.g., Votrient® by GlaxoSmithKline), imatinib and imatinib mesylate (e.g., 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, PCT(as described in WO02 / 066470), pasireotide (e.g., SOM230, as described in WO02 / 010192), sorafenib (e.g., Nexavar®); HER2 receptor inhibitor: trastuzumab (e.g., Herceptin® by Genentech / Roche), neratinib (or HKI-272, as described in WO05 / 028443), lapatinib or lapatinib ditosylate (e.g., Tykerb® by GlaxoSmithKline); CD20 antibody: rituximab (e.g., Riuxan® and MabThera® by Genentech / Roche), tositumomab (e.g., Bexxar® by GlaxoSmithKline), ofatumumab by GlaxoSmithKline (e.g., Arzerra®); Bcr / Abl kinase inhibitor: nilotinib hydrochloride (e.g., Tasigna® by Novartis); DNA synthesis inhibitor: capecitabine (e.g., Xeloda® by Roche), gemcitabine hydrochloride (e.g., Gemzar® by Eli Lilly and Company), nelarabine (or Arranon® and Atriance® by GlaxoSmithKline); anti-tumor agent: oxaliplatin (e.g., Eloxatin® by Sanofi-Aventis as described in US4,169,846); epidermal growth factor receptor (EGFR) inhibitor: gefitinib (or Iressa®), afatinib (or Tovok® by Boehringer Ingelheim), cetuximab (e.g., Bristol-MyersErbitux (registered trademark) by Squibb, panitumumab (e.g., Vectibix (registered trademark) by Amgen); HER dimerization inhibitor: pertuzumab (e.g., Omnitarg (registered trademark) by Genentech); human granulocyte colony-stimulating factor (G-CSF) modifying agent: filgrastim (e.g., Neupogen (registered trademark) by Amgen); immunomodulatory agent: afucosylated monoclonal antibody (registered trademark) by Roche, pegfilgrastim (e.g., Neulasta (registered trademark) by Amgen), lenalidomide (e.g., CC-5013, e.g., Revlimid (registered trademark)), thalidomide (e.g., Thalomid (registered trademark)); (m)CD40 inhibitor: dacetuzumab (e.g., SGN-40 or huS2C6 by Seattle Genetics, Inc); apoptosis promoting receptor agonist (PARA): dulaglutide (e.g., AMG-951 by Amgen / Genentech); hedgehog antagonist: vismodegib (or GDC-0449, described in WO06 / 028958); PI3K inhibitor: 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 inhibitor: anagrelide (e.g., Agrylin (registered trademark)); BCL-2 inhibitor: navitoclax (or ABT-263, described in WO09 / 155386); mitogen-activated protein kinase kinase (MEK) inhibitor: XL-518 (ACCCorp.'s Cas No. 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., Hycamtin® by GlaxoSmithKline); Topoisomerase II inhibitors: etoposide (e.g., VP-16 and etoposide phosphate, e.g., Toposar®, VePesid®, and Etopophos®), teniposide (e.g., VM-26, e.g., Vumon®), mTOR inhibitors: temsirolimus (e.g., Torisel®, Pfizer), ridaforolimus (formerly known as deforolimus, (or AP23573 and MK8669, described in WO 03 / 064383), everolimus (e.g., Afinitor® by Novartis), Osteoclast bone resorption inhibitors: zoledronic acid (or Zometa® by Novartis), CD33 antibody-drug conjugate: gemtuzumab ozogamicin (e.g., Mylotarg® by 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 analog: octreotide (e.g., octreotide acetate, e.g., Sandostatin® and SandostatinLAR (registered trademark), synthetic interleukin-11 (IL-11): oprelvekin (e.g., Neumega (registered trademark), Pfizer / Wyeth), synthetic erythropoietin: darbepoetin alfa (e.g., Aranesp (registered trademark), Amgen), receptor activator of nuclear factor kappa B (RANK) inhibitor: denosumab (e.g., Prolia (registered trademark), Amgen), thrombopoietin-mimetic peptibody: romiplostim (e.g., Nplate (registered trademark), Amgen), cell growth stimulant: palifermin (e.g., Kepivance (registered trademark), Amgen), anti-insulin-like growth factor 1 receptor (IGF-1R) antibody: figitumumab (e.g., CP-751,871, ACC Corp), robatumumab (CAS No. 934235-44-6), anti-CS1 antibody: elotuzumab (HuLuc63, CAS No. 915296-00-3), CD52 antibody: alemtuzumab (e.g., Campath (registered trademark)), CTLA-4 inhibitor: tremelimumab (IgG2 monoclonal antibody, Pfizer, previously known as ticilimumab, CP-675,206), ipilimumab (CTLA-4 antibody, e.g., MDX-010, CASNo. 477202-00-9), histone deacetylase inhibitors (HDIs): vorinostat (e.g., Zolinza (registered trademark), Merck), alkylating agents: temozolomide (e.g., Temodar (registered trademark) and Temodal (registered trademark), Schering - Plough / Merck), dactinomycin (e.g., actinomycin D and e.g., Cosmegen (registered trademark)), melphalan (e.g., L - PAM, L - sarcolysin and phenylalanine mustard, e.g., Alkeran (registered trademark)), altretamine (e.g., hexamethylmelamine (HMM), e.g., Hexalen (registered trademark)), carmustine (e.g., BiCNU (registered trademark)), bendamustine (e.g., Treanda (registered trademark)), busulfan (e.g., Busulfex (registered trademark) and Myleran (registered trademark)), carboplatin (e.g., Paraplatin (registered trademark)), lomustine (e.g., CCNU, e.g., CeeNU (registered trademark)), cisplatin (e.g., CDDP, e.g., Platinol (registered trademark) and Platinol (registered trademark) - AQ), chlorambucil (e.g., Leukeran (registered trademark)), cyclophosphamide (e.g., Cytoxan (registered trademark) and Neosar (registered trademark)), dacarbazine (e.g., DTIC, DIC and imidazole - carboxamide, e.g., DTIC - Dome (registered trademark)), altretamine (e.g., hexamethylmelamine (HMM), e.g., Hexalen (registered trademark)), ifosfamide (e.g., Ifex (registered trademark)), procarbazine (e.g., Matulane (registered trademark)), mechlorethamine (e.g., nitrogen mustard, mustine, and mechloroethamine hydrochloride, e.g., Mustargen (registered trademark)), streptozocin (e.g., Zanosar (registered trademark)), thiotepa (e.g., thiophosphoramide, TESPA and TSPA, e.g., Thioplex (registered trademark)), biological response modifiers:: Bacillus Calmette - Guérin (e.g., theraCys (registered trademark) and TICE (registered trademark) 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 liposome (daunorubicin citrate liposome, e.g., DaunoXome®), mitoxantrone (e.g., DHAD, e.g., Novantrone®), epirubicin (e.g., Ellence™), idarubicin (e.g., Idamycin® and Idamycin PFS®), mitomycin C (e.g., Mutamycin®), high microtubule agents: estramustine (e.g., Emcyl®), cathepsin K inhibitors: odanacatib (or MK-0822, Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, described in WO 03 / 075836), epothilone B analogs: ixabepilone (e.g., Lxempra®, Bristol-Myers Squibb), heat shock protein (HSP) inhibitors: tanespimycin (17-allylamino-17-demethoxygeldanamycin, e.g., KOS-953 and 17-AAG, SIGMA, described in US 4,261,989), TpoR agonists: eltrombopag (e.g., Promacta® and Revolade®, GlaxoSmithKline), anti-[ Mitotic agents: docetaxel (e.g., Taxotere (registered trademark), Sanofi - Aventis), adrenal steroid inhibitors: aminoglutethimide (e.g., Cytadren (registered trademark)), anti - androgens: nilutamide (e.g., Nilandron (registered trademark) and Anandron (registered trademark)), bicalutamide (trade name Casodex (registered trademark)), flutamide (e.g., Fulexin (trademark)), androgens: fluoxymesterone (e.g., halotestin (registered trademark)), proteasome inhibitors: bortezomib (e.g., Velcade (registered trademark)), CDK1 inhibitors: alvocidib (e.g., flavopirdol or HMR - 1275, described in US 5,621,002), gonadotropin - releasing hormone (GnRH) receptor agonists: leuprolide or leuprolide acetate (e.g., Viadure (registered trademark), Bayer AG, Eligard (registered trademark), Sanofi - Aventis, and Lupron (registered trademark), Abbott Lab), taxane anti - neoplastic agents: cabazitaxel, larotaxel, 5HT1a receptor agonists: xaliproden (or SR57746, described in US 5,266,573), HPC vaccines: Cervarix (registered trademark), sold by GlaxoSmithKline, Gardasil (registered trademark), sold by Merck, iron chelating agents: deferasirox (e.g., Exjade (registered trademark), sold by Novartis), antimetabolites: cladribine (2 - chlorodeoxyadenosine, e.g., leustatin (registered trademark)), 5 - fluorouracil (e.g., Adrucil (registered trademark)), 6 - thioguanine (e.g., Purinethol (registered trademark)), pemetrexed (e.g., Alimta (registered trademark)), cytarabine (e.g., arabinosylcytosine (Ara - C), e.g., Cytosar - U (registered trademark)), liposomal cytarabine (e.g., LiposomalAra-C, for example, 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 VincasarPfs (Registered Trademark)), Vinorelbine (e.g., Navelbine (Registered Trademark)), Paclitaxel (e.g., Taxol and Onxal (Trademark)), Retinoids: Alitretinoin (e.g., Panretin (Registered Trademark)), Tretinoin (all-trans retinoic acid, e.g., ATRA, e.g., Vesanoid (Registered Trademark)), Isotretinoin (13-cis-retinoic acid, e.g., Accutane (Registered Trademark), Amnesteem (Registered Trademark), Claravis (Registered Trademark), Clarus (Registered Trademark), Decutan (Registered Trademark), Isotane (Registered Trademark), Izotech (Registered Trademark), Oratane (Registered Trademark), Isotret (Registered Trademark), and Sotret (Registered Trademark)), Bexarotene (e.g., Targretin (Registered Trademark)), Glucocorticosteroids: Hydrocortisone (e.g., Cortisone, Hydrocortisone Sodium Succinate, Hydrocortisone Sodium Phosphate, and e.g., Ala-Cort (Registered Trademark), Hydrocortisone Phosphate, Solu-Cortef (Registered Trademark), Hydrocort Acetate (Registered Trademark), and Lanacort (Registered Trademark)), Dexamethasone, Prednisolone (e.g., Delta-Cortel (Registered Trademark), Orapred (Registered Trademark), Pediapred (Registered Trademark) and Prelone (Registered Trademark)), Prednisone (e.g., Deltasone (Registered Trademark), LiquidRed (Registered Trademark), Meticorten (Registered Trademark) and Orasone (Registered Trademark)), methylprednisolone (e.g., 6-methylprednisolone, methylprednisolone acetate, sodium succinate methylprednisolone, e.g., Duralone (Registered Trademark), Medralone (Registered Trademark), Medrol (Registered Trademark), M-Prednisol (Registered Trademark) and Solu-Medrol (Registered Trademark)), cytokines: interleukin-2 (e.g., Aldesleukin and IL-2, e.g., Proleukin (Registered Trademark)), interleukin-11 (e.g., oprelvekin, e.g., Neumega (Registered Trademark)), alpha interferon alpha (e.g., IFN-alpha, e.g., Intron (Registered Trademark) A, and Roferon-A (Registered Trademark)); luteinizing hormone releasing hormone (LHRH) agonist: goserelin (e.g., Zoladex (Registered Trademark)), progesterone megestrol (e.g., megestrol acetate, e.g., Megace (Registered Trademark)), mixed cytotoxic agent: arsenic trioxide (e.g., Trisenox (Registered Trademark)), asparaginase (e.g., L-asparaginase, Erwinia L-asparaginase, e.g., Elspar (Registered Trademark) and Kidrolase (Registered Trademark)), antiemetic: NK-1 receptor antagonist: casopitant (e.g., Rezonic (Registered Trademark) and Zunrisa (Registered Trademark), GlaxoSmithKline), and cytoprotective agent: amifostine (e.g., Ethyol (Registered Trademark)), leucovorin (e.g., calcium leucovorin, citrovorum factor and folic acid) are expected to be administered in combination. [Embodiment] Exemplary Embodiment Embodiment 1: A compound of the following formula (I’), [Chemical Formula] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein W is CH or N, Z is one or more RZ is an optionally substituted 3- to 12-membered heterocycloalkyl, each R Z is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, and -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Za and each R Za is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 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 optionally substituted with one or more R T and each R T is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, -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- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Ta and each R Ta is independently 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 optionally substituted with one or more R A1 to give a C6-C 10 aryl, each R A1 is 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, -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 is optionally substituted with one or more R A1a and 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; -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 represented by one or more R A1b Optionally replaced by, and Each R A1b are independently halogen, CN, -OH, or -NH2. Embodiment 2: The compound according to any one of the preceding embodiments, wherein the compound is a compound of formula (I'), or a pharma- ceutically 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, -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-C10 Aryl, 3- or 5- to 10-membered heteroaryl is optionally substituted with one or more R Za and is optionally substituted with one or more R Each R Za is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 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 optionally substituted with one or more R T and is optionally substituted with one or more R Each R T is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, and -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Ta and is optionally substituted with one or more R Each R Ta is independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 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, where -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, -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 Optionally replaced by, and Each R A1b are independently halogen, CN, -OH, or -NH2; However, Z is [ka] When Ar 1 is a C6-C alkyl group 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 pharma- ceutically 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 is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C 10 cycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl, and -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C 10 cycloalkyl, C6-C 10 aryl, 3- or 5- to 10-membered heteroaryl is optionally substituted with one or more R Za s, each R Za is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 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 optionally substituted with one or more R T s, each R T is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 7-membered monocyclic heterocycloalkyl, or 5- to 10-membered heteroaryl, and -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 Cycloalkyl, C6-C 10 Aryl, 3- to 7-membered monocyclic heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Ta and each R is independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C Ta cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, 10 and Ar 1 is C6-C aryl optionally substituted with one or more R A1 and each R 10 is independently halogen, CN, -OH, -NH2, -OR -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 optionally substituted with one or more R A1 and each R A1a is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, 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 optionally substituted with one or more R A1a and each R is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, 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 optionally substituted with one or more R A1a and each R A1b is independently halogen, CN, -OH, or -NH2, provided that Z is A1b and wherein

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Claims

1. A compound of formula (I'): 【Chemistry 1】 or a pharma- ceutically 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 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, 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 The aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be one or more R Ｚａ , optionally replaced by Each R Ｚａ are 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, 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 one or more R Ｔ , optionally replaced by Each R Ｔ are 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, 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 The aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be one or more R Ｔａ , optionally replaced by Each R Ｔａ are 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 one or more R Ａ１ C optionally substituted with ６ -C １０ is aryl, Each R Ａ１ are independently halogen, CN, -OH, -NH ２ , -OR Ａ１ａ , -O-(C １ -C ６ alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, 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, 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 The aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be one or more R Ａ１ａ Optionally replaced by Each R Ａ１ａ are 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, 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 The aryl, 3- to 10-membered heterocycloalkyl, or 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 A compound.

2. The compound is of formula (I') or a pharma- ceutically 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 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, or 5- to 10-membered heteroaryl, 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- or 5- to 10-membered heteroaryl may be one or more R Ｚａ Optionally replaced by Each R Ｚａ are 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, 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 one or more R Ｔ Optionally replaced by Each R Ｔ are independently halogen, CN, -OH, -NH ２ , -O-(C １ -C ６ Alkyl), 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 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ An aryl, a 3- to 7-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be represented by one or more R Ｔａ Optionally replaced by Each R Ｔａ are independently halogen, CN, -OH, -NH ２ , -C(=O)OH, -O-(C １ -C ６ Alkyl 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 one or more R Ａ１ C optionally substituted with ６ -C １０ is aryl, Each R Ａ１ are independently halogen, CN, -OH, -NH ２ , -OR Ａ１ａ , -O-(C １ -C ６ alkyl), -NH(C １ -C ６ alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ alkynyl, １ -C ６ alkyl), -NH(C １ -C ６ alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkynyl is one or more R Ａ１ａ Optionally replaced by, and Each R Ａ１ａ are 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, or C ２ -C ６ alkynyl, １ -C ６ alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkynyl is one or more R Ａ１ｂ Optionally replaced by, and Each R Ａ１ｂ are independently halogen, CN, -OH, or -NH ２ and However, Z is 【Chemistry 2】 When Ar １ is C optionally substituted with one or more halogens ６ -C １０ The compound of claim 1 which is aryl.

3. The compound is of formula (I') or a pharma- ceutically acceptable salt or stereoisomer thereof; 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—(C １ -C ６ Alkyl), C １ -C ６ alkyl, or 3- to 10-membered heterocycloalkyl, １ -C ６ Alkyl), C １ -C ６ alkyl or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogens; T is -O-(C １ -C ６ alkyl), -NH-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ alkynyl, １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkynyl is one or more R Ｔ Optionally replaced by Each R Ｔ are independently halogen, —OH, —O—(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ or 3- to 7-membered heterocycloalkyl, １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ or 3- to 7-membered heterocycloalkyl optionally substituted with one or more -C(=O)OH; Ar １ is one or more R Ａ１ C optionally substituted with ６ -C １０ is aryl, Each R Ａ１ are independently halogen, -OR Ａ１ａ , or one or more R Ａ１ａ -O-(C １ -C ６ alkyl), and Each R Ａ１ａ is independent, C ６ -C １０ aryl or 5- to 10-membered heteroaryl, ６ -C １０ The compound of claim 1 or 2, wherein the aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogens.

4. The compound is of formula (I') or a pharma- ceutically acceptable salt or stereoisomer thereof; 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—(C １ -C ６ alkyl), or C １ -C ６ alkyl, and the —O—(C １ -C ６ alkyl) or C １ -C ６ The alkyl is optionally substituted with one or more halogens; T is -O-(C １ -C ６ alkyl), -NH-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ alkynyl, １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkynyl is one or more R Ｔ Optionally replaced by Each R Ｔ are independently halogen, —OH, —O—(C １ -C ６ alkyl), or 3- to 7-membered heterocycloalkyl, １ -C ６ alkyl), or 3- to 7-membered heterocycloalkyl optionally substituted with one or more -C(=O)OH; Ar １ is one or more R Ａ１ C optionally substituted with ６ -C １０ is aryl, Each R Ａ１ are independently halogen, -OR Ａ１ａ , or one or more R Ａ１ａ -O-(C １ -C ６ alkyl), and Each R Ａ１ａ is independent, C ６ -C １０ aryl or 5- to 10-membered heteroaryl, ６ -C １０ aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogens; However, Z is 【Chemistry 3】 When Ar １ is C optionally substituted with one or more halogens ６ -C １０ The compound according to any one of claims 1 to 3, which is aryl.

5. The compound is of formula (I') or a pharma- ceutically acceptable salt or stereoisomer thereof; 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—(C １ -C ６ alkyl), or C １ -C ６ alkyl, and the —O—(C １ -C ６ alkyl) or C １ -C ６ The alkyl is optionally substituted with one or more halogens; T is -O-(C １ -C ６ alkyl), -NH-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ alkynyl, １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkynyl is one or more R Ｔ Optionally replaced by Each R Ｔ are independently halogen, —OH, —O—(C １ -C ６ alkyl), or 3- to 7-membered heterocycloalkyl, １ -C ６ alkyl), or 3- to 7-membered heterocycloalkyl optionally substituted with one or more -C(=O)OH; Ar １ is C optionally substituted with one or more halogens ６ -C １０ The compound according to any one of claims 1 to 4, which is aryl.

6. The compound is of formula (I') or a pharma- ceutically acceptable salt or stereoisomer thereof; W is CH; Z is one or more C １ -C ６ is a 3- to 12-membered heterocycloalkyl optionally substituted with alkyl; T is a C optionally substituted with one or more 6-membered heterocycloalkyl. ２ -C ６ alkenyl, and Ar １ is C optionally substituted with one or more halogens ６ The compound according to any one of claims 1 to 5, which is aryl.

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

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

9. Z is 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 of any one of claims 1 to 8, optionally substituted with

10. 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 of any one of claims 1 to 9, optionally substituted with

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

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

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

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

15. At least one R Ｚ is one or more R Ｚａ -O-(C １ -C ６ The compound according to any one of claims 1 to 14, wherein the aryl group is aryl, aryl, or aryl.

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

17. At least one R Ｚ But, C １ -C ６ The compound according to any one of claims 1 to 16, which is alkyl.

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

19. At least one R Ｚ is substituted with one or more halogens １ -C ６ The compound according to any one of claims 1 to 18, which is alkyl.

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

21. At least one R Ｚ is one or more R Ｚａ 21. The compound of any one of claims 1 to 20, which is a 3-10 membered heterocycloalkyl optionally substituted with:

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

23. T is -O-(C １ -C ６ alkyl), -NH-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ alkynyl, 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 one or more R Ｔ Optionally replaced by Each R Ｔ are independently halogen, CN, -OH, -NH ２ , -O-(C １ -C ６ Alkyl), 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 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ An aryl, a 3- to 7-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be represented by one or more R Ｔａ Optionally replaced by, and Each R Ｔａ are independently halogen, CN, -OH, -NH ２ , -C(=O)OH, -O-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ The compound of any one of claims 1 to 22, which is aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

24. T is -O-(C １ -C ６ alkyl), -NH-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ alkynyl, １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkynyl is one or more R Ｔ Optionally replaced by, and Each R Ｔ are independently halogen, —OH, —O—(C １ -C ６ alkyl), -N(C １ -C ６ Alkyl) ２ or 3- to 7-membered heterocycloalkyl, １ -C ６ alkyl), -N(C １ -C ６ Alkyl) ２ or 3-7 membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

25. T is -O-(C １ -C ６ alkyl), -NH-(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ alkynyl, １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ Alkynyl is one or more R Ｔ Optionally replaced by, and Each R Ｔ are independently halogen, —OH, —O—(C １ -C ６ alkyl), or 3- to 7-membered heterocycloalkyl, １ -C ６ 25. The compound of any one of claims 1 to 24, wherein said aryl, aryl group ...

26. T is one or more R Ｔ -O-(C １ -C ６ 26. The compound according to any one of claims 1 to 25, wherein the aryl group is aryl, aryl, or aryl.

27. T is one or more R Ｔ -NH-(C １ -C ６ 27. The compound according to any one of claims 1 to 26, wherein the aryl group is aryl, aryl, or aryl.

28. T is one or more R Ｔ C optionally substituted with １ -C ６ The compound of any one of claims 1 to 27, which is alkyl.

29. T is C １ -C ６ The compound of any one of claims 1 to 28, which is alkyl.

30. T is C substituted with one or more halogens. １ -C ６ The compound of any one of claims 1 to 29, which is alkyl.

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

32. T is C ２ -C ６ The compound of any one of claims 1 to 31, which is alkenyl.

33. T is one or more of -OH, -O-(C １ -C ６ alkyl), -N(C １ -C ６ Alkyl) ２ or C substituted with 3- to 10-membered heterocycloalkyl ２ -C ６ The compound of any one of claims 1 to 32, wherein said 3 to 10 membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

34. T is C ２ -C ６ The compound of any one of claims 1 to 33, which is alkynyl.

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

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

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

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

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

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

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

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

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

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

45. Ar １ But one or more R Ａ１ C substituted with ６ -C １０ The compound of any one of claims 1 to 44, which is aryl.

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

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

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

49. Ar １ is phenyl optionally substituted with one or more halogens, said phenyl being further substituted with -O-phenyl or -O-pyridinyl, said -O-phenyl or -O-pyridinyl being optionally substituted with one or more halogens.

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

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

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

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

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

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

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

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

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

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

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

61. The compound is a compound of the following formula (II'): 【Chemistry 12】 or a pharma- ceutically acceptable salt or stereoisomer thereof.

62. The compound is a compound of the following formula (II'): 【Chemistry 13】 or a pharma- ceutically acceptable salt or stereoisomer thereof.

63. The compound is represented by the following formula (III') or (III'-a): 【Chemistry 14】 or a pharma- ceutically acceptable salt or stereoisomer thereof.

64. The compound is represented by the following formula (IV') or (IV'-a): 【Chemistry 15】 or a pharma- ceutically acceptable salt or stereoisomer thereof.

65. The compound is a compound of formula I 【Chemistry 16】 or a pharma- ceutically acceptable salt or stereoisomer thereof; W is CH or N; X １ is -O-, -S-, -NR ３ - and R ａ , R ｂ are each independently hydrogen or C １－４ alkyl, or R ａ One of them is X １ is NR ３ If so, then X １ Forming a ring with -(CH ２ ) ｐ - or R ａ One of them is R ２ Forming a ring with -(CH ２ ) ｐ - and R ｃ , R ｄ are each 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 Forming a ring together with R ａ Form a ring with one of the -(CH ２ ) ｑ - and R ３ is hydrogen or C １－４ alkyl, preferably hydrogen or methyl, or R ２ Forming a ring with -(CH ２ ) 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, -CF ３ , C １－６ Alkyl, C １－６ Alkoxy, C ３－７ Cycloalkyl, Hydroxy C １－５ Alkyl, C １－６ Alkoxy-C １－６ Alkyl, C １－６ Alkoxy-C ６ Aryl, C １－６ Alkoxy-C ５－６ Heteroaryl, Amino, Amino C １－４ Alkyl, C １－６ Alkylamino, C １－６ Aminoalkyl-C ６ Aryl, C １－６ Aminoalkyl-C ５－６ Heteroaryl, C １－６ Alkoxycarbonyl, C １－６ Alkoxyaminocarbonyl, Aryl C １－６ Alkoxy or C ６ 65. The compound of any one of claims 1 to 64, which is a 6-membered aryl substituted with one or more groups selected from aryl.

66. Ar １ is a compound of formula i, or a pharma- ceutically acceptable salt or stereoisomer thereof; 【Chemistry 17】 During the ceremony, R ４ is hydrogen, halogen, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ Cycloalkyl, Hydroxy C １－５ Alkyl, C １－６ Alkoxy-C １－６ Alkyl, C １－６ Alkoxy-C ６ Aryl, C １－６ Alkoxy-C ５－６ Heteroaryl, Amino C １－４ Alkyl, C １－６ Alkylamino, C １－６ Aminoalkyl-C ６ Aryl, C １－６ Aminoalkyl-C ５－６ Heteroaryl, C １－６ Alkoxycarbonyl, C １－６ Alkoxyaminocarbonyl, Aryl C １－６ Alkoxy, or C ６ is aryl, R ５ , R ５ ', R ６ , R ６ ' are each independently hydrogen, -CF ３ or halogen, preferably F or Cl.

67. Ar １ is a compound of formula ii-1, ii-2, ii-3, or ii-4, or a pharma- ceutically acceptable salt or stereoisomer thereof; 【Chemistry 18】 During the ceremony, X ２ is O, NH, or NMe; X ３ is CH or N, o is 0 or 1; R ４ is hydrogen or halogen, preferably F or Cl, R ５ , R ５ ', R ６ , R ６ ' are each independently hydrogen, -CF ３ or halogen, preferably F or Cl; R ７ A compound according to any one of claims 1 to 66, wherein is hydrogen or halogen, preferably F.

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

69. Ar １ 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 pharma- ceutically acceptable salt or stereoisomer thereof; 【Chemistry 20】 During the ceremony, o is 0 or 1; R ４ is hydrogen or halogen, preferably F or Cl, R ５ , R ５ ', R ６ , R ６ ' are each independently hydrogen, -CF ３ or halogen, preferably F or Cl; R ７ A compound according to any one of claims 1 to 68, wherein is hydrogen or halogen, preferably F.

70. A compound of formula IIa or IIb, 【Chemistry 21】 or a pharma- ceutically acceptable salt or stereoisomer thereof; X １ is -O- or -NR ３ - and R １ is H or F, R ２ is hydrogen or C １－４ alkyl, preferably methyl, or R ３ Forming a ring with -(CH ２ ) ｑ - and R ３ is hydrogen or C １－４ alkyl, preferably hydrogen or methyl, or R ２ Forming a ring with -(CH ２ ) 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, -CF ３ , C １－６ Alkyl, C １－６ Alkoxy, C ３－７ Cycloalkyl, Hydroxy C １－５ Alkyl, C １－６ Alkoxy-C １－６ Alkyl, C １－６ Alkoxy-C ６ Aryl, C １－６ Alkoxy-C ５－６ Heteroaryl, Amino, Amino C １－４ Alkyl, C １－６ Alkylamino, C １－６ Aminoalkyl-C ６ Aryl, C １－６ Aminoalkyl-C ５－６ Heteroaryl, C １－６ Alkoxycarbonyl, C １－６ Alkoxyaminocarbonyl, Aryl C １－６ Alkoxy or C ６ 70. The compound of any one of claims 1 to 69, which is a 6-membered aryl substituted with one or more groups selected from aryl.

71. A compound of formula III, 【Chemical 22】 or a pharma- ceutically acceptable salt or stereoisomer thereof; R １ is H or F, Ar １ is unsubstituted or is a halogen, -CF ３ , C １－６ Alkyl, C １－６ Alkoxy, C ３－７ Cycloalkyl, Hydroxy C １－５ Alkyl, C １－６ Alkoxy-C １－６ Alkyl, C １－６ Alkoxy-C ６ Aryl, C １－６ Alkoxy-C ５－６ Heteroaryl, Amino, Amino C １－４ Alkyl, C １－６ Alkylamino, C １－６ Aminoalkyl-C ６ Aryl, C １－６ Aminoalkyl-C ５－６ Heteroaryl, C １－６ Alkoxycarbonyl, C １－６ Alkoxyaminocarbonyl, or C ６ aryl; The compound according to any one of claims 1 to 70, wherein Z is selected from the following: 【Chemistry 23】

72. A compound of formula IV, 【Chemistry 24】 or a pharma- ceutically acceptable salt or stereoisomer thereof; R １ is H or F, R ４ is hydrogen, halogen, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ Cycloalkyl, Hydroxy C １－５ Alkyl, C １－６ Alkoxy-C １－６ Alkyl, C １－６ Alkoxy-C ６ Aryl, C １－６ Alkoxy-C ５－６ Heteroaryl, Amino C １－４ Alkyl, C １－６ Alkylamino, C １－６ Aminoalkyl-C ６ Aryl, C １－６ Aminoalkyl-C ５－６ Heteroaryl, C １－６ Alkoxycarbonyl, C １－６ Alkoxyaminocarbonyl, or C ６ is aryl, R ５ , R ５ ', R ６ , R ６ ' are each independently hydrogen, -CF ３ or halogen, preferably F or Cl; The compound according to any one of claims 1 to 71, wherein Z is selected from the following: 【Chemistry 25】

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

74. Compounds of formula VI-1, VI-2, VI-3, or VI-4, 【Chemistry 28】 or a pharma- ceutically acceptable salt or stereoisomer thereof; R １ is H or F, X ２ is O, NH, or NMe; X ３ is C or N, o is 0 or 1; R ４ is hydrogen or halogen, preferably F or Cl, R ５ , R ６ are each independently hydrogen, -CF ３ or halogen, preferably F or Cl, R ７ is hydrogen or halogen, preferably F, The compound according to any one of claims 1 to 73, wherein Z is selected from the following: 【Chemical 29】

75. Compounds of formula VII-1, VII-2, VII-3, or VII-4, VII-5, VII-6, VII-7, VII-8, or VII-9, 【Chemistry 30】 or a pharma- ceutically acceptable salt or stereoisomer thereof; 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 each independently hydrogen, -CF ３ or halogen, preferably F or Cl, R ７ is hydrogen or halogen, preferably F, The compound according to any one of claims 1 to 74, wherein Z is selected from the following: 【Chemistry 31】

76. 76. The compound according to any one of claims 1 to 75, selected from the compounds set forth in Tables 1 and 2, pharma- ceutically acceptable salts, and stereoisomers thereof.

77. 77. A composition comprising a compound according to any one of claims 1 to 76, and a pharma- ceutically acceptable carrier.

78. 82. A method of inhibiting an oncogenic variant of an ErbB receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 77.

79. A method of preventing or treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 78.

80. A compound according to any one of claims 1 to 76 for use in the prevention or treatment of cancer.

81. A compound according to any one of claims 1 to 76 for use in inhibiting an oncogenic variant of an ErbB receptor.

82. 82. The method or compound of any one of claims 1 to 81, wherein the cancer is a solid tumor.

83. 83. The method or compound of any one of claims 1 to 82, wherein the cancer is bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma (GBM), head and neck cancer, lung cancer, non-small cell lung cancer (NSCLC), or any subtype thereof.

84. 84. The method or compound of any one of claims 1 to 83, wherein said cancer is glioblastoma (GBM) or any subtype thereof.

85. 85. The method or compound of any one of claims 1 to 84, wherein the cancer is glioblastoma.

86. 86. The method or compound of any one of claims 1 to 85, wherein the cancer or tumor, or cells thereof, express an oncogenic variant of an ErbB receptor.

87. 87. The method or compound of any one of claims 1 to 86, wherein the oncogenic variant of the ErbB receptor comprises an allosteric mutation.

88. 88. The method or compound of any one of claims 1 to 87, wherein said oncogenic variant of an ErbB receptor is an allosteric variant of said ErbB receptor.

89. 89. The method or compound of any one of claims 1 to 88, wherein the oncogenic variant or mutation is detected by a Food and Drug Administration (FDA) approved diagnostic method.

90. 90. A method for preventing or treating glioblastoma, comprising administering to said subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 89.

91. A compound according to any one of claims 1 to 89 for use in the prevention or treatment of glioblastoma.

92. 92. The method or compound of any one of claims 1 to 91, wherein the compound is selected from the compounds set forth in Tables 1 and 2, pharma- ceutically acceptable salts, and stereoisomers thereof.

93. 93. The method or compound of any one of claims 1 to 92, wherein the compound is selected from the compounds set forth in Tables 1 and 2, and pharma- ceutically acceptable salts thereof.

94. 94. The method or compound of any one of claims 1 to 93, wherein the compound is selected from the compounds listed in Tables 1 and 2.

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