ALKINYL QUINAZOLINE COMPOUNDS

Description

RELATED APPLICATIONS

[0001] This application claims priority to, and the benefit of, U.S. Application Nos. 63 / 065,028, filed August 13, 2020, and 62 / 887,392, filed August 15, 2019.FIELD OF DISCLOSURE

[0002] The present disclosure relates to new compounds as inhibitors of receptor tyrosine kinases (RTK), in particular oncogenic mutants of ErbB-receptors. The disclosure also relates to methods of preparation these compounds, compositions comprising these compounds, and methods of using them in the prevention or treatment of abnormal cell growth in mammals, especially humans.BACKGROUND

[0003] Mutations affecting either the intracellular catalytic domain or extracellular ligand binding domain of an ErbB receptor can generate oncogenic activity (the ErbB protein family consists of 4 members including ErbB-1, also named epidermal growth factor receptor (EGFR) and Erb-2, also named HER2 in humans). ErbB inhibitors are a known treatment for a number of cancers. However, not every patient is responsive satisfactorily to this treatment. Thus, there is a long-felt need in the art for new therapies that are able to address the variable responsiveness of cancer patients to known therapies. Each of WO2012 / 122058, WO2014 / 177038, WO2020 / 068867, EP1369418, and EP1792898 describe substituted quinazoline compounds. The present disclosure provides compositions and methods for preventing or treating cancer in patients with these oncogenic mutations without the variable responsiveness observed when patients having these ErbB mutants are treated using the existing standard of care.SUMMARY OF DISCLOSURE

[0004] The subject matter of the invention is defined by the appended claims. Accordingly, in some aspects, the present disclosure provides a compound which is: a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0005] In some aspects, the present disclosure is directed to a composition comprising a compound according to the above aspect, and a pharmaceutically acceptable carrier.

[0006] In some aspects, the present disclosure is directed to the above compound or composition for use in the prevention or treatment of cancer.

[0007] Further aspects of the invention are set out in the appended claims.DETAILED DESCRIPTION

[0008] The present disclosure relates to compounds useful as inhibitors of receptor tyrosine kinases (RTK), in particular oncogenic mutants of ErbB-receptors. In some embodiments of the invention, oncogenic mutants of ErbB-receptors are also allosteric mutants of ErbB-receptors. In some embodiments, allosteric mutants may comprise or consist of an ErbB receptor variant having a mutation in a sequence outside of an ATP-binding site. In some embodiments, allosteric mutants may comprise or consist of an ErbB receptor variant having a mutation in a sequence within one or more of exon 19, exon 20 or a C1-C2 extracellular dimerization interface.

[0009] Mutations affecting either the intracellular catalytic domain or extracellular ligand binding domain of an ErbB receptor can generate oncogenic activity (the ErbB protein family consists of 4 members including ErbB-1, also named epidermal growth factor receptor (EGFR) and Erb-2, also named HER2 in humans). Extracellular mutants of ErbB receptors in cancer, including EGFR-Viii (also EGFR-V3) and HER2-S310F, are constitutively activated in the absence of ligand, exhibit sustained 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 with poor long term overall survival.

[0010] In glioblastoma (also glioblastoma multiforma or GBM), EGFR-Viii is expressed by 20% of tumors (Sugawa, Ekstrand et al. 1990, Brennan, Verhaak et al. 2013). Expression of EGFR-Viii in GBM tends to be mutually exclusive with expression of other RTK oncogenes, which are co-expressed with EGFR variants in only 7% of GBM tumors (Furnari, Cloughesy et al. 2015). These data demonstrate how EGFR-Viii in GBM has a dominant and mutually exclusive expression pattern compared with other oncogenic drivers. EGFR-Viii is also expressed by approximately 30% of SCCHN tumors (Sok, Coppelli et al. 2006, Keller, Shroyer et al. 2010, Wheeler, Suzuki et al. 2010, Tinhofer, Klinghammer et al. 2011, Wheeler, Egloff et al. 2015) and 10% of squamous NSCLC (Ji, Zhao et al. 2006, Sasaki, Kawano et al. 2007), and is associated with resistance to current therapeutics including the anti-EGFR antibody cetuximab (Sok, Coppelli et al. 2006, Tinhofer, Klinghammer et al. 2011). Normal tissues do not express this oncogenic receptor variants.

[0011] RNA sequencing data has revealed that EGFR-Viii is just one of several aberrantly spliced variants of EGFR expressed in GBM tumors. Two others result in truncation of exons 12-13 (EGFR-Vvi) and 14-15 (EGFR-Vii). Like EGFR-Viii, EGFR-Vii is both transforming and tumorigenic. In addition to splice variants, GBM tumors also express a collection of EGFR point mutations including C620Y, A289V and G598V, which are transforming and tumorigenic.

[0012] HER2-S310F is the most common mutation of HER2 expressed in human tumors, expressed by approximately 0.5% of all tumors. HER2-S310F expression is mutually exclusive with expression of HER2 amplification. HER2-S310F is highly oncogenic, transforming BaF3 cells (a murine interleukin-3 (IL-3) dependent pro-B cell line) to IL-3 independence and promoting tumor growth in vivo.

[0013] Short insertions of within Exon 20 of EGFR and HER2 are expressed by lung adenocarcinoma tumors and other tumor groups. ErbB Exon 20 insertion mutants are expressed by 4-5% of lung adenocarcinoma tumors. Examples include HER2-YVMA, EGFR-SVD, and EGFR-NPH. These ErbB Exon 20 insertion mutants are highly oncogenic, transforming BaF3 cells to IL-3 independence and promoting tumor growth in vivo.

[0014] ErbB inhibitors are a known treatment for a number of cancers. However, not every patient is responsive satisfactorily to this treatment. Thus, there is a long-felt need in the art for new therapies that are able to address the variable responsiveness of cancer patients to known therapies. The present disclosure is able to overcome some of these drawbacks of the standard of care, as it existed prior to the development of the compositions and methods disclosed herein.Paradoxic ErbB Receptor Activation

[0015] Although the mechanisms described herein apply to any form of cancer in which these EGFR variants of the disclosure are expressed, the prevalence of these variants in glioblastoma (GBM) are provide by way of example. Other cancers expressing the EGFR variants of the disclosure include, but are not limited to, solid cancers, epithelial cancers and / or cancers of epithelial origin, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma (GBM), head and neck cancer, lung cancer, and non-small cell lung cancer (NSCLC).

[0016] In GBM tumors EGFR is frequently the target of genomic mutations and alternative splicing events that result in alteration of the extracellular dimer interface. Many tumors express more than one aberrant isoform. The disclosure provides the mechanism of activation for the most commonly occurring variants, EGFR-Viii, EGFR-Vii, EGFR-Vvi, EGFR-G598V and EGFR-A289V. Although each isoform / point mutant is the result of a distinct ectodomain alteration, all are activated by a common mechanism involving covalent ligand-independent dimerization.

[0017] 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 the produces an immunological response selectively against tumor cells expressing EGFR-Viii but not 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 may limit the breadth and duration of treatment benefit for an ErbB inhibitor that is selective only for EGFR-Viii. Therefore, it may be useful to exclude patients whose tumors express EGFR-Vii, EGFR-Vvi, or EGFR ectodomain point mutants from treatment with an EGFR-Viii selective therapy.

[0018] The heterogenic expression pattern for multiple ectodomain variants of ErbB receptors in tumors indicates that a small molecule inhibitor that inhibits all variants is preferred. The family of covalently-activated EGFR isoforms responds very differently to small molecule ErbB inhibitors compared to EGFR catalytic domain mutations observed in NSCLC. Importantly, Type I inhibitors, including erlotinib, all induce the formation of covalent EGFR dimers and increase EGFR phosphorylation at sub-saturating concentrations, an activity that is further enhanced when ErbB inhibitor is washed away. This manifests in paradoxical activation of proliferation at sub-saturating concentrations.

[0019] The discovery of paradoxical activation of proliferation at sub-saturating concentrations of Type I ErbB inhibitors is further demonstrated for a series of extracellular variants of HER2, prevalent in a number of cancers including breast and bladder. All variants existed as covalently activated receptors, and levels of covalent dimers increased following treatment with Type I inhibitors including sapitinib and afatinib. As with covalently-activated EGFR variants, sub-saturating doses of Type I inhibitors paradoxically increased phosphorylation of HER2 variants, increasing the proliferation of cells expressing them.

[0020] In contrast to Type I inhibitors, the disclosure demonstrates that Non-Type I (e.g. Type II) inhibitors including neratinib are devoid of paradoxical activation for cells expressing ErbB ectodomain variants. Neratinib is found to exemplify a preferred molecule that is both potent and selective for each member of the covalently-activated EGFR family versus wild type EGFR.

[0021] Collectively, the disclosure provides a structure / functional relationship for predicting how structural variations affecting receptor regions distal to the active site can confer dramatically different responses to small molecule active site inhibitors. The discovery described herein of paradoxical activation of covalently-activated ErbB receptor variants by Type I inhibitors has important clinical implications. The data of the disclosure provide a mechanistic explanation for the failed clinical studies for Type I inhibitors in tumor types where expression of covalently-activated ErbB receptors is prevalent. This includes erlotinib and gefitinib in GBM tumors, erlotinib in SCCHN tumors, and sapitinib in breast tumors.Glioblastoma

[0022] Glioblastoma (GBM), grade IV astrocytoma, is the most common form of brain cancer. The outcome for this disease is dismal. Surgery followed by a therapeutic regimen of radiation and temozolomide is standard of care, however this produces a median overall survival (OS) of only 14.6 months and few patients survive for five years. There has been little progress made in extending survival for GBM patients over the past decade. Although bevacizumab showed an improved progression free survival benefit in the recurrent setting, the addition of bevacizumab to standard of care therapy in the front-line setting did not result in an OS benefit.

[0023] EGFR is the most frequently altered oncogene in GBM. In addition to EGFR gene amplification, many tumors express variants generated by aberrant splicing or genomic mutation. The first recognized variant is EGFR-Viii, resulting from truncation of exons 2-7 and expressed by approximately 20% of GBM tumors. EGFR-Viii is oncogenic. EGFR-Viii is constitutively activated in the absence of EGF ligand, exhibiting sustained signaling that is resistant to downregulation. Therefore, EGFR-Viii is both transforming and tumorigenic. Expression of EGFR-Viii is associated with poor long term overall survival in GBM.

[0024] RNA sequencing data has revealed that EGFR-Viii is just one of several aberrantly spliced variants of EGFR expressed in GBM tumors. Two others result in truncation of exons 12-13 (EGFR-Vvi and 14-15 (EGFR-Vii). Like EGFR-Viii, EGFR-Vii is both transforming and tumorigenic. In addition to splice variants, GBM tumors also express a collection of EGFR point mutations including C620Y, A289V and G598V, which are transforming and tumorigenic. The complex landscape of EGFR alterations in GBM is further compounded by the observation that many tumors express more than one receptor variant.

[0025] Because the expression of multiple EGFR variants in GBM gives rise to transforming and tumorigenic activity and because EGFR is the most frequently altered oncogene present in GBM tumors, EGFR is an especially attractive target for small molecule ErbB inhibitors. Following the success for small molecule EGFR therapeutics against NSCLC tumors harboring activating mutations in EGFR (erlotinib, gefitinib, and afatinib), these drugs were tested in GBM. Despite intense clinical investigation of this group of ErbB inhibitors in GBM, involving >30 clinical trials and >1500 patients, all failed to produce any benefit, even for those tumors that expressed EGFR-Viii. Strikingly, some evidence suggests that erlotinib promoted disease progression. A phase 2 study evaluating erlotinib in combination with radiation and temozolomide showed median PFS (mPFS) and median OS (mOS) of 2.8 months and 8.6 months, as compared to 6.9 months and 14.6 months for patients receiving radiation and temozolomide alone. Another randomized phase II trial with erlotinib showed that patients who received erlotinib, including those whose tumors expressed EGFR-Viii, progressed more poorly as compared to those patients who received standard of care therapy. The clinical failures for ErbB inhibitors such as erlotinib in GBM tumors has cast doubt on the role of EGFR as a driver of tumor growth in GBM and led to inquiry as to why ErbB inhibitors that were so effective in treating EGFR mutations in lung cancer were so ineffective in treating EGFR variants in GBM.

[0026] A distinctive feature for the EGFR variants expressed in GBM is their location within the extracellular domain. This is in contrast to activating mutations of EGFR found in lung cancer, which often reside 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 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. Nearly all EGFR splicing events and mutations in GBM affect the extracellular region, specifically two cysteine rich regions (CR1 and CR2) that form the extracellular dimer interface. The CR regions contain >40 cysteine residues, all of which form intramolecular disulfide bonds. In EGFR-Viii, truncation of exons 2-7 results in partial loss of sequence encoding the CR1 region. A consequence is loss of one cysteine from the Cys295-Cys307 pair, leaving Cys307 as a free unpaired cysteine. For EGFR-Viii, this cysteine can form an intermolecular disulfide bond with another EGFR monomer to drive a covalently dimerized and constitutively activated receptor. Mutation of Cysteine 307 to a Serine (C307S) prevents the formation of covalently dimerized EGFR-Viii and is inactive.

[0027] Although several recent preclinical studies have suggested that EGFR kinase inhibitors such as erlotinib are quite ineffective at inhibiting EGFR-Viii, there has been no mechanism proposed for this effect. There is also a lack in current understanding for the mechanism responsible for activation of other ectodomain variants in GBM, including EGFR-Vii and EGFR-A289V. The disclosure provides a mechanism of receptor activation and impact on ErbB inhibitor activity for a group of four of the most common ectodomain variants in GBM, EGFR-Viii, EGFR-Vii, EGFR-Vvi, EGFR-G598V and EGFR-A289V.

[0028] The disclosure demonstrates that like EGFR-Viii, an additional group of commonly occurring EGFR variants in GBM (EGFR-Vii, EGFR-Vvi, EGFR-G598V and EGFR-A289V) all exist as constitutively active covalent dimers and together form a family of EGFR isoforms that are activated by this common mechanism. Furthermore, the disclosure shows that the propensity of these variants to covalently dimerize is coupled to the conformation of the intracellular catalytic site, conferring distinct activity for classes of small molecules inhibitors binding to this distal site. Inhibitors that stabilize the active conformation of the kinase (Type I inhibitors, including erlotinib) induce the formation of covalent dimers for all covalently-activated EGFR isoforms. This is associated with the propensity of Type I inhibitors to increase EGFR phosphorylation at sub-saturating concentrations and to paradoxically stimulate the proliferation of cells expressing covalently-activated EGFR isoforms.

[0029] Neither enhanced dimerization nor paradoxical activation of EGFR is seen with small molecule inhibitors that stabilize the inactive kinase conformation (Type II inhibitors, including lapatinib and neratinib). Examples of Type II inhibitors were identified that were potent inhibitors of covalently-activated EGFR isoforms and which were selective for this family compared to WT-EGFR.

[0030] Similar to the mutations identified for EGFR, the disclosure identifies a group of splice events and mutations affecting the CR domains of HER2 and HER4. The disclosure demonstrates that this group of splice events and mutations affecting the CR domains of HER2 and HER4 exists as covalent dimers and are paradoxically activated by agents with a Type I binding mode. These data provide a mechanistic explanation for the failure of multiple clinical trials involving Type I inhibitors, including >30 clinical trials of Type I ErbB inhibitors in GBM. Collectively these data indicate that tumors expressing covalently-activated EGFR isoforms should be excluded from treatment with Type I ErbB inhibitors such as erlotinib because of paradoxical activation. These data further demonstrate the utility for optimizing Type II ErbB inhibitors against the covalently-activated ErbB family.Definitions

[0031] Unless specified otherwise the following general definitions apply to all compounds of the disclosure according to the description.

[0032] The term "compound of the disclosure," as used herein, refers to compounds represented by any of the formulaes described herein (e.g. Formulae (I')-(IV') and (I) to (VII)) and any of the specific examples disclosed herein.

[0033] Further, it will be understood that while compounds disclosed herein may be presented without specified configuration (e.g., without specified stereochemistry). Such presentation intends to encompass all available isomers, tautomers, regioisomers, and stereoisomers of the compound. In some embodiments, the presentation of a compound herein without specified configuration intends to refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof.

[0034] As used herein, the term "isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture."

[0035] As used herein, the term "chiral centre" refers to a carbon atom bonded to four nonidentical substituents.

[0036] As used herein, the term "chiral isomer" means a compound with at least one chiral centre. Compounds with more than one chiral centre may exist either as an individual diastereomer or as a mixture of diastereomers, termed "diastereomeric mixture." When one chiral centre is present, a stereoisomer may be characterised by the absolute configuration (R or S) of that chiral centre. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral centre. The substituents attached to the chiral centre under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn 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).

[0037] As used herein, the term "geometric isomer" means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0038] It is understood that "independently of each other" means that when a group is occurring more than one time in any compound, its definition on each occurrence is independent from any other occurrence.

[0039] It is further understood that a dashed line (or a wave being transverse to a bond) depicts the site of attachment of a residue (i.e. a partial formula).

[0040] The term "halogen" or "hal" as used herein may be fluoro, chloro, bromo or iodo preferably fluoro, chloro.

[0041] As used herein, "alkyl", "C 1 , C 2 , C 3 , C 4 , C 5 or C 6 alkyl" or "C 1 -C 6 alkyl" is intended to include C 1 , C 2 , C 3 , C 4 , C 5 or C 6 straight chain (linear) saturated aliphatic hydrocarbon groups and C 3 , C 4 , C 5 or C 6 branched saturated aliphatic hydrocarbon groups. For example, C 1 -C 6 alkyl is intends to include C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C 1 -C 6 for straight chain, C 3 -C 6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms. In some embodiments, the term "alkyl" as used herein 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, isobutyl, tert-butyl.

[0042] As used herein, the term "optionally substituted alkyl" refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0043] As used herein, the term "alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term "alkenyl" includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain). The term "C 2 -C 6 " includes alkenyl groups containing two to six carbon atoms. The term "C 3 -C 6 " includes alkenyl groups containing three to six carbon atoms.

[0044] As used herein, the term "optionally substituted alkenyl" refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0045] As used herein, the term "alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, "alkynyl" includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain). The term "C 2 -C 6 " includes alkynyl groups containing two to six carbon atoms. The term "C 3 -C 6 " includes alkynyl groups containing three to six carbon atoms. As used herein, "C 2 -C 6 alkenylene linker" or "C 2 -C 6 alkynylene linker" is intended to include C 2 , C 3 , C 4 , C 5 or C 6 chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C 2 -C 6 alkenylene linker is intended to include C 2 , C 3 , C 4 , C 5 and C 6 alkenylene linker groups.

[0046] As used herein, the term "optionally substituted alkynyl" refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0047] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated 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.

[0048] The term "alkoxy" or "alkoxyl" as used herein includes substituted and unsubstituted alkyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups.

[0049] The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, adamantly, hexahydroindacenyl. It is understood that for polycyclic (e.g., fused, bridged, or spiro rings) system, only one of the rings therein needs to be non-aromatic.

[0050] The term "aryl" as used herein refers to groups with aromaticity, including "conjugated," or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In some embodiments, the aryl is phenyl.

[0051] As used herein, the term "heterocycloalkyl" refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulphur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyiido[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 multicyclic 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, wherein 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.

[0052] As used herein, the term "heteroaryl" is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulphur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulphur heteroatoms may optionally be oxidised (i.e., N→O and S(O) p , where p = 1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1. In some embodiments, the term "heteroaryl", refers to a (fully) aromatic ring system having 3, 4, 5, or 6 ring atoms, preferably 6 ring atoms, selected from C, N, O, or S, preferably C, N, or O, more preferably C, N, with the number of N atoms preferably being 0, 1, 2 or 3 and the number of O and S atoms each being 0, 1 or 2. Examples of "heteroaryl" include furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl), pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl, and the like. Preferred examples of "heteroaryl" include pyridinyl.

[0053] In some embodiments, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. In some embodiments, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with halogen (e.g., F or Cl).

[0054] As used herein, the term "substituted," means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N).

[0055] The terms "nucleic acid" and "polynucleotide" are used interchangeably herein to refer to single- or double-stranded RNA, DNA, or mixed polymers. Polynucleotides may include genomic sequences, extra-genomic and plasmid sequences, and smaller engineered gene segments that express, or may be adapted to express polypeptides.

[0056] An "isolated nucleic acid" is a nucleic acid that is substantially separated from other genome DNA sequences as well as proteins or complexes such as ribosomes and polymerases, which naturally accompany a native sequence. The term embraces a nucleic acid sequence that has been removed from its naturally occurring environment, and includes recombinant or cloned DNA isolates and chemically synthesized analogues or analogues biologically synthesized by heterologous systems. A substantially pure nucleic acid includes isolated forms of the nucleic acid. Of course, this refers to the nucleic acid as originally isolated and does not exclude genes or sequences later added to the isolated nucleic acid by the hand of man.

[0057] The term "polypeptide" is used in its conventional meaning, i.e., as a sequence of amino acids. The polypeptides are not limited to a specific length of the product. Peptides, oligopeptides, and proteins are included within the definition of polypeptide, and such terms may be used interchangeably herein unless specifically indicated otherwise. This term also does not refer to or exclude post-expression modifications of the polypeptide, for example, glycosylations, acetylations, phosphorylations and the like, as well as other modifications known in the art, both naturally occurring and non-naturally occurring. A polypeptide may be an entire protein, or a subsequence thereof.

[0058] An "isolated polypeptide" is one that has been identified and separated and / or recovered from a component of its natural environment. In preferred embodiments, the isolated polypeptide will be purified (1) to greater than 95% by weight of polypeptide as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or, preferably, silver stain. Isolated polypeptide includes the polypeptide in situ within recombinant cells since at least one component of the polypeptide's natural environment will not be present. Ordinarily, however, isolated polypeptide will be prepared by at least one purification step.

[0059] A "native sequence" polynucleotide is one that has the same nucleotide sequence as a polynucleotide derived from nature. A "native sequence" polypeptide is one that has the same amino acid sequence as a polypeptide (e.g. EGFR) derived from nature (e.g., from any species). Such native sequence polynucleotides and polypeptides can be isolated from nature or can be produced by recombinant or synthetic means.

[0060] A polynucleotide "variant," as the term is used herein, is a polynucleotide that typically differs from a polynucleotide specifically disclosed herein in one or more substitutions, deletions, additions and / or insertions.

[0061] A polypeptide "variant," as the term is used herein, is a polypeptide that typically differs from a polypeptide specifically disclosed herein in one or more substitutions, deletions, additions and / or insertions, or inversions. Such variants may be naturally occurring, non-naturally occurring, or may be synthetically generated.

[0062] EGFR mutations (or variants) of the disclosure may comprise one or more substitutions, deletions, additions and / or insertions, or inversions of the amino acid sequence that are alter the function of the resultant protein. Mutations may be detected, for example, by comparison or alignment of a nucleic or amino acid sequence with a wild type sequence.

[0063] When comparing polynucleotide and polypeptide sequences, two sequences are said to be "identical" if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence, as described below. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. A "comparison window" as used herein, refers to a segment of at least about 20 contiguous positions, usually 30 to about 75, 40 to about 50, in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.

[0064] Optimal alignment of sequences for comparison may be conducted using the Megalign program in 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.

[0065] Alternatively, optimal alignment of sequences for comparison may be conducted by the local identity algorithm of Smith and Waterman (1981) Add. APL. Math 2:482, by the identity alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, by the search for similarity methods of Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85: 2444, by computerized implementations of these algorithms (GAP, BESTFIT, BLAST, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group (GCG), 575 Science Dr., Madison, WI), or by inspection.

[0066] One preferred example of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nucl. Acids Res. 25:3389-3402 and Altschul et al. (1990) J. Mol. Biol. 215:403-410, respectively. BLAST and BLAST 2.0 can be used, for example with the parameters described herein, to determine percent sequence identity for the polynucleotides and polypeptides of the disclosure. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information.

[0067] In one illustrative example, cumulative scores can be calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0). Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a wordlength (W) of 11, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89:10915) alignments, (B) of 50, expectation (E) of 10, M=5, N=-4 and a comparison of both strands.

[0068] For amino acid sequences, a scoring matrix can be used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment.

[0069] In one approach, the "percentage of sequence identity" is determined by comparing two optimally aligned sequences over a window of comparison of at least 20 positions, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference sequences (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid bases or amino acid residues occur in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence (i.e., the window size) and multiplying the results by 100 to yield the percentage of sequence identity.

[0070] A wild type EGFR sequence of the disclosure may comprise or consist of the amino acid sequence of:

[0071] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of:

[0072] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of:

[0073] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of:

[0074] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of:

[0075] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of:

[0076] Based on the definitions given throughout the application the skilled person knows which combinations are synthetically feasible and realistic, e.g. typically combinations of groups leading to heteroatoms directly linked to each other are not contemplated.Compounds of the Present Disclosure

[0077] The scope of the present invention is that of the claims. Subject matter referred to embodiments incompatible with the subject matter of the claims is present only for reference purposes. In some aspects, the present disclosure provides 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 Z< independently is halogen, CN, -OH, -NH 2 , -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), - N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C 1 -C 6 alkyl), - NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Za< ; each R Za< independently is halogen, CN, -OH, -NH 2 , -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), - N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is halogen, CN, -OH, -NH 2 , -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), - N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C 1 -C 6 alkyl), - NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Ta< ; each R Ta< independently is 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 C 6 -C 10 aryl optionally substituted with one or more R A1< ; each R A1< independently is 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; wherein the -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R A1a< ; and each R A1a< independently is halogen, CN, -OH, -NH 2 , -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C 1 -C 6 alkyl), - NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R A1b< ; and each R A1b< independently is halogen, CN, -OH, or -NH 2 .

[0078] In some aspects, the compound is 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 Z< independently is 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; wherein the -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3or 5- to 10-membered heteroaryl is optionally substituted with one or more R Za< ; each R Za< independently is halogen, CN, -OH, -NH 2 , -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), - N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is 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; wherein the -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 is optionally substituted with one or more R Ta< ; each R Ta< independently is halogen, CN, -OH, -NH 2 , -C(=O)OH, -O-(C 1 -C 6 alkylC 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 C 6 -C 10 aryl optionally substituted with one or more R A1< ; each R A1< independently is 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; wherein the -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R A1a< ; and each R A1a< independently is 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; wherein the -O-(C 1 -C 6 alkyl), - NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R A1b< ; and each R A1b< independently is halogen, CN, -OH, or -NH 2 ; provided that when Z is then Ar 1< is C 6 -C 10 aryl optionally substituted with one or more halogen.

[0079] In some aspects, the compound is 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 Z< independently is 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; wherein the -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3or 5- to 10-membered heteroaryl is optionally substituted with one or more R Za< ; each R Za< independently is halogen, CN, -OH, -NH 2 , -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), - N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is 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 monocyclic heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the -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 is optionally substituted with one or more R Ta< ; each R Ta< independently is halogen, CN, -OH, -NH 2 , -C(=O)OH, -O-(C 1 -C 6 alkylC 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 C 6 -C 10 aryl optionally substituted with one or more R A1< ; each R A1< independently is 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; wherein the -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R A1a< ; and each R A1a< independently is 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; wherein the -O-(C 1 -C 6 alkyl), - NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R A1b< ; and each R A1b< independently is halogen, CN, -OH, or -NH 2 ; provided that when Z is then Ar 1< is C 6 -C 10 aryl optionally substituted with one or more halogen.

[0080] In some embodiments, the compound is 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< ; each R Z< independently is halogen, -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, or 3- to 10-membered heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogen; T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 7-membered heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH; Ar 1< is C 6 -C 10 aryl optionally substituted with one or more R A1< ; each R A1< independently is halogen, -OR A1a< , or -O-(C 1 -C 6 alkyl) optionally substituted with one or more R A1a< ; and each R A1a< independently is C 6 -C 10 aryl or 5- to 10-membered heteroaryl; wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen.

[0081] In some embodiments, the compound is 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< ; each R Z< independently is halogen, -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, or 3- to 10-membered heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogen; T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 7-membered monocyclic heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH; Ar 1< is C 6 -C 10 aryl optionally substituted with one or more R A1< ; each R A1< independently is halogen, -OR A1a< , or -O-(C 1 -C 6 alkyl) optionally substituted with one or more R A1a< ; and each R A1a< independently is C 6 -C 10 aryl or 5- to 10-membered heteroaryl; wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen.

[0082] In some embodiments, the compound is 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< ; each R Z< independently is halogen, -O-(C 1 -C 6 alkyl), or C 1 -C 6 alkyl; wherein the -O-(C 1 -C 6 alkyl) or C 1 -C 6 alkyl is optionally substituted with one or more halogen; T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), or 3- to 7-membered heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH; Ar 1< is C 6 -C 10 aryl optionally substituted with one or more R A1< ; each R A1< independently is halogen, -OR A1a< , or -O-(C 1 -C 6 alkyl) optionally substituted with one or more R A1a< ; and each R A1a< independently is C 6 -C 10 aryl or 5- to 10-membered heteroaryl; wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen; provided that when Z is then Ar 1< is C 6 -C 10 aryl optionally substituted with one or more halogen.

[0083] In some embodiments, the compound is 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< ; each R Z< independently is halogen, -O-(C 1 -C 6 alkyl), or C 1 -C 6 alkyl; wherein the -O-(C 1 -C 6 alkyl) or C 1 -C 6 alkyl is optionally substituted with one or more halogen; T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), or 3- to 7-membered monocyclic heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH; Ar 1< is C 6 -C 10 aryl optionally substituted with one or more R A1< ; each R A1< independently is halogen, -OR A1a< , or -O-(C 1 -C 6 alkyl) optionally substituted with one or more R A1a< ; and each R A1a< independently is C 6 -C 10 aryl or 5- to 10-membered heteroaryl; wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen; provided that when Z is then Ar 1< is C 6 -C 10 aryl optionally substituted with one or more halogen.

[0084] In some embodiments, the compound is 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< ; each R Z< independently is halogen, -O-(C 1 -C 6 alkyl), or C 1 -C 6 alkyl; wherein the -O-(C 1 -C 6 alkyl) or C 1 -C 6 alkyl is optionally substituted with one or more halogen; T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), or 3- to 7-membered heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH; Ar 1< is C 6 -C 10 aryl optionally substituted with one or more halogen.

[0085] In some embodiments, the compound is 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< ; each R Z< independently is halogen, -O-(C 1 -C 6 alkyl), or C 1 -C 6 alkyl; wherein the -O-(C 1 -C 6 alkyl) or C 1 -C 6 alkyl is optionally substituted with one or more halogen; T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), or 3- to 7-membered monocyclic heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH; Ar 1< is C 6 -C 10 aryl optionally substituted with one or more halogen.

[0086] In some embodiments, the compound is 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 C 1 -C 6 alkyl; T is C 2 -C 6 alkenyl optionally substituted with one or more 6-membered heterocycloalkyl; and Ar 1< is C 6 aryl optionally substituted with one or more halogen.

[0087] In some embodiments, the compound is 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 C 1 -C 6 alkyl; T is C 2 -C 6 alkenyl optionally substituted with one or more 6-membered monocyclic heterocycloalkyl; and Ar 1< is C 6 aryl optionally substituted with one or more halogen. Variable W

[0088] In some embodiments, W is CH.

[0089] In some embodiments, W is N.Variables Z, R Z< , and R Za<

[0090] In some embodiments, Z is 3- to 12-membered heterocycloalkyl optionally substituted with one or more R Z< ; and each R Z< independently is halogen, -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, or 3- to 10-membered heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogen.

[0091] In some embodiments, Z is 3- to 12-membered heterocycloalkyl.

[0092] In some embodiments, Z is 3- to 12-membered heterocycloalkyl substituted with one or more R Z< .

[0093] 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, wherein 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 optionally substituted with one or more R Z< .

[0094] 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, wherein 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 optionally substituted with one or more R Z< .

[0095] In some embodiments, Z is

[0096] In some embodiments, Z is or

[0097] In some embodiments, Z is

[0098] In some embodiments, Z is

[0099] In some embodiments, Z is

[0100] In some embodiments, Z is

[0101] In some embodiments, Z is

[0102] In some embodiments, Z is

[0103] In some embodiments, Z is

[0104] In some embodiments, Z is

[0105] In some embodiments, Z is

[0106] In some embodiments, Z is

[0107] In some embodiments, at least one R Z< is halogen.

[0108] In some embodiments, at least one R Z< is F or Cl.

[0109] In some embodiments, at least one R Z< is F.

[0110] In some embodiments, at least one R Z< is Cl.

[0111] In some embodiments, at least one R Z< is F, and at least one R Z< is Cl.

[0112] In some embodiments, at least one R Z< is CN, -OH, or -NH 2 .

[0113] In some embodiments, at least one R Z< is -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C 1 -C 6 alkyl), - NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Za< .

[0114] In some embodiments, at least one R Z< is -O-(C 1 -C 6 alkyl) optionally substituted with one or more R Za< .

[0115] In some embodiments, at least one R Z< is -O-(C 1 -C 6 alkyl).

[0116] In some embodiments, at least one R Z< is -OCH 3 .

[0117] In some embodiments, at least one R Z< is -O-(C 1 -C 6 alkyl) substituted with one or more R Za< .

[0118] In some embodiments, at least one R Z< is -O-(C 1 -C 6 alkyl) substituted with one or more halogen (e.g., F or Cl).

[0119] In some embodiments, at least one R Z< is -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 , wherein the -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 is optionally substituted with one or more R Za< .

[0120] In some embodiments, at least one R Z< is C 1 -C 6 alkyl optionally substituted with one or more R Za< .

[0121] In some embodiments, at least one R Z< is C 1 -C 6 alkyl.

[0122] In some embodiments, at least one R Z< is methyl, ethyl, or propyl (e.g., i-propyl).

[0123] In some embodiments, at least one R Z< is C 1 -C 6 alkyl substituted with one or more R Za< .

[0124] In some embodiments, at least one R Z< is C 1 -C 6 alkyl substituted with one or more halogen (e.g., F or Cl).

[0125] In some embodiments, at least one R Z< is C 1 -C 6 alkyl substituted with one or more F.

[0126] In some embodiments, at least one R Z< is CF 3 .

[0127] In some embodiments, at least one R Z< is C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, wherein the C 2 -C 6 alkenyl or C 2 -C 6 alkynyl is optionally substituted with one or more R Za< .

[0128] In some embodiments, at least one R Z< is C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3-to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Za< .

[0129] In some embodiments, at least one R Z< is C 3 -C 10 cycloalkyl optionally substituted with one or more R Za< .

[0130] In some embodiments, at least one R Z< is C 6 -C 10 aryl optionally substituted with one or more R Za< .

[0131] In some embodiments, at least one R Z< is 3- to 10-membered heterocycloalkyl optionally substituted with one or more R Za< .

[0132] In some embodiments, at least one R Z< is 4-membered heterocycloalkyl optionally substituted with one or more R Za< .

[0133] In some embodiments, at least one R Z< is 4-membered heterocycloalkyl.

[0134] In some embodiments, at least one R Z< is oxetanyl.

[0135] In some embodiments, at least one R Z< is 5- to 10-membered heteroaryl optionally substituted with one or more R Za< .

[0136] In some embodiments, at least one R Za< is halogen.

[0137] In some embodiments, at least one R Za< is F or Cl.

[0138] In some embodiments, at least one R Za< is F.

[0139] In some embodiments, at least one R Za< is Cl.

[0140] In some embodiments, at least one R Za< is 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.Variables T, R T< , and R Ta<

[0141] In some embodiments, T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is 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; wherein the -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 is optionally substituted with one or more R Ta< ; and each R Ta< independently is 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.

[0142] In some embodiments, T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is 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 monocyclic heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the -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 monocyclic heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Ta< ; and each R Ta< independently is 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.

[0143] In some embodiments, T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; and each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 7-membered heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0144] In some embodiments, T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; and each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), or 3- to 7-membered heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0145] In some embodiments, T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; and each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 7-membered monocyclic heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0146] In some embodiments, T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; and each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), or 3- to 7-membered heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0147] In some embodiments, T is -O-(C 1 -C 6 alkyl) optionally substituted with one or more R T< .

[0148] In some embodiments, T is -O-(C 1 -C 6 alkyl).

[0149] In some embodiments, T is -OCH 3 .

[0150] In some embodiments, T is -NH-(C 1 -C 6 alkyl) optionally substituted with one or more R T< .

[0151] In some embodiments, T is -NH-(C 1 -C 6 alkyl).

[0152] In some embodiments, T is -NHCH 3 .

[0153] In some embodiments, T is C 1 -C 6 alkyl optionally substituted with one or more R T< .

[0154] In some embodiments, T is C 1 -C 6 alkyl.

[0155] In some embodiments, T is methyl or ethyl.

[0156] In some embodiments, T is methyl.

[0157] In some embodiments, T is ethyl.

[0158] In some embodiments, T is C 1 -C 6 alkyl substituted with one or more R T< .

[0159] In some embodiments, T is C 1 -C 6 alkyl substituted with one or more halogen (e.g., F or Cl).

[0160] In some embodiments, T is methyl substituted with one or more halogen (e.g., F or Cl).

[0161] In some embodiments, T is -CHFCl.

[0162] In some embodiments, T is C 1 -C 6 alkyl substituted with one or more CN.

[0163] In some embodiments, T is -CH 2 CN.

[0164] In some embodiments, T is C 2 -C 6 alkenyl optionally substituted with one or more R T< .

[0165] In some embodiments, T is C 2 -C 6 alkenyl.

[0166] In some embodiments, T is ethenyl (i.e., -CH=CH 2 ).

[0167] In some embodiments, T is propenyl (e.g., -C(CH 3 )=CH 2 or -CH=CH-CH 3 ).

[0168] In some embodiments, T is pentenyl (e.g., -CH=CH-C(CH 3 ) 2 ).

[0169] In some embodiments, T is C 2 -C 6 alkenyl substituted with one or more R T< .

[0170] In some embodiments, T is C 2 -C 6 alkenyl substituted with one or more -OH, -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 10-membered heterocycloalkyl; wherein the 3- to 10-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0171] In some embodiments, T is C 2 -C 6 alkenyl substituted with one or more -OH

[0172] In some embodiments, T is C 2 -C 6 alkenyl substituted with one or more -O-(C 1 -C 6 alkyl).

[0173] In some embodiments, T is C 2 -C 6 alkenyl substituted with one or more -OCH 3 .

[0174] In some embodiments, T is C 2 -C 6 alkenyl substituted with one or more -N(C 1 -C 6 alkyl) 2 .

[0175] In some embodiments, T is C 2 -C 6 alkenyl substituted with one or more -N(CH 3 ) 2 .

[0176] In some embodiments, T is C 2 -C 6 alkenyl substituted with one or more 3- to 10-membered heterocycloalkyl.

[0177] In some embodiments, T is C 2 -C 6 alkenyl substituted with one or more 3- to 10-membered heterocycloalkyl; wherein the 3- to 10-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0178] In some embodiments, T is C 2 -C 6 alkenyl substituted with one or more 3- to 7-membered heterocycloalkyl.

[0179] In some embodiments, T is C 2 -C 6 alkenyl substituted with one or more 3- to 7-membered heterocycloalkyl; wherein the 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0180] In some embodiments, T is C 2 -C 6 alkenyl substituted with one or more 3- to 7-membered heterocycloalkyl.

[0181] In some embodiments, T is C 2 -C 6 alkenyl substituted with one or more 3- to 7-membered monocyclic heterocycloalkyl.

[0182] In some embodiments, T is C 2 -C 6 alkenyl substituted with one or more 3- to 7-membered monocyclic heterocycloalkyl; wherein the 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0183] In some embodiments, T is C 2 -C 6 alkenyl substituted with one or more 3- to 7-membered monocyclic heterocycloalkyl.

[0184] In some embodiments, T is C 2 -C 6 alkenyl substituted with one or more 6-membered heterocycloalkyl; wherein the 6-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0185] In some embodiments, T is C 2 -C 6 alkenyl substituted with one or more 6-membered heterocycloalkyl.

[0186] In some embodiments, T is C 2 -C 6 alkenyl substituted with one or more 6-membered monocyclic heterocycloalkyl; wherein the 6-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0187] In some embodiments, T is C 2 -C 6 alkenyl substituted with one or more 6-membered monocyclic heterocycloalkyl.

[0188] In some embodiments, T is C 2 -C 6 alkynyl optionally substituted with one or more R T< .

[0189] In some embodiments, T is C 2 -C 6 alkynyl.

[0190] In some embodiments, T is propynyl (e.g., -C≡C-CH 3 ).

[0191] In some embodiments, T is C 2 -C 6 alkynyl substituted with one or more R T< .

[0192] In some embodiments, T is propynyl substituted with one or more R T< .

[0193] In some embodiments, T is -C≡C-CH 2 -R T< .

[0194] In some embodiments, T is C 2 -C 6 alkynyl substituted with one or more 3- to 10-membered heterocycloalkyl.

[0195] In some embodiments, T is propynyl substituted with one or more 3- to 10-membered heterocycloalkyl.

[0196] In some embodiments, T is C 2 -C 6 alkynyl substituted with one or more 3- to 7-membered heterocycloalkyl.

[0197] In some embodiments, T is propynyl substituted with one or more 3- to 7-membered heterocycloalkyl.

[0198] In some embodiments, T is , or

[0199] In some embodiments, T is or

[0200] In some embodiments, T is

[0201] In some embodiments, T is

[0202] In some embodiments, T is

[0203] In some embodiments, T is

[0204] In some embodiments, T is or

[0205] In some embodiments, T is

[0206] In some embodiments, at least one R T< is halogen (e.g., F or Cl).

[0207] In some embodiments, at least one R T< is F.

[0208] In some embodiments, at least one R T< is Cl.

[0209] In some embodiments, at least one R T< is CN, -OH, or -NH 2 .

[0210] In some embodiments, at least one R T< is CN.

[0211] In some embodiments, at least one R T< is -OH.

[0212] In some embodiments, at least one R T< is -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 ; wherein the O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 is optionally substituted with one or more R Ta< .

[0213] In some embodiments, at least one R T< is -O-(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 ; wherein the O-(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 is optionally substituted with one or more R Ta< .

[0214] In some embodiments, at least one R T< is -O-(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 .

[0215] In some embodiments, at least one R T< is -O-(C 1 -C 6 alkyl).

[0216] In some embodiments, at least one R T< is -N(C 1 -C 6 alkyl) 2 .

[0217] In some embodiments, at least one R T< is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R Ta< .

[0218] In some embodiments, at least one R T< is C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3-to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Ta< .

[0219] In some embodiments, at least one R T< is 3- to 10-membered heterocycloalkyl optionally substituted with one or more R Ta< .

[0220] In some embodiments, at least one R T< is 3- to 10-membered heterocycloalkyl substituted with one or more R Ta< .

[0221] In some embodiments, at least one R T< is 3- to 10-membered heterocycloalkyl substituted with one or more C(=O)OH.

[0222] In some embodiments, at least one R T< is 3- to 7-membered heterocycloalkyl optionally substituted with one or more R Ta< .

[0223] In some embodiments, at least one R T< is 3- to 7-membered heterocycloalkyl.

[0224] In some embodiments, at least one R T< is 3- to 7-membered heterocycloalkyl substituted with one or more R Ta< .

[0225] In some embodiments, at least one R T< is 3- to 7-membered heterocycloalkyl substituted with one or more C(=O)OH.

[0226] In some embodiments, at least one R T< is 6-membered heterocycloalkyl optionally substituted with one or more R Ta< .

[0227] In some embodiments, at least one R T< is 6-membered heterocycloalkyl.

[0228] In some embodiments, at least one R T< is 6-membered heterocycloalkyl substituted with one or more R Ta< .

[0229] In some embodiments, at least one R T< is 6-membered heterocycloalkyl substituted with one or more C(=O)OH.

[0230] In some embodiments, at least one R T< is 3- to 7-membered monocyclic heterocycloalkyl optionally substituted with one or more R Ta< .

[0231] In some embodiments, at least one R T< is 3- to 7-membered monocyclic heterocycloalkyl.

[0232] In some embodiments, at least one R T< is 3- to 7-membered monocyclic heterocycloalkyl substituted with one or more R Ta< .

[0233] In some embodiments, at least one R T< is 3- to 7-membered monocyclic heterocycloalkyl substituted with one or more C(=O)OH.

[0234] In some embodiments, at least one R T< is 6-membered monocyclic heterocycloalkyl optionally substituted with one or more R Ta< .

[0235] In some embodiments, at least one R T< is 6-membered monocyclic heterocycloalkyl.

[0236] In some embodiments, at least one R T< is 6-membered monocyclic heterocycloalkyl substituted with one or more R Ta< .

[0237] In some embodiments, at least one R T< is 6-membered monocyclic heterocycloalkyl substituted with one or more C(=O)OH.

[0238] In some embodiments, at least one R Ta< is C(=O)OH.

[0239] In some embodiments, at least one R Ta< is 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.Variables Ar 1< , R A1< , R A1a< , and R A1b<

[0240] In some embodiments, Ar 1< is C 6 -C 10 aryl optionally substituted with one or more R A1< ; each R A1< independently is 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; wherein the -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R A1a< ; each R A1a< independently is 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; wherein the -O-(C 1 -C 6 alkyl), - NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R A1b< ; and each R A1b< independently is halogen, CN, -OH, or -NH 2 .

[0241] In some embodiments, Ar 1< is C 6 -C 10 aryl.

[0242] In some embodiments, Ar 1< is C 6 -C 10 aryl substituted with one or more R A1< .

[0243] In some embodiments, Ar 1< is phenyl substituted with one or more R A1<

[0244] In some embodiments, Ar 1< is phenyl substituted with one or more halogen, -OR A1a< , or -O-(C 1 -C 6 alkyl); wherein the -O-(C 1 -C 6 alkyl) is optionally substituted with one or more R A1a< ; and each R A1a< independently is C 6 -C 10 aryl or 5- to 10-membered heteroaryl; wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen.

[0245] In some embodiments, Ar 1< is phenyl substituted with one or more halogen

[0246] In some embodiments, Ar 1< is phenyl substituted with one or more F or Cl.

[0247] In some embodiments, Ar 1< is phenyl substituted with one F and one Cl.

[0248] In some embodiments, Ar 1< is phenyl optionally substituted with one or more halogen, wherein the phenyl is further substituted with -O-(C 6 -C 10 aryl) or -O-(5- to 10-membered heteroaryl); wherein the -O-(C 6 -C 10 aryl) or -O-(5- to 10-membered heteroaryl) is optionally substituted with one or more halogen.

[0249] In some embodiments, Ar 1< is phenyl optionally substituted with one or more halogen, wherein the phenyl is further substituted with -O-phenyl or -O-pyridinyl; wherein the -O-phenyl or -O-pyridinyl is optionally substituted with one or more halogen.

[0250] In some embodiments, Ar 1< is phenyl optionally substituted with one or more halogen, wherein the phenyl is further substituted with -O-phenyl; wherein the -O-phenyl is optionally substituted with one or more halogen.

[0251] In some embodiments, Ar 1< is phenyl optionally substituted with one or more halogen, wherein the phenyl is further substituted with -O-pyridinyl; wherein the -O-pyridinyl is optionally substituted with one or more halogen.

[0252] In some embodiments, Ar 1< is or

[0253] In some embodiments, Ar 1< is

[0254] In some embodiments, Ar 1< is

[0255] In some embodiments, Ar 1< is

[0256] In some embodiments, Ar 1< is

[0257] In some embodiments, Ar 1< is

[0258] In some embodiments, Ar 1< is or

[0259] In some embodiments, Ar 1< is

[0260] In some embodiments, Ar 1< is

[0261] In some embodiments, Ar 1< is

[0262] In some embodiments, Ar 1< is

[0263] In some embodiments, Ar 1< is

[0264] In some embodiments, Ar 1< is

[0265] In some embodiments, Ar 1< is

[0266] In some embodiments, at least one R A1< is halogen (e.g., F or Cl).

[0267] In some embodiments, at least one R A1< is F.

[0268] In some embodiments, at least one R A1< is Cl.

[0269] In some embodiments, at least one R A1< is F, and at least one R A1< is Cl.

[0270] In some embodiments, at least one R A1< is CN, -OH, or -NH 2 .

[0271] In some embodiments, at least one R A1< is -OR A1a< .

[0272] In some embodiments, at least one R A1< is -O-(C 6 -C 10 aryl) or -O-(5- to 10-membered heteroaryl); wherein the -O-(C 6 -C 10 aryl) or -O-(5- to 10-membered heteroaryl) is optionally substituted with one or more R A1b< .

[0273] In some embodiments, at least one R A1< is -O-(C 6 -C 10 aryl) or -O-(5- to 10-membered heteroaryl); wherein the -O-(C 6 -C 10 aryl) or -O-(5- to 10-membered heteroaryl) is optionally substituted with one or more halogen.

[0274] In some embodiments, at least one R A1< is -O-phenyl or -O-pyridinyl; wherein the -O-phenyl or -O-pyridinyl is optionally substituted with one or more halogen.

[0275] In some embodiments, at least one R A1< is -O-phenyl optionally substituted with one or more halogen.

[0276] In some embodiments, at least one R A1< is -O-pyridinyl optionally substituted with one or more halogen.

[0277] In some embodiments, at least one R A1< is -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, wherein the -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R A1a< .

[0278] In some embodiments, at least one R A1< is -O-(C 1 -C 6 alkyl) optionally substituted with one or more R A1a< .

[0279] In some embodiments, at least one R A1< is -O-(C 1 -C 6 alkyl) substituted with one or more R A1a< .

[0280] In some embodiments, at least one R A1< is -O-(C 1 -C 6 alkyl) substituted with one or more C 6 -C 10 aryl or 5- to 10-membered heteroaryl, wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen.

[0281] In some embodiments, at least one R A1< is -O-CH 2 -R A1a< .

[0282] In some embodiments, at least one R A1< is -O-CH 2 -(C 6 -C 10 aryl) or -O-CH 2 -(5- to 10-membered heteroaryl), wherein the-O-CH 2 -(C 6 -C 10 aryl) or -O-CH 2 -(5- to 10-membered heteroaryl) is optionally substituted with one or more halogen.

[0283] In some embodiments, at least one R A1< is -O-CH 2 -phenyl or -O-CH 2 -pyridinyl, wherein the -O-CH 2 -phenyl or -O-CH 2 -pyridinyl is optionally substituted with one or more halogen.

[0284] In some embodiments, at least one R A1< is -O-CH 2 -phenyl optionally substituted with one or more halogen.

[0285] In some embodiments, at least one R A1< is -O-CH 2 -pyridinyl optionally substituted with one or more halogen.

[0286] In some embodiments, at least one R A1< is C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R A1a< .

[0287] In some embodiments, at least one R A1a< is 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, wherein the -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R A1b< .

[0288] In some embodiments, at least one R A1a< is C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R A1b< .

[0289] In some embodiments, at least one R A1a< is C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen.

[0290] In some embodiments, at least one R A1a< is C 6 -C 10 aryl or 5- to 10-membered heteroaryl; wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen.

[0291] In some embodiments, at least one R A1a< is phenyl or pyridinyl; wherein the phenyl or pyridinyl is optionally substituted with one or more halogen.

[0292] In some embodiments, at least one R A1a< is phenyl optionally substituted with one or more halogen.

[0293] In some embodiments, at least one R A1a< is pyridinyl optionally substituted with one or more halogen.

[0294] In some embodiments, at least one R A1b< is halogen.

[0295] In some embodiments, at least one R A1b< is F.

[0296] In some embodiments, at least one R A1b< is Cl.

[0297] In some embodiments, at least one R A1b< is F, and at least one R A1b< is Cl.

[0298] In some embodiments, at least one R A1b< is CN, -OH, or -NH 2 .Exemplary Embodiments of the Compounds

[0299] In some embodiments, when Z is then T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; and wherein the C 2 -C 6 alkenyl is substituted with one or more R T< each R T< independently is 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 10-membered heterocycloalkyl, or 5-to 10-membered heteroaryl; wherein the -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 is optionally substituted with one or more R Ta< ; and each R Ta< independently is 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.

[0300] In some embodiments, when Z is then T is not

[0301] In some embodiments, when Z is then Ar 1< is C 6 -C 10 aryl optionally substituted with one or more halogen.

[0302] In some embodiments, Z is not

[0303] In some embodiments, Z is not

[0304] In some embodiments, T is not

[0305] In some embodiments, the compound is of formula (II'): or a pharmaceutically acceptable salt or stereoisomer thereof.

[0306] In some embodiments, the compound is of formula (II'): or a pharmaceutically acceptable salt or stereoisomer thereof.

[0307] In some embodiments, the compound is of formula (III') or (III'-a): or a pharmaceutically acceptable salt or stereoisomer thereof.

[0308] In some embodiments, the compound is of formula (IV') or (IV'-a): or a pharmaceutically acceptable salt or stereoisomer thereof.

[0309] In some aspects, the disclosure provides a compound or pharmaceutically acceptable salts or stereoisomers thereof of formula I wherein W is CH or N, preferably CH; X 1< is -O-, -S-, -NR 3< -; R a< , R b< are independently of each other hydrogen or C 1-4 alkyl or one of R a< is -(CH 2 ) p -which forms a ring with X 1< if X 1< is NR 3< or one of R a< is -(CH 2 ) p - which forms a ring with R 2< ; R c< , R d< are independently of each other hydrogen or C 1-4 alkyl; R 1< is H or F; R 2< is hydrogen or C 1-4 alkyl, or is -(CH 2 ) q - which forms a ring with R 3< or with one of R a< ; R 3< is hydrogen or C 1-4 alkyl, preferably hydrogen or methyl, or is -(CH 2 ) p - which forms a ring with R 2< ; 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 a 6-membered aryl, which is unsubstituted or substituted with one or more of a group selected from halogen, -CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, hydroxy C 1-5 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 6 aryl, C 1-6 alkoxy-C 5-6 heteroaryl, amino, amino C 1-4 alkyl, C 1-6 alkylamino, C 1-6 aminoalkyl-C 6 aryl, C 1-6 aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 alkoxyaminocarbonyl, aryl C 1-6 alkoxy, or C 6 aryl.

[0310] In some embodiments of a compound of formula I, W is CH.

[0311] In some embodiments, when n is 0, R 2< is -(CH 2 ) q - which forms a ring with R 3< or with one of R a< .

[0312] In some embodiments, when n is 0, R 2< is -(CH 2 ) q - which forms a ring with R 3< .

[0313] In some embodiments, n is 0, and R 2< is -(CH 2 ) q - which forms a ring with R 3< or with one of R a< .

[0314] In some embodiments, n is 0, and R 2< is -(CH 2 ) q - which forms a ring with R 3< .

[0315] In some embodiments of a compound of formula I, X 1< is -O- or -NR 3< -, more preferably -NR 3< -.

[0316] In some embodiments of a compound of formula I, R b< is always hydrogen, such that only R a< may be not hydrogen. For example, R b< may be hydrogen and R a< may be selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl, or -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 2< . Preferably, R b< may be hydrogen and R a< may be methyl or -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 2< . Furthermore, both R a< and R b< may be hydrogen.

[0317] In some embodiments the ring of which X 1< is part of is a monocycle or bicycle.

[0318] In some embodiments of a compound of formula I, R c< is always hydrogen, such that only R d< may be not 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. Furthermore, both R c< and R d< may be hydrogen.

[0319] In some embodiments of a compound of formula I, R 1< is hydrogen.

[0320] In some embodiments of a compound of formula I, R c< and R d< are hydrogen. In some embodiments of a compound of formula I, R b< , R c< and R d< are hydrogen. In some embodiments of a compound of formula I, R 1< , R b< , R c< and R d< are hydrogen.

[0321] In some embodiments of a compound of formula I in which one of R a< forms a ring with R 3< , the ring formed is a 4, 5, or 6-membered ring, or a 5 or 6 membered ring, or a 5 membered ring.

[0322] In some embodiments of a compound of formula I in which one of R a< forms a ring with R 3< , the ring formed is a 3, 4, 5, or 6-membered ring.

[0323] In some embodiments of a compound of formula I in which one of R 2< forms a ring with R 3< , the ring formed is a 4, 5, or 6-membered ring or a 5 or 6 membered ring, or a 6 membered ring. In some embodiments of a compound of formula I, R 2< is C 1-4 alkyl, or is -(CH 2 ) q - which forms a ring with R 3< or R a< . 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 -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< , or R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with one of R a< . Preferably, R 2< may be selected from methyl, ethyl, n-propyl, i-propyl, n-butyl or i-butyl or R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< , or R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with one of R a< . More preferably, R 2< may be methyl.

[0324] In some embodiments of a compound of formula I, R 3< is hydrogen or methyl or R 3< is - (CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 2< .

[0325] In some embodiments of a 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.

[0326] In some embodiments of a compound of formula I, X 1< may form a heterocycle with the carbon to which R 2< is directly bound. For example, X 1< may form a 4, 5, 6 or 7 membered heterocycle. In some embodiments of a 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.

[0327] In some embodiments of a compound of formula I, Ar 1< is of formula i or pharmaceutically acceptable salts or stereoisomers thereof wherein R 4< hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, hydroxy C 1-5 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-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 aryl; R 5< , R 5'< , R 6< , R 6'< are independently of each other hydrogen, -CF 3 or halogen, preferably F, Cl.

[0328] In some embodiments of a compound of formula I, wherein Ar 1< is 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-C 6 aryl, C 1-4 alkoxy-C 5-6 heteroaryl, amino C 1-4 alkyl, C 1-4 alkylamino, C 1-4 aminoalkyl-C 6 aryl, C 1-4 aminoalkyl-C 6 heteroaryl, C 1-4 alkoxycarbonyl, C 1-4 alkoxyaminocarbonyl or C 6 aryl.

[0329] In some embodiments of a compound of formula I, wherein Ar 1< is 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-C 6 aryl, C 1-4 alkoxy-C 5-6 heteroaryl or C 6 aryl.

[0330] In some embodiments of a compound of formula I, wherein Ar 1< is of formula i, R 4< is in general 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, hydroxy methyl, hydroxy ethyl, hydroxyl propyl, hydroxyl butyl, hydroxyl pentyl, methoxy methyl, method ethyl, methoxy propyl, methoxy butyl, methoxy pentyl, mehoxy hexyl, ethoxy methyl, ethoxy ethyl, ethoxy propyl, ethoxy butyl, ethoxy pentyl, ethoxy hexyl, propoxy methyl, propoxy ethyl, propoxy propyl, propoxy butyl, propoxy pentyl, propoxy hexyl, butoxy methyl, butoxy ethyl, butoxy propyl, butoxy butyl, butoxy pentyl, butoxy hexyl, pentoxy methyl, pentoxy ethyl, pentoxy propyl, pentoxy butyl, pentoxy pentyl, pentoxy hexyl, hexoxy methyl, hexoxy ethyl, hexoxy propyl, hexoxy butyl, hexoxy pentyl, hexoxy hexyl, amino methyl, amino ethyl, amino propyl, amino butyl, amino pentyl, amino hexyl, methylamino ethylamino, propylamino, butylamino, pentylamino, hexylamino, methoxy carbonyl, ethoxy carbonyl, propoxy carbonyl, butoxy carbonyl, pentoxy carbonyl, hexoxy carbonyl, methoxyamino carbonyl, ethoxyamino carbonyl, propoxyamino carbonyl, butoxyamino carbonyl, pentoxyamino carbonyl, hexoxyamino carbonyl, phenyl methoxy, phenyl ethoxy, phenyl propoxy, phenyl butoxy, phenyl pentoxy, phenyl hexoxy, m-fluorophenyl methoxy, m-fluorophenylphenyl ethoxy, m-fluorophenylphenyl propoxy, m-fluorophenylphenyl butoxy, m-fluorophenylphenyl pentoxy, m-fluorophenylphenyl hexoxy, pyridinyl methoxy, pyridinyl ethoxy, pyridinyl propoxy, pyridinyl butoxy, pyridinyl pentoxy, pyridinyl hexoxy, phenyl, pyridinyl or naphtyl. In some embodiments of a compound of formula I, wherein Ar 1< is of formula i, R 5< and R 6< are independently of each other hydrogen, -CF 3 , F or Cl and R 5'< and R 6'< are hydrogen. Preferably, R 4< hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, hydroxy C 1-5 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-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 aryl.

[0331] In some embodiments of a compound of formula I, wherein Ar 1< is of formula i, R 5< and R 6< are independently of each other hydrogen, -CF 3 , 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, hydroxy C 1-5 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy-C 6 aryl, C 1-4 alkoxy-C 5-6 heteroaryl, amino C 1-4 alkyl, C 1-4 alkylamino, C 1-4 aminoalkyl-C 6 aryl, C 1-4 aminoalkyl-C 6 heteroaryl, C 1-4 alkoxycarbonyl, C 1-4 alkoxyaminocarbonyl or C 6 aryl.

[0332] In some embodiments of a compound of formula I, wherein Ar 1< is of formula i, Ar 1< comprises only 1, 2 or 3 substituents which are not hydrogen. Thus, at least two of R 4< , R 5< . R 5'< , R 6< or R 6'< may be hydrogen.

[0333] In some embodiments of a compound of formula I, wherein Ar 1< is of formula i, R 1< may be hydrogen and / or R 2< may be methyl or R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< , or R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with one of R a< .

[0334] In some embodiments of a compound of formula I, wherein Ar 1< is of formula i, R c< and R d< are hydrogen. In some embodiments of a compound of formula I, wherein Ar 1< is of formula I, R b< , R c< and R d< are hydrogen.

[0335] In some embodiments compound of formula I wherein Ar 1< is of formula i, in which with one of R a< forms a ring with R 3< , the ring formed is a 4, 5, or 6-membered ring, or a 5 or 6 membered ring, or a 5 membered ring.

[0336] In some embodiments compound of formula I wherein Ar 1< is of formula i, in which with one of R a< forms a ring with R 3< , the ring formed is a 3, 4, 5, or 6-membered ring.

[0337] In some embodiments compound of formula I wherein Ar 1< is of formula i, in which one of R 2< forms a ring with R 3< , the ring formed is a 4, 5, or 6-membered ring or a 5 or 6 membered ring, or a 6 membered ring.

[0338] In some embodiments of a compound of formula I, Ar 1< is of formula ii-1 or pharmaceutically acceptable salts or stereoisomers thereof wherein R 4< is hydrogen, F or Cl; R 5< , R 5'< , R 6< , R 6'< are independently of each other hydrogen, -CF 3 or halogen, preferably F, Cl.

[0339] In some embodiments of a compound of formula I, Ar 1< is of formula ii-2, ii-3 or ii-4 or pharmaceutically acceptable salts or stereoisomers thereof wherein X 2< is O, NH or NMe; X 3< is CH or N; o is 0 or 1; R 5< , R 5'< , R 6< , R 6'< are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F.

[0340] The skilled person understands that if X 3< stands for CH, R 7< may in general also be bound to this carbon, such that X 3< may be CR 7< . Preferably, the corresponding aryl or heteroaryl is substituted only with a single R 7< . Furthermore, it is understood that when X 3< is N, R 7< can in general not be bound to N.

[0341] In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1, ii-2, ii-3 or ii-4, R 5< and R 6< are independently of each other hydrogen, -CF 3 , F or Cl and R 5'< and R 6'< are hydrogen.

[0342] In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1, ii-2, ii-3 or ii-4, R 7< is hydrogen if X 3< is N and / or R 7< is F if X 3< is CH.

[0343] In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1, ii-2, ii-3 or ii-4, o is 1.

[0344] In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1, ii-2, ii-3 or ii-4, R 5< is F and / or R 6< is F or Cl.

[0345] In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1, ii-2, ii-3 or ii-4, R c< and R d< are hydrogen. In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1, ii-2, ii-3 or ii-4, R b< , R c< and R d< are hydrogen.

[0346] In some embodiments compound of formula I wherein Ar 1< is of formula ii-1, ii-2, ii-3 or ii-4, in which with one of R a< forms a ring with R 3< , the ring formed is a 4, 5, or 6-membered ring, or a 5 or 6 membered ring, or a 5 membered ring.

[0347] In some embodiments compound of formula I wherein Ar 1< is of formula ii-1, ii-2, ii-3 or ii-4, in which with one of R a< forms a ring with R 3< , the ring formed is a 3, 4, 5, or 6-membered ring.

[0348] In some embodiments compound of formula I wherein Ar 1< is of formula ii-1, ii-2, ii-3 or ii-4, in which one of R 2< forms a ring with R 3< , the ring formed is a 4, 5, or 6-membered ring or a 5 or 6 membered ring, or a 6 membered ring.

[0349] In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1, ii-2, ii-3 or ii-4, R 2< is methyl or R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< , or R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with one of R a< .

[0350] In some embodiments, X 2< is O, such that Ar 1< is of formula ii-1a or pharmaceutically acceptable salts or stereoisomers thereof wherein R 4< is hydrogen, F or Cl; R 5< , R 5'< , R 6< , R 6'< are independently of each other hydrogen, -CF 3 or halogen, preferably F, Cl.

[0351] In some embodiments, X 2< is O, such that Ar 1< is of formula ii-2a, ii-3a or ii-4a or pharmaceutically acceptable salts or stereoisomers thereof wherein X 3< is CH or N, preferably N; o is 0 or 1; R 5< , R 5'< , R 6< , R 6'< are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F.

[0352] In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1a, ii-2a, ii-3a or ii-4a, R 5< and R 6< are independently of each other hydrogen, -CF 3 , F or Cl and R 5'< and R 6'< are hydrogen.

[0353] In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1a, ii-2a, ii-3a or ii-4a, o is 1.

[0354] In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1a, ii-2a, ii-3a or ii-4a, R 5< is F and / or R 6< is F or Cl.

[0355] In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1a, ii-2a, ii-3a or ii-4a, R 7< is hydrogen if X 3< is N and / or R 7< is F if X 3< is CH.

[0356] In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1a, ii-2a, ii-3a or ii-4a, R 2< is methyl or R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< , or R 2< is - (CH 2 )- or -(CH 2 ) 2 - which forms a ring with one of R a< .

[0357] In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1a, ii-2a, ii-3a or ii-4a, R c< and R d< are hydrogen. In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1a, ii-2a, ii-3a or ii-4a, R b< , R c< and R d< are hydrogen.

[0358] In some embodiments compound of formula I wherein Ar 1< is of formula ii-1a, ii-2a, ii-3a or ii-4a, in which with one of R a< forms a ring with R 3< , the ring formed is a 4, 5, or 6-membered ring, or a 5 or 6 membered ring, or a 5 membered ring.

[0359] In some embodiments compound of formula I wherein Ar 1< is of formula ii-1a, ii-2a, ii-3a or ii-4a, in which with one of R a< forms a ring with R 3< , the ring formed is a 3, 4, 5, or 6-membered ring.

[0360] In some embodiments compound of formula I wherein Ar 1< is of formula ii-1a, ii-2a, ii-3a or ii-4a, in which one of R 2< forms a ring with R 3< , the ring formed is a 4, 5, or 6-membered ring or a 5 or 6 membered ring, or a 6 membered ring.

[0361] In some embodiments, X 3< is N, such that Ar 1< is of formula ii-1b or pharmaceutically acceptable salts or stereoisomers thereof wherein R 4< is hydrogen, F or Cl; R 5< , R 5'< , R 6< , R 6'< are independently of each other hydrogen, -CF 3 or halogen, preferably F, Cl.

[0362] In some embodiments, X 3< is N, such that Ar 1< is of formula ii-2b, ii-3b, ii-4b, ii-5b or pharmaceutically acceptable salts or stereoisomers thereof 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 each other hydrogen, -CF 3 or halogen, preferably F, Cl R 7< is hydrogen or halogen, preferably F.

[0363] In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 5< and R 6< are independently of each other hydrogen, -CF 3 , F or Cl and R 5'< and R 6'< are hydrogen.

[0364] In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, o is 1.

[0365] In some of a compound of formula I, wherein Ar 1< is of ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 5< is F and / or R 6< is F or Cl.

[0366] In some of a compound of formula I, wherein Ar 1< is ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 7< is F.

[0367] In some of a compound of formula I, wherein Ar 1< is of formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 2< is methyl or R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< , or R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with one of R a< .

[0368] In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1b, ii-2b, ii-3b or ii-4b, R c< and R d< are hydrogen. In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1b, ii-2b, ii-3b or ii-4b, R b< , R c< and R d< are hydrogen.

[0369] In some embodiments compound of formula I wherein Ar 1< is of formula ii-1b, ii-2b, ii-3b or ii-4b, in which one of R a< forms a ring with R 3< , the ring formed is a 4, 5, or 6-membered ring, or a 5 or 6 membered ring, or a 5 membered ring.

[0370] In some embodiments compound of formula I wherein Ar 1< is of formula ii-1b, ii-2b, ii-3b or ii-4b, in which one of R a< forms a ring with R 3< , the ring formed is a 3, 4, 5, or 6-membered ring.

[0371] In some embodiments compound of formula I wherein Ar 1< is of ii-1b, ii-2b, ii-3b or ii-4b, in which one of R 2< forms a ring with R 3< , the ring formed is a 4, 5, or 6-membered ring or a 5 or 6 membered ring, or a 6 membered ring.

[0372] In some embodiments, X 2< is O and X 3< is N, such that Ar 1< is of formula ii-1c or pharmaceutically acceptable salts or stereoisomers thereof wherein R 4< is hydrogen, F or Cl; R 5< , R 5'< , R 6< , R 6'< are independently of each other hydrogen, -CF 3 or halogen, preferably F, Cl.

[0373] In some embodiments, X 2< is O and X 3< is N, such that Ar 1< is of formula ii-2c, ii-3c, ii-4c, ii-5c or pharmaceutically acceptable salts or stereoisomers thereof 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, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F.

[0374] In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 5< and R 6< are independently of each other hydrogen, -CF 3 , F or Cl and R 5'< and R 6'< are hydrogen.

[0375] In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, o is 1.

[0376] In some embodiments of a compound of formula I, wherein Ar 1< is 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.

[0377] In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 7< is F.

[0378] In some embodiments of a compound of formula I, wherein Ar 1< is of ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 2< is methyl or R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< , or R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with one of R a< .

[0379] In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1c, ii-2c, ii-3c or ii-4c, R c< and R d< are hydrogen. In some embodiments of a compound of formula I, wherein Ar 1< is of formula ii-1c, ii-2c, ii-3c or ii-4c, R b< , R c< and R d< are hydrogen.

[0380] In some embodiments compound of formula I wherein Ar 1< is of formula ii-1c, ii-2c, ii-3c or ii-4c, in which one of R a< forms a ring with R 3< , the ring formed is a 4, 5, or 6-membered ring, or a 5 or 6 membered ring, or a 5 membered ring.

[0381] In some embodiments compound of formula I wherein Ar 1< is of formula ii-1c, ii-2c, ii-3c or ii-4c, in which one of R a< forms a ring with R 3< , the ring formed is a 3, 4, 5, or 6-membered ring.

[0382] In some embodiments compound of formula I wherein Ar 1< is of ii-1c, ii-2c, ii-3c or ii-4c, in which one of R 2< forms a ring with R 3< , the ring formed is a 4, 5, or 6-membered ring or a 5 or 6 membered ring, or a 6 membered ring.

[0383] In some embodiments of a compound of formula I, Ar 1< is of formula iii-1 or pharmaceutically acceptable salts or stereoisomers thereof wherein R 4< is hydrogen or halogen, preferably F or Cl; R 5< , R 6< are independently of each other hydrogen, -CF 3 or halogen, preferably F, Cl.

[0384] In some embodiments of a compound of formula I, Ar 1< is of formula iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7 or pharmaceutically acceptable salts or stereoisomers thereof wherein X 3< is CH or N, preferably N; o is 0 or 1; R 5< , R 6< are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F.

[0385] In some embodiments a compound of formula I, wherein Ar 1< is 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, -CF 3 , F or Cl and R 5'< and R 6'< are hydrogen.

[0386] In some embodiments a compound of formula I, wherein Ar 1< is of formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, o is 1.

[0387] In some embodiments a compound of formula I, wherein Ar 1< is 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.

[0388] In some embodiments of a compound of formula I, wherein Ar 1< is of formula iii-1, iii-2, iii-3 or iii-4, R 7< is hydrogen if X 3< is N and / or R 7< is F if X 3< is CH.

[0389] In some embodiments a compound of formula I, wherein Ar 1< is 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 -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< , or R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with one of R a< .

[0390] In some embodiments of a compound of formula I, wherein Ar 1< is 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. In some embodiments of a compound of formula I, wherein Ar 1< is 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.

[0391] In some embodiments compound of formula I wherein Ar 1< is of formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, in which one of R a< forms a ring with R 3< , the ring formed is a 4, 5, or 6-membered ring, or a 5 or 6 membered ring, or a 5 membered ring.

[0392] In some embodiments compound of formula I wherein Ar 1< is of iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, in which one of R a< forms a ring with R 3< , the ring formed is a 3, 4, 5, or 6-membered ring.

[0393] In some embodiments compound of formula I wherein Ar 1< is of iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, in which one of R 2< forms a ring with R 3< , the ring formed is a 4, 5, or 6-membered ring or a 5 or 6 membered ring, or a 6 membered ring.

[0394] In some embodiments, X 3< is N, such that Ar 1< is of formula iv-2, iv-3 or iv-4, iv-5, iv-6 or iv-7, or X 3< is C such that Ar 1< is of formula iv-8 or iv-9 wherein o is 0 or 1; R 5< , R 6< are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F.

[0395] In some embodiments of a compound of formula I, wherein Ar 1< is 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, -CF 3 , F or Cl and R 5'< and R 6'< are hydrogen.

[0396] In some embodiments of a compound of formula I, wherein Ar 1< is of iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, o is 1.

[0397] In some embodiments of a compound of formula I, wherein Ar 1< is 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.

[0398] In some embodiments of a compound of formula I, wherein Ar 1< is of iiv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, R 7< is F.

[0399] In some embodiments of a compound of formula I, wherein Ar 1< is of 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 -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< , or R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with one of R a< .

[0400] In some embodiments of a compound of formula I, wherein Ar 1< is of 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. In some embodiments of a compound of formula I, wherein 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, R b< , R c< and R d< are hydrogen.

[0401] In some embodiments compound of formula I wherein Ar 1< is of formula iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, in which one of R a< forms a ring with R 3< , the ring formed is a 4, 5, or 6-membered ring, or a 5 or 6 membered ring, or a 5 membered ring.

[0402] In some embodiments compound of formula I wherein Ar 1< is of iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, in which one of R a< forms a ring with R 3< , the ring formed is a 3, 4, 5, or 6-membered ring.

[0403] In some embodiments compound of formula I wherein Ar 1< is of iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, in which one of R 2< forms a ring with R 3< , the ring formed is a 4, 5, or 6-membered ring or a 5 or 6 membered ring, or a 6 membered ring.

[0404] In some embodiments, the present disclosure provides a compound or pharmaceutically acceptable salts or stereoisomers thereof of formula IIa or IIb wherein X 1< is -O-, -NR 3< -; R 1< is H or F; R 2< is hydrogen or C 1-4 alkyl, preferably methyl or is -(CH 2 ) q - which forms a ring with R 3< ; R 3< is hydrogen or C 1-4 alkyl, preferably hydrogen or methyl, or is -(CH 2 ) p - which forms a ring with R 2< ; 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 a 6-membered aryl, which is unsubstituted or substituted with one or more of a group selected from halogen, -CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, hydroxy C 1-5 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 6 aryl, C 1-6 alkoxy-C 5-6 heteroaryl, amino, amino C 1-4 alkyl, C 1-6 alkylamino, C 1-6 aminoalkyl-C 6 aryl, C 1-6 aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 alkoxyaminocarbonyl, aryl C 1-6 alkoxy, or C 6 aryl.

[0405] In some embodiments of a compound of formula IIa or IIb, X 1< is -NR 3< -.

[0406] In some embodiments of a compound of formula IIa or IIb, R 1< is hydrogen.

[0407] In some embodiments of a compound of formula IIa or IIb, R 2< is C 1-4 alkyl or is -(CH 2 ) q -which forms a ring with R 3< . For example, R 2< may be selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< . Preferably, R 2< may be selected from methyl, ethyl, n-propyl, i-propyl, n-butyl or i-butyl R 2< is - (CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< . More preferably, R 2< may be methyl R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< .

[0408] In some embodiments of a compound of formula IIa or IIb, R 3< is hydrogen or methyl is - (CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 2< .

[0409] In some embodiments of a compound of formula IIa or IIb, X 1< is NR 3< .

[0410] In some embodiments of a compound of formula IIa, n is 0 and m is 1, 2 or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2 or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2, or 3; or n is 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1; or n is 1 or 2 and m is 1, 2 or 3; or n is 1 or 2 and m is 1 or 2; or n is 1 or 2 and m is 1 or 3; or n is 1 or 2 and m is 2 or 3.

[0411] In some embodiments of a compound of formula IIb, r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0412] In some embodiments of a compound of formula IIa or IIb, X 1< may form a heterocycle with the carbon to which R 2< is directly bound. For example, X 1< may form a 4, 5, 6 or 7 membered heterocycle or a heterobicycle. In some embodiments of a 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.

[0413] In some embodiments of a compound of formula IIa or IIb, Ar 1< is of formula i or pharmaceutically acceptable salts or stereoisomers thereof wherein 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 aryl; R 5< , R 5'< , R 6< , R 6'< are independently of each other hydrogen, -CF 3 or halogen, preferably F, Cl.

[0414] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is 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-C 6 aryl, C 1-4 alkoxy-C 5-6 heteroaryl, amino C 1-4 alkyl, C 1-4 alkylamino, C 1-4 aminoalkyl-C 6 aryl, C 1-4 aminoalkyl-C 6 heteroaryl, C 1-4 alkoxycarbonyl, C 1-4 alkoxyaminocarbonyl or C 6 aryl.

[0415] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is 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-C 6 aryl, C 1-4 alkoxy-C 5-6 heteroaryl or C 6 aryl.

[0416] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula i, R 4< is in general 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, hydroxy methyl, hydroxy ethyl, hydroxyl propyl, hydroxyl butyl, hydroxyl pentyl, methoxy methyl, method ethyl, methoxy propyl, methoxy butyl, methoxy pentyl, mehoxy hexyl, ethoxy methyl, ethoxy ethyl, ethoxy propyl, ethoxy butyl, ethoxy pentyl, ethoxy hexyl, propoxy methyl, propoxy ethyl, propoxy propyl, propoxy butyl, propoxy pentyl, propoxy hexyl, butoxy methyl, butoxy ethyl, butoxy propyl, butoxy butyl, butoxy pentyl, butoxy hexyl, pentoxy methyl, pentoxy ethyl, pentoxy propyl, pentoxy butyl, pentoxy pentyl, pentoxy hexyl, hexoxy methyl, hexoxy ethyl, hexoxy propyl, hexoxy butyl, hexoxy pentyl, hexoxy hexyl, amino methyl, amino ethyl, amino propyl, amino butyl, amino pentyl, amino hexyl, methylamino ethylamino, propylamino, butylamino, pentylamino, hexylamino, methoxy carbonyl, ethoxy carbonyl, propoxy carbonyl, butoxy carbonyl, pentoxy carbonyl, hexoxy carbonyl, methoxyamino carbonyl, ethoxyamino carbonyl, propoxyamino carbonyl, butoxyamino carbonyl, pentoxyamino carbonyl, hexoxyamino carbonyl, phenyl methoxy, phenyl ethoxy, phenyl propoxy, phenyl butoxy, phenyl pentoxy, phenyl hexoxy, m-fluorophenyl methoxy, m-fluorophenylphenyl ethoxy, m-fluorophenylphenyl propoxy, m-fluorophenylphenyl butoxy, m-fluorophenylphenyl pentoxy, m-fluorophenylphenyl hexoxy, pyridinyl methoxy, pyridinyl ethoxy, pyridinyl propoxy, pyridinyl butoxy, pyridinyl pentoxy, pyridinyl hexoxy, phenyl, pyridinyl or naphtyl.

[0417] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula i, R 5< and R 6< are independently of each other hydrogen, -CF 3 , 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, 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 aryl.

[0418] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula i, R 5< and R 6< are independently of each other hydrogen, -CF 3 , 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, hydroxy C 1-5 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy-C 6 aryl, C 1-4 alkoxy-C 5-6 heteroaryl, amino C 1-4 alkyl, C 1-4 alkylamino, C 1-4 aminoalkyl-C 6 aryl, C 1-4 aminoalkyl-C 6 heteroaryl, C 1-4 alkoxycarbonyl, C 1-4 alkoxyaminocarbonyl or C 6 aryl.

[0419] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula i, Ar 1< comprises only 1, 2 or 3 substituents which are not hydrogen. Thus, at least two of R 4< , R 5< . R 5'< , R 6< or R 6'< may be hydrogen.

[0420] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula i, R 1< may be hydrogen and / or R 2< may be methyl or may be -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< .

[0421] In some embodiments of a compound of formula IIa or IIb, Ar 1< is of formula ii-1 or pharmaceutically acceptable salts or stereoisomers thereof wherein R 4< is hydrogen, F or Cl; R 5< , R 5< ', R 6< , R 6< ' are independently of each other hydrogen, -CF 3 or halogen, preferably F, Cl.

[0422] In some embodiments of a compound of formula IIa or IIb, Ar 1< is of formula ii-2, ii-3 or ii-4 or pharmaceutically acceptable salts or stereoisomers thereof 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 each other hydrogen, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F.

[0423] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula ii-1, ii-2, ii-3 or ii-4, R 5< and R 6< are independently of each other hydrogen, -CF 3 , F or Cl and R 5'< and R 6'< are hydrogen.

[0424] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula ii-1, ii-2, ii-3 or ii-4, o is 1.

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

[0426] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula ii-1, ii-2, ii-3 or ii-4, R 2< is methyl or is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< .

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

[0428] In some embodiments of a compound of formula IIa, wherein Ar 1< is of formula ii-1, ii-2, ii-3 or ii-4, n is 0 and m is 1, 2 or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2 or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2, or 3; or n is 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1; 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.

[0429] In some embodiments of a compound of formula IIb, wherein Ar 1< is of formula ii-1, ii-2, ii-3 or ii-4, r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0430] In some embodiments, X 2< is O, such that Ar 1< is of formula ii-1a or pharmaceutically acceptable salts or stereoisomers thereof wherein R 4< is hydrogen, F or Cl; R 5< , R 5< ', R 6< , R 6< ' are independently of each other hydrogen, -CF 3 or halogen, preferably F, Cl.

[0431] In some embodiments, X 2< is O, such that Ar 1< is of formula ii-2a, ii-3a or ii-4a or pharmaceutically acceptable salts or stereoisomers thereof wherein X 3< is CH or N, preferably N; o is 0 or 1; R 5< , R 5< ', R 6< , R 6< ' are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F.

[0432] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula ii-1a, ii-2a, ii-3a or ii-4a, R 5< and R 6< are independently of each other hydrogen, -CF 3 , F or Cl and R 5'< and R 6'< are hydrogen.

[0433] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula ii-1a, ii-2a, ii-3a or ii-4a, o is 1.

[0434] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula ii-1a, ii-2a, ii-3a or ii-4a, R 5< is F and / or R 6< is F or Cl.

[0435] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula ii-1a, ii-2a, ii-3a or ii-4a, R 7< is hydrogen if X 3< is N and / or R 7< is F if X 3< is CH.

[0436] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula ii-1a, ii-2a, ii-3a or ii-4a, R 2< is methyl or is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< .

[0437] In some embodiments of a compound of formula IIa, wherein Ar 1< is 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.

[0438] In some embodiments of a compound of formula IIb, wherein Ar 1< is 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.

[0439] In some embodiments of a compound of formula IIa or IIb, X 3< is N, such that Ar 1< is of formula ii-1b or pharmaceutically acceptable salts or stereoisomers thereof wherein R 4< is hydrogen, F or Cl; R 5< , R 5< ', R 6< , R 6< ' are independently of each other hydrogen, -CF 3 or halogen, preferably F, Cl.

[0440] In some embodiments of a compound of formula IIa or IIb, X 3< is N, such that Ar 1< is of formula ii-2b, ii-3b, ii-4b, ii-5b or pharmaceutically acceptable salts or stereoisomers thereof 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 each other hydrogen, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F.

[0441] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 5< and R 6< are independently of each other hydrogen, -CF 3 , F or Cl and R 5'< and R 6'< are hydrogen.

[0442] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, o is 1.

[0443] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is 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.

[0444] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 7< is F.

[0445] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 2< is methyl or is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< .

[0446] In some embodiments of a compound of formula IIa, wherein Ar 1< is 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.

[0447] In some embodiments of a compound of formula IIb, wherein Ar 1< is 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.

[0448] In some embodiments of a compound of formula IIa or IIb Ar 1< is of formula ii-1c or pharmaceutically acceptable salts or stereoisomers thereof wherein R 4< is hydrogen, F or Cl; R 5< , R 5< ', R 6< , R 6< ' are independently of each other hydrogen, -CF 3 or halogen, preferably F, Cl.

[0449] In some embodiments of a compound of formula IIa or IIb, X 2< is O and X 3< is N, such that Ar 1< is of formula ii-2c, ii-3c, ii-4c, ii-5c or pharmaceutically acceptable salts or stereoisomers thereof wherein o is 0 or 1; R 5< , R 5< ', R 6< , R 6< ' are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F.

[0450] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 5< and R 6< are independently of each other hydrogen, -CF 3 , F or Cl and R 5'< and R 6'< are hydrogen.

[0451] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, o is 1.

[0452] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is 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.

[0453] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 7< is F.

[0454] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 2< is methyl or is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< .

[0455] In some embodiments of a compound of formula IIa, wherein Ar 1< is of formula ii-1c, ii-2c, ii-3c or ii-4c, n is 0 and m is 1, 2 or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2 or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2, or 3; or n is 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1; 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.

[0456] In some embodiments of a compound of formula IIb, wherein Ar 1< is of formula ii-1c, ii-2c, ii-3c or ii-4c, r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0457] In some embodiments of a compound of formula IIa or IIb, Ar 1< is of formula iii-1 or pharmaceutically acceptable salts or stereoisomers thereof wherein R 4< is hydrogen or halogen, preferably F or Cl; R 5< , R 6< are independently of each other hydrogen, -CF 3 or halogen, preferably F, Cl.

[0458] In some embodiments of a compound of formula IIa or IIb, Ar 1< is of formula iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7 or pharmaceutically acceptable salts or stereoisomers thereof wherein X 3< is CH or N, preferably N; o is 0 or 1; R 5< , R 6< are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F.

[0459] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is 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, -CF 3 , F or Cl and R 5'< and R 6'< are hydrogen.

[0460] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, o is 1.

[0461] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is 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.

[0462] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of formula iii-1, iii-2, iii-3 or iii-4, R 7< is hydrogen if X 3< is N and / or R 7< is F if X 3< is CH.

[0463] In some embodiments a compound of formula IIa or IIb, wherein Ar 1< is of formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, R 2< is methyl or is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< .

[0464] In some embodiments of a compound of formula IIa, wherein Ar 1< is of formula iii-1, iii-2, ii-3 or iii-4, n is 0 and m is 1, 2 or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2 or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2, or 3; or n is 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1; 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.

[0465] In some embodiments of a compound of formula IIb, wherein Ar 1< is of formula iii-1, iii-2, iii-3 or iii-4, r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0466] In some embodiments, X 3< is N, such that Ar 1< is of formula iv-2, iv-3 or iv-4, iv-5, iv-6 or iv-7, or X 3< is C such that Ar 1< is of formula iv-8 or iv-9 wherein o is 0 or 1; R 5< , R 6< are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F.

[0467] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is 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, - CF 3 , F or Cl and R 5'< and R 6'< are hydrogen.

[0468] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, o is 1.

[0469] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is 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] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is of iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, R 7< is F.

[0471] In some embodiments of a compound of formula IIa or IIb, wherein Ar 1< is 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 is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< .

[0472] In some embodiments of a compound of formula IIa, wherein Ar 1< is 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.

[0473] In some embodiments of a compound of formula IIb, wherein Ar 1< is of formula iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0474] In some embodiments, the present disclosure provides a compound or pharmaceutically acceptable salts or stereoisomers thereof of formula III wherein R 1< is H or F; Ar 1< is a 6-membered aryl, which is unsubstituted or substituted with one or more of a group selected from halogen, -CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, hydroxy C 1-5 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 6 aryl, C 1-6 alkoxy-C 5-6 heteroaryl, amino, amino C 1-4 alkyl, C 1-6 alkylamino, C 1-6 aminoalkyl-C 6 aryl, C 1-6 aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 alkoxyaminocarbonyl, aryl C 1-6 alkoxy, or C 6 aryl; Z is selected from

[0475] In some embodiments of a compound of formula III, R 1< is hydrogen.

[0476] In some embodiments, the present disclosure provides a compound or pharmaceutically acceptable salts or stereoisomers thereof of formula IV wherein 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, aryl C 1-6 alkoxy, or C 6 aryl; R 5< , R 5< ', R 6< , R 6< ' are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; Z is selected from

[0477] In some embodiments of a compound of formula IV, 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-C 6 aryl, C 1-4 alkoxy-C 5-6 heteroaryl, amino C 1-4 alkyl, C 1-4 alkylamino, C 1-4 aminoalkyl-C 6 aryl, C 1-4 aminoalkyl-C 6 heteroaryl, C 1-4 alkoxycarbonyl, C 1-4 alkoxyaminocarbonyl or C 6 aryl.

[0478] In some embodiments of a 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-C 6 aryl, C 1-4 alkoxy-C 5-6 heteroaryl or C 6 aryl.

[0479] In some embodiments of a compound of formula IV, R 4< is in general 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, hydroxy methyl, hydroxy ethyl, hydroxyl propyl, hydroxyl butyl, hydroxyl pentyl, methoxy methyl, method ethyl, methoxy propyl, methoxy butyl, methoxy pentyl, mehoxy hexyl, ethoxy methyl, ethoxy ethyl, ethoxy propyl, ethoxy butyl, ethoxy pentyl, ethoxy hexyl, propoxy methyl, propoxy ethyl, propoxy propyl, propoxy butyl, propoxy pentyl, propoxy hexyl, butoxy methyl, butoxy ethyl, butoxy propyl, butoxy butyl, butoxy pentyl, butoxy hexyl, pentoxy methyl, pentoxy ethyl, pentoxy propyl, pentoxy butyl, pentoxy pentyl, pentoxy hexyl, hexoxy methyl, hexoxy ethyl, hexoxy propyl, hexoxy butyl, hexoxy pentyl, hexoxy hexyl, amino methyl, amino ethyl, amino propyl, amino butyl, amino pentyl, amino hexyl, methylamino ethylamino, propylamino, butylamino, pentylamino, hexylamino, methoxy carbonyl, ethoxy carbonyl, propoxy carbonyl, butoxy carbonyl, pentoxy carbonyl, hexoxy carbonyl, methoxyamino carbonyl, ethoxyamino carbonyl, propoxyamino carbonyl, butoxyamino carbonyl, pentoxyamino carbonyl, hexoxyamino carbonyl, phenyl methoxy, phenyl ethoxy, phenyl propoxy, phenyl butoxy, phenyl pentoxy, phenyl hexoxy, m-fluorophenyl methoxy, m-fluorophenylphenyl ethoxy, m-fluorophenylphenyl propoxy, m-fluorophenylphenyl butoxy, m-fluorophenylphenyl pentoxy, m-fluorophenylphenyl hexoxy, pyridinyl methoxy, pyridinyl ethoxy, pyridinyl propoxy, pyridinyl butoxy, pyridinyl pentoxy, pyridinyl hexoxy, phenyl, pyridinyl or naphtyl.

[0480] In some embodiments of of a compound of formula IV, R 5< and R 6< are independently of each other hydrogen, -CF 3 , 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, 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 aryl.

[0481] In some embodiments embodiments of a compound of formula IV, R 5< and R 6< are independently of each other hydrogen, -CF 3 , 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, hydroxy C 1-5 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy-C 6 aryl, C 1-4 alkoxy-C 5-6 heteroaryl, amino C 1-4 alkyl, C 1-4 alkylamino, C 1-4 aminoalkyl-C 6 aryl, C 1-4 aminoalkyl-C 6 heteroaryl, C 1-4 alkoxycarbonyl, C 1-4 alkoxyaminocarbonyl or C 6 aryl.

[0482] In some embodiments of a compound of formula IV, Ar 1< comprises only 1, 2 or 3 substituents which are not hydrogen. Thus, at least two of R 4< , R 5< . R 5'< , R 6< or R 6'< may be hydrogen.

[0483] In some embodiments of a compound of formula IV, R 1< may be hydrogen.

[0484] In some embodiments, the present disclosure provides a compound or pharmaceutically acceptable salts or stereoisomers thereof of formula V-1 wherein R 1< is H or F; R 4< is hydrogen or halogen, preferably F or Cl; R 5< , R 5< ', R 6< , R 6< ' are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; Z is selected from

[0485] In some embodiments, the present disclosure provides a compound or pharmaceutically acceptable salts or stereoisomers thereof of formula V-2, V-3 or V-4 wherein X 2< is O or NH or NMe; X 3< is CH or N; R 1< is H or F; R 5< , R 5< ', R 6< , R 6< ' are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; o is 0 or 1; R 7< is hydrogen or halogen, preferably F; Z is selected from

[0486] In some embodiments of a compound of formula V-1, V-2, V-3 or V-4, R 4< is hydrogen, chloro or fluoro.

[0487] In some embodiments of a compound of formula V-1, V-2, V-3 or V-4, R 5< and R 6< are independently of each other hydrogen, -CF 3 , F or Cl and R 5'< and R 6'< are hydrogen. Preferably, R 4< is hydrogen, chloro or fluoro.

[0488] In some embodiments of a compound of formula V-1, V-2, V-3 or V-4, R 5< and R 6< are independently of each other hydrogen, -CF 3 , F or Cl and R 5'< and R 6'< are hydrogen. Preferably, R 4< is hydrogen, chloro or fluoro.

[0489] In some embodiments of a compound of formula V-1, V-2, V-3 or V-4, Ar 1< comprises only 1, 2 or 3 substituents which are not hydrogen. Thus, at least two of R 4< , R 5< . R 5'< , R 6< or R 6'< may be hydrogen.

[0490] In some embodiments of a compound of formula V-1, V-2, V-3 or V-4, R 7< is hydrogen if X 3< is N and / or R 7< is F if X 3< is CH.

[0491] In some embodiments of a compound of formula V-1, V-2, V-3 or V-4, o is 1.

[0492] In some embodiments of a compound of formula V-1, V-2, V-3 or V-4, R 1< may be hydrogen.

[0493] In some embodiments of a compound of formula V-2, V-3 or V-4, X 2< is O, resulting in a compound or pharmaceutically acceptable salts or stereoisomers thereof of formula V-2a, V-3a or V-4a wherein X 3< is CH or N; R 1< is H or F; R 5< , R 5< ', R 6< , R 6< ' are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; o is 0 or 1; R 7< is hydrogen or halogen, preferably F; Z is selected from

[0494] In some embodiments of a compound of formula V-1, V-2a, V-3a or V-4a, R 4< is hydrogen, fluoro or chloro.

[0495] In some embodiments of a compound of formula V-1, V-2a, V-3a or V-4a, R 5< and R 6< are independently of each other hydrogen, -CF 3 , F or Cl and R 5'< and R 6'< are hydrogen. Preferably, R 4< is hydrogen, chloro or fluoro.

[0496] In some embodiments of a compound of formula V-1, V-2a, V-3a or V-4a, R 5< and R 6< are independently of each other hydrogen, -CF 3 , F or Cl and R 5'< and R 6'< are hydrogen. Preferably, R 4< is hydrogen, chloro or fluoro.

[0497] In some embodiments of a compound of formula V-1, V-2a, V-3a or V-4a, Ar 1< comprises only 1, 2 or 3 substituents which are not hydrogen. Thus, at least two of R 4< , R 5< . R 5'< , R 6< or R 6'< may be hydrogen.

[0498] In some embodiments of a compound of formula V-1, V-2a, V-3a or V-4a, R 7< is hydrogen if X 3< is N and / or R 7< is F if X 3< is CH.

[0499] In some embodiments of a compound of formula V-1, V-2a, V-3a or V-4a, o is 1.

[0500] In some embodiments of a compound of formula V-1, V-2a, V-3a or V-4a, R 1< may be hydrogen.

[0501] In some embodiments of a compound of formula V-2, V-3 or V-4, X 3< is N, resulting in a compound or pharmaceutically acceptable salts or stereoisomers thereof of formula V-2b, V-3b, V-4b or X 3< is C, resulting in a compound or pharmaceutically acceptable salts or stereoisomers thereof of formula V-5b wherein X 2< is O, NH or NMe R 1< is H or F; R 5< , R 5< ', R 6< , R 6< ' are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; o is 0 or 1; R 7< is hydrogen or halogen, preferably F; Z is selected from

[0502] In some embodiments of a compound of formula V-1, V-2b, V-3b, V-4b or V-5b, R 4< is hydrogen, fluoro, chloro.

[0503] In some embodiments of a compound of formula V-1, V-2b, V-3b, V-4b or V-5b, R 5< and R 6< are independently of each other hydrogen, -CF 3 , F or Cl and R 5'< and R 6'< are hydrogen. Preferably, R 4< is hydrogen, chloro or fluoro.

[0504] In some embodiments of a compound of formula V-1, V-2b, V-3b, V-4b or V-5b, R 5< and R 6< are independently of each other hydrogen, -CF 3 , 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, hydroxy C 1-5 alkyl, C 1-4 alkoxy-C 1-4 alkyl, amino C 1-4 alkyl, C 1-4 alkylamino, C 1-4 alkoxycarbonyl, C 1-4 alkoxyaminocarbonyl, aryl C 1-4 alkoxy, heteroaryl C 1-4 alkoxy or aryl.

[0505] In some embodiments of a compound of formula V-1, V-2b, V-3b, V-4b or V-5b, Ar 1< comprises only 1, 2 or 3 substituents which are not hydrogen. Thus, at least two of R 4< , R 5< . R 5'< , R 6< or R 6'< may be hydrogen.

[0506] In some embodiments V-2b, V-3b, V-4b or V-5b, o is 1.

[0507] In some embodiments of a compound of formula V-1, V-2b, V-3b, V-4b or V-5b, R 7< is F.

[0508] In some embodiments of a compound of formula V-1, V-2b, V-3b, V-4b or V-5b, R 1< may be hydrogen.

[0509] In some embodiments, the present disclosure provides a compound or pharmaceutically acceptable salts or stereoisomers thereof of formula VI-1 wherein R 1< is H or F; R 4< is hydrogen or halogen, preferably F or Cl; R 5< , R 6< are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F; Z is selected from

[0510] In some embodiments, the present disclosure provides a compound or pharmaceutically acceptable salts or stereoisomers thereof of formula VI-2, VI-3 or VI-4 wherein X 2< is O, NH or NMe; X 3< is CH or N; R 1< is H or F; o is 0 or 1; R 5< , R 6< are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F; Z is selected from

[0511] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4, R 4< is hydrogen, chloro or fluoro.

[0512] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4, o is 1.

[0513] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4, R 5< is F and / or R 6< is F or Cl.

[0514] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4, R 7< is hydrogen if X 3< is N and / or R 7< is F if X 3< is CH.

[0515] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4, R 1< may be hydrogen.

[0516] In some embodiments of a compound of formula VI-2, VI-3 or VI-4, X 2< is O, resulting in a compound or pharmaceutically acceptable salts or stereoisomers thereof of formula VI-2a, VI-3a or VI-4a wherein X 3< is CH or N; R 1< is H or F; R 5< , R 6< are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; o is 0 or 1; R 7< is hydrogen or halogen, preferably F; Z is selected from

[0517] In some embodiments of a compound of formula VI-1, VI-2a, VI-3a or VI-4a, R 4< is hydrogen, fluoro or chloro.

[0518] In some embodiments of a compound of formula VI-1, VI-2a, VI-3a or VI-4a, o is 1.

[0519] In some embodiments of a compound of formula VI-1, VI-2a, VI-3a or VI-4a, R 5< is F and / or R 6< is F or Cl.

[0520] In some embodiments of a compound of formula VI-1, VI-2a, VI-3a or VI-4a, R 7< is hydrogen if X 3< is N and / or R 7< is F if X 3< is CH.

[0521] In some embodiments of a compound of formula VI-1, VI-2a, VI-3a or VI-4a, R 1< may be hydrogen.

[0522] In some embodiments of a compound of formula VI-2, VI-3 or VI-4, X 3< is N, resulting in a compound or pharmaceutically acceptable salts or stereoisomers thereof of formula VI-2b, VI-3b or VI-4b or X 3< is C, resulting in a compound or pharmaceutically acceptable salts or stereoisomers thereof of formula VI-5b wherein X 2< is O, NH or NMe R 1< is H or F; R 5< , R 6< are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; o is 0 or 1; R 7< is hydrogen or halogen, preferably F; Z is selected from

[0523] In some embodiments of a compound of formula VI-1, VI-2b, VI-3b, VI-4b or VI-5b, R 4< is hydrogen, fluoro or chloro.

[0524] In some embodiments of a compound of formula VI-1, VI-2b, VI-3b, VI-4b or VI-5b, o is 1.

[0525] In some embodiments of a compound of formula VI-1b, VI-2b, VI-3b, VI-4b or VI-5b, R 5< is F and / or R 6< is F or Cl.

[0526] In some embodiments of a compound of formula VI-1, VI-2b, VI-3b, VI-4b or VI-5b, R 7< is F.

[0527] In some embodiments of a compound of formula VI-1, VI-2b, VI-3b, VI-4b or VI-5b, R 1< may be hydrogen.

[0528] In some embodiments, the present disclosure provides a compound or pharmaceutically acceptable salts or stereoisomers thereof of formula VII-1 wherein R 1< is H or F, preferably H; R 4< is hydrogen or halogen, preferably F or Cl; R 5< , R 6< are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; Z is selected from

[0529] In some embodiments, the present disclosure provides a compound or pharmaceutically acceptable salts or stereoisomers thereof of formula VII-2, VII-3 or VII-4, VII-5, VII-6 VII-7, VII-8 or VII-9 wherein R 1< is H or F, preferably H; o is 0 or 1; R 5< , R 6< are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F; Z is selected from

[0530] In some embodiments of a compound 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.

[0531] In some embodiments of a compound of formula formula VII-1, VII-2, VII-3 or VII-4, VII-5, VII-6 VII-7, VII-8 or VII-9, o is 1.

[0532] In some embodiments of a compound of formula 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 wherein R 6< is F or Cl.

[0533] In some embodiments of a compound 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.

[0534] In some embodiments of a compound of formula 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.

[0535] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2, pharmaceutically acceptable salts thereof, and stereoisomers thereof.

[0536] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2 and pharmaceutically acceptable salts thereof.

[0537] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2.

[0538] In some embodiments, the compound is selected from the compounds described in Table 1, pharmaceutically acceptable salts thereof, and stereoisomers thereof.

[0539] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0540] In some embodiments, the compound is selected from the compounds described in Table 1.

[0541] In some embodiments, the compound is selected from the compounds described in Table 2, pharmaceutically acceptable salts thereof, and stereoisomers thereof.

[0542] In some embodiments, the compound is selected from the compounds described in Table 2 and pharmaceutically acceptable salts thereof.

[0543] In some embodiments, the compound is selected from the compounds described in Table 2. Compounds 37, 37A, and 37B are compounds of the invention. Table 1 Compound No. Structure 1 2 3 4 5 6 7 8 10 11 12 13 14 16 17 Table 2 Compound No. Structure 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 37A 37B 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84

[0544] In some aspects, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.

[0545] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Tables 1 and 2, pharmaceutically acceptable salts thereof, and stereoisomers thereof.

[0546] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Tables 1 and 2 and pharmaceutically acceptable salts thereof.

[0547] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Tables 1 and 2.

[0548] It is understood that the isotopic derivative can be prepared using any of a variety of art-recognised techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0549] In some embodiments, the isotopic derivative is a deuterium labeled compound.

[0550] In some embodiments, the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.

[0551] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Tables 1 and 2, pharmaceutically acceptable salts thereof, and stereoisomers thereof.

[0552] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Tables 1 and 2 and pharmaceutically acceptable salts thereof.

[0553] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Tables 1 and 2.

[0554] In some embodiments, the compound is selected from the compound described Table 3, pharmaceutically acceptable salts thereof, and stereoisomers thereof.

[0555] In some embodiments, the compound is selected from the compound described Table 3 and pharmaceutically acceptable salts thereof.

[0556] In some embodiments, the compound is the compound described Table 3. Table 3 Compound No. Structure D-1

[0557] It is understood that the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.

[0558] In some embodiments, the deuterium labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term "deuterium enrichment factor" means the ratio between the deuterium abundance and the natural abundance of a deuterium.

[0559] It is understood that the deuterium labeled compound can be prepared using any of a variety of art-recognised techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a deuterium labeled reagent for a non-deuterium labeled reagent.

[0560] A compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the disclosure. Further, substitution with deuterium (i.e., 2< H) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0561] The compounds of the disclosure can contain one or more asymmetric centers in the molecule. A compound without designation of the stereochemistry is to be understood to include all the optical isomers (e.g., diastereomers, enantiomers, etc) in pure or substantially pure form, as well as mixtures thereof (e.g. a racemic mixture, or an enantiomerically enriched mixture). It is well known in the art how to prepare such optically active forms (e.g. by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, by chromatographic separation using a chiral stationary phase, and other methods).

[0562] The compounds can be isotopically-labeled compounds, for example, compounds including various isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, or chlorine. The disclosed compounds may exist in tautomeric forms and mixtures and separate individual tautomers are contemplated. In addition, some compounds may exhibit polymorphism.

[0563] The compounds of the disclosure include the free form as well as the pharmaceutically acceptable salts and stereoisomers thereof. The pharmaceutically acceptable salts include all the typical pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the present compounds can be synthesized from the compounds of this disclosure which contain a basic or acidic moiety by conventional chemical methods, see e.g. Berge et al, "Pharmaceutical Salts," J. Pharm. ScL, 1977:66:1-19.

[0564] For example, conventional pharmaceutically acceptable salts for a basic compound include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like. Conventional pharmaceutically acceptable salts for an acidic compound include those derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.

[0565] The compounds of the disclosure may exist in solid, i.e. crystalline or noncrystalline form (optionally as solvates) or liquid form. In the solid state, it may exist in, or as a mixture thereof. In crystalline solvates, solvent molecules are incorporated into the crystalline lattice during crystallization. The formation of solvates may include non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or aqueous solvents such as water (also called "hydrates"). It is common knowledge that crystalline forms (and solvates thereof) may exhibit polymorphism, i.e. exist in different crystalline structures known as "polymorphs", that have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties, and may display different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. Such different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, during preparation of the compound of the disclosure.

[0566] In some aspects, the disclosure also provides methods of preparation of the compounds of the disclosure. Typically they are prepared according to the syntheses shown in the experimental section.

[0567] It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0568] It is to be understood that compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) are useful and recognised reference textbooks of organic synthesis known to those in the art

[0569] One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognise that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999.Biological Assays

[0570] Compounds designed, selected and / or optimised by methods described herein, once produced, can be characterised using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterised by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and / or binding specificity.

[0571] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

[0572] Various in vitro or in vivo biological assays are may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.Pharmaceutical Compositions

[0573] In some aspects, the disclosure further provides a pharmaceutical composition comprising a therapeutically-effective amount of one or more of the compounds of the disclosure or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and / or excipients (also referred to as diluents). The excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient). The term "therapeutically-effective amount" as used herein refers to the amount of a compound (as such or in form of a pharmaceutical composition) of the present disclosure which is effective for producing some desired therapeutic effect.

[0574] Pharmaceutical compositions may be in unit dose form containing a predetermined amount of a compound of the disclosure per unit dose. Such a unit may contain a therapeutically effective dose of a compound of the disclosure or salt thereof or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of a compound of the disclosure or salt thereof.

[0575] The compounds of the disclosure may be administered by any aceptable means in solid or liquid form, including (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8) nasally; (9) pulmonary; or (10) intrathecally.

[0576] The phrase "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical compositions.

[0577] Such compositions may contain further components conventional in pharmaceutical preparations, e.g. wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants, pH modifiers, bulking agents, and further active agents. Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0578] Such compositions may be prepared by any method known in the art, for example, by bringing into association the active ingredient with one or more carriers and / or excipients. Different compositions and examples of carriers and / or excipients are well known to the skilled person and are described in detail in, e.g., Remington: The Science and Practice of Pharmacy. Pharmaceutical Press, 2013; Rowe, Sheskey, Quinn: Handbook of Pharmaceutical Excipients.Pharmaceutical Press, 2009. Excipients that may be used in the preparation of the pharmaceutical compositions may include one or more of buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide a composition suitable for an administration of choice.

[0579] As indicated above, the compounds of the present disclosure may be in solid or liquid form and administered by various routes in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.

[0580] In solid dosage forms of the disclosure for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), a compound is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and nonionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets, and other solid dosage forms of the pharmaceutical compositions of the present disclosure, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0581] Liquid dosage forms for oral administration of the compounds of the disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. An oral composition can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0582] In form of suspensions, a compound may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0583] Dosage forms for rectal or vaginal administration of a compound of the disclosure include a suppository, which may be prepared by mixing one or more compounds of the disclosure with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. Other suitable forms include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0584] Dosage forms for the topical or transdermal administration of a compound of the disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required. Such ointments, pastes, creams and gels may contain, in addition to a compound of the disclosure, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0585] Dosage forms such as powders and sprays for administration of a compound of the disclosure, may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0586] Dosage forms such as transdermal patches for administration of a compound of the disclosure may include absorption enhancers or retarders to increase or decrease the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel. Other dosage forms contemplated include ophthalmic formulations, eye ointments, powders, solutions and the like. It is understood that all contemplated compositions must be stable under the conditions of manufacture and storage, and preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0587] The dosage levels of a compound of the disclosure in the pharmaceutical compositions of the disclosure may be adjusted in order to obtain an amount of a compound of the disclosure which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being deleterious to the patient. The dosage of choice will depend upon a variety of factors including the nature of the particular compound of the present disclosure used, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound used, the rate and extent of absorption, the duration of the prevention or treatment, other drugs, compounds and / or materials used in combination with the particular compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A medical practitioner having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.

[0588] Typically, a suitable daily dose of a compound of the disclosure will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this disclosure for a patient, when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg, more usual 0.1 to 100 mg / kg per kilogram of body weight of recipient (patient, mammal) per day. Acceptable daily dosages may be from about 1 to about 1000 mg / day, and for example, from about 1 to about 100 mg / day.

[0589] The effective dose of a compound of the disclosure may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout a specified period (per day or per week or per month), optionally, in unit dosage forms. Preferred dosing also depends on factors as indicated above, e.g. on the administration, and can be readily arrived at by one skilled in medicine or the pharmacy art.Uses of the Compounds and Compositions

[0590] The compounds of the disclosure inhibit or modulate the activity of a receptor tyrosine kinase, in particular extracellular mutants of ErbB-receptors, such as, but not limited to, EGFR-Viii, EGFR-Vii, EGFR-Vvi, EGFR-A289V and EGFR-G598V and HER2-S310F. Thus, the compounds and compositions of the disclosure can be useful as a medicament, i.e. as a medicament in therapy, more specifically for the prevention or treatment of cancer, as detailed below. Therefore, in a further aspect, the present disclosure provides a method of prevention or treatment of a mammal, for example, a human, suffering from cancer, as detailed below. References to methods of treatment in this description are to be interpreted as references to the compounds and compositions of the present disclosure for use in those methods.

[0591] The term "prevention" or "preventing" refers to reducing or eliminating the onset of the symptoms or complications of a disease (e.g., cancer). Such prevention comprises the step of administering a therapeutically effective amount of a compound of Formula I or salt thereof (or of a pharmaceutical composition containing a compound of Formula I or salt thereof) to said mammal, for example, a human.

[0592] The term "treatment" or "treating" is intended to encompass therapy and cure. Such treatment comprises the step of administering a therapeutically effective amount of a compound of Formula I or salt thereof (or of a pharmaceutical composition containing a compound of Formula I or salt thereof) to said mammal, for example, a human.

[0593] Thus, the disclosure provides the use of the compounds of the disclosure or pharmaceutically acceptable salts or stereoisomers thereof or a pharmaceutical composition thereof for the prevention or treatment of cancer, as detailed below, in a mammal, for example a human.

[0594] In some aspects, the present disclosure is directed to a method of inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR), comprising administering the subject in need thereof a therapeutically effective amount of a compound described herein.

[0595] In some aspects, the present disclosure is directed to a method of inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR), comprising administering the subject in need thereof a composition described herein.

[0596] In some aspects, the present disclosure is directed to a method of preventing or treating cancer, comprising administering the subject in need thereof a therapeutically effective amount of a compound described herein.

[0597] In some aspects, the present disclosure is directed to a method of preventing or treating cancer, comprising administering the subject in need thereof a composition described herein.

[0598] In some aspects, the present disclosure is directed to a compound described herein for use in the inhibition of an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR).

[0599] In some aspects, the present disclosure is directed to a compound described herein for use in the prevention or treatment of cancer.

[0600] In some aspects, the present disclosure is directed to a composition described herein for use in the inhibition of an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR).

[0601] In some aspects, the present disclosure is directed to a composition described herein for use in the prevention or treatment of cancer.

[0602] In some aspects, the present disclosure is directed to 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 an EGFR).

[0603] In some aspects, the present disclosure is directed to use of a compound described herein in the manufacture of a medicament for preventing or treating cancer.

[0604] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2, pharmaceutically acceptable salts thereof, and stereoisomers thereof.

[0605] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2 and pharmaceutically acceptable salts thereof.

[0606] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2.

[0607] In some embodiments, cancer is a solid tumor.

[0608] In some embodiments, the cancer is a bladder cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, a non-small cell lung cancer (NSCLC), or any subtype thereof.

[0609] In some embodiments, the cancer is glioblastoma (GBM) or any subtype thereof.

[0610] In some embodiments, the cancer is glioblastoma.

[0611] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an ErbB receptor.

[0612] In some embodiments, the oncogenic variant of the ErbB receptor comprises an allosteric mutation.

[0613] In some embodiments, the oncogenic variant of an ErbB receptor is an allosteric variant of the ErbB receptor.

[0614] In some embodiments, the ErbB receptor is an epidermal growth factor receptor (EGFR) or a human epidermal growth factor receptor 2 (HER2) receptor.

[0615] In some embodiments, the ErbB receptor is an epidermal growth factor receptor (EGFR).

[0616] In some embodiments, the ErbB receptor is a HER2 receptor.

[0617] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an epidermal growth factor receptor (EGFR).

[0618] In some embodiments, the oncogenic variant of EGFR is an allosteric variant of EGFR.

[0619] In some embodiments, the oncogenic variant of EGFR comprises an allosteric mutation.

[0620] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER2 receptor.

[0621] In some embodiments, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor.

[0622] In some embodiments, the oncogenic variant of the HER2 receptor comprises an allosteric mutation.

[0623] In some embodiments, the oncogenic variant of an EGFR comprises an EGFR variant III (EGFR-Viii) mutation.

[0624] In some embodiments, the oncogenic variant of EGFR comprises an EGFR variant II (EGFR-Vii) mutation.

[0625] In some embodiments, the oncogenic variant of EGFR comprises an EGFR variant VI (EGFR-Vvi) mutation.

[0626] In some embodiments, the oncogenic variant of an EGFR comprises a substitution of a valine (V) for an alanine (A) at position 289 of SEQ ID NO: 1.

[0627] In some embodiments, the oncogenic variant of EGFR comprises a substitution of a valine (V) for a glycine (G) at position 598 of SEQ ID NO: 1.

[0628] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an EGFR and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, the oncogenic variant of an EGFR comprises a modification of a structure of the EGFR, wherein the oncogenic variant of an EGFR is a capable of forming a covalently linked dimer, wherein the covalently linked dimer is constitutively active and wherein the covalently linked dimer enhances an activity of EGFR when contacted to a Type I ErbB inhibitor. In some embodiments, the modification of the structure of the EGFR comprises a modification of one or more 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 the EGFR occurs within a first cysteine rich (CR1) and / or second cysteine rich (CR2) region of EGFR. In some embodiments, the first cysteine rich (CR1) and / or second cysteine rich (CR2) region of EGFR comprises amino acid residues T211-R334 and / or C526-S645 of SEQ ID NO: 1, respectively. In some embodiments, the oncogenic variant of an EGFR generates a physical barrier to formation of a disulfide bond within the CR1 and / or the CR2 region. In some embodiments, the oncogenic variant of an EGFR removes a physical barrier to formation of a disulfide bond within the CR1 and / or the CR2 region. In some embodiments, the oncogenic variant of an EGFR comprises one or more free or unpaired Cysteine (C) residues located at a dimer interface of the EGFR. In some embodiments, the oncogenic variant of an 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 occurs within 10 angstroms or less of an intramolecular disulfide bond 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.

[0629] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of EGFR and the oncogenic variant of EGFR is a mutation of EGFR, a nucleotide sequence encoding the oncogenic variant of an EGFR comprises a deletion or the substitution comprises one or more amino acids that encode an adenosine triphosphate (ATP) binding site. In some embodiments, the ATP binding site comprises amino acids E746 to A750 of SEQ ID NO: 1. In some embodiments, the ATP binding site or the deletion or substitution thereof comprises K858 of SEQ ID NO: 1. In some embodiments, the deletion comprises K858 of SEQ ID NO: 1. In some embodiments, an arginine (R) is substituted for the lysine (K) at position 858 (K858R) of SEQ ID NO: 1.

[0630] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an EGFR and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, a nucleotide sequence encoding the oncogenic variant of an EGFR comprises an insertion within a sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding KEILDEAYVMASVDNPHVCAR (SEQ ID NO: 7). In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding a C-helix, a terminal end of the C-helix or a loop following the C-helix. In some embodiments, the insertion comprises the amino acid sequence of ASV, SVD, NPH, or FQEA. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises one or more of: (a) an insertion of the amino acid sequence ASV between positions V769 and D770 of SEQ ID NO: 1; (b) an insertion of the amino acid sequence SVD between positions D770 and N771 of SEQ ID NO: 1; (c) an insertion of the amino acid sequence NPH between positions H773 and V774 of SEQ ID NO: 1; (d) an insertion of the amino acid sequence FQEA between positions A763 and Y764 of SEQ ID NO: 1; (e) an insertion of the amino acid sequence PH between positions H773 and V774 of SEQ ID NO: 1; (f) an insertion of the amino acid G between positions D770 and N771 of SEQ ID NO: 1; (g) an insertion of the amino acid H between positions H773 and V774 of SEQ ID NO: 1; (h) an insertion of the amino acid sequence HV between positions V774 and C775 of SEQ ID NO: 1; (i) an insertion of the amino acid sequence AH between positions H773 and V774 of SEQ ID NO: 1; (j) an insertion of the amino acid sequence SVA between positions A767 and S768 of SEQ ID NO: 1; (k) a substitution of the amino acid sequence GYN for the DN between positions 770 and 771 of SEQ ID NO: 1; (l) an insertion of the amino acid H between positions N771 and P772 of SEQ ID NO: 1; (m) an insertion of the amino acid Y between positions H773 and V774 of SEQ ID NO: 1; (n) an insertion of the amino acid sequence PHVC between positions C775 and R776 of SEQ ID NO: 1; (o) a substitution of the amino acid sequence YNPY for the H at position 773 of SEQ ID NO: 1; (p) an insertion of the amino acid sequence DNP between positions P772 and H773 of SEQ ID NO: 1; (q) an insertion of the amino acid sequence VDS between positions S768 and V769 of SEQ ID NO: 1; (r) an insertion of the amino acid H between positions D770 and N771 of SEQ ID NO: 1; (s) an insertion of the amino acid N between positions N771 and P772 of SEQ ID NO: 1; (t) an insertion of the amino acid sequence PNP between positions P772 and H773 of SEQ ID NO: 1; (u) a substitution of the amino acid sequence GSVDN for the DN between positions 770 and 771 of SEQ ID NO: 1; (v) a substitution of the amino acid sequence GYP for the NP between positions 771 and 772 of SEQ ID NO: 1; (w) an insertion of the amino acid G between positions N771 and P772 of SEQ ID NO: 1; (x) an insertion of the amino acid sequence GNP between positions P772 and H773 of SEQ ID NO: 1; (y) an insertion of the amino acid sequence GSV between positions V769 and D770 of SEQ ID NO: 1; (z) a substitution of the amino acid sequence GNPHVC for the VC between positions 774 and 775 of SEQ ID NO: 1; (aa) an insertion of the amino acid sequence LQEA between positions A763 and Y764 of SEQ ID NO: 1; (bb) an insertion of the amino acid sequence GL between positions D770 and N771 of SEQ ID NO: 1; (cc) an insertion of the amino acid Y between positions D770 and N771 of SEQ ID NO: 1; (dd) an insertion of the amino acid sequence NPY between positions H773 and V774 of SEQ ID NO: 1; (ee) an insertion of the amino acid sequence TH between positions H773 and V774 of SEQ ID NO: 1; (ff) a substitution of the amino acid sequence KGP for the NP between positions 771 and 772 of SEQ ID NO: 1; (gg) a substitution of the amino acid sequence SVDNP for the NP between positions 771 and 772 of SEQ ID NO: 1; (hh) an insertion of the amino acid sequence NN between positions N771 and P772 of SEQ ID NO: 1; (ii) an insertion of the amino acid T between positions N771 and P772 of SEQ ID NO: 1; and (jj) a substitution of the amino acid sequence STLASV for the SV between positions 768 and 769 of SEQ ID NO: 1.

[0631] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an EGFR and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, the oncogenic variant of an EGFR comprises 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.

[0632] In some embodiments, the cancer, or a tumor or a cell thereof, expresses one or more of: (a) a wild type human epidermal growth factor receptor 2 (HER2) receptor or an oncogenic variant of a HER-2 receptor.

[0633] In some embodiments, the cancer, or a tumor or a cell thereof, expresses a wild type HER-2 receptor, the wild type HER2 receptor comprises the amino acid sequence of SEQ ID NO: 2, 3, 4, 5, or 6.

[0634] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER-2 receptor, the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor.

[0635] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a phenylalanine (F) for a serine (S) at position 310 of SEQ ID NO: 2 or 5.

[0636] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a tyrosine (Y) for a serine (S) at position 310 of SEQ ID NO: 2 or 5.

[0637] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a glutamine (Q) for an arginine (R) at position 678 of SEQ ID NO: 2 or 5.

[0638] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a leucine (L) for a valine (V) at position 777 of SEQ ID NO: 2 or 5.

[0639] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a methionine (M) for a valine (V) at position 777 of SEQ ID NO: 2 or 5.

[0640] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of an isoleucine (I) for a valine (V) at position 842 of SEQ ID NO: 2 or 5.

[0641] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of an alanine (A) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5.

[0642] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a proline (P) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5.

[0643] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a serine (S) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5.

[0644] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, a nucleotide sequence encoding the oncogenic variant of a HER2 receptor comprises an insertion within a sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding KEILDEAYVMAGVGSPYVSR(SEQ ID NO: 8). In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding a C-helix, a terminal end of the C-helix or a loop following the C-helix. In some embodiments, the insertion comprises the amino acid sequence of GSP or YVMA. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises one or more of: (a) an insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (b) an insertion of the amino acid sequence GSP between positions P780 and Y781 of SEQ ID NO: 2; (c) an insertion of the amino acid sequence YVMA between positions A771 and Y772 of SEQ ID NO: 2; (d) an insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (e) an insertion of the amino acid V between positions V777 and G778 of SEQ ID NO: 2; (f) an insertion of the amino acid V between positions V777 and G778 of SEQ ID NO: 2; (g) a substitution of the amino acid sequence AVGCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (h) a substitution of the amino acid sequence LC for the G between position 776 of SEQ ID NO: 2; (i) a substitution of the amino acid sequence LCV for the G between position 776 of SEQ ID NO: 2; (j) an insertion of the amino acid sequence GSP between positions V777 and G778 of SEQ ID NO: 2; (k) a substitution of the amino acid sequence PS for the LRE between positions 755 and 757 of SEQ ID NO: 2; (l) a substitution of the amino acid sequence CPGSP for the SP between positions 779 and 780 of SEQ ID NO: 2; (m) an insertion of the amino acid C between positions V777 and G778 of SEQ ID NO: 2; (n) a substitution of the amino acid sequence VVMA for the AG between positions 775 and 776 of SEQ ID NO: 2; (o) a substitution of the amino acid sequence VV for the G at position 776 of SEQ ID NO: 2; (p) a substitution of the amino acid sequence AVCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (q) a substitution of the amino acid sequence VCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (r) an insertion of the amino acid G between positions G778 and S779 of SEQ ID NO: 2; (s) a substitution of the amino acid sequence PK for the LRE between positions 755 and 757 of SEQ ID NO: 2; (t) an insertion of the amino acid V between positions A775 and G776 of SEQ ID NO: 2; (u) an insertion of the amino acid sequence YAMA between positions A775 and G776 of SEQ ID NO: 2; (v) a substitution of the amino acid sequence CV for the G at position 776 of SEQ ID NO: 2; (w) a substitution of the amino acid sequence AVCGG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (x) a substitution of the amino acid sequence CVCG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (y) a substitution of the amino acid sequence VVVG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (z) a substitution of the amino acid sequence SVGG for the GVGS between positions 776 and 779 of SEQ ID NO: 2; (aa) a substitution of the amino acid sequence VVGES for the GVGS between positions 776 and 779 of SEQ ID NO: 2; (bb) a substitution of the amino acid sequence AVGSGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (cc) a substitution of the amino acid sequence CVC for the GV between positions 776 and 777 of SEQ ID NO: 2; (dd) a substitution of the amino acid sequence HVC for the GV between positions 776 and 777 of SEQ ID NO: 2; (ee) a substitution of the amino acid sequence VAAGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (ff) a substitution of the amino acid sequence VAGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (gg) a substitution of the amino acid sequence VVV for the GV between positions 776 and 777 of SEQ ID NO: 2; (hh) an insertion of the amino acid sequence FPG between positions G778 and S779 of SEQ ID NO: 2; (ii) an insertion of the amino acid sequence GS between positions S779 and P780 of SEQ ID NO: 2; (jj) a substitution of the amino acid sequence VPS for the VLRE between positions 754 and 757 of SEQ ID NO: 2; (kk) an insertion of the amino acid E between positions V777 and G778 of SEQ ID NO: 2; (ll) an insertion of the amino acid sequence MAGV between positions V777 and G778 of SEQ ID NO: 2; (mm) an insertion of the amino acid S between positions V777 and G778 of SEQ ID NO: 2; (nn) an insertion of the amino acid sequence SCV between positions V777 and G778 of SEQ ID NO: 2; and (oo) an insertion of the amino acid sequence LMAY between positions Y772 and V773 of SEQ ID NO: 2.

[0645] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises HER2-Δ16, HER2-C311R, HER2-S310F, p95-HER2-M611 or any combination thereof.

[0646] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a 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 a HER4 receptor comprises deletion of exon 16 (HER4-Δ16).

[0647] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an EGFR, wherein the sequence encoding the oncogenic variant of the EGFR comprises a deletion of exon 20 or a portion thereof and wherein the the cancer, the tumor or the cell thereof does not comprise a second oncogenic variation in a sequence other than exon 20 of EGFR. In some embodiments, the second oncogenic variation comprises a sequence encoding one or more of an EGFR kinase domain (KD), BRAF, NTRK, and KRAS.

[0648] In some embodiments, the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an EGFR, wherein the sequence encoding the oncogenic variant of the EGFR comprises a deletion of exon 20 or a portion thereof and wherein the the cancer, the tumor or the cell thereof does not comprise a marker indicating responsiveness to immunotherapy.

[0649] In some embodiments, the oncogenic variant (e.g., allosteric variant) or the oncogenic mutation (e.g., allosteric mutation) is detiected by a Food and Drug Aministration (FDA)-approved diagnosis.

[0650] In some embodiments, prior to the treatment with the compound of the present disclosure, the subject is treated with a therapeutic agent different from the compound of the present disclosure.

[0651] In some embodiments, the cancer, or a tumor or a cell thereof, is insensitive or resistant to treatment with a therapeutic agent different from the compound of the present disclosure. In some embodiments, the cancer, or a tumor or a cell thereof, is insensitive or resistant to treatment with a Type I inhibitor. In some embodiments, the cancer, or a tumor or a cell thereof, is insensitive or resistant to treatment with one or more of gefinitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686 and AZD9291.

[0652] 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 gefinitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686 and AZD9291. In some embodiments, the adverse reaction is an activation of the oncogenic variant of an EGFR and wherein the oncogenic variant comprises a mutation in an extracellular domain of the receptor. In some embodiments, the adverse reaction is an activation of the oncogenic variant of a HER-2 Receptor and wherein the oncogenic variant comprises a mutation in an extracellular domain of the receptor.

[0653] In some embodiments, the method further comprises administering to the 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.

[0654] In some embodiments, the method further comprises administering to the 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.

[0655] 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.

[0656] 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.

[0657] In some embodiments, the therapeutically effective amount reduces a severity of a sign or symptom of the cancer.

[0658] In some embodiments, the sign of the cancer comprises a tumor grade and wherein a reduction of the severity of the sign comprises a decrease of the tumor grade.

[0659] In some embodiments, the sign of the cancer comprises a tumor metastasis and wherein a reduction of the severity of the sign comprises an elimination of the metastasis or a reduction in the rate or extent the metastasis.

[0660] In some embodiments, the sign of the cancer comprises a tumor volume and wherein a reduction of the severity of the sign comprises an elimination of the tumor or a reduction in the volume.

[0661] In some embodiments, the symptom of the cancer comprises pain and wherein a reduction of the severity of the sign comprises an elimination or a reduction in the pain.

[0662] In some embodiments, the therapeutically effective amount induces a period of remission.

[0663] In some embodiments, the therapeutically effective amount improves a prognosis of the subject.

[0664] Such a use (or method of prevention or treatment) of a subject comprises administering to a subject in need of such prevention or treatment a therapeutically effective amount of a compound of the disclosure or pharmaceutically acceptable salts thereof or a pharmaceutical composition thereof by targeting allosteric and / or oncogenic variants of EGFR and HER-2 receptor.

[0665] The present disclosure contemplates administration of a compound of the disclosure alone or in combination with one or more additional therapeutic agents, such as other Tyrosine kinase inhibitors: Erlotinib hydrochloride (e.g. Tarceva(R) by Genentech / Roche), Linifanib (or ABT 869, by Genentech), sunitinib malate (e.g. Sutent(R) by Pfizer), bosutinib (or SKI-606, described in US 6,780,996 ), dasatinib (e.g. Sprycel(R) by Bristol-Myers Squibb), armala (e.g. pazopanib, e.g. Votrient(R) by GlaxoSmithKline), imatinib and imatinib mesylate (e.g. Gilvec(R) and Gleevec(R) by Novartis); Vascular Endothelial Growth Factor (VEG) receptor inhibitors (Bevacizumab, or Avastin(R) by Genentech / Roche), axitinib, (or AG013736, described in WO 01 / 002369), Brivanib Alaninate (or BMS-582664), motesanib (or AMG-706, described in PCT WO 02 / 066470), pasireotide (e.g. SOM230, described in WO 02 / 010192), sorafenib (e.g. Nexavar(R)); HER2 receptor inhibitors: Trastuzumab (e.g. Herceptin(R) by Genentech / Roche), neratinib (or HKI-272, described WO 05 / 028443), lapatinib or lapatinib ditosylate (e.g. Tykerb(R) by GlaxoSmithKline); CD20 antibodies: Rituximab (e.g. Riuxan(R) and MabThera(R) by Genentech / Roche), tositumomab (e.g. Bexxar(R) by GlaxoSmithKline), ofatumumab (e.g. Arzerra(R) by GlaxoSmithKline); Bcr / Abl kinase inhibitors: nilotinib hydrochloride (e.g. Tasigna(R) by Novartis); DNA Synthesis inhibitors: Capecitabine (e.g. Xeloda(R) by Roche), gemcitabine hydrochloride (e.g. Gemzar(R) by Eli Lilly and Company), nelarabine (or Arranon(R) and Atriance(R) by GlaxoSmithKline); Antineoplastic agents: oxaliplatin (e.g. Eloxatin(R) ay Sanofi-Aventis described in US 4,169,846 ); Epidermal growth factor receptor (EGFR) inhibitors: Gefitinib (or Iressa(R)), Afatinib (or Tovok(R) by Boehringer Ingelheim), cetuximab (e.g. Erbitux(R) by Bristol-Myers Squibb), panitumumab (e.g. Vectibix(R) by Amgen); HER dimerization inhibitors: Pertuzumab (e.g. Omnitarg(R), by Genentech); Human Granulocyte colony-stimulatingfactor (G-CSF) modulators: Filgrastim (e.g. Neupogen(R) by Amgen); Immunomodulators: Afutuzumab (by Roche(R)), pegfilgrastim (e.g. Neulasta(R) by Amgen), lenalidomide (e.g. CC-5013, e.g. Revlimid(R)), thalidomide (e.g. Thalomid(R)); (m) CD40 inhibitors: Dacetuzumab (e.g. SGN-40 or huS2C6, by Seattle Genetics, Inc); Pro-apoptotic receptor agonists (PARAs): Dulanermin (e.g. AMG-951, by Amgen / Genentech); Hedgehog antagonists: Vismodegib (or GDC-0449, described in WO 06 / 028958); PI3K inhibitors: Pictilisib (or GDC-0941 described in WO 09 / 036082 and WO 09 / 055730 ), Dactolisib (orBEZ 235 or NVP-BEZ 235, described in WO 06 / 122806); Phospholipase A2 inhibitors: Anagrelide (e.g. Agrylin(R)); BCL-2 inhibitors: Navitoclax (or ABT-263, described in WO 09 / 155386); Mitogen-activated protein kinase kinase (MEK) inhibitors: XL-518 (Cas No. 1029872-29-4, by ACC Corp.); Aromatase inhibitors: Exemestane (e.g. Aromasin(R) by Pfizer), letrozole (e.g. Femara(R) by Novartis), anastrozole (e.g. Arimidex(R)); Topoisomerase I inhibitors: Irinotecan (e.g. Camptosar(R) by Pfizer), topotecan hydrochloride (e.g. Hycamtin(R) by GlaxoSmithKline); Topoisomerase II inhibitors: etoposide (e.g. VP-16 and Etoposide phosphate, e.g. Toposar(R), VePesid(R) and Etopophos(R)), teniposide (e.g. VM-26, e.g. Vumon(R)); mTOR inhibitors: Temsirolimus (e.g. Torisel(R) by Pfizer), ridaforolimus (formally known as deferolimus, (or AP23573 and MK8669, described in WO 03 / 064383), everolimus (e.g. Afinitor(R) by Novartis); Osteoclastic bone resorption inhibitors: zoledronic acid (or Zometa(R) by Novartis); CD33 Antibody Drug Conjugates: Gemtuzumab ozogamicin (e.g. Mylotarg(R) by Pfizer / Wyeth); CD22 Antibody Drug Conjugates: Inotuzumab ozogamicin (also referred to as CMC-544 and WAY-207294, by Hangzhou Sage Chemical Co., Ltd.); CD20 Antibody Drug Conjugates: Ibritumomab tiuxetan (e.g. Zevalin(R)); Somatostain analogs: octreotide (e.g. octreotide acetate, e.g. Sandostatin(R) and Sandostatin LAR(R)); Synthetic Interleukin-11 (IL-11): oprelvekin (e.g. Neumega(R) by Pfizer / Wyeth); Synthetic erythropoietin: Darbepoetin alfa (e.g. Aranesp(R) by Amgen); Receptor Activator for Nuclear Factor kappa B (RANK) inhibitors: Denosumab (e.g. Prolia(R) by Amgen); Thrombopoietin mimetic peptibodies: Romiplostim (e.g. Nplate(R) by Amgen; Cell growth stimulators: Palifermin (e.g. Kepivance(R) by Amgen); Anti-Insulin-like Growth Factor-1 receptor (IGF-1R) antibodies: Figitumumab (e.g. CP-751,871, by ACC Corp), robatumumab (CAS No. 934235-44-6); Anti-CS1 antibodies: Elotuzumab (HuLuc63, CAS No. 915296-00-3); CD52 antibodies: Alemtuzumab (e.g. Campath(R)); CTLA-4 inhibitors: Tremelimumab (IgG2 monoclonal antibody by Pfizer, formerly known as ticilimumab, CP-675,206), ipilimumab (CTLA-4 antibody, e.g. MDX-010, CAS No. 477202-00-9); Histone deacetylase inhibitors (HDI): Voninostat (e.g. Zolinza(R) by Merck); Alkylating agents: Temozolomide (e.g. Temodar(R) and Temodal(R) by Schering-Plough / Merck), dactinomycin (e.g. actinomycin-D and e.g. Cosmegen(R)), melphalan (e.g. L-PAM, L-sarcolysin, and phenylalanine mustard, e.g. Alkeran(R)), altretamine (e.g. hexamethylmelamine (HMM), e.g. Hexalen(R)), carmustine (e.g. BiCNU(R)), bendamustine (e.g. Treanda(R)), busulfan (e.g. Busulfex(R) and Myleran(R)), carboplatin (e.g. Paraplatin(R)), lomustine (e.g. CCNU, e.g. CeeNU(R)), cisplatin (e.g. CDDP, e.g. Platinol(R) and Platinol(R)-AQ), chlorambucil (e.g. Leukeran(R)), cyclophosphamide (e.g. Cytoxan(R) and Neosar(R)), dacarbazine (e.g. DTIC, DIC and imidazole carboxamide, e.g. DTIC-Dome(R)), altretamine (e.g. hexamethylmelamine (HMM) e.g. Hexalen(R)), ifosfamide (e.g. Ifex(R)), procarbazine (e.g. Matulane(R)), mechlorethamine (e.g. nitrogen mustard, mustine and mechloroethamine hydrochloride, e.g. Mustargen(R)), streptozocin (e.g. Zanosar(R)), thiotepa (e.g. thiophosphoamide, TESPA and TSPA, e.g. Thioplex(R); Biologic response modifiers: bacillus calmette-guerin (e.g. theraCys(R) and TICE(R) BCG), denileukin diftitox (e.g. Ontak(R)); Anti-tumor antibiotics: doxorubicin (e.g. Adriamycin(R) and Rubex(R)), bleomycin (e.g. lenoxane(R)), daunorubicin (e.g. dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, e.g. Cerubidine(R)), daunorubicin liposomal (daunorubicin citrate liposome, e.g. DaunoXome(R)), mitoxantrone (e.g. DHAD, e.g. Novantrone(R)), epirubicin (e.g. Ellence ™< ), idarubicin (e.g. Idamycin(R), Idamycin PFS(R)), mitomycin C (e.g. Mutamycin(R)); Anti-microtubule agents: Estramustine (e.g. Emcyl(R)); Cathepsin K inhibitors: Odanacatib (or MK-0822, by Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, described in WO 03 / 075836); Epothilone B analogs: Ixabepilone (e.g. Lxempra(R) by Bristol-Myers Squibb); Heat Shock Protein (HSP) inhibitors: Tanespimycin (17-allylamino-17-demethoxygeldanamycin, e.g. KOS-953 and 17-AAG, by SIGMA, described in US 4,261,989); TpoR agonists: Eltrombopag (e.g. Promacta(R) and Revolade(R) by GlaxoSmithKline); Anti-mitotic agents: Docetaxel (e.g. Taxotere(R) by Sanofi-Aventis); Adrenal steroid inhibitors: aminoglutethimide (e.g. Cytadren(R)); Anti-androgens: Nilutamide (e.g. Nilandron(R) and Anandron(R)), bicalutamide (sold under tradename Casodex(R)), flutamide (e.g. Fulexin ™< ); Androgens: Fluoxymesterone (e.g. halotestin(R)); Proteasome inhibitors: Bortezomib (e.g. Velcade(R)); CDK1 inhibitors: Alvocidib (e.g. flovopirdol or HMR-1275, described in US 5,621,002); Gonadotropin-releasing hormone (GnRH) receptor agonists: Leuprolide or leuprolide acetate (e.g. Viadure(R) by Bayer AG, Eligard(R) by Sanofi-Aventis and Lupron(R) by Abbott Lab); Taxane anti-neoplastic agents: Cabazitaxel, larotaxel; 5HT1a receptor agonists: Xaliproden (or SR57746, described in US 5,266,573); HPC vaccines: Cervarix(R) sold by GlaxoSmithKline, Gardasil(R) sold by Merck; Iron Chelating agents: Deferasinox (e.g. Exjade(R) by Novartis); Antimetabolites: Claribine (2-chlorodeoxyadenosine, e.g. leustatin(R)), 5-fluorouracil (e.g. Adrucil(R)), 6-thioguanine (e.g. Purinethol(R)), pemetrexed (e.g. Alimta(R)), cytarabine (e.g. arabinosylcytosine (Ara-C), e.g. Cytosar-U(R)), cytarabine liposomal (e.g. Liposomal Ara-C, e.g. DepoCyt ™< ), decitabine (e.g. Dacogen(R)), hydroxyurea (e.g. Hydrea(R), Droxia ™< and Mylocel ™< ), fludarabine (e.g. Fludara(R)), floxuridine (e.g. FUDR(R)), cladribine (e.g. 2-chlorodeoxyadenosine (2-CdA) e.g. Leustatin ™< ), methotrexate (e.g. amethopterin, methotrexate sodim (MTX), e.g. Rheumatrex(R) and Trexall ™< ), pentostatin (e.g. Nipent(R)); Bisphosphonates: Pamidronate (e.g. Aredia(R)), zoledronic acid (e.g. Zometa(R)); Demethylating agents: 5-azacitidine (e.g. Vidaza(R)), decitabine (e.g. Dacogen(R)); Plant Alkaloids: Paclitaxel protein-bound (e.g. Abraxane(R)), vinblastine (e.g. vinblastine sulfate, vincaleukoblastine and VLB, e.g. Alkaban-AQ(R) and Velban(R)), vincristine (e.g. vincristine sulfate, LCR, and VCR, e.g. Oncovin(R) and Vincasar Pfs(R)), vinorelbine (e.g. Navelbine(R)), paclitaxel (e.g. Taxol and Onxal ™< ); Retinoids: Alitretinoin (e.g. Panretin(R)), tretinoin (all-trans retinoic acid, e.g. ATRA, e.g. Vesanoid(R)), Isotretinoin (13-cis-retinoic acid, e.g. Accutane(R), Amnesteem(R), Claravis(R), Clarus(R), Decutan(R), Isotane(R), Izotech(R), Oratane(R), Isotret(R), and Sotret(R)), bexarotene (e.g. Targretin(R)); Glucocorticosteroids: Hydrocortisone (e.g. cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and e.g. Ala-Cort(R), Hydrocortisone Phosphate, Solu-Cortef(R), Hydrocort Acetate(R) and Lanacort(R)), dexamethasone, prednisolone (e.g. Delta-Cortel(R), Orapred(R), Pediapred(R) and Prelone(R)), prednisone (e.g. Deltasone(R), Liquid Red(R), Meticorten(R) and Orasone(R)), methylprednisolone (e.g. 6-Methylprednisolone, Methylprednisolone Acetate, Methylprednisolone Sodium Succinate, e.g. Duralone(R), Medralone(R), Medrol(R), M-Prednisol(R) and Solu-Medrol(R)); Cytokines: interleukin-2 (e.g. aldesleukin and IL-2, e.g. Proleukin(R)), interleukin-11 (e.g. oprevelkin, e.g. Neumega(R)), alpha interferon alfa (e.g. IFN-alpha, e.g. Intron(R) A, and Roferon-A(R)); Lutinizing hormone releasing hormone (LHRH) agonists: Goserelin (e.g. Zoladex(R)); Progesterones: megestrol (e.g. megestrol acetate, e.g. Megace(R)); Miscellaneous cytotoxic agents: Arsenic trioxide (e.g. Trisenox(R)), asparaginase (e.g. L-asparaginase, Erwinia L-asparaginase, e.g. Elspar(R) and Kidrolase(R)); Anti-nausea drugs: NK-1 receptor antagonists: Casopitant (e.g. Rezonic(R) and Zunrisa(R) by GlaxoSmithKline); and Cytoprotective agents: Amifostine (e.g. Ethyol(R)), leucovorin (e.g. calcium leucovorin, citrovorum factor and folinic acid).Exemplary Embodiments

[0666] Embodiment No. 1: 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 Z< independently is halogen, CN, -OH, -NH 2 , -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), - N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C 1 -C 6 alkyl), - NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Za< ; each R Za< independently is halogen, CN, -OH, -NH 2 , -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), - N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is halogen, CN, -OH, -NH 2 , -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), - N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C 1 -C 6 alkyl), - NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Ta< ; each R Ta< independently is 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 C 6 -C 10 aryl optionally substituted with one or more R A1< ; each R A1< independently is 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; wherein the -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R A1a< ; and each R A1a< independently is halogen, CN, -OH, -NH 2 , -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C 1 -C 6 alkyl), - NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R A1b< ; and each R A1b< independently is halogen, CN, -OH, or -NH 2 .

[0667] Embodiment No. 2: The compound of any one of the preceding Embodiments, wherein the compound is 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 Z< independently is 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; wherein the -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3or 5- to 10-membered heteroaryl is optionally substituted with one or more R Za< ; each R Za< independently is halogen, CN, -OH, -NH 2 , -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), - N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is 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; wherein the -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 is optionally substituted with one or more R Ta< ; each R Ta< independently is halogen, CN, -OH, -NH 2 , -C(=O)OH, -O-(C 1 -C 6 alkylC 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 C 6 -C 10 aryl optionally substituted with one or more R A1< ; each R A1< independently is 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; wherein the -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R A1a< ; and each R A1a< independently is 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; wherein the -O-(C 1 -C 6 alkyl), - NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R A1b< ; and each R A1b< independently is halogen, CN, -OH, or -NH 2 ; provided that when Z is then Ar 1< is C 6 -C 10 aryl optionally substituted with one or more halogen.

[0668] Embodiment No. 3: The compound of any one of the preceding Embodiments, wherein the compound is 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 Z< independently is 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; wherein the -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3or 5- to 10-membered heteroaryl is optionally substituted with one or more R Za< ; each R Za< independently is halogen, CN, -OH, -NH 2 , -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), - N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is 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 monocyclic heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the -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 monocyclic heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Ta< ; each R Ta< independently is halogen, CN, -OH, -NH 2 , -C(=O)OH, -O-(C 1 -C 6 alkylC 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 C 6 -C 10 aryl optionally substituted with one or more R A1< ; each R A1< independently is 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; wherein the -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R A1a< ; and each R A1a< independently is 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; wherein the -O-(C 1 -C 6 alkyl), - NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R A1b< ; and each R A1b< independently is halogen, CN, -OH, or -NH 2 ; provided that when Z is then Ar 1< is C 6 -C 10 aryl optionally substituted with one or more halogen.

[0669] Embodiment No. 4: The compound of any one of the preceding Embodiments, wherein the compound is 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< ; each R Z< independently is halogen, -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, or 3- to 10-membered heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogen; T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 7-membered heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH; Ar 1< is C 6 -C 10 aryl optionally substituted with one or more R A1< ; each R A1< independently is halogen, -OR A1a< , or -O-(C 1 -C 6 alkyl) optionally substituted with one or more R A1a< ; and each R A1a< independently is C 6 -C 10 aryl or 5- to 10-membered heteroaryl; wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen.

[0670] Embodiment No. 5: The compound of any one of the preceding Embodiments, wherein the compound is 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< ; each R Z< independently is halogen, -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, or 3- to 10-membered heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogen; T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 7-membered monocyclic heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH; Ar 1< is C 6 -C 10 aryl optionally substituted with one or more R A1< ; each R A1< independently is halogen, -OR A1a< , or -O-(C 1 -C 6 alkyl) optionally substituted with one or more R A1a< ; and each R A1a< independently is C 6 -C 10 aryl or 5- to 10-membered heteroaryl; wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen.

[0671] Embodiment No. 6: The compound of any one of the preceding Embodiments, wherein the compound is 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< ; each R Z< independently is halogen, -O-(C 1 -C 6 alkyl), or C 1 -C 6 alkyl; wherein the -O-(C 1 -C 6 alkyl) or C 1 -C 6 alkyl is optionally substituted with one or more halogen; T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), or 3- to 7-membered heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH; Ar 1< is C 6 -C 10 aryl optionally substituted with one or more R A1< ; each R A1< independently is halogen, -OR A1a< , or -O-(C 1 -C 6 alkyl) optionally substituted with one or more R A1a< ; and each R A1a< independently is C 6 -C 10 aryl or 5- to 10-membered heteroaryl; wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen; provided that when Z is then Ar 1< is C 6 -C 10 aryl optionally substituted with one or more halogen.

[0672] Embodiment No. 7: The compound of any one of the preceding Embodiments, wherein the compound is 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< ; each R Z< independently is halogen, -O-(C 1 -C 6 alkyl), or C 1 -C 6 alkyl; wherein the -O-(C 1 -C 6 alkyl) or C 1 -C 6 alkyl is optionally substituted with one or more halogen; T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), or 3- to 7-membered monocyclic heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH; Ar 1< is C 6 -C 10 aryl optionally substituted with one or more R A1< ; each R A1< independently is halogen, -OR A1a< , or -O-(C 1 -C 6 alkyl) optionally substituted with one or more R A1a< ; and each R A1a< independently is C 6 -C 10 aryl or 5- to 10-membered heteroaryl; wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen; provided that when Z is then Ar 1< is C 6 -C 10 aryl optionally substituted with one or more halogen.

[0673] Embodiment No. 8: The compound of any one of the preceding Embodiments, wherein the compound is 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< ; each R Z< independently is halogen, -O-(C 1 -C 6 alkyl), or C 1 -C 6 alkyl; wherein the -O-(C 1 -C 6 alkyl) or C 1 -C 6 alkyl is optionally substituted with one or more halogen; T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), or 3- to 7-membered heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH; Ar 1< is C 6 -C 10 aryl optionally substituted with one or more halogen.

[0674] Embodiment No. 9: The compound of any one of the preceding Embodiments, wherein the compound is 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< ; each R Z< independently is halogen, -O-(C 1 -C 6 alkyl), or C 1 -C 6 alkyl; wherein the -O-(C 1 -C 6 alkyl) or C 1 -C 6 alkyl is optionally substituted with one or more halogen; T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), or 3- to 7-membered monocyclic heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH; Ar 1< is C 6 -C 10 aryl optionally substituted with one or more halogen.

[0675] Embodiment No.10: The compound of any one of the preceding Embodiments, wherein the compound is 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 C 1 -C 6 alkyl; T is C 2 -C 6 alkenyl optionally substituted with one or more 6-membered heterocycloalkyl; and Ar 1< is C 6 aryl optionally substituted with one or more halogen.

[0676] Embodiment No. 11: The compound of any one of the preceding Embodiments, wherein the compound is 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 C 1 -C 6 alkyl; T is C 2 -C 6 alkenyl optionally substituted with one or more 6-membered monocyclic heterocycloalkyl; and Ar 1< is C 6 aryl optionally substituted with one or more halogen.

[0677] Embodiment No. 12: The compound of any one of the preceding Embodiments, wherein W is CH.

[0678] Embodiment No. 13: The compound of any one of the preceding Embodiments, wherein W is N.

[0679] Embodiment No. 14: The compound of any one of the preceding Embodiments, wherein Z is 3- to 12-membered heterocycloalkyl optionally substituted with one or more R Z< ; and each R Z< independently is halogen, -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, or 3- to 10-membered heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogen.

[0680] Embodiment No. 15: The compound of any one of the preceding Embodiments, wherein Z is oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexanyl,3-azabicyclo[3.1.0]hexanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-5-azaspiro[3.4]octanyl, wherein 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 optionally substituted with one or more R Z< .

[0681] Embodiment No. 16: The compound of any one of the preceding Embodiments, wherein Z is oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexanyl,3-azabicyclo[3.1.0]hexanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-5-azaspiro[3.4]octanyl, wherein 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 optionally substituted with one or more R Z< .

[0682] Embodiment No. 17: The compound of any one of the preceding Embodiments, wherein Z is or

[0683] Embodiment No. 18: The compound of any one of the preceding Embodiments, wherein Z is

[0684] Embodiment No. 19: The compound of any one of the preceding Embodiments, wherein at least one R Z< is halogen.

[0685] Embodiment No. 20: The compound of any one of the preceding Embodiments, wherein at least one R Z< is F or Cl.

[0686] Embodiment No. 21: The compound of any one of the preceding Embodiments, wherein at least one R Z< is CN, -OH, or -NH 2 .

[0687] Embodiment No. 22: The compound of any one of the preceding Embodiments, wherein at least one R Z< is -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Za< .

[0688] Embodiment No. 23: The compound of any one of the preceding Embodiments, wherein at least one R Z< is -O-(C 1 -C 6 alkyl) optionally substituted with one or more R Za< .

[0689] Embodiment No. 24: The compound of any one of the preceding Embodiments, wherein at least one R Z< is -OCH 3 .

[0690] Embodiment No. 25: The compound of any one of the preceding Embodiments, wherein at least one R Z< is -O-(C 1 -C 6 alkyl) substituted with one or more halogen.

[0691] Embodiment No. 26: The compound of any one of the preceding Embodiments, wherein at least one R Z< is C 1 -C 6 alkyl.

[0692] Embodiment No. 27: The compound of any one of the preceding Embodiments, wherein at least one R Z< is methyl, ethyl, or propyl.

[0693] Embodiment No. 28: The compound of any one of the preceding Embodiments, wherein at least one R Z< is C 1 -C 6 alkyl substituted with one or more halogen.

[0694] Embodiment No. 29: The compound of any one of the preceding Embodiments, wherein at least one R Z< is CF 3 .

[0695] Embodiment No. 30: The compound of any one of the preceding Embodiments, wherein at least one R Z< is C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Za< .

[0696] Embodiment No. 31: The compound of any one of the preceding Embodiments, wherein at least one R Z< is 3- to 10-membered heterocycloalkyl optionally substituted with one or more R Za< .

[0697] Embodiment No. 32: The compound of any one of the preceding Embodiments, wherein at least one R Z< is 4-membered heterocycloalkyl optionally substituted with one or more R Za< .

[0698] Embodiment No. 33: The compound of any one of the preceding Embodiments, wherein at least one R Z< is oxetanyl.

[0699] Embodiment No. 34: The compound of any one of the preceding Embodiments, wherein at least one R Za< is halogen.

[0700] Embodiment No. 35: The compound of any one of the preceding Embodiments, wherein at least one R Za< is F or Cl.

[0701] Embodiment No. 36: The compound of any one of the preceding Embodiments, wherein at least one R Za< is 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.

[0702] Embodiment No. 37: The compound of any one of the preceding Embodiments, wherein T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is 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; wherein the -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 is optionally substituted with one or more R Ta< ; and each R Ta< independently is 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.

[0703] Embodiment No. 38: The compound of any one of the preceding Embodiments, wherein T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; each R T< independently is 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 monocyclic heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the -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 monocyclic heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Ta< ; and each R Ta< independently is 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.

[0704] Embodiment No. 39: The compound of any one of the preceding Embodiments, wherein T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; and each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 7-membered heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0705] Embodiment No. 40: The compound of any one of the preceding Embodiments, wherein T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; and each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 7-membered monocyclic heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH. Embodiment No. 41: The compound of any one of the preceding Embodiments, wherein T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; and each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), or 3- to 7-membered heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0706] Embodiment No. 42: The compound of any one of the preceding Embodiments, wherein T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; and each R T< independently is halogen, -OH, -O-(C 1 -C 6 alkyl), or 3- to 7-membered monocyclic heterocycloalkyl; wherein the -O-(C 1 -C 6 alkyl), or 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0707] Embodiment No. 43: The compound of any one of the preceding Embodiments, wherein T is -O-(C 1 -C 6 alkyl) optionally substituted with one or more R T< .

[0708] Embodiment No. 44: The compound of any one of the preceding Embodiments, wherein T is -OCH 3 .

[0709] Embodiment No. 45: The compound of any one of the preceding Embodiments, wherein T is -NH-(C 1 -C 6 alkyl) optionally substituted with one or more R T< .

[0710] Embodiment No. 46: The compound of any one of the preceding Embodiments, wherein T is -NHCH 3 .

[0711] Embodiment No. 47: The compound of any one of the preceding Embodiments, wherein T is C 1 -C 6 alkyl optionally substituted with one or more R T< .

[0712] Embodiment No. 48: The compound of any one of the preceding Embodiments, wherein T is C 1 -C 6 alkyl.

[0713] Embodiment No. 49: The compound of any one of the preceding Embodiments, wherein T is methyl or ethyl.

[0714] Embodiment No. 50: The compound of any one of the preceding Embodiments, wherein T is C 1 -C 6 alkyl substituted with one or more halogen.

[0715] Embodiment No. 51: The compound of any one of the preceding Embodiments, wherein T is -CHFCl.

[0716] Embodiment No. 52: The compound of any one of the preceding Embodiments, wherein T is C 2 -C 6 alkenyl optionally substituted with one or more R T< .

[0717] Embodiment No. 53: The compound of any one of the preceding Embodiments, wherein T is C 2 -C 6 alkenyl.

[0718] Embodiment No. 54: The compound of any one of the preceding Embodiments, wherein T is ethenyl.

[0719] Embodiment No. 55: The compound of any one of the preceding Embodiments, wherein T is propenyl.

[0720] Embodiment No. 56: The compound of any one of the preceding Embodiments, wherein T is pentenyl.

[0721] Embodiment No. 57: The compound of any one of the preceding Embodiments, wherein T is C 2 -C 6 alkenyl substituted with one or more R T< .

[0722] Embodiment No. 58: The compound of any one of the preceding Embodiments, wherein T is C 2 -C 6 alkenyl substituted with one or more -OH, -O-(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or 3- to 10-membered heterocycloalkyl; wherein the 3- to 10-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0723] Embodiment No. 59: The compound of any one of the preceding Embodiments, wherein T is C 2 -C 6 alkynyl.

[0724] Embodiment No. 60: The compound of any one of the preceding Embodiments, wherein T is propynyl.

[0725] Embodiment No. 61: The compound of any one of the preceding Embodiments, wherein T is C 2 -C 6 alkynyl substituted with one or more R T< .

[0726] Embodiment No. 62: The compound of any one of the preceding Embodiments, wherein T is propynyl substituted with one or more R T< .

[0727] Embodiment No. 63: The compound of any one of the preceding Embodiments, wherein T is propynyl substituted with one or more 3- to 10-membered heterocycloalkyl .

[0728] Embodiment No. 64: The compound of any one of the preceding Embodiments, wherein T is or

[0729] Embodiment No. 65: The compound of any one of the preceding Embodiments, wherein T is

[0730] Embodiment No. 66: The compound of any one of the preceding Embodiments, wherein at least one R T< is halogen.

[0731] Embodiment No. 67: The compound of any one of the preceding Embodiments, wherein at least one R T< is CN, -OH, or -NH 2 .

[0732] Embodiment No. 68: The compound of any one of the preceding Embodiments, wherein at least one R T< is -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 ; wherein the O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 is optionally substituted with one or more R Ta< .

[0733] Embodiment No. 69: The compound of any one of the preceding Embodiments, wherein at least one R T< is -O-(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 .

[0734] Embodiment No. 70: The compound of any one of the preceding Embodiments, wherein at least one R T< is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R Ta< .

[0735] Embodiment No. 71: The compound of any one of the preceding Embodiments, wherein at least one R T< is C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Ta< .

[0736] Embodiment No. 72: The compound of any one of the preceding Embodiments, wherein at least one R T< is 3- to 10-membered heterocycloalkyl substituted with one or more C(=O)OH.

[0737] Embodiment No. 73: The compound of any one of the preceding Embodiments, wherein at least one R Ta< is C(=O)OH.

[0738] Embodiment No. 74: The compound of any one of the preceding Embodiments, wherein at least one R Ta< is 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.

[0739] Embodiment No. 75: The compound of any one of the preceding Embodiments, wherein Ar 1< is C 6 -C 10 aryl optionally substituted with one or more R A1< ; each R A1< independently is 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; wherein the -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R A1a< ; each R A1a< independently is 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; wherein the -O-(C 1 -C 6 alkyl), - NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R A1b< ; and each R A1b< independently is halogen, CN, -OH, or -NH 2 .

[0740] Embodiment No. 76: The compound of any one of the preceding Embodiments, wherein Ar 1< is C 6 -C 10 aryl,

[0741] Embodiment No. 77: The compound of any one of the preceding Embodiments, wherein Ar 1< is C 6 -C 10 aryl substituted with one or more R A1<

[0742] Embodiment No. 78: The compound of any one of the preceding Embodiments, wherein Ar 1< is phenyl substituted with one or more halogen, -OR A1a< , or -O-(C 1 -C 6 alkyl); wherein the -O-(C 1 -C 6 alkyl) is optionally substituted with one or more R A1a< ; and each R A1a< independently is C 6 -C 10 aryl or 5- to 10-membered heteroaryl; wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen.

[0743] Embodiment No. 79: The compound of any one of the preceding Embodiments, wherein Ar 1< is phenyl substituted with one or more halogen

[0744] Embodiment No. 80: The compound of any one of the preceding Embodiments, wherein Ar 1< is phenyl substituted with one F and one Cl.

[0745] Embodiment No. 81: The compound of any one of the preceding Embodiments, wherein Ar 1< is phenyl optionally substituted with one or more halogen, wherein the phenyl is further substituted with -O-(C 6 -C 10 aryl) or -O-(5- to 10-membered heteroaryl); wherein the -O-(C 6 -C 10 aryl) or -O-(5- to 10-membered heteroaryl) is optionally substituted with one or more halogen.

[0746] Embodiment No. 82: The compound of any one of the preceding Embodiments, wherein Ar 1< is phenyl optionally substituted with one or more halogen, wherein the phenyl is further substituted with -O-phenyl or -O-pyridinyl; wherein the -O-phenyl or -O-pyridinyl is optionally substituted with one or more halogen.

[0747] Embodiment No. 83: The compound of any one of the preceding Embodiments, wherein Ar 1< is

[0748] Embodiment No. 84: The compound of any one of the preceding Embodiments, wherein Ar 1< is

[0749] Embodiment No. 85: The compound of any one of the preceding Embodiments, wherein Ar 1< is

[0750] Embodiment No. 86: The compound of any one of the preceding Embodiments, wherein Ar 1< is

[0751] Embodiment No. 87: The compound of any one of the preceding Embodiments, wherein at least one R A1< is halogen.

[0752] Embodiment No. 88: The compound of any one of the preceding Embodiments, wherein at least one R A1< is F, and at least one R A1< is Cl.

[0753] Embodiment No. 89: The compound of any one of the preceding Embodiments, wherein at least one R A1< is CN, -OH, or -NH 2 .

[0754] Embodiment No. 90: The compound of any one of the preceding Embodiments, wherein at least one R A1< is -OR A1a< .

[0755] Embodiment No. 91: The compound of any one of the preceding Embodiments, wherein at least one R A1< is -O-(C 6 -C 10 aryl) or -O-(5- to 10-membered heteroaryl); wherein the -O-(C 6 -C 10 aryl) or -O-(5- to 10-membered heteroaryl) is optionally substituted with one or more R A1b< .

[0756] Embodiment No. 92: The compound of any one of the preceding Embodiments, wherein at least one R A1< is -O-(C 6 -C 10 aryl) or -O-(5- to 10-membered heteroaryl); wherein the -O-(C 6 -C 10 aryl) or -O-(5- to 10-membered heteroaryl) is optionally substituted with one or more halogen.

[0757] Embodiment No. 93: The compound of any one of the preceding Embodiments, wherein at least one R A1< is -O-phenyl or -O-pyridinyl; wherein the -O-phenyl or -O-pyridinyl is optionally substituted with one or more halogen.

[0758] Embodiment No. 94: The compound of any one of the preceding Embodiments, wherein at least one R A1< is -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, wherein the -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R A1a<

[0759] Embodiment No. 95: The compound of any one of the preceding Embodiments, wherein at least one R A1< is -O-(C 1 -C 6 alkyl) substituted with one or more C 6 -C 10 aryl or 5- to 10-membered heteroaryl, wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen.

[0760] Embodiment No. 96: The compound of any one of the preceding Embodiments, wherein at least one R A1< is -O-CH 2 -(C 6 -C 10 aryl) or -O-CH 2 -(5- to 10-membered heteroaryl), wherein the-O-CH 2 -(C 6 -C 10 aryl) or -O-CH 2 -(5- to 10-membered heteroaryl) is optionally substituted with one or more halogen.

[0761] Embodiment No. 97: The compound of any one of the preceding Embodiments, wherein at least one R A1< is -O-CH 2 -phenyl or -O-CH 2 -pyridinyl, wherein the -O-CH 2 -phenyl or -O-CH 2 -pyridinyl is optionally substituted with one or more halogen.

[0762] Embodiment No. 98: The compound of any one of the preceding Embodiments, wherein at least one R A1< is C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R A1a< .

[0763] Embodiment No. 99: The compound of any one of the preceding Embodiments, wherein at least one R A1a< is 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, wherein the -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), - N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R A1b< .

[0764] Embodiment No. 100: The compound of any one of the preceding Embodiments, wherein at least one R A1a< is C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R A1b< .

[0765] Embodiment No. 101: The compound of any one of the preceding Embodiments, wherein at least one R A1a< is C 6 -C 10 aryl or 5- to 10-membered heteroaryl; wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen.

[0766] Embodiment No. 102: The compound of any one of the preceding Embodiments, wherein at least one R A1a< is phenyl or pyridinyl; wherein the phenyl or pyridinyl is optionally substituted with one or more halogen.

[0767] Embodiment No. 103: The compound of any one of the preceding Embodiments, wherein at least one R A1b< is halogen.

[0768] Embodiment No. 104: The compound of any one of the preceding Embodiments, wherein at least one R A1b< is F, and at least one R A1b< is Cl.

[0769] Embodiment No. 105: The compound of any one of the preceding Embodiments, wherein at least one R A1b< is CN, -OH, or -NH 2 .

[0770] Embodiment No. 106: The compound of any one of the preceding Embodiments, wherein when Z is then T is -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R T< ; and wherein the C 2 -C 6 alkenyl is substituted with one or more R T< each R T< independently is 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; wherein the -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 is optionally substituted with one or more R Ta< ; and each R Ta< independently is 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.

[0771] Embodiment No. 107: The compound of any one of the preceding Embodiments, wherein when Z is then T is not

[0772] Embodiment No. 108: The compound of any one of the preceding Embodiments, wherein when Z is then Ar 1< is C 6 -C 10 aryl optionally substituted with one or more halogen.

[0773] Embodiment No. 109: The compound of any one of the preceding Embodiments, wherein Z is not

[0774] Embodiment No. 110: The compound of any one of the preceding Embodiments, wherein Z is not

[0775] Embodiment No. 111: The compound of any one of the preceding Embodiments, wherein T is not

[0776] Embodiment No. 112: The compound of any one of the preceding Embodiments, wherein the compound is of formula (II'): or a pharmaceutically acceptable salt or stereoisomer thereof.

[0777] Embodiment No. 113: The compound of any one of the preceding Embodiments, wherein the compound is of formula (II'): or a pharmaceutically acceptable salt or stereoisomer thereof.

[0778] Embodiment No. 114: The compound of any one of the preceding Embodiments, wherein the compound is of formula (III') or (III'-a): or a pharmaceutically acceptable salt or stereoisomer thereof.

[0779] Embodiment No. 115: The compound of any one of the preceding Embodiments, wherein the compound is of formula (IV') or (IV'-a): or a pharmaceutically acceptable salt or stereoisomer thereof.

[0780] Embodiment No. 116: The compound of any one of the preceding Embodiments, where in the compound is of formula I or a pharmaceutically acceptable salt or stereoisomer thereof, wherein W is CH or N; X 1< is -O-, -S-, -NR 3< -; R a< , R b< are independently of each other hydrogen, C 1-4 alkyl or one of R a< is -(CH 2 ) p - which forms a ring with X 1< if X 1< is NR 3< or one of R a< is -(CH 2 ) p - which forms a ring with R 2< R c< , R d< are independently of each other hydrogen or C 1-4 alkyl; R 1< is H or F; R 2< is hydrogen or C 1-4 alkyl, or is -(CH 2 ) q - which forms a ring with R 3< or with one of R a< ; R 3< is hydrogen or C 1-4 alkyl, preferably hydrogen or methyl, or is -(CH 2 ) p - which forms a ring with R 2< ; 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 a 6-membered aryl, which is unsubstituted or substituted with one or more of a group selected from halogen, -CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, hydroxy C 1-5 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 6 aryl, C 1-6 alkoxy-C 5-6 heteroaryl, amino, amino C 1-4 alkyl, C 1-6 alkylamino, C 1-6 aminoalkyl-C 6 aryl, C 1-6 aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 alkoxyaminocarbonyl, aryl C 1-6 alkoxy, or C 6 aryl.

[0781] Embodiment No. 117: The compound of any one of the preceding Embodiments, wherein when X 1< is -NR 3< -, R 2< is not hydrogen.

[0782] Embodiment No. 118: The compound of any one of the preceding Embodiments, wherein when X 1< is -NR 3< -, R 2< is C 1-4 alkyl, or is -(CH 2 ) q - which forms a ring with R 3< or with one of R a< .

[0783] Embodiment No. 119: The compound of any one of the preceding Embodiments, wherein X 1< is -NR 3< -, and R 2< is not hydrogen.

[0784] Embodiment No. 120: The compound of any one of the preceding Embodiments, wherein X 1< is -NR 3< -, and R 2< is C 1-4 alkyl, or is -(CH 2 ) q - which forms a ring with R 3< or with one of R a< .

[0785] Embodiment No. 121: The compound of any one of the preceding Embodiments, wherein when n is 0, R 2< is -(CH 2 ) q - which forms a ring with R 3< or with one of R a< .

[0786] Embodiment No. 122: The compound of any one of the preceding Embodiments, wherein when n is 0, R 2< is -(CH 2 ) q - which forms a ring with R 3< .

[0787] Embodiment No. 123: The compound of any one of the preceding Embodiments, wherein n is 0, and R 2< is -(CH 2 ) q - which forms a ring with R 3< or with one of R a< .

[0788] Embodiment No. 124: The compound of any one of the preceding Embodiments, wherein n is 0, and R 2< is -(CH 2 ) q - which forms a ring with R 3< .

[0789] Embodiment No. 125: The compound of any one of the preceding Embodiments, wherein X 1< is NR 3< or O and wherein R 3< is methyl, ethyl, n-propyl or n-butyl.

[0790] Embodiment No. 126: The compound of any one of the preceding Embodiments, wherein R 1< is hydrogen.

[0791] Embodiment No. 127: The compound of any one of the preceding Embodiments, wherein R 2< is methyl, ethyl, n-propyl or n-butyl-, preferably methyl or wherein R 2< is -(CH 2 )- or -(CH 2 ) 2 -which forms a ring with R 3< , or wherein R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with one of R a< .

[0792] Embodiment No. 128: The compound of any one of the preceding Embodiments, wherein Ar 1< is of formula i or pharmaceutically acceptable salts or stereoisomers thereof wherein 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 aryl; R 5< , R 5< ', R 6< , R 6< ' are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl.

[0793] Embodiment No. 129: The compound of any one of the preceding Embodiments, wherein R 5< is F and / or wherein R 6< is F or Cl.

[0794] Embodiment No. 130: The compound of any one of the preceding Embodiments, wherein R 1< is hydrogen.

[0795] Embodiment No. 131: The compound of any one of the preceding Embodiments, wherein R 2< is methyl or wherein R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< , or wherein R 2< is - (CH 2 )- or -(CH 2 ) 2 - which forms a ring with one of R a< .

[0796] Embodiment No. 132: The compound of any one of the preceding Embodiments, wherein Ar 1< is of formula ii-1, ii-2, ii-3 or ii-4 or pharmaceutically acceptable salts or stereoisomers thereof wherein X 2< is O, NH or NMe; X 3< is CH or N; o is 0 or 1; R 4< is hydrogen or halogen, preferably F or Cl; R 5< , R 5'< , R 6< , R 6< ' are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F.

[0797] Embodiment No. 133: The compound of any one of the preceding Embodiments, wherein R 5< is F and / or wherein R 6< is F or Cl.

[0798] Embodiment No. 134: The compound of any one of the preceding Embodiments, wherein R 1< is hydrogen.

[0799] Embodiment No. 135: The compound of any one of the preceding Embodiments, wherein R 2< is methyl or wherein R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< wherein R 2< is - (CH 2 )- or -(CH 2 ) 2 - which forms a ring with one of R a< .

[0800] Embodiment No. 136: The compound of any one of the preceding Embodiments, wherein Ar 1< is of formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7 or pharmaceutically acceptable salts or stereoisomers thereof wherein 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 independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F.

[0801] Embodiment No. 137: The compound of any one of the preceding Embodiments, wherein R 5< is F and / or wherein R 6< is F or Cl.

[0802] Embodiment No. 138: The compound of any one of the preceding Embodiments, wherein R 1< is hydrogen.

[0803] Embodiment No. 139: The compound of any one of the preceding Embodiments, wherein R 2< is methyl or wherein R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< wherein R 2< is - (CH 2 )- or -(CH 2 ) 2 - which forms a ring with one of R a< .

[0804] Embodiment No. 140: The compound of any one of the preceding Embodiments, wherein 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 pharmaceutically acceptable salts or stereoisomers thereof wherein o is 0 or 1; R 4< is hydrogen or halogen, preferably F or Cl; R 5< , R 5'< , R 6< , R 6< ' are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F.

[0805] Embodiment No. 141: The compound of any one of the preceding Embodiments, wherein R 5< is F and / or wherein R 6< is F or Cl.

[0806] Embodiment No. 142: The compound of any one of the preceding Embodiments, wherein R 1< is hydrogen.

[0807] Embodiment No. 143: The compound of any one of the preceding Embodiments, wherein R 2< is methyl or wherein R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< wherein R 2< is - (CH 2 )- or -(CH 2 ) 2 - which forms a ring with one of R a< .

[0808] Embodiment No. 144: The compound of any one of the preceding Embodiments, being of formula IIa or IIb or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X 1< is -O- or -NR 3< -; R 1< is H or F; R 2< is hydrogen or C 1-4 alkyl, preferably methyl or is -(CH 2 ) q - which forms a ring with R 3< ; R 3< is hydrogen or C 1-4 alkyl, preferably hydrogen or methyl, or is -(CH 2 ) p - which forms a ring with R 2< ; 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 a 6-membered aryl, which is unsubstituted or substituted with one or more of a group selected from halogen, -CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, hydroxy C 1-5 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 6 aryl, C 1-6 alkoxy-C 5-6 heteroaryl, amino, amino C 1-4 alkyl, C 1-6 alkylamino, C 1-6 aminoalkyl-C 6 aryl, C 1-6 aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 alkoxyaminocarbonyl, aryl C 1-6 alkoxy, or C 6 aryl.

[0809] Embodiment No. 145: The compound of any one of the preceding Embodiments, wherein R 1< is hydrogen.

[0810] Embodiment No. 146: The compound of any one of the preceding Embodiments, wherein R 2< is methyl or wherein R 2< is -(CH 2 )- or -(CH 2 ) 2 - which forms a ring with R 3< .

[0811] Embodiment No. 147: The compound of any one of the preceding Embodiments, being of formula III or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1< is H or F; Ar 1< is a 6-membered aryl, which is unsubstituted or substituted with one or more of a group selected from halogen, -CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, hydroxy C 1-5 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 6 aryl, C 1-6 alkoxy-C 5-6 heteroaryl, amino, amino C 1-4 alkyl, C 1-6 alkylamino, C 1-6 aminoalkyl-C 6 aryl, C 1-6 aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 alkoxyaminocarbonyl, or C 6 aryl; Z is selected from

[0812] Embodiment No. 148: The compound of any one of the preceding Embodiments, wherein R 1< is hydrogen.

[0813] Embodiment No. 149: The compound of any one of the preceding Embodiments, being of formula IV or a pharmaceutically acceptable salt or stereoisomer thereof, wherein 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 aryl; R 5< , R 5'< , R 6< , R 6< ' are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; Z is selected from

[0814] Embodiment No. 150: The compound of any one of the preceding Embodiments, wherein R 5< is F and / or wherein R 6< is F or Cl.

[0815] Embodiment No. 151: The compound of any one of the preceding Embodiments, wherein R 1< is hydrogen.

[0816] Embodiment No. 152: The compound of any one of the preceding Embodiments, being of formula V-1, V-2, V-3 or V-4 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein 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 independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F; Z is selected from

[0817] Embodiment No. 153: The compound of any one of the preceding Embodiments, wherein R 5< is F and / or wherein R 6< is F or Cl.

[0818] Embodiment No. 154: The compound of any one of the preceding Embodiments, wherein R 1< is hydrogen.

[0819] Embodiment No. 155: The compound of any one of the preceding Embodiments, being of formula VI-1, VI-2, VI-3 or VI-4 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein 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 independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F: Z is selected from

[0820] Embodiment No. 156: The compound of any one of the preceding Embodiments, wherein R 5< is F and / or wherein R 6< is F or Cl.

[0821] Embodiment No. 157: The compound of any one of the preceding Embodiments, wherein R 1< is hydrogen.

[0822] Embodiment No. 158: The compound of any one of the preceding Embodiments, being of formula VII-1, VII-2, VII-3 or VII-4, VII-5, VII-6 VII-7, VII-8 or VII-9 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1< is H or F; o is 0 or 1; R 4< is hydrogen or halogen, preferably F or Cl; R 5< , R 6< are independently of each other hydrogen, -CF 3 or halogen, preferably F or Cl; R 7< is hydrogen or halogen, preferably F; Z is selected from

[0823] Embodiment No. 159: The compound of any one of the preceding Embodiments, wherein R 5< is F and / or wherein R 6< is F or Cl.

[0824] Embodiment No. 160: The compound of any one of the preceding Embodiments, wherein R 1< is hydrogen.

[0825] Embodiment No. 161: The compound of any one of the preceding Embodiments, being selected from the compounds described in Tables 1 and 2, pharmaceutically acceptable salts thereof, and stereoisomers thereof.

[0826] Embodiment No. 162: The compound of any one of the preceding Embodiments, being selected from the compounds described in Tables 1 and 2 and pharmaceutically acceptable salts thereof.

[0827] Embodiment No. 163: The compound of any one of the preceding Embodiments, being selected from the compounds described in Tables 1 and 2.

[0828] Embodiment No. 164: A composition comprising to the compound of any one of the preceding Embodiments, and a pharmaceutically acceptable carrier.

[0829] Embodiment No. 165: The composition of any one of the preceding Embodiments, further comprising a second therapeutically active agent.

[0830] Embodiment No. 166: A method of inhibiting an oncogenic variant of an ErbB receptor, comprising administering the subject in need thereof a therapeutically effective amount of the compound of any one of the preceding Embodiments.

[0831] Embodiment No. 167: A method of inhibiting an oncogenic variant of an ErbB receptor, comprising administering the subject in need thereof the composition of any one of the preceding Embodiments.

[0832] Embodiment No. 168: A method of preventing or treating cancer, comprising administering the subject in need thereof a therapeutically effective amount of the compound of any one of the preceding Embodiments.

[0833] Embodiment No. 169: A method of preventing or treating cancer, comprising administering the subject in need thereof the composition of any one of the preceding Embodiments.

[0834] Embodiment No. 170: The compound of any one of the preceding Embodiments for use in the prevention or treatment of cancer.

[0835] Embodiment No. 171: The compound of any one of the preceding Embodiments for use in the inhibition of an oncogenic variant of an ErbB receptor.

[0836] Embodiment No. 172: The composition of any one of the preceding Embodiments for use in the inhibition of an oncogenic variant of an ErbB receptor.

[0837] Embodiment No. 173: The composition of any one of the preceding Embodiments for use in the prevention or treatment of cancer.

[0838] Embodiment No. 174: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the cancer is a solid tumor.

[0839] Embodiment No. 175: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the cancer is a bladder cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, a non-small cell lung cancer (NSCLC), or any subtype thereof.

[0840] Embodiment No. 176: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the cancer is glioblastoma (GBM) or any subtype thereof.

[0841] Embodiment No. 177: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the cancer is glioblastoma.

[0842] Embodiment No. 178: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an ErbB receptor.

[0843] Embodiment No. 179: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the oncogenic variant of the ErbB receptor comprises an allosteric mutation.

[0844] Embodiment No. 180: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the oncogenic variant of an ErbB receptor is is an allosteric variant of the ErbB receptor.

[0845] Embodiment No. 181: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an epidermal growth factor receptor (EGFR).

[0846] Embodiment No. 182: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the oncogenic variant of EGFR is an allosteric variant of EGFR.

[0847] Embodiment No. 183: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the oncogenic variant of EGFR comprises an allosteric mutation.

[0848] Embodiment No. 184: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of a human epidermal growth factor receptor 2 (HER2) receptor.

[0849] Embodiment No. 185: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor.

[0850] Embodiment No. 186: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the oncogenic variant of the HER2 receptor comprises an allosteric mutation.

[0851] Embodiment No. 187: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the oncogenic variant or the oncogenic mutation is detected by a Food and Drug Aministration (FDA)-approved diagnosis.

[0852] Embodiment No. 188: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein prior to the treatment with the compound of the present disclosure, the subject is treated with a therapeutic agent different from the compound of any one of the preceding Embodiments.

[0853] Embodiment No. 189: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the cancer, or a tumor or a cell thereof, is insensitive or resistant to treatment with the therapeutic agent different from the compound of any one of the preceding Embodiments.

[0854] Embodiment No. 190: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the subject has an adverse reaction to treatment with a therapeutic agent different from the compound of any one of the preceding Embodiments.

[0855] Embodiment No. 191: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the therapeutically effective amount reduces a severity of a sign or symptom of the cancer.

[0856] Embodiment No. 192: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the sign of the cancer comprises a tumor grade and wherein a reduction of the severity of the sign comprises a decrease of the tumor grade.

[0857] Embodiment No. 193: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the sign of the cancer comprises a tumor metastasis and wherein a reduction of the severity of the sign comprises an elimination of the metastasis or a reduction in the rate or extent the metastasis.

[0858] Embodiment No. 194: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the sign of the cancer comprises a tumor volume and wherein a reduction of the severity of the sign comprises an elimination of the tumor or a reduction in the volume.

[0859] Embodiment No. 195: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the symptom of the cancer comprises pain and wherein a reduction of the severity of the sign comprises an elimination or a reduction in the pain.

[0860] Embodiment No. 196: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the therapeutically effective amount induces a period of remission.

[0861] Embodiment No. 197: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the therapeutically effective amount improves a prognosis of the subject.

[0862] Embodiment No. 198: A method of preventing or treating glioblastoma, comprising administering the subject in need thereof a therapeutically effective amount of the compound of any one of the preceding Embodiments.

[0863] Embodiment No. 199: A method of preventing or treating glioblastoma, comprising administering the subject in need thereof the composition of any one of the preceding Embodiments.

[0864] Embodiment No. 200: The compound of any one of the preceding Embodimentsfor use in the prevention or treatment of glioblastoma.

[0865] Embodiment No. 201: The composition of any one of the preceding Embodiments for use in the prevention or treatment of glioblastoma.

[0866] Embodiment No. 202: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the compound is selected from the compounds described in Tables 1 and 2, pharmaceutically acceptable salts thereof, and stereoisomers thereof.

[0867] Embodiment No. 203: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the compound is selected from the compounds described in Tables 1 and 2 and pharmaceutically acceptable salts thereof.

[0868] Embodiment No. 204: The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the compound is selected from the compounds described in Table 1 and 2.EXAMPLESPreparation of (R)-tert-butyl 2-ethynyl-2-methylpyrrolidine-1-carboxylate (S5)

[0869]

[0870] S2: To a solution of (R)-2-methylpyrrolidine-2-carboxylic acid S1 (3.00 g, 23.3 mmol, 1.00 eq) and triethylamine (7.05 g, 69.7 mmol, 9.70 mL, 3.00 eq) in a mixture solvent of water (20.0 mL) and acetonitrile (20.0 mL) was added di-tert-butyl dicarbonate (5.58 g, 25.6 mmol, 5.87 mL, 1.10 eq). The mixture was stirred at 25 °C for 10 h. The pH of the reaction mixture was adjusted to around 2.00 by progressively adding aqueous solution of hydrochloric acid (2.00 M, 15.0 ml). The mixture was filtered and concentrated to give (R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine -2-carboxylic acid S2 (4.20 g, crude) as a white solid. 1< H NMR (400MHz, CDCl3) δ = 3.65 - 3.46 (m, 4H), 2.59 (br d, J = 5.1 Hz, 1H), 2.34 - 2.25 (m, 1H), 2.03 - 1.92 (m, 2H), 1.91 - 1.79 (m, 4H), 1.63 (s, 3H), 1.55 - 1.53 (m, 3H), 1.49 (s, 9H).

[0871] S3: To a solution of (R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid S2 (5.30 g, 23.1 mmol, 1.00 eq) in tetrahydrofuran (50.0 mL) was added borane dimethyl sulfide complex (10.0 M, 4.62 mL, 2.00 eq) dropwise at 0 °C. Then the mixture was stirred at 70 °C for 12 h. The reaction mixture was quenched by methanol (15.0 ml) and concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to afford (R)-tert-butyl 2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate S3 (1.10 g, 5.11 mmol, 22% yield) as yellow oil. 1< H NMR (400 MHz, CDCl 3 ) δ = 3.72 - 3.64 (m, 1H), 3.63 - 3.50 (m, 2H), 3.38 - 3.27 (m, 1H), 2.03 - 1.70 (m, 4H), 1.47 (s, 9H), 1.38 (s, 3H).

[0872] S4: To a solution of (R)-tert-butyl 2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate S3 (1.10 g, 5.11 mmol, 1.00 eq) in dichloromethane (15.0 mL) was added (1,1-diacetoxy-3-oxo-1,2-benziodoxol-1-yl) acetate (2.60 g, 6.13 mmol, 1.90 mL, 1.20 eq). The mixture was stirred at 25 °C for 10 h. The reaction mixture was filtered and the filtrate was poured into saturated aqueous solution of sodium carbonate (60.0 mL). The aqueous phase was extracted with ethyl acetate (3 × 40.0 mL). The combined organic phase was washed with brine (2 × 30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford (R)-tert-butyl 2-formyl-2-methylpyrrolidine-1-carboxylate S4 ...

Claims

1. A compound which is: a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

2. The compound of claim 1, which is:

3. The compound of claim 1, which is a pharmaceutically acceptable salt of 4. The compound of claim 1, which is: a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

5. The compound of claim 1 or claim 4, which is:

6. The compound of claim 1 or claim 4, which is a pharmaceutically acceptable salt of 7. The compound of claim 1, which is a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

8. The compound of claim 1 or claim 7, which is:

9. The compound of claim 1 or claim 7, which is a pharmaceutically acceptable salt of 10. A composition comprising a compound of any one of the preceding claims, and a pharmaceutically acceptable carrier.

11. The compound of any one of claims 1 to 9, or the composition of claim 10, for use in the prevention or treatment of cancer; optionally wherein the cancer is a solid tumor.

12. The compound or composition for use of claim 11, wherein the cancer is a bladder cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, or a non-small cell lung cancer (NSCLC), or a subtype of any of the foregoing.

13. The compound or composition for use of claim 11 or 12, wherein the cancer is glioblastoma (GBM) or any subtype thereof; optionally wherein the cancer is glioblastoma.

14. The compound or composition for use of claim 11 or 12, wherein the cancer is non-small cell lung cancer (NSCLC) or any subtype thereof; optionally wherein the cancer is NSCLC.

15. The compound or composition for use of any one of claims 11 to 14, wherein the cancer expresses an oncogenic variant of an ErbB receptor; optionally, the oncogenic variant of the ErbB receptor comprises an allosteric mutation; and optionally, the oncogenic variant of an ErbB receptor is an allosteric variant of the ErbB receptor.