Fused tetracyclic quinazoline derivatives as inhibitors of ERBB2

Abstract

The present disclosure relates generally to compounds and compositions for the inhibition of ErbB2, e.g., mutant forms of ErbB2, particularly those carrying exon 20 mutations, methods for preparing the compounds and compositions, and their use in the treatment or prevention of various cancers, such as lung cancer, glioma, skin cancer, head and neck cancer, salivary gland cancer, breast cancer, esophageal cancer, liver cancer, gastric cancer, uterine cancer, cervical cancer, biliary tract cancer, pancreatic cancer, colorectal cancer, kidney cancer, bladder cancer, or prostate cancer.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of International Patent Application No. PCT / CN2021 / 128110, filed November 2, 2021, and U.S. Provisional Patent Application No. 63 / 417,219, filed October 18, 2022, the disclosures of each of which are incorporated herein by reference in their entireties.

[0002] The present disclosure relates generally to compounds and compositions thereof for the inhibition of ErbB2, e.g., mutant forms of ErbB2, particularly those carrying exon 20 mutations, methods for preparing the compounds and compositions, and their use in the treatment or prevention of various cancers, such as lung cancer, glioma, skin cancer, head and neck cancer, salivary gland cancer, breast cancer, esophageal cancer, liver cancer, gastric cancer, uterine cancer, cervical cancer, biliary tract cancer, pancreatic cancer, colorectal cancer, kidney cancer, bladder cancer, or prostate cancer. [Background technology]

[0003] ErbB2 (or HER2) is a member of the ErbB receptor tyrosine kinase family, which consists of four related receptors, including ErbB1 (also known as epidermal growth factor receptor, or EGFR), ErbB3, and ErbB4. While no ligands are known to bind to ErbB2 monomers, ErbB2 can dimerize with other ErbB receptors, particularly ErbB3, to regulate downstream signaling cascades, including, but not limited to, the MAPK and PI3K pathways, which promote cell proliferation and survival. Abnormal overexpression of ErbB2 or specific genetic alterations (including point mutations leading to specific amino acid substitutions or small in-frame insertions in exon 20 leading to deletions and / or insertions of specific small amino acid stretches) have been shown to confer elevated or constitutive tyrosine kinase activation to the receptor. Therefore, overexpression or mutations of ErbB2 are highly associated with advanced solid cancers, including breast, ovarian, gastric, and lung cancers (NSCLC).

[0004] Currently, only a few treatments are approved for cancers associated with ErbB2 overexpression, including tyrosine kinase inhibitors (TKIs) such as tucatinib. While these TKIs can be effective in ameliorating cancers associated with ErbB2 overexpression, their therapeutic utility is often limited by insufficient selectivity for ErbB2 over EGFR, and as a result, their therapeutic utility is often limited by toxicity concerns associated with EGFR inhibition, particularly gastrointestinal and skin-related toxicities. These toxicities force restrictive dosing regimens, resulting in suboptimal target engagement and limited therapeutic benefit. Furthermore, while current TKIs provide therapeutic benefit for cancers caused by ErbB2 overexpression, their efficacy may be limited in patients with certain genetic alterations associated with ErbB family ligands, such as EGFR or ERBB2 exon 20 insertions, specific point mutations, or fusions in the NRG1 gene.

[0005] For example, in a small proportion of lung cancer patients, certain highly deleterious EGFR and ErbB2 mutations, known as EGFR exon 20 insertions / ErbB2 insertions, are significantly less sensitive to first- and second-generation reversible TKIs. A further challenge to the development of viable treatments for these specific ErbB exon 20 mutants (20ins or E20I) is the fact that these alterations are heterogeneous and encompass a variety of amino acid insertions / deletions. In addition to the E20I mutation, many other genetic alterations in the receptor, particularly point mutations resulting in single amino acid substitutions, have been associated with the development of various cancers, including lung cancer. While the resistance mechanisms associated with each of these mutations have not been fully elucidated, it is believed that they share a commonality: they promote ligand-independent activation of the kinase. Further investigation into the underlying mechanisms and the development of TKIs tailored to these mutations are warranted.

[0006] In other advanced, intractable cancers that overexpress ErbB2, rearrangements of the NRG1 gene have been identified, resulting in novel fusion proteins. NRG1 gene fusions can induce overproduction of neuregulin-1, the cognate ligand of ErbB3. The simultaneous overexpression of ErbB2 and overproduction of neuregulin-1 can lead to excessive activation of the ErbB2-ErbB3 heterodimer, resulting in hyperplasia.

[0007] Therefore, there remains a need for novel therapeutic agents for the treatment of cancers caused by abnormalities in ErbB2 receptor kinase activity that not only have improved safety and selectivity for ErbB2 over EGFR, but also have high efficacy against mutation-associated subvariants of ErbB2 (e.g., E20I mutation and NRG1 gene fusion). Summary of the Invention

[0008] In one embodiment, a compound of formula (I') [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: Ring A is [ka] and E is -C(=O)-R 1 and G is -O-, -C(=O)-, -S-, -S(O)-, -S(O)2-, or -CH2-; V is O, S, or NR 2 and each X 1 are independently N or CH; X 2 is O, S, or NR 3 and Y is N or CR y where R yis -H or -F, Z is -H, halogen, -C≡CH, -OCH3, or C1-C2 alkyl; R 1 is a C2-C4 alkenyl or a C2-C4 alkynyl, each of which is independently halogen, C1-C3 alkyl, a 3- to 7-membered carbon-linked N-heterocycloalkyl, or —NR 1a R 1b and optionally substituted with 1 to 4 substituents selected from the group consisting of: 1a and R 1b are independently -H, C1-C3 alkyl, or -CD3, or a geminal R 1a and R 1b each pair of can be taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered N-heterocyclyl, where the nitrogen atom of each heterocyclyl, if present, is independently optionally substituted with C-C alkyl; R 2 is C1-C6 alkyl or C1-C6 cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines; R 3 is -H, C1-C6 alkyl, -CD3 or C1-C6 cycloalkyl; R 4 is -H or a halogen, R 5 is -H or a halogen, R 6 is -H or a halogen, R 7 is -H, halogen, C1-C6 alkyl, -CD3 or C1-C6 cycloalkyl; n is 1 or 2, p is 0 or 1, q is 1 or 2.

[0009] In one embodiment, a compound of formula (I) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: Ring A is [ka] and E is -C(=O)-R 1 and G is -O-, -C(=O)-, -S-, -S(O)-, -S(O)2-, or -CH2-; V is O, S, or NR 2 and each X 1 are independently N or CH; X 2 is O, S, or NR 3 and Y is N or CR y where R y is -H or -F, Z is -H, halogen, -C≡CH, -OCH3, or C1-C2 alkyl; R 1 is a C2-C4 alkenyl or a C2-C4 alkynyl, each of which is independently halogen, C1-C3 alkyl, a 3- to 7-membered carbon-linked N-heterocycloalkyl, or —NR 1a R 1b and optionally substituted with 1 to 4 substituents selected from the group consisting of: 1a and R 1b are independently -H, C1-C3 alkyl, or -CD3, or a geminal R 1a and R 1b each pair of can be taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered N-heterocyclyl, where the nitrogen atom of each heterocyclyl, if present, is independently optionally substituted with C-C alkyl; R 2 is C1-C6 alkyl or C1-C6 cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines; R 3 is -H, C1-C6 alkyl, -CD3 or C1-C6 cycloalkyl; R 4 is -H or a halogen, R 5 is -H or a halogen, R 6 is —H or a halogen.

[0010] In some embodiments of this aspect, ring A is [ka] In certain embodiments, ring A is [ka] In certain other embodiments of this aspect, ring A is: [ka] In some embodiments, ring A is [ka] In other embodiments, ring A is: [ka] In other embodiments, ring A is: [ka] is.

[0011] In some embodiments that may be combined with any of the preceding embodiments, R 3is -CH3. In some embodiments that can be combined with any of the preceding embodiments, Z is -H, -F, -Cl, -C≡CH, -OCH3, or -CH3. In certain embodiments, Z is -CH3. In some embodiments that can be combined with any of the preceding embodiments, R 1 is C2-C4 alkenyl, -NR 1a R 1b In certain embodiments, R 1 is -CH=CH2. In certain other embodiments, R 1 is -CH=CH-CH2-N(CH3)2. In still other embodiments that may be combined with any of the preceding embodiments, R 1 is C2-C4 alkynyl, -NR 1a R 1b In certain embodiments, R 1 is -C≡C-CH3.

[0012] In some embodiments that may be combined with any of the preceding embodiments, R 3 is —CH. In some embodiments that may be combined with any of the preceding embodiments, R 7 is -CH3, -CH2CH3, or F. In some embodiments that may be combined with any of the preceding embodiments, Z is -H, -F, -Cl, -C≡CH, -OCH3, or -CH3. In certain embodiments, Z is -CH3. In some embodiments that may be combined with any of the preceding embodiments, R 1 is C2-C4 alkenyl, -NR 1a R 1b In certain embodiments, R 1 is -CH=CH2. In certain other embodiments, R 1is -CH=CH-CH2-N(CH3)2 or -CH=CH-CH(CH3)-N(CH3)2. In still other embodiments that may be combined with any of the preceding embodiments, R 1 is C2-C4 alkynyl, -NR 1a R 1b In certain embodiments, R 1 is -C≡C-CH3.

[0013] In some embodiments, Y is N. In other embodiments, Y is CR y In certain embodiments, Y is CR y and R y is -H. In certain other embodiments, Y is CR y and R y is -F. In some embodiments, V is O. In other embodiments, V is S. In still other embodiments, V is NR 2 In some embodiments, G is -O-. In other embodiments, G is -C(=O)-. In still other embodiments, G is -S-, -S(O)-, or -S(O)-. In still other embodiments, G is -CH-. In some embodiments, R 4 is —H. In other embodiments, R 4 is halogen. In some embodiments, R 5 is —H. In other embodiments, R 5 is halogen. In some embodiments, R 6 is —H. In other embodiments, R 6 is a halogen.

[0014] In another aspect, provided herein is a compound in Table 1 described herein. In yet another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (F), Formula (I) or Table 1 described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and at least one pharmaceutically acceptable excipient.

[0015] In one aspect, provided herein is a method for inhibiting the kinase activity of human receptor tyrosine kinase ErbB2 or a mutant form of human ErbB2, comprising contacting ErbB2 or the mutant with a therapeutically effective amount of a compound of Formula (I') described herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments of this aspect, the mutant form of human ErbB2 comprises a mutation in exon 20. In some embodiments of this aspect, the mutant human ErbB2 is selected from the group consisting of A775_A776insYVMA, A775_A776insAYVM, A775_A776insYVMS, A775_A776insVVMA, A775_A776insMMAY, A775_A776insYVMA-R678Q, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G776delinsLV, G776delinsVV , G776insIC, G776delinsCVC, G776delinsAVGS, G776delinsAVGA, G776delinsAVGCG776_V777insLeu, G776_V777insVGS, G778_S779InsCPG; V777_G778insGSP, V777_G778insGC, V777_G778insCG, V777_G778insQ, V777_G778insG, G778_S779insLPS, and G778_S779insAVG. In a further embodiment of this aspect, the mutant human ErbB2 comprises one or more mutations that introduce a deletion and / or insertion of an amino acid selected from the group consisting of A775_A776insYVMA, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G778_S779InsCPG, and V777_G778insGSP.In another embodiment of this aspect, the mutant human ErbB2 comprises a disease-associated point mutation of ErbB2. In another embodiment of this aspect, the mutant human ErbB2 comprises (a) P122L, R217C, I263T, A293T, S305C, S310F / Y / P, H470Q, I655V, V659E / D, L674F, G660D, R678Q / C, L755R / S / P / Y / M, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E or (b) one or more point mutations in ErbB2 that introduce an amino acid substitution selected from the group consisting of 930K / D, E1021Q, F1030C, V1128I, N1219S, G222C, A1057V, V842I, G776S / C / V / A, V773M, L869R, Y803F, H878Y, R896G, and E1195G, or a frameshift at A1232. In still further embodiments of this aspect, the mutant human ErbB2 comprises one or more point mutations in ErbB2 that introduce an amino acid substitution selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y, H470Q, I655V, V659E, G660D, R678Q / C, L755R / S / P, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, N1219S, and A1232fs. In another embodiment, the mutant human ErbB2 comprises one or more point mutations in ErbB2 that introduce (a) an amino acid substitution selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y, H470Q, I655V, V659E, G660D, R678Q / C, L755R / S / P, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, and N1219S, or (b) a frameshift at A1232. In another embodiment, the mutant human ErbB2 comprises an amino-terminally truncated carboxyl-terminal fragment of HER2, collectively referred to as p95HER2.

[0016] In yet another aspect, provided herein is a method of treating a patient having cancer, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I') described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, or a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments of this aspect, the cancer comprises cells or cell tissues with increased ErbB2 kinase activity. In some embodiments of this aspect, the cancer comprises cells or cell tissues with increased ErbB2 kinase activity compared to a control. In certain embodiments, the cancer comprises cells or cell tissues with increased ErbB2 kinase activity compared to ErbB2 kinase activity in control cells or control cell tissues. In further embodiments of this aspect, the cancer comprises cells or cell tissues with one or more mutations in exon 20 of ErbB2. In certain variations, the one or more mutations in exon 20 of ErbB2 are selected from the group consisting of A775_A776insYVMA, A775_A776insAYVM, A775_A776insYVMS, A775_A776insVVMA, A775_A776insMMAY, A775_A776insYVMA-R678Q, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G776delinsLV, G776d Deletion and / or insertion of certain amino acids selected from the group consisting of: V777_G778insVV, G776insIC, G776delinsCVC, G776delinsAVGS, G776delinsAVGA, G776delinsAVGCG776_V777insLeu, G776_V777insVGS, G778_S779insCPG; V777_G778insGSP, V777_G778insGC, V777_G778insCG, V777_G778insQ, V777_G778insG, G778_S779insLPS, and G778_S779insAVG is introduced.In certain embodiments, the cancer comprises cells or cell tissues having one or more mutations in exon 20 of ErbB2 that introduce deletions and / or insertions of amino acids selected from the group consisting of A775_A776insYVMA, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G778_S779InsCPG, and V777_G778insGSP. In certain embodiments, the cancer is characterized by (a) P122L, R217C, I263T, A293T, S305C, S310F / Y / P, H470Q, I655V, V659E / D, L674F, G660D, R678Q / C, L755R / S / P / Y / M, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, In another embodiment, the cancer comprises cells or cell tissues with one or more disease-associated point mutations in ErbB2. In certain other embodiments, the cancer comprises cells or cell tissues with one or more point mutations introducing an amino acid substitution selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y, H470Q, I655V, V659E, G660D, R678Q / C, L755R / S / P, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, N1219S, and A1232fs.In certain embodiments, the cancer comprises cells or cell tissues with one or more point mutations that introduce (a) an amino acid substitution selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y, H470Q, I655V, V659E, G660D, R678Q / C, L755R / S / P, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, and N1219S, or (b) a frameshift at A1232.

[0017] In some embodiments of this aspect that can be combined with any of the preceding embodiments, the cancer is lung cancer, glioma, skin cancer, head and neck cancer, salivary gland cancer, breast cancer, esophageal cancer, liver cancer, gastric cancer, uterine cancer, cervical cancer, biliary tract cancer, pancreatic cancer, colorectal cancer, kidney cancer, bladder cancer, or prostate cancer. In certain embodiments, the cancer is non-small cell lung cancer. In still other embodiments that can be combined with any of the preceding embodiments, the patient has received at least one, at least two, or at least three prior therapies for the cancer. In certain embodiments, one or more of the prior therapies is selected from the group consisting of lapatinib, neratinib, afatinib, pyrotinib, poziotinib, TAK-788, and tucatinib. In some embodiments, the method further comprises administering one or more additional anti-cancer agents. In some embodiments, the method further comprises administering an anti-HER2 antibody or an anti-HER2 drug conjugate. In certain embodiments, the method further comprises administering KADCYLA® (ado-trastuzumab emtansine), ENHERTU® (fam-trastuzumab deruxtecan-nxki), or any biosimilar thereof. DETAILED DESCRIPTION OF THE INVENTION

[0018] The following description sets forth exemplary methods, parameters, etc. However, it should be recognized that such description is not intended to limit the scope of the present disclosure, but rather is provided as a description of exemplary embodiments.

[0019] I. Definition As used herein, the following definitions shall apply unless otherwise specified: Furthermore, if any term or symbol used herein is not defined below, it shall have its ordinary meaning in the art.

[0020] As used herein, the term "excipient" refers to an inactive or non-active substance that can be used in the manufacture of a drug or pharmaceutical agent, such as a tablet containing a compound of the present disclosure as an active ingredient. The term excipient can encompass a variety of substances, including, but not limited to, binders, disintegrants, coating agents, compression / encapsulation aids, creams or lotions, lubricants, parenteral solutions, chewable tablet materials, sweeteners or flavoring agents, suspending / gelling agents, or any substance used as a wet granulator. Binders include, for example, carbomer, povidone, xanthan gum, etc.; coatings include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression aids / encapsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrous or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, for example, Examples of suitable lubricants include maltodextrin, carrageenan, etc.; lubricants include magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; chewable tablet materials include dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending / gelling agents include carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulating agents include calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0021] The terms "individual," "subject," and "patient" refer to mammals, including humans and non-human mammals. Examples of patients include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, a patient refers to a human.

[0022] As used herein, the term "mammal" includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep.

[0023] "Pharmaceutically acceptable" refers to safe and non-toxic and suitable for administration in vivo or to humans.

[0024] As used herein, the term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight- or branched-chain hydrocarbon radical having the specified number of carbon atoms (i.e., C1-C6 means 1 to 6 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. In some embodiments, the term "alkyl" can encompass C1-C6 alkyl, C2-C6 alkyl, C3-C6 alkyl, C4-C6 alkyl, C5-C6 alkyl, C1-C5 alkyl, C2-C5 alkyl, C3-C5 alkyl, C4-C5 alkyl, C1-C4 alkyl, C2-C4 alkyl, C3-C4 alkyl, C1-C3 alkyl, C2-C3 alkyl, or C1-C2 alkyl.

[0025] As used herein, the term "alkenyl" refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon double bond. The group may be in either the cis or trans (Z or E) configuration about the double bond(s). Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl), and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl). In some embodiments, an alkenyl group may be attached to the remainder of the molecule by a carbon atom of a carbon-carbon double bond. In other embodiments, an "alkenyl" may be attached to the remainder of the molecule by a saturated carbon atom, with the carbon-carbon double bond being located elsewhere along the branched or straight-chain alkyl group.

[0026] As used herein, the term "alkynyl" refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond. Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl), and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl). In some embodiments, an alkynyl group may be attached to the remainder of the molecule by a carbon atom of the carbon-carbon triple bond. In other embodiments, an "alkynyl" may be attached to the remainder of the molecule by a saturated carbon atom, with the carbon-carbon triple bond located elsewhere along the branched or straight-chain alkyl group.

[0027] The terms "cycloalkyl," "carbocyclic," or "carbocycle" refer to a hydrocarbon ring having the indicated number of ring atoms (e.g., C3-C6 cycloalkyl means 3 to 6 carbons) and that is either fully saturated or has only one double bond between the ring vertices. In some embodiments, "cycloalkyl" includes C3-C7 cycloalkyl, C4-C7 cycloalkyl, C5-C7 cycloalkyl, C5-C7 cycloalkyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, C5-C6 cycloalkyl, C3-C5 cycloalkyl, C4-C5 cycloalkyl, or C3-C4 cycloalkyl. In some embodiments, the term "cycloalkyl" may be further described as "spirocycloalkyl" or "fused cycloalkyl." The term "spirocycloalkyl" refers to a hydrocarbon ring having the indicated number of ring atoms (e.g., C3-C6 cycloalkyl means 3 to 6 carbons) that is fully saturated or has only one double bond between the ring vertices, and that is attached to the rest of the molecule at one ring vertex (e.g., ring carbon atom) by two covalent bonds. The term "fused cycloalkyl" refers to a hydrocarbon ring having the indicated number of ring atoms (e.g., C3-C6 cycloalkyl means 3 to 6 carbons) that is fully saturated or has only one double bond between the ring vertices, and that is attached to the rest of the molecule at two ring vertices (e.g., two carbon atoms) by two covalent bonds. In some embodiments, "cycloalkyl", "cycloalkyl", "carbocyclic", or "carbocycle" refers to bicyclic, polycyclic, and spirocyclic hydrocarbon rings, such as bicyclo[2.2.1]heptane, pinane, bicyclo[2.2.2]octane, adamantane, norborene, spirocyclic C 5-12and the like. Additionally, one ring of a polycyclic cycloalkyl group may be aromatic, provided that the polycyclic cycloalkyl group is attached to the parent structure through a non-aromatic carbon atom. For example, 1,2,3,4-tetrahydronaphthalen-1-yl (which is attached to the parent structure through a non-aromatic carbon atom) is a cycloalkyl group, while 1,2,3,4-tetrahydronaphthalen-5-yl (which is attached to the parent structure through an aromatic carbon atom) is not considered a cycloalkyl group.

[0028] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight- or branched-chain hydrocarbon radical consisting of the stated number of carbon atoms and one to three heteroatoms selected from the group consisting of O, N, Si, and S, where the nitrogen and sulfur atoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized. The heteroatom(s) O, N, and S can be located at any interior position of the heteroalkyl group. The heteroatom Si can be located at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. "Heteroalkyl" can contain up to three units of unsaturation and also includes mono- and polyhalogenated variations, or combinations thereof. Examples include -CH2-CH2-O-CH3, -CH2-CH2-O-CF3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH=N(CH3)-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.

[0029] The terms "heterocycloalkyl," "heterocyclic," "heterocyclyl," or "heterocycle" refer to a cycloalkyl radical group (e.g., a 5- or 6-membered heterocycloalkyl) having the indicated number of ring atoms containing 1 to 5 heteroatoms selected from the group consisting of N, O, and S, wherein the nitrogen and sulfur ring atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. In some embodiments, a "heterocycloalkyl ring," "heterocyclic ring," or "heterocycle" can be a monocyclic, bicyclic, bridged or fused ring system, spirocyclic, or polycyclic ring system. Non-limiting examples of "heterocycloalkyl rings," "heterocyclic," or "heterocycles" include pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-5-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, etc. A "heterocycloalkyl," "heterocyclic," or "heterocycle" group can be attached to the remainder of the molecule through one or more ring carbons or heteroatoms.In some embodiments, "heterocycloalkyl" includes 3-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heterocycloalkyl, 6-10 membered heterocycloalkyl, 7-10 membered heterocycloalkyl, 8-10 membered heterocycloalkyl, 9-10 membered heterocycloalkyl, 3-9 membered heterocycloalkyl, 4-9 membered heterocycloalkyl, 5-9 membered heterocycloalkyl, 6-9 membered heterocycloalkyl, 7-9 membered heterocycloalkyl, 8-9 membered heterocycloalkyl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkyl, 5-8 membered heterocycloalkyl, 6-8 membered heterocycloalkyl, 7-8 membered heterocycloalkyl, 3-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl, 5-7 membered heterocycloalkyl, 6-7 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl, 3-10 membered heterocycloalkyl, 4-5 membered heterocycloalkyl, or 3-4 membered heterocycloalkyl. In other embodiments, "heterocycloalkyl" may be characterized by the number of carbon atoms in the ring, provided that the ring contains at least one heteroatom. For example, in some embodiments, "heterocycloalkyl" includes C3-C9 heterocycloalkyl, C3-C8 heterocycloalkyl, C3-C7 heterocycloalkyl, C3-C6 heterocycloalkyl, C3-C5 heterocycloalkyl, C3-C4 heterocycloalkyl, C4-C9 heterocycloalkyl, C4-C8 heterocycloalkyl, C4-C7 heterocycloalkyl, C4-C6 heterocycloalkyl, C4-C5 heterocycloalkyl, C5-C9 heterocycloalkyl, C5-C8 heterocycloalkyl, C5-C7 heterocycloalkyl, C5-C6 heterocycloalkyl, C6-C9 heterocycloalkyl, C6-C8 heterocycloalkyl, C6-C7 heterocycloalkyl, C6-C9 heterocycloalkyl, C6-C8 heterocycloalkyl, C6-C7 heterocycloalkyl, C7-C9 heterocycloalkyl, C7-C8 heterocycloalkyl, or C8-C9 heterocycloalkyl. It is understood that "heterocycloalkyls" described by the number of ring atoms can also be described by the number of carbon atoms in the ring.For example, a piperazinyl ring can be described as a C4 heterocycloalkyl ring or a 6-membered heterocycloalkyl ring, and an azetidinyl or oxetanyl ring can be described as a C3 heterocycloalkyl ring or a 4-membered heterocycloalkyl ring, respectively.

[0030] The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkane and is exemplified by -CHCHCHCH-. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms. In some embodiments, an alkyl (or alkylene) group has 10 or fewer carbon atoms.

[0031] The term "heteroalkylene" by itself or as part of another substituent means a saturated or unsaturated or polyunsaturated divalent radical derived from heteroalkyl and is exemplified by -CH-CH-S-CHCH-, -CH-S-CH-CH-NH-CH-, -O-CH-CH=CH-, -CH-CH=C(H)CH-O-CH-, and -S-CH-C≡C-. In heteroalkylene groups, heteroatoms can also occupy either or both chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).

[0032] The term "heterocycloalkylene" by itself or as part of another substituent means a saturated or unsaturated or polyunsaturated divalent radical derived from a heterocycloalkyl. In a heterocycloalkylene group, heteroatoms can also occupy either or both of the chain termini.

[0033] The terms "alkoxy" and "alkylamino" are used in the conventional sense to refer to an alkyl group attached to the remainder of the molecule via an oxygen atom or an amino group, respectively.

[0034] The term "heterocycloalkoxy" refers to a heterocycloalkyl-O- group in which the heterocycloalkyl group is as previously described herein.

[0035] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "C1-C4 haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like.

[0036] The term "haloalkyl-OH" refers to a haloalkyl group as defined above that is further substituted with one or more hydroxyl groups. The term "haloalkyl-OH" is intended to include haloalkyl substituted with one hydroxyl group and haloalkyl substituted with multiple hydroxyl groups. For example, the term "haloalkyl-OH" includes -CH(F)OH, -CHCFHCHOH, -CH(OH)CF, and the like.

[0037] The term "alkyl-OH" refers to an alkyl substituted with one or more hydroxyl groups. The term "alkyl-OH" is intended to include alkyl substituted with one hydroxyl group and alkyl substituted with multiple hydroxyl groups. For example, the term "alkyl-OH" includes -CHOH, -CH(OH)CH, -CHCHOH, etc.

[0038] The term "aryl," unless otherwise specified, refers to a polyunsaturated hydrocarbon group, typically an aromatic hydrocarbon group, which may be a single ring or multiple rings (up to three rings) fused together. In some embodiments, "aryl" refers to a C6-C 14 Aryl, C8-C 14 Aryl, C 10 -C 14Aryl, C 12 -C 14 Aryl, C6-C 12 Aryl, C8-C 12 Aryl, C 10 -C 12 Aryl, C6-C 10 Aryl, C8-C 10 aryl, or C6-C8 aryl. In some cases, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other cases, a polycyclic aryl group can include a non-aromatic ring fused to an aromatic ring, provided that the polycyclic aryl group is attached to the parent structure through an atom in the aromatic ring. Thus, a 1,2,3,4-tetrahydronaphthalen-5-yl group (which is attached to the parent structure through an aromatic carbon atom) is considered an aryl group, while a 1,2,3,4-tetrahydronaphthalen-1-yl group (which is attached to the parent structure through a non-aromatic carbon atom) is not considered an aryl group. Similarly, a 1,2,3,4-tetrahydroquinolin-8-yl group (which is attached to the parent structure through an aromatic carbon atom) is considered an aryl group, while a 1,2,3,4-tetrahydroquinolin-1-yl group (which is attached to the parent structure through a non-aromatic nitrogen atom) is not considered an aryl group. However, the term "aryl" does not encompass or overlap with "heteroaryl," as defined herein, regardless of point of attachment (e.g., quinolin-5-yl and quinolin-2-yl are both heteroaryl groups). In some cases, aryl is phenyl or naphthyl. In certain cases, aryl is phenyl.

[0039] The term "heteroaryl" refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from the group consisting of N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom, valence permitting. In some cases, both rings of a polycyclic heteroaryl group are aromatic. In other cases, a polycyclic heteroaryl group can contain a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, provided that the polycyclic heteroaryl group is attached to the parent structure through an atom in an aromatic ring. For example, a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (which is attached to the parent structure through an aromatic carbon atom) is considered a heteroaryl group, while a 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl group (which is attached to the parent structure through a non-aromatic carbon atom) is not considered a heteroaryl group.

[0040] Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, and non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindol ... Examples thereof include indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, and thienyl. In some embodiments, the term "heteroaryl" includes 5-10 membered heteroaryl, 6-10 membered heteroaryl, 7-10 membered heteroaryl, 8-10 membered heteroaryl, 9-10 membered heteroaryl, 5-9 membered heteroaryl, 6-9 membered heteroaryl, 7-9 membered heteroaryl, 8-9 membered heteroaryl, 5-8 membered heteroaryl, 6-8 membered heteroaryl, 7-8 membered heteroaryl, 5-7 membered heteroaryl, 6-7 membered heteroaryl, or 5-6 membered heteroaryl.

[0041] In some embodiments, the above terms (e.g., "alkyl," "aryl," and "heteroaryl") include both substituted and unsubstituted forms of the indicated radical. The term "substituted" means that the specified group or moiety has one or more substituents, for example, but not limited to, alkoxy, acyl, acyloxy, alkoxycarbonyl, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, and the like. The term "unsubstituted" means that the specified group has no substituents. When the term "substituted" is used to describe a structural system, it is meant that substitution occurs in any position allowed by the valences of the system. When a group or moiety has multiple substituents, it is understood that the substituents may be the same or different from one another. In some embodiments, a substituted group or moiety has 1 to 5 substituents. In some embodiments, a substituted group or moiety has 1 substituent. In some embodiments, a substituted group or moiety has 2 substituents. In some embodiments, a substituted group or moiety has 3 substituents. In some embodiments, a substituted group or moiety has 4 substituents. In some embodiments, a substituted group or moiety has 5 substituents.

[0042] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description is intended to encompass both the occurrence and non-occurrence of the event or circumstance. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl," as defined herein. Those of skill in the art will understand that with respect to any group containing one or more substituents, it is not intended that such group introduce any substitution or substitution pattern that is sterically impractical, synthetically impractical, and / or inherently unstable. It will also be understood that when a group or moiety is optionally substituted, the present disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.

[0043] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), boron (B), and silicon (Si).

[0044] As used herein, the term "chiral" refers to a molecule that has the property of not being superimposable on its mirror image partner, while the term "achiral" refers to a molecule that is superimposable on its mirror image partner.

[0045] As used herein, the term "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0046] As used herein, a wavy line "" crossing a bond in a chemical structure [ka] " indicates the point of attachment of the atom to which the wavy bond is connected in the chemical structure to the rest of the molecule or the rest of a molecular fragment.

[0047] As used herein, the group within the brackets (e.g., X a) followed by a subscript to represent an integer range (e.g., (X a ) 0-1 ) means that the group can have the number of occurrences indicated by the integer range. For example, (X a ) 0-1 is X a This means that the group is absent or occurs once.

[0048] "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers differ in physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography.

[0049] "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0050] Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994. The compounds of the present disclosure may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present disclosure, including but not limited to diastereomers, enantiomers, and atropisomers, as well as mixtures thereof, such as racemic mixtures, are intended to form part of the present disclosure. Many organic compounds exist in optically active forms, i.e., have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are used to indicate the sign of rotation of plane-polarized light by a compound; (-) or l means the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0051] As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0052] As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules with a compound of the present disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water. Certain compounds of the present disclosure can exist in solvated forms, including hydrated forms, as well as unsolvated forms. In general, solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure.

[0053] As used herein, the term "cocrystal" refers to a solid that is not a solvate or a simple salt and is a crystalline, single-phase substance generally composed of two or more different molecular or ionic compounds in a stoichiometric ratio. A cocrystal consists of two or more components that form a unique crystal structure with unique properties. Cocrystals are typically characterized by a crystal structure that is generally held together by freely reversible, non-covalent interactions. As used herein, a cocrystal refers to a compound of the present disclosure and at least one other component that form a crystal structure in a defined stoichiometric ratio.

[0054] As used herein, the term "protecting group" refers to a substituent typically employed to block or protect a particular functional group in a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality of the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of a carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl, and the like. For a general description of protecting groups and their use, see P. G. M. Butts and T. W. Greene, "Greene's Protective Groups in Organic Synthesis 4" th See, e.g., Wiley-Interscience, New York, 2006.

[0055] As used herein, the term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. When a compound of the present disclosure contains a relatively acidic functionality, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholinium, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present disclosure contains a relatively basic functionality, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.Also included are salts of amino acids such as arginine acid, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0056] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of this disclosure.

[0057] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; all racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., separate enantiomers) are intended to be encompassed within the scope of the present disclosure.

[0058] The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more atomic positions that constitute such compounds.For example, the present disclosure also encompasses isotopically labeled variants of the present disclosure, which are identical to those detailed herein, except that one or more atoms are replaced with atoms that have atomic masses or mass numbers different from the primary atomic masses or mass numbers that are normally found for such atoms in nature.All isotopes of any specified specific atoms or elements are intended to be within the scope of the compounds of the present disclosure, including isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example, 2 H("D"), 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Certain isotopically labeled compounds of the present disclosure, such as 3 H or 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon 14 ( 14 C) isotopes are useful for their ease of preparation and detectability. Heavier isotopes, such as deuterium (i.e., 2 Further substitution with positron-emitting isotopes, such as H, may be preferred in some circumstances as they may offer certain therapeutic advantages resulting from increased metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). 15 O. 13 N, 11 C, and 18 F is useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared following procedures analogous to those disclosed in the following schemes and / or examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0059] "Treating" or "treatment" of a patient's disease refers to inhibiting or reducing the occurrence of the disease; or ameliorating or causing regression of the disease. As used herein, "treatment" or "treating" is an effort to achieve a beneficial or desired result, including a clinical result. For purposes of this disclosure, a beneficial or desired result includes, but is not limited to, one or more of the following: reducing one or more symptoms attributable to a patient's disease or disorder, attenuating the severity of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying worsening of the disease or disorder), delaying the onset or recurrence of the disease or disorder, delaying or slowing the progression of the disease or disorder, improving the state of the disease or disorder, causing remission (whether partial or complete) of the disease or disorder, reducing the dose of one or more other drugs required to treat the disease or disorder, enhancing the effectiveness of another drug used to treat the disease or disorder, delaying the progression of the disease or disorder, improving quality of life, and / or prolonging survival. Alleviation of the pathological consequences of a disease or disorder is also encompassed by “treatment.” The methods of the present disclosure contemplate any one or more of these aspects of treatment.

[0060] "Preventing," "prevention," or "prophylaxis" of a disease in a patient refers to barring the occurrence of the disease in a patient who is predisposed to or who does not yet exhibit symptoms of the disease.

[0061] The phrase "therapeutically effective amount" refers to an amount of a compound of the present disclosure that (i) treats or prevents a particular disease, condition, or disorder described herein, (ii) attenuates, ameliorate, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder.

[0062] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

[0063] For clarity, certain features of the present disclosure are described in the context of separate embodiments, but it is recognized that they can also be provided in combination in a single embodiment. Conversely, for brevity, various features of the present invention are described in the context of a single embodiment, but they can also be provided separately or in any suitable subcombination. All combinations of the embodiments with respect to chemical groups represented by the variables are specifically encompassed by the present invention and are disclosed herein as if every combination were individually and explicitly disclosed, to the extent that such combinations include compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of chemical groups listed in the embodiments describing such variables are also specifically encompassed by the present invention and are disclosed herein as if every subcombination of such chemical groups were individually and explicitly disclosed.

[0064] II. Compounds In one embodiment, a compound of formula (I') [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: Ring A is [ka] and E is -C(=O)-R 1 and G is -O-, -C(=O)-, -S-, -S(O)-, -S(O)2-, or -CH2-; V is O, S, or NR 2 and each X 1are independently N or CH; X 2 is O, S, or NR 3 and Y is N or CR y where R y is -H or -F, Z is -H, halogen, -C≡CH, -OCH3, or C1-C2 alkyl; R 1 is a C2-C4 alkenyl or a C2-C4 alkynyl, each of which is independently halogen, C1-C3 alkyl, a 3- to 7-membered carbon-linked N-heterocycloalkyl, or —NR 1a R 1b and optionally substituted with 1 to 4 substituents selected from the group consisting of: 1a and R 1b are independently -H, C1-C3 alkyl, or -CD3, or a geminal R 1a and R 1b each pair of can be taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered N-heterocyclyl, where the nitrogen atom of each heterocyclyl, if present, is independently optionally substituted with C-C alkyl; R 2 is C1-C6 alkyl or C1-C6 cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines; R 3 is -H, C1-C6 alkyl, -CD3 or C1-C6 cycloalkyl; R 4 is -H or a halogen, R 5 is -H or a halogen, R 6 is -H or a halogen, R 7 is -H, halogen, C1-C6 alkyl, -CD3 or C1-C6 cycloalkyl; n is 1 or 2, p is 0 or 1, q is 1 or 2.

[0065] In some embodiments, n is 1 or 2. In some embodiments, n is 1. In other embodiments, n is 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In other embodiments, p is 1. In some embodiments, q is 1 or 2. In some embodiments, q is 1. In other embodiments, q is 2. In some embodiments, n is 1, p is 0, and q is 1. In some embodiments, n is 1, p is 0, and q is 2. In some embodiments, n is 1, p is 1, and q is 1. In some embodiments, n is 1, p is 1, and q is 2. In some embodiments, n is 2, p is 0, and q is 1. In some embodiments, n is 2, p is 0, and q is 2. In some embodiments, n is 2, p is 1, and q is 1. In some embodiments, n is 2, p is 1, and q is 2.

[0066] In some embodiments, the compound of formula (I') is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: Ring A is [ka] and E is -C(=O)-R 1 and G is -O-, -C(=O)-, -S-, -S(O)-, -S(O)2-, or -CH2-; V is O, S, or NR 2 and each X 1 are independently N or CH; X 2 is O, S, or NR 3 and Y is N or CR y where R y is -H or -F, Z is -H, halogen, -C≡CH, -OCH3, or C1-C2 alkyl; R 1 is a C2-C4 alkenyl or a C2-C4 alkynyl, each of which is independently halogen, C1-C3 alkyl, a 3- to 7-membered carbon-linked N-heterocycloalkyl, or —NR 1a R 1b and optionally substituted with 1 to 4 substituents selected from the group consisting of: 1a and R 1b are independently -H, C1-C3 alkyl, or -CD3, or a geminal R 1a and R 1b each pair of can be taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered N-heterocyclyl, where the nitrogen atom of each heterocyclyl, if present, is independently optionally substituted with C-C alkyl; R 2 is C1-C6 alkyl or C1-C6 cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines; R 3 is -H, C1-C6 alkyl, -CD3 or C1-C6 cycloalkyl; R 4 is -H or a halogen, R 5 is -H or a halogen, R 6 is —H or a halogen.

[0067] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0068] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0069] In some embodiments, ring A is [ka] and R3 is -H, C1-C6 alkyl, -CD3, or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0070] In some embodiments, ring A is [ka] is.

[0071] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0072] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, the ring is [ka] is.

[0073] In some embodiments, R 3 is -H, C1-C6 alkyl, -CD3, or C1-C6 cycloalkyl. In some embodiments, R 3 is —H. In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, [ka] In some embodiments, R 3 is -H or -CH3. In some embodiments, R 3 is —H. In some embodiments, R 3 is -CH3. In some embodiments, R 3 is -CD3.

[0074] In some embodiments, R 7 is -H, halogen, C1-C6 alkyl, -CD3, or C1-C6 cycloalkyl. 7 is —H. In some embodiments, R 7 is halogen. In some embodiments, R 7 is F, Cl, or I. In some embodiments, R 7 is F. In some embodiments, R 7 is Cl. In some embodiments, R 7 is C1-C6 alkyl. In some embodiments, R 7 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, [ka] In some embodiments, R 7 is -H, F, -CH, or -CHCH. In some embodiments, R 7 is —H. In some embodiments, R 7 is F. In some embodiments, R 7 is -CH3. In some embodiments, R 7 is -CH2CH3. In some embodiments, R 7 is -CD3.

[0075] In some embodiments, R 3 is C1-C6 cycloalkyl. In some embodiments, R 3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0076] In some embodiments, ring A is [ka] and R 3 is -H, C1-C6 alkyl, -CD3, or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] and R 3 is -H, C1-C6 alkyl, -CD3, or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] and R 3 is —H or C1-C6 alkyl. In some embodiments, ring A is [ka] and R 3 is C1-C6 alkyl or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] and R 3 is —H or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] and R 3 In some embodiments, ring A is -CD3. [ka] In some embodiments, ring A is [ka] and R 3 is -H, C1-C6 alkyl, -CD3, or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] and R 3 is —H or C1-C6 alkyl. In some embodiments, ring A is [ka] and R 3 is C1-C6 alkyl or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] and R 3 is —H or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] and R 3 In some embodiments, ring A is -CD3. [ka] is.

[0077] In some embodiments, ring A is [ka] and R 3 is -H, C1-C6 alkyl, -CD3, or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] and R 3 is —H or C1-C6 alkyl. In some embodiments, ring A is [ka] and R 3 is —H or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] and R 3 is C1-C6 alkyl or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] and R 3 is C1-C6 alkyl. In some embodiments, ring A is [ka] and R 3 In some embodiments, ring A is -CD3. [ka] and R 3 is -H, C1-C6 alkyl, -CD3, or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] and R 3 is —H or C1-C6 alkyl. In some embodiments, ring A is [ka] and R 3 is —H or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] and R 3 is C1-C6 alkyl or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] and R 3 is C1-C6 alkyl. In some embodiments, ring A is [ka] and R 3 In some embodiments, ring A is -CD3. [ka] and R 3 is C1-C6 cycloalkyl. In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0078] In some embodiments, ring A is [ka] and R 7 is -H, halogen, C1-C6 alkyl, -CD3, or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] and R 7is -H, or halogen. In some embodiments, ring A is [ka] and R 7 is —H, or C1-C6 alkyl. In some embodiments, ring A is [ka] and R 7 is —H or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] and R 7 is C1-C6 alkyl or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] and R 7 is halogen or C1-C6 alkyl. In some embodiments, ring A is [ka] and R 7 is halogen. In some embodiments, ring A is [ka] and R 7 is C1-C6 alkyl. In some embodiments, ring A is [ka] and R 7 In some embodiments, ring A is -CD3. [ka] and R 7is -H, halogen, C1-C6 alkyl, -CD3, or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] and R 7 is -H, or halogen. In some embodiments, ring A is [ka] and R 7 is —H, or C1-C6 alkyl. In some embodiments, ring A is [ka] and R 7 is —H or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] and R 7 is halogen, or C1-C6 alkyl. In some embodiments, ring A is [ka] and R 7 is C1-C6 alkyl or C1-C6 cycloalkyl. In some embodiments, ring A is [ka] and R 7 is C1-C6 alkyl. In some embodiments, ring A is [ka] and R 7 In some embodiments, ring A is -CD3. [ka] and R7 is C1-C6 alkyl. In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] and R 7 is halogen. In some embodiments, ring A is [ka] is.

[0079] In some embodiments, Z is -H, halogen, -C≡CH, -OCH3, or C1-C2 alkyl. In some embodiments, Z is -H, -F-Cl, -Br, -I, -C≡CH, -OCH3, -CH3, or -CH2CH3. In some embodiments, Z is -H, -F, -Cl, -C≡CH, -OCH3, or -CH3. In some embodiments, Z is -H, -F, -Cl, or -CH3. In some embodiments, Z is -H, -F, -Cl, -CH3, or -CH2CH3. In some embodiments, Z is -CH3. In some embodiments, Z is -H, -F, -Cl, or -CH3. In some embodiments, Z is -F, -Cl, -CH3, or -CH2CH3. In some embodiments, Z is -H, -F, -Cl, or -CH3. In some embodiments, Z is -F, -Cl, -CH3, or -CH2CH3. In some embodiments, Z is -H, -F, or -Cl. In some embodiments, Z is -F or -Cl. In some embodiments, Z is -H or -F. In some embodiments, Z is -H or -Cl. In some embodiments, Z is -H, -CH3, or -CH2CH3. In some embodiments, Z is -H or -CH3. In some embodiments, Z is -CH3 or -CH2CH3. In some embodiments, Z is -H. In some embodiments, Z is halogen. In some embodiments, Z is -F. In some embodiments, Z is -Cl. In some embodiments, Z is -C≡CH. In some embodiments, Z is -OCH3. In some embodiments, Z is -CH3. In some embodiments, Z is -CH2CH3.

[0080] In some embodiments, R 1 is C2-C4 alkenyl and is not a halogen or -NR 1a R 1b and optionally substituted with 1 to 4 substituents selected from the group consisting of: 1a and R 1bare independently -H, C1-C3 alkyl, or -CD3, or a geminal R 1a and R 1b Each pair of can be taken together with the nitrogen atom to which they are attached to form a 3-6 membered N-heterocyclyl, where the nitrogen atom of each heterocyclyl, if present, is independently optionally substituted with C1-C3 alkyl. 1 is unsubstituted C-C alkenyl. In some embodiments, R 1 is -CH=CH2, -CH=CH-CH3, or -C(CH3)=CH2. In some embodiments, R 1 is -CH=CH2, -CH=CH-CH3, -CH=CH-CH2-CH3 or -C(CH3)=CH2.

[0081] In some embodiments, R 1 is a C2-C4 alkenyl, optionally substituted with 1 to 4 substituents selected from the group consisting of halogen. 1 is C2-C4 alkenyl, optionally substituted with 1 to 4 substituents selected from the group consisting of -F, -Cl, -Br, and -I. In some embodiments, R 1 is -CH=CH2, -CH=CH-CH3, or -C(CH3)=CH2, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of -F, -Cl, -Br, and -I. In some embodiments, R 1 is -CH=CH2 or -CH=CH-CH3, and is optionally substituted with 1 to 4 substituents selected from the group consisting of -F, -Cl, -Br, and -I. 1 is -CF=CH2.

[0082] In some embodiments, R 1is C2-C4 alkenyl, optionally substituted with 1 to 4 substituents selected from the group consisting of C1-C3 alkyl. 1 is C2-C4 alkenyl, optionally substituted with 1 to 4 substituents selected from the group consisting of C1-C3 alkyl. 1 is -CH=CH2, -CH=CH-CH3, or -C(CH3)=CH2, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of C1-C3 alkyl. In some embodiments, R 1 is -CH=CH2 or -CH=CH-CH3, optionally substituted with 1 to 4 substituents selected from the group consisting of C1-C3 alkyl.

[0083] In some embodiments, R 1 is a C2-C4 alkenyl, optionally substituted with 1 to 4 substituents selected from the group consisting of 3- to 7-membered carbon-linked N-heterocycloalkyl. 1 is a C2-C4 alkenyl optionally substituted with 1 to 4 substituents selected from the group consisting of 3-7 membered carbon-linked N-heterocycloalkyl, where the nitrogen atom of each heterocyclyl, if present, is independently optionally substituted with a C1-C3 alkyl. 1 is -CH=CH2, -CH=CH-CH3, or -C(CH3)=CH2, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3-7 membered carbon-linked N-heterocycloalkyl, where the nitrogen atom of each heterocyclyl, if present, is independently optionally substituted with C1-C3 alkyl. 1is -CH=CH2 or -CH=CH-CH3, optionally substituted with 1 to 4 substituents selected from the group consisting of 3-7 membered carbon-linked N-heterocycloalkyl, where the nitrogen atom of each heterocyclyl, if present, is independently optionally substituted with C1-C3 alkyl. 1 is CH=CH2 or -CH=CH-CH3, each of which independently represents [ka] is optionally substituted with 1 to 4 substituents selected from the group consisting of:

[0084] In other embodiments, R 1 is C2-C4 alkenyl, -NR 1a R 1b and optionally substituted with 1 to 4 substituents selected from the group consisting of: 1a and R 1b are independently -H, C1-C3 alkyl, or -CD3, or a geminal R 1a and R 1b Each pair of can be taken together with the nitrogen atom to which they are attached to form a 3-6 membered N-heterocyclyl, where the nitrogen atom of each heterocyclyl, if present, is independently optionally substituted with C1-C3 alkyl. 1 is C2-C4 alkenyl, -NR 1a R 1b and optionally substituted with 1 to 4 substituents selected from the group consisting of: 1a and R 1b is independently -H, C1-C3 alkyl, or -CD3. In other embodiments, R 1 is C2-C4 alkenyl, -NR 1a R 1b and optionally substituted with 1 to 4 substituents selected from the group consisting of: 1a and R 1bEach pair of can be taken together with the nitrogen atom to which they are attached to form a 3-6 membered N-heterocyclyl, where the nitrogen atom of each heterocyclyl, if present, is independently optionally substituted with C1-C3 alkyl. 1 is -CH=CH2, -CH=CH-CH3, or -C(CH3)=CH2, each of which is independently -NH2, -NH(methyl), -NH(ethyl), -NH(n-propyl), -NH(isopropyl), -N(methyl)(methyl), -N(methyl)(ethyl), -N(methyl)(n-propyl), -N(methyl)(isopropyl), -N(ethyl)(ethyl), -N(ethyl)(n-propyl), -N(ethyl)(isopropyl), -N(n-propyl)(n-propyl), -N(n-propyl)(isopropyl), -N(isopropyl)(isopropyl), [ka] In some embodiments, R 1 is -CH=CH2. In another embodiment, R 1 is -CH=CH-CH2-N(CH3)2.

[0085] In some embodiments, R 1 is C2-C4 alkynyl and is halogen or -NR 1a R 1b and optionally substituted with 1 to 4 substituents selected from the group consisting of: 1a and R 1b are independently -H, C1-C3 alkyl, or -CD3, or a geminal R 1a and R 1b Each pair of can be taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered N-heterocyclyl. 1 is an unsubstituted C2-C4 alkynyl. In some embodiments, R 1is -C≡CH, -C≡C-CH, or -CH-C≡CH. In some embodiments, R 1 is -C≡C-CH3.

[0086] In some embodiments, R 1 is a C2-C4 alkynyl, optionally substituted with 1 to 4 substituents selected from the group consisting of halogen. 1 is a C2-C4 alkynyl, optionally substituted with 1 to 4 substituents selected from the group consisting of -F, -Cl, -Br, and -I. 1 is -C≡CH, -C≡C-CH, or -CH-C≡CH, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of -F, -Cl, -Br, and -I. In some embodiments, R 1 is —C≡CH or —C≡C—CH 3 , optionally substituted with 1 to 4 substituents selected from the group consisting of —F, —Cl, —Br, and —I.

[0087] In some embodiments, R 1 is a C2-C4 alkynyl, optionally substituted with 1 to 4 substituents selected from the group consisting of C1-C3 alkyl. 1 is -C≡CH, -C≡C-CH, or -CH-C≡CH, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of C-C alkyl. 1 is -C≡CH or -C≡C-CH3, optionally substituted with 1 to 4 substituents selected from the group consisting of C1-C3 alkyl.

[0088] In some embodiments, R 1is a C2-C4 alkynyl optionally substituted with 1 to 4 substituents selected from the group consisting of 3-7 membered carbon-linked N-heterocycloalkyl, wherein the nitrogen atom of each heterocyclyl, if present, is independently optionally substituted with a C1-C3 alkyl. 1 is -C≡CH, -C≡C-CH, or -CH-C≡CH, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3-7 membered carbon-linked N-heterocycloalkyl, where the nitrogen atom of each heterocyclyl, if present, is independently optionally substituted with C-C alkyl. 1 is -C≡CH or -C≡C-CH3 and is optionally substituted with 1 to 4 substituents selected from the group consisting of 3-7 membered carbon-linked N-heterocycloalkyl, where the nitrogen atom of each heterocyclyl, if present, is independently optionally substituted with C1-C3 alkyl. 1 is —C≡CH or —C≡C—CH3, each of which independently represents [ka] is optionally substituted with 1 to 4 substituents selected from the group consisting of:

[0089] In some embodiments, R 1 is C2-C4 alkynyl, -NR 1a R 1b and optionally substituted with 1 to 4 substituents selected from the group consisting of: 1a and R 1b are independently -H, C1-C3 alkyl, or -CD3, or a geminal R 1a and R 1bEach pair of can be taken together with the nitrogen atom to which they are attached to form a 3-6 membered N-heterocyclyl, where the nitrogen atom of each heterocyclyl, if present, is independently optionally substituted with C1-C3 alkyl. 1 is C2-C4 alkynyl and is halogen or -NR 1a R 1b and optionally substituted with 1 to 4 substituents selected from the group consisting of: 1a and R 1b is independently -H, C1-C3 alkyl, or -CD3. In some embodiments, R 1 is C2-C4 alkynyl and is halogen or -NR 1a R 1b and optionally substituted with 1 to 4 substituents selected from the group consisting of: 1a and R 1b Each pair of can be taken together with the nitrogen atom to which they are attached to form a 3-6 membered N-heterocyclyl, where the nitrogen atom of each heterocyclyl, if present, is independently optionally substituted with C1-C3 alkyl. 1 is -C≡CH, -C≡C-CH, or -CH-C≡CH, each of which is independently -NH, -NH(methyl), -NH(ethyl), -NH(n-propyl), -NH(isopropyl), -N(methyl)(methyl), -N(methyl)(ethyl), -N(methyl)(n-propyl), -N(methyl)(isopropyl), -N(ethyl)(ethyl), -N(ethyl)(n-propyl), -N(ethyl)(isopropyl), -N(n-propyl)(n-propyl), -N(n-propyl)(isopropyl), -N(isopropyl)(isopropyl), [ka] is optionally substituted with 1 to 4 substituents selected from the group consisting of:

[0090] In some embodiments, R 1The double bond of a C2-C4 alkenyl or the triple bond of a C2-C4 alkynyl is R 1 is conjugated to the carbonyl to which it is attached.

[0091] In some embodiments, Y is N. In other embodiments, Y is CR y where R y is -H or -F. In some embodiments, Y is CR y where R y In other embodiments, Y is -CR y where R y In some embodiments, Y is N or CR y where R y In some embodiments, Y is N or CR y where R y is -F.

[0092] In some embodiments, V is O or S. In some embodiments, V is O or NR 2 In some embodiments, V is S or NR 2 In some embodiments, V is O. In other embodiments, V is S. In other embodiments, V is NR 2 is.

[0093] In some embodiments, V is NR 2 and R 2 is C1-C6 alkyl optionally substituted with 1 to 4 fluorines. In some embodiments, V is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, [ka] is.

[0094] In some embodiments, V is NR 2 and R 2 is C1-C6 cycloalkyl optionally substituted with 1 to 4 fluorines. In some embodiments, V is NR 2 and R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0095] In some embodiments, Y is N and V is O or S. In some embodiments, Y is N and V is O or NR 2 In some embodiments, Y is N and V is S or NR 2 In some embodiments, Y is CR y and V is O or NR 2 In some embodiments, Y is CR y and V is S or NR 2 In some embodiments, Y is N or CR y and V is O. In some embodiments, Y is N or CR y and V is S. In some embodiments, Y is N or CR y and V is NR 2 is.

[0096] In some embodiments, Y is N and V is O. In some embodiments, Y is N and V is S. In some embodiments, Y is N and V is NR 2 In some embodiments, Y is CR y and V is O or S. In some embodiments, Y is CR y and V is O. In some embodiments, Y is CR y and V is S. In some embodiments, Y is CR y and V is NR 2 is.

[0097] In some embodiments, G is -O-, -C(=O)-, -S-, -S(O)-, -S(O)2-, or -CH2-. In some embodiments, G is -O-, -S-, or -CH2-. In some embodiments, G is -C(=O)-, -S(O)-, or -S(O)2-. In some embodiments, G is -O-, -C(=O)-, or -CH2-. In some embodiments, G is -O- or -S-. In some embodiments, G is -O- or -CH2-. In some embodiments, G is -C(=O) or -S(O)-. In some embodiments, G is -O-. In other embodiments, G is -C(=O)-. In other embodiments, G is -S-, -S(O)-, or -S(O)2-. In other embodiments, G is -CH2-.

[0098] In some embodiments, R 4 is —H. In other embodiments, R 4 is halogen. In some embodiments, R 4 is -F, -Cl, -Br, or -I. In other embodiments, R 4 is -F. In some embodiments, R 5 is —H. In other embodiments, R 5 is halogen. In some embodiments, R 5 is -F, -Cl, -Br, or -I. In some embodiments, R 5 is -F. In some embodiments, R 4 is -H, and R 5 is —H. In some embodiments, R 4 is -H, and R 5 is -F. In some embodiments, R 4 is -F and R 5 is —H. In some embodiments, R 4 is -F and R 5 is -F.

[0099] In some embodiments, R 6 is —H. In other embodiments, R 6 is halogen. In some embodiments, R 6 is -F, -Cl, -Br, or -I. In some embodiments, R 6 is -H, -F, or -Cl. In some embodiments, R 6 is -F. In other embodiments, R 6 is -Cl.

[0100] In some embodiments, the compound of Formula (I) is a compound of Formula (Ia-1), (Ia-2), or (Ia-3): [ka] and In the formula, R 4 , R 5 , E, Y, Z, G, and ring A are as defined for Formula (I). In some embodiments, the compound is a compound of Formula (Ia-1). In some embodiments, the compound is a compound of Formula (Ia-2). In some embodiments, the compound is a compound of Formula (Ia-3). In any variation of Formula (Ia-1), (Ia-2), or (Ia-3), Z is -H, -F-Cl, -Br, -I, -C≡CH, -OCH3, -CH3, or -CH2CH3; Y is N, CH, or CF; G is -O-, -C(=O)-, -S-, -S(O)-, -S(O)2-, or -CH2-; and ring A is [ka] In some embodiments, ring A is [ka] and R 3is —H, C1-C6 alkyl, —CD3, or C1-C6 cycloalkyl. In some variations, R in Formula (Ia-1), (Ia-2), or (Ia-3) 4 , R 5 , E, Y, Z, G, and ring A are as defined for a compound of formula (I'), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.

[0101] In some embodiments, the compound of Formula (I') is a compound of Formula (I'-a-1), (I'-a-2), or (I'-a-3): [ka] and In the formula, R 4 , R 5 , R 7 , E, Y, Z, G, ring A, n, p, and q are as defined for (I'). In some embodiments, the compound is a compound of formula (I'-a-1). In some embodiments, the compound is a compound of formula (I'-a-2). In some embodiments, the compound is a compound of formula (I'-a-3). In any variation of formula (I'-a-1), (I'-a-2), or (I'-a-3), Z is -H, -F, -Cl, -Br, -I, -C≡CH, -OCH3, -CH3, or -CH2CH3; Y is N, CH, or CF; G is -O-, -C(=O)-, -S-, -S(O)-, -S(O)2-, or -CH2-; and ring A is [ka] In some embodiments, ring A is [ka] where R 3 is -H, C1-C6 alkyl, -CD3 or C1-C6 cycloalkyl, and R 7is -H, halogen, C1-C6 alkyl, -CD3, or C1-C6 cycloalkyl.

[0102] In some embodiments, the compound of Formula (I) is a compound of Formula (Ib-1) or (Ib-2): [ka] and In the formula, R 4 , R 5 ,E,V,R y , Z, G, and ring A are as defined for Formula (I). In some embodiments, the compound is a compound of Formula (Ib-1). In some embodiments, the compound is a compound of Formula (Ib-2). In any variation of Formula (Ib-1) or (Ib-2), Z is -H, -F, -Cl, -Br, -I, -C≡CH, -OCH3, -CH3, or -CH2CH3; V is O, S, or NR 2 where R 2 is C1-C6 alkyl or C1-C6 cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines; G is -O-, -C(=O)-, -S-, -S(O)-, -S(O)2-, or -CH2-; and ring A is [ka] In some embodiments, ring A is [ka] and R 3 is —H, C1-C6 alkyl, —CD3, or C1-C6 cycloalkyl. In some variations, R of formula (Ib-1) or (I-b-2) 4 , R 5 ,E,V,R y , Z, G, and ring A are as defined for a compound of formula (I'), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.

[0103] In some embodiments, the compound of formula (I') is a compound of formula (I'-b-1) or (I'-b-2): [ka] and In the formula, R 4 , R 5 , R 7 ,E,V,R y , Z, G, ring A, n, p, and q are as defined for formula (I'). In some embodiments, the compound is a compound of formula (I'-b-1). In some embodiments, the compound is a compound of formula (I'-b-2). In any variation of formula (I'-b-1) or (I'-b-2), Z is -H, -F, -Cl, -Br, -I, -C≡CH, -OCH3, -CH3, or -CH2CH3; V is O, S, or NR 2 where R 2 is C1-C6 alkyl or C1-C6 cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines; G is -O-, -C(=O)-, -S-, -S(O)-, -S(O)2-, or -CH2-; and ring A is [ka] In some embodiments, ring A is [ka] where R 3 is -H, C1-C6 alkyl, -CD3 or C1-C6 cycloalkyl, and R 7 is -H, halogen, C1-C6 alkyl, -CD3, or C1-C6 cycloalkyl.

[0104] In some embodiments, the compound of Formula (I) is a compound of Formula (Ic-1), (Ic-2), (Ic-3), (Ic-4), (Ic-5), or (Ic-6): [ka] and In the formula, R 4 , R 5 , E, V, Y, Z, and ring A are as defined for Formula (I). In some embodiments, the compound is a compound of Formula (Ic-1). In some embodiments, the compound is a compound of Formula (Ic-2). In some embodiments, the compound is a compound of Formula (Ic-3). In some embodiments, the compound is a compound of Formula (Ic-4). In some embodiments, the compound is a compound of Formula (Ic-5). In some embodiments, the compound is a compound of Formula (Ic-6). In any variation of Formula (Ic-1), (Ic-2), (Ic-3), (Ic-4), (Ic-5), or (Ic-6), Z is -H, -F, -Cl, -Br, -I, -C≡CH, -OCH, -CH, or -CHCH; Y is N, CH, or CF; and V is O, S, or NR 2 where R 2 is C1-C6 alkyl or C1-C6 cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines, and Ring A is [ka] In some embodiments, ring A is [ka] and R 3 is —H, C1-C6 alkyl, —CD3, or C1-C6 cycloalkyl. In some variations, R of formula (Ic-1), (Ic-2), (Ic-3), (Ic-4), (Ic-5), or (Ic-6) 4 , R 5, E, V, Y, Z, and ring A are as defined for a compound of formula (I'), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.

[0105] In some embodiments, the compound of Formula (I') is a compound of Formula (I'-c-1), (I'-c-2), (I'-c-3), (I'-c-4), (I'-c-5), or (I'-c-6): [ka] and In the formula, R 4 , R 5 , R 7 , E, V, Y, Z, ring A, n, p, and q are as defined for formula (I'). In some embodiments, the compound is a compound of formula (I'-c-1). In some embodiments, the compound is a compound of formula (I'-c-2). In some embodiments, the compound is a compound of formula (I'-c-3). In some embodiments, the compound is a compound of formula (I'-c-4). In some embodiments, the compound is a compound of formula (I'-c-5). In some embodiments, the compound is a compound of formula (I'-c-6). In any variation of formula (I'-c-1), (I'-c-2), (I'-c-3), (I'-c-4), (I'-c-5), or (I'-c-6), Z is -H, -F, -Cl, -Br, -I, -C≡CH, -OCH, -CH, or -CHCH; Y is N, CH, or CF; and V is O, S, or NR 2 where R 2 is C1-C6 alkyl or C1-C6 cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines, and Ring A is [ka] In some embodiments, ring A is [ka] where R 3 is -H, C1-C6 alkyl, -CD3 or C1-C6 cycloalkyl, and R 7 is -H, halogen, C1-C6 alkyl, -CD3, or C1-C6 cycloalkyl.

[0106] In some embodiments, the compound of Formula (I) is a compound of Formula (Id-1), (Id-2), (Id-3), (Id-4), (Id-5), (Id-6), or (Id-7): [ka] and In the formula, R 1a , R 1b , R 4 , R 5 , V, Y, Z, G, and ring A are as defined for Formula (I). In some embodiments, the compound is a compound of Formula (Id-1). In some embodiments, the compound is a compound of Formula (Id-2). In some embodiments, the compound is a compound of Formula (Id-3). In some embodiments, the compound is a compound of Formula (Id-4). In some embodiments, the compound is a compound of Formula (Id-5). In some embodiments, the compound is a compound of Formula (Id-6). In some embodiments, the compound is a compound of Formula (Id-7). In any variation of formula (Id-1), (Id-2), (Id-3), (Id-4), (Id-5), (Id-6), or (Id-7), Z is -H, -F, -Cl, -Br, -I, -C≡CH, -OCH, -CH, or -CHCH; Y is N, CH, or CF; and V is O, S, or NR 2 where R 2is C1-C6 alkyl or C1-C6 cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines; G is -O-, -C(=O)-, -S-, -S(O)-, -S(O)2-, or -CH2-; and ring A is [ka] In some embodiments, ring A is [ka] and R 3 is —H, C1-C6 alkyl, —CD3, or C1-C6 cycloalkyl. In some variations, R of formula (Id-1), (Id-2), (Id-3), (Id-4), (Id-5), (Id-6), or (Id-7) 1a , R 1b , R 4 , R 5 , V, Y, Z, G, and ring A are as defined for a compound of formula (I'), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.

[0107] In some embodiments, the compound of Formula (I') is a compound of Formula (I'-d-1), (I'-d-2), (I'-d-3), (I'-d-4), (I'-d-5), (I'-d-6), or (I'-d-7): [ka] and In the formula, R 1a , R 1b , R 4 , R 5 , R 7, V, Y, Z, G, ring A, n, p, and q are as defined for formula (I'). In some embodiments, the compound is a compound of formula (I'-d-1). In some embodiments, the compound is a compound of formula (I'-d-2). In some embodiments, the compound is a compound of formula (I'-d-3). In some embodiments, the compound is a compound of formula (I'-d-4). In some embodiments, the compound is a compound of formula (I'-d-5). In some embodiments, the compound is a compound of formula (I'-d-6). In some embodiments, the compound is a compound of formula (I'-d-7). In any variation of formula (I'-d-1), (I'-d-2), (I'-d-3), (I'-d-4), (I'-d-5), (I'-d-6), or (I'-d-7), Z is -H, -F, -Cl, -Br, -I, -C≡CH, -OCH, -CH, or -CHCH; Y is N, CH, or CF; and V is O, S, or NR 2 where R 2 is C1-C6 alkyl or C1-C6 cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines; G is -O-, -C(=O)-, -S-, -S(O)-, -S(O)2-, or -CH2-; and ring A is [ka] In some embodiments, ring A is [ka] and R 3 is -H, C1-C6 alkyl, -CD3 or C1-C6 cycloalkyl, and R 7 is -H, halogen, C1-C6 alkyl, -CD3, or C1-C6 cycloalkyl.

[0108] In some embodiments, the compound of Formula (I) is a compound of Formula (Ie-1), (Ie-2), (Ie-3), (Ie-4), (Ie-5), (Ie-6), or (Ie-7): [ka] and In the formula, E, R 3 , R 4 , R 5 , V, Y, Z, G, X 1 , and X 2 is as defined for Formula (I). In some embodiments, the compound is a compound of Formula (Ie-1). In some embodiments, the compound is a compound of Formula (Ie-2). In some embodiments, the compound is a compound of Formula (Ie-3). In some embodiments, the compound is a compound of Formula (Ie-4). In some embodiments, the compound is a compound of Formula (Ie-5). In some embodiments, the compound is a compound of Formula (Ie-6). In some embodiments, the compound is a compound of Formula (Ie-7). In any variation of Formula (Ie-1), (Ie-2), (Ie-3), (Ie-4), (Ie-5), (Ie-6), or (Ie-7), Z is -H, -F, -Cl, -Br, -I, -C≡CH, -OCH, -CH, or -CHCH; Y is N, CH, or CF; and V is O, S, or NR 2 where R 2 is C1-C6 alkyl or C1-C6 cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines, and G is -O-, -C(=O)-, -S-, -S(O)-, -S(O)2-, or -CH2-. In some variations, E, R of formula (Ie-1), (Ie-2), (Ie-3), (Ie-4), (Ie-5), (Ie-6), or (Ie-7) 3 , R 4 , R 5 , V, Y, Z, G, X 1 , and X 2is as defined for a compound of formula (I'), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.

[0109] In some embodiments, the compound of Formula (I') is a compound of Formula (I'-e-1), (I'-e-2), (I'-e-3), (I'-e-4), (I'-e-5), (I'-e-6), (I'-e-7), or (I'-e-8): [ka] and In the formula, E, R 3 , R 4 , R 5 , R 7 , V, Y, Z, G, X 1 , X 2 , n, p, and q are as defined for Formula (I'). In some embodiments, the compound is a compound of Formula (I'-e-1). In some embodiments, the compound is a compound of Formula (I'-e-2). In some embodiments, the compound is a compound of Formula (I'-e-3). In some embodiments, the compound is a compound of Formula (I'-e-4). In some embodiments, the compound is a compound of Formula (I'-e-5). In some embodiments, the compound is a compound of Formula (I'-e-6). In some embodiments, the compound is a compound of Formula (I'-e-7). In some embodiments, the compound is a compound of Formula (I'-e-8). In any variation of formula (I'-e-1), (I'-e-2), (I'-e-3), (I'-e-4), (I'-e-5), (I'-e-6), (I'-e-7), or (I'-e-8), Z is -H, -F, -Cl, -Br, -I, -C≡CH, -OCH, -CH, or -CHCH; Y is N, CH, or CF; and V is O, S, or NR 2 where R 2is C-C alkyl or C-C cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines, and G is -O-, -C(=O)-, -S-, -S(O)-, -S(O)2-, or -CH2-.

[0110] In some embodiments, the compound of formula (I) is a compound of formula (If-1), (If-2), (If-3), (If-4), (If-5), or (If-6): [ka] and

[0111] In the formula, E, R 4 , R 5 , Y, Z, X 1 and X 2 is as defined for Formula (I). In some embodiments, the compound is a compound of Formula (If-1). In some embodiments, the compound is a compound of Formula (If-2). In some embodiments, the compound is a compound of Formula (If-3). In some embodiments, the compound is a compound of Formula (If-4). In some embodiments, the compound is a compound of Formula (If-5). In some embodiments, the compound is a compound of Formula (If-6). In any variation of Formula (If-1), (If-2), (If-3), (If-4), (If-5), or (If-6), ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, Y is N or CH. In some embodiments, Z is -H, -F, -Cl, -Br, -I, -C≡CH, -OCH, -CH, or -CHCH; and R 4 is -H or -F, and R5 is -H or -F. In some variations, E, R of formula (If-1), (If-2), (If-3), (If-4), (If-5), or (If-6) 4 , R 5 , Y, Z, X 1 and X 2 is as defined for a compound of formula (I'), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.

[0112] In some embodiments, the compound of Formula (I') is a compound of Formula (I'-f-1), (I'-f-2), (I'-f-3), (I'-f-4), (I'-f-5), or (I'-f-6): [ka] and In the formula, E, R 4 , R 5 , Y, Z, X 1 , X 2 , n, p, and q are as defined for Formula (F). In some embodiments, the compound is a compound of Formula (F-f-1). In some embodiments, the compound is a compound of Formula (F-f-2). In some embodiments, the compound is a compound of Formula (F-f-3). In some embodiments, the compound is a compound of Formula (F-f-4). In some embodiments, the compound is a compound of Formula (F-f-5). In some embodiments, the compound is a compound of Formula (F-f-6). In any variation of Formula (F-f-1), (F-f-2), (F-f-3), (F-f-4), (F-f-5), or (F-f-6), ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, Y is N or CH. In some embodiments, Z is -H, -F, -Cl, -Br, -I, -C≡CH, -OCH, -CH, or -CHCH; and R 4 is -H or -F, and R 5 is -H or -F.

[0113] In some embodiments, the compound of Formula (I) is a compound of Formula (Ig-1), (Ig-2), (Ig-3), (Ig-4), (Ig-5), (Ig-6), or (Ig-7): [ka] and In the formula, E, R 3 , R 4 , R 5 , V, Y, Z, G, X 1 , and X 2 is as defined for Formula (I). In some embodiments, the compound is a compound of Formula (Ig-1). In some embodiments, the compound is a compound of Formula (Ig-2). In some embodiments, the compound is a compound of Formula (Ig-3). In some embodiments, the compound is a compound of Formula (Ig-4). In some embodiments, the compound is a compound of Formula (Ig-5). In some embodiments, the compound is a compound of Formula (Ig-6). In some embodiments, the compound is a compound of Formula (Ig-7). In any variation of Formula (Ig-1), (Ig-2), (Ig-3), (Ig-4), (Ig-5), (Ig-6), or (Ig-7), Z is -H, -F, -Cl, -Br, -I, -C≡CH, -OCH, -CH, or -CHCH; Y is N, CH, or CF; and V is O, S, or NR 2 where R 2is C1-C6 alkyl or C1-C6 cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines, and G is -O-, -C(=O)-, -S-, -S(O)-, -S(O)2-, or -CH2-. In some variations, E, R of formula (Ig-1), (Ig-2), (Ig-3), (Ig-4), (Ig-5), (Ig-6), or (Ig-7) 3 , R 4 , R 5 , V, Y, Z, G, X 1 , and X 2 is as defined for a compound of formula (I'), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.

[0114] In some embodiments, the compound of Formula (I') is a compound of Formula (I'-g-1), (I'-g-2), (I'-g-3), (I'-g-4), (I'-g-5), (I'-g-6), (I'-g-7), or (I'-g-8): [ka] and In the formula, E, R 3 , R 4 , R 5 , R 7 , V, Y, Z, G, X 1 , X 2, n, p, and q are as defined for Formula (I'). In some embodiments, the compound is a compound of Formula (I'-g-1). In some embodiments, the compound is a compound of Formula (I'-g-2). In some embodiments, the compound is a compound of Formula (I'-g-3). In some embodiments, the compound is a compound of Formula (I'-g-4). In some embodiments, the compound is a compound of Formula (I'-g-5). In some embodiments, the compound is a compound of Formula (I'-g-6). In some embodiments, the compound is a compound of Formula (I'-g-7). In some embodiments, the compound is a compound of Formula (I'-g-8). In any variation of formula (I'-g-1), (I'-g-2), (I'-g-3), (I'-g-4), (I'-g-5), (I'-g-6), or (I'-g-7), (I'-g-8), Z is -H, -F, -Cl, -Br, -I, -C≡CH, -OCH3, -CH3, or -CH2CH3; Y is N, CH, or CF; and V is O, S, or NR 2 where R 2 is C-C alkyl or C-C cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines, and G is -O-, -C(=O)-, -S-, -S(O)-, -S(O)2-, or -CH2-.

[0115] In some embodiments, the compound of Formula (I) is a compound of Formula (Ih-1), (Ih-2), (Ih-3), (Ih-4), (Ih-5), (Ih-6), or (Ih-7): [ka] and In the formula, E, R 3 , R 4 , R 5 , Y, Z, X 1 , and X 2is as defined for Formula (I). In some embodiments, the compound is a compound of Formula (Ih-1). In some embodiments, the compound is a compound of Formula (Ih-2). In some embodiments, the compound is a compound of Formula (Ih-3). In some embodiments, the compound is a compound of Formula (Ih-4). In some embodiments, the compound is a compound of Formula (Ih-5). In some embodiments, the compound is a compound of Formula (Ih-6). In some embodiments, the compound is a compound of Formula (Ih-7). In any variation of Formula (Ih-1), (Ih-2), (Ih-3), (Ih-4), (Ih-5), (Ih-6), or (Ih-7), Z is -H, -F, -Cl, -Br, -I, -C≡CH, -OCH, -CH, or -CHCH; Y is N, CH, or CF; and V is O, S, or NR 2 and R 2 is C1-C6 alkyl or C1-C6 cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines. In some variations, E, R of formula (Ih-1), (Ih-2), (Ih-3), (Ih-4), (Ih-5), (Ih-6), or (Ih-7) 3 , R 4 , R 5 , Y, Z, X 1 , and X 2 is as defined for a compound of formula (I'), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.

[0116] In some embodiments, the compound of Formula (I') is a compound of Formula (I'-h-1), (I'-h-2), (I'-h-3), (I'-h-4), (I'-h-5), (I'-h-6), (I'-h-7) or (I'-h-8): [ka] and In the formula, n, p, q, E, R3 , R 4 , R 5 , R 7 , Y, Z, X 1 , and X 2 is as defined for Formula (I'). In some embodiments, the compound is a compound of Formula (I'-h-1). In some embodiments, the compound is a compound of Formula (I'-h-2). In some embodiments, the compound is a compound of Formula (I'-h-3). In some embodiments, the compound is a compound of Formula (I'-h-4). In some embodiments, the compound is a compound of Formula (I'-h-5). In some embodiments, the compound is a compound of Formula (I'-h-6). In some embodiments, the compound is a compound of Formula (I'-h-7). In some embodiments, the compound is a compound of Formula (I'-h-8). In any variation of formula (I'-h-1), (I'-h-2), (I'-h-3), (I'-h-4), (I'-h-5), (I'-h-6), (I'-h-7) or (I'-h-8), Z is -H, -F, -Cl, -Br, -I, -C≡CH, -OCH, -CH, or -CHCH; Y is N, CH, or CF; and V is O, S, or NR 2 and R 2 is C1-C6 alkyl or C1-C6 cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines.

[0117] In some embodiments, the compound of Formula (I') is a compound of Formula (I'-i-1), (I'-i-2), (I'-i-3), or (I'-i-4): [ka] and In the formula, R 4 , R 5, E, V, Z, G, Y, and ring A are as defined for Formula (I'). In some embodiments, the compound is a compound of Formula (I'-i-1). In some embodiments, the compound is a compound of Formula (I'-i-2). In some embodiments, the compound is a compound of Formula (I'-i-3). In some embodiments, the compound is a compound of Formula (I'-i-4). In any variation of Formula (I'-i-1), (I'-i-2), (I'-i-3), or (I'-i-4), Z is -H, -F, -Cl, -Br, -I, -C≡CH, -OCH3, -CH3, or -CH2CH3; Y is N, CH, or CF; and V is O, S, or NR 2 where R 2 is C1-C6 alkyl or C1-C6 cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines; G is -O-, -C(=O)-, -S-, -S(O)-, -S(O)2-, or -CH2-; and ring A is [ka] In some embodiments, ring A is [ka] and R 3 is -H, C1-C6 alkyl, -CD3 or C1-C6 cycloalkyl, and R 7 is -H, halogen, C1-C6 alkyl, -CD3, or C1-C6 cycloalkyl.

[0118] In some embodiments, a compound of Formula (I') or Formula (I) selected from the compounds in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

[0119] Although some compounds described in Table 1 are depicted in a particular stereoisomeric and / or non-stereochemical form, it is understood that all non-stereochemical and all stereochemical forms are described herein, including any enantiomeric or diastereomeric form and any tautomeric or other form of any of the compounds in Table 1. In some embodiments, the compounds described herein are selected from Compound Nos. 1-59.

[0120] The present disclosure also includes all salts of the compounds referred to herein, e.g., pharmaceutically acceptable salts. The present disclosure also includes all stereochemical forms, including any enantiomeric or diastereomeric forms of the described compounds, and any tautomeric or other forms, e.g., N-oxides, solvates, hydrates, or isotopomers. The present disclosure also includes cocrystals of the compounds described herein. Unless stereochemistry is explicitly stated in a chemical structure or chemical name, the structure or name is intended to encompass all possible stereoisomers of the depicted compound. In addition, when a specific stereochemical form is depicted, it is understood that other stereochemical forms are also encompassed by the present invention. All forms of the compounds, such as crystalline or amorphous forms of the compounds, are also encompassed by the present invention. Compositions comprising the compounds of the present invention, e.g., compositions of substantially pure compounds comprising a specific stereochemical form, are also contemplated. Compositions comprising mixtures of the compounds of the present invention in any ratio, for example, mixtures of two or more stereochemical forms of the compounds of the present invention in any ratio, are also encompassed by the present invention, including racemic, non-racemic, enantiomerically enriched, and scalemic mixtures of the compounds.

[0121] III. Pharmaceutical Compositions and Formulations Any of the compounds described herein can be formulated as a pharmaceutically acceptable composition.

[0122] Any pharmaceutical composition of the compounds detailed herein is encompassed by the present disclosure.Accordingly, the present disclosure includes a pharmaceutical composition comprising a compound detailed herein, or its pharmaceutically acceptable salt, solvate, hydrate, or cocrystal, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient.In one aspect, the pharmaceutically acceptable salt is an acid addition salt, for example, a salt formed with an inorganic or organic acid.The pharmaceutical composition may be in a form suitable for oral, buccal, parenteral, nasal, topical, or rectal administration, or in a form suitable for administration by inhalation.

[0123] In one aspect, the compounds detailed herein can be in purified form, and compositions comprising the compounds in purified form are described herein. Compositions comprising the compounds detailed herein, or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals, or mixtures of any of the foregoing, e.g., compositions of substantially pure compounds, are provided. In some embodiments, compositions containing the compounds detailed herein, or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals, or mixtures of any of the foregoing, are in substantially pure form. In one variation, "substantially pure" refers to a composition containing 35% or less impurities, where the impurities refer to compounds other than the compound or salt thereof that constitutes the majority of the composition. For example, a composition of a substantially pure compound selected from the compounds of Table 1 refers to a composition containing 35% or less impurities, where the impurities refer to compounds other than the compound of Table 1. In one variation, a composition of a substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided, wherein the composition contains 25% or less impurities. In another variation, a composition of a substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided, wherein the composition contains 20% or less impurities. In yet another variation, a composition of a substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided, wherein the composition contains 10% or less impurities. In a further variation, a composition of a substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided, wherein the composition contains 5% or less impurities. In another variation, a composition of a substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided, wherein the composition contains 3% or less impurities.In yet another variation, a composition of a substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, is provided, wherein the composition contains 1% or less of impurities. In a further variation, a composition of a substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, is provided, wherein the composition contains 0.5% or less of impurities. In yet another variation, a composition of a substantially pure compound means that the composition contains 15% or less, 10% or less, 5% or less, 3% or less, or 1% or less of impurities, which may be compounds of different stereochemical forms. For example, and without limitation, a composition of a substantially pure (S) compound means that the composition contains 15% or less, or 10% or less, or 5% or less, or 3% or less, or 1% or less of the (R) form of the compound.

[0124] In one variation, the compound is a synthetic compound prepared for administration to an individual. In another variation, a composition containing the compound in a substantially pure form is provided. In another variation, the present disclosure encompasses a pharmaceutical composition comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, a method of administering the compound is provided. The purified form, pharmaceutical composition, and method of administering the compound are suitable for any compound or form thereof detailed herein. In some embodiments, the compounds and compositions provided herein are sterile. Sterilization methods known in the art may be suitable for any compound or form thereof and compositions thereof detailed herein.

[0125] The compounds detailed herein, or pharmaceutically acceptable salts, solvates, hydrates, or co-crystals thereof, or mixtures of any of the foregoing, may be formulated for any available delivery route, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery forms. The compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, can be formulated with a suitable carrier to provide a delivery form, including, but not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, poultices (cowplasters), pastes, powders, dressings, creams, liquids, patches, aerosols (e.g., nasal drops or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions, and elixirs.

[0126] The compounds detailed herein, or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals, or mixtures of any of the foregoing, can be used to prepare formulations, such as pharmaceutical formulations, by combining the compound or compounds, or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals, or mixtures of any of the foregoing, with a pharmaceutically acceptable carrier. Depending on the therapeutic form of the system (e.g., transdermal patch or oral tablet), the carrier can take various forms. In addition, pharmaceutical formulations can contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, modifiers, and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants. Formulations containing compounds can also contain other substances with beneficial therapeutic properties. Pharmaceutical formulations can be prepared by known pharmaceutical methods. Suitable formulations can be found, for example, in Remington's The Science and Practice of Pharmacy, Academic Press, 23 rded. (2020), which is incorporated herein by reference.

[0127] The compounds detailed herein, or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals, or mixtures of any of the foregoing, can be administered to individuals in the form of commonly accepted oral compositions, such as tablets, coated tablets, and hard- or soft-shell gel capsules, emulsions, or suspensions. Examples of carriers that can be used to prepare such compositions include lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof, and the like. Acceptable carriers for soft-shell gel capsules include, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, and the like. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants.

[0128] Any of the compounds described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, can be formulated into a tablet of any dosage form described, for example, a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, can be formulated as a 10 mg tablet.

[0129] Also described are compositions comprising a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing. In one variation, the composition comprises the compound, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of a substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, is provided. In some embodiments, the composition is for use as a pharmaceutical for human or veterinary use. In some embodiments, the composition is for use in a method described herein. In some embodiments, the composition is for use in the treatment of a disease or disorder described herein.

[0130] Also described are compositions formulated for co-administration of the compounds provided herein with one or more additional agents. Co-administration can be simultaneous administration or sequential administration in any order. The compounds provided herein can be formulated for co-administration with one or more additional agents in the same dosage form (e.g., a single tablet or a single intravenous administration) or in separate dosage forms (e.g., two separate tablets, two separate intravenous administrations, or one tablet and one intravenous administration). Furthermore, co-administration can be, for example, 1) simultaneous delivery by the same delivery route (e.g., tablet or intravenous administration), 2) sequential delivery on the same day by the same delivery route or different delivery routes, or 3) delivery on different days by the same delivery route or different delivery routes.

[0131] IV.How to use The compounds and compositions detailed herein, e.g., pharmaceutical compositions containing a compound of Formula (I') or Formula (I) or any variation thereof provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient, can be used in the methods of administration and treatment provided herein. The compounds and compositions can also be used in in vitro methods, e.g., in vitro methods in which the compound or composition is administered to cells for screening purposes and / or to perform quality control analyses.

[0132] In one aspect, provided herein is a method for inhibiting the kinase activity of human receptor tyrosine kinase ErbB2 or a mutant form of human ErbB2, comprising contacting ErbB2 or a mutant with a therapeutically effective amount of a compound or composition provided herein. In some embodiments, provided herein is a method for inhibiting the kinase activity of human receptor tyrosine kinase ErbB2 or a mutant form of human ErbB2 in a cell, comprising administering to the cell an effective amount of a compound or composition of the present disclosure. In some embodiments, provided herein is a method for inhibiting the kinase activity of human receptor tyrosine kinase ErbB2 or a mutant form of human ErbB2 in an individual in need thereof, comprising administering to the individual an effective amount of a compound or composition of the present disclosure.

[0133] In some embodiments of this aspect, the mutant human ErbB2 is selected from the group consisting of A775_A776insYVMA, A775_A776insAYVM, A775_A776insYVMS, A775_A776insVVMA, A775_A776insMMAY, A775_A776insYVMA-R678Q, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G776delinsLV, G776delinsVV , G776insIC, G776delinsCVC, G776delinsAVGS, G776delinsAVGA, G776delinsAVGCG776_V777insLeu, G776_V777insVGS, G778_S779InsCPG; V777_G778insGSP, V777_G778insGC, V777_G778insCG, V777_G778insQ, V777_G778insG, G778_S779insLPS, and G778_S779insAVG. In some embodiments, the mutant human ErbB2 comprises a mutation in exon 20 that introduces a deletion and / or insertion of certain amino acids selected from the group consisting of A775_A776insYVMA, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G778_S779InsCPG, V777_G778insGSP.In another embodiment of this aspect, the mutant human ErbB2 is (a) P122L, R217C, I263T, A293T, S305C, S310F / Y / P, H470Q, I655V, V659E / D, L674F, G660D, R678Q / C, L755R / S / P / Y / M, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E or (b) one or more point mutations in ErbB2 that introduce an amino acid substitution selected from the group consisting of 930K / D, E1021Q, F1030C, V1128I, N1219S, G222C, A1057V, V842I, G776S / C / V / A, V773M, L869R, Y803F, H878Y, R896G, and E1195G, or a frameshift at A1232. In other embodiments, the mutant human ErbB2 comprises one or more mutations that introduce certain amino acid substitutions selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y, H470Q, I655V, V659E, G660D, R678Q / C, L755R / S / P, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, N1219S, and A1232fs. In still further embodiments of this aspect, the mutant human ErbB2 comprises one or more point mutations in ErbB2 that introduce (a) an amino acid substitution selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y, H470Q, I655V, V659E, G660D, R678Q / C, L755R / S / P, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, and N1219S, or (b) a frameshift at A1232. In other embodiments, the mutant human ErbB2 comprises an amino-terminally truncated carboxyl-terminal fragment of HER2, collectively referred to as p95HER2.

[0134] In some variations, the compounds provided herein selectively inhibit the human receptor tyrosine kinase ErbB2. Thus, in some embodiments, provided herein are methods of selectively inhibiting the human receptor tyrosine kinase ErbB2 relative to other receptor tyrosine kinases, including, but not limited to, ErbB1 (EGFR), ErbB3, or ErbB4.

[0135] The compounds and compositions described herein can be used in methods of treating a disease or disorder in an individual, where the individual has a cell or cell tissue that has increased ErbB2 kinase activity, e.g., compared to the ErbB2 kinase activity of a corresponding cell type or cell tissue from a healthy individual. In some embodiments, the compound or composition is administered according to the dosages described herein.

[0136] In some embodiments, provided herein are methods for treating a disease or disorder in an individual, wherein the individual has cells or cell tissues with increased ErbB2 kinase activity, comprising administering to the individual in need of treatment a therapeutically effective amount of a compound of Formula (I') or Formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, or a therapeutically effective amount of a composition described herein. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is lung cancer, glioma, head and / or neck cancer, salivary gland cancer, breast cancer, esophageal cancer, liver cancer, gastric cancer, uterine cancer, cervical cancer, biliary tract cancer, pancreatic cancer, colorectal cancer, kidney cancer, bladder cancer, or prostate cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the individual has received at least one, at least two, or at least three prior therapies for cancer. In certain embodiments, the one or more prior therapies are selected from the group consisting of lapatinib, neratinib, afatinib, pyrotinib, poziotinib, TAK-788, and tucatinib.

[0137] In some embodiments, the disease or disorder is refractory or resistant to first-line, second-line, and / or third-line therapy. In certain embodiments, the condition with increased activation of ErbB2 kinase activity is refractory or resistant to treatment with one or more tyrosine kinase inhibitors selected from the group consisting of lapatinib, neratinib, afatinib, pyrotinib, poziotinib, TAK-788, and tucatinib.

[0138] The resistance subtype of tyrosine kinase-mediated disease or disorder can be associated with many ErbB2-independent resistance mechanisms.In some embodiments, the disease or disorder of individuals with cells or tissues with increased ErbB2 kinase activity is refractory to treatment, the disease or disorder is characterized by being associated with one or more ErbB2-dependent resistance mechanisms.ErbB2-dependent resistance mechanisms include, but are not limited to, one or more mutations in exon 20 of ErbB2 or other disease-related point mutations. The one or more mutations in ErbB2 may include deletions and / or insertions of certain amino acids, e.g., A775_A776insYVMA, A775_A776insAYVM, A775_A776insYVMS, A775_A776insVVMA, A775_A776insMMAY, A775_A776insYVMA-R678Q, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G776delinsVVMA, G776delinsVVMA, G776delinsVVMA, G776delinsVVMA-R678Q, G778 ... Introduce delinsLV, G776delinsVV, G776insIC, G776delinsCVC, G776delinsAVGS, G776delinsAVGA, G776delinsAVGCG776_V777insLeu, G776_V777insVGS, G778_S779InsCPG; V777_G778insGSP, V777_G778insGC, V777_G778insCG, V777_G778insQ, V777_G778insG, G778_S779insLPS, and / or G778_S779insAVG. In other variations, the mutations introduce certain amino acid substitutions, such as P122L, R217C, I263T, A293T, S305C, S310F / Y, H470Q, I655V, V659E, G660D, R678Q / C, L755R / S / P, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, N1219S, and / or A1232fs.In some variations, the mutations are specific (a) amino acid substitutions, e.g., P122L, R217C, I263T, A293T, S305C, S310F / Y / P, H470Q, I655V, V659E / D, L674F, G660D, R678Q / C, L755R / S / P / Y / M, I767M, D769H / N / Y, V777L / M, V842I , R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, and N1219S, G222C, A1057V, V842I, G776S / C / V / A, V773M, L869R, Y803F, H878Y, R896G, and E1195G, and / or (b) a frameshift such as a frameshift at A1232. In other embodiments, the ErbB2-dependent resistance mechanism includes expression or overexpression of an amino-terminally truncated carboxyl-terminal fragment of HER2, collectively referred to as p95HER2. In some variations, refractory disease or disorders in individuals with increased activation of ErbB2 kinase activity are associated with one or more mutations in exon 20 of ErbB2.In certain variations, the one or more mutations in exon 20 of ErbB2 are selected from the group consisting of A775_A776insYVMA, A775_A776insAYVM, A775_A776insYVMS, A775_A776insVVMA, A775_A776insMMAY, A775_A776insYVMA-R678Q, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G776delinsLV, G776d Deletion and / or insertion of certain amino acids selected from the group consisting of: V777_G778insVV, G776insIC, G776delinsCVC, G776delinsAVGS, G776delinsAVGA, G776delinsAVGCG776_V777insLeu, G776_V777insVGS, G778_S779insCPG; V777_G778insGSP, V777_G778insGC, V777_G778insCG, V777_G778insQ, V777_G778insG, G778_S779insLPS, and G778_S779insAVG is introduced. In certain variations, the one or more mutations in exon 20 of ErbB2 introduce a deletion and / or insertion of certain amino acids selected from the group consisting of A775_A776insYVMA, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G778_S779InsCPG, and V777_G778insGSP. In other variations, the refractory disease or disorder in an individual with increased activation of ErbB2 kinase activity is associated with one or more disease-associated point mutations.In certain variations, the one or more point mutations are (a) P122L, R217C, I263T, A293T, S305C, S310F / Y / P, H470Q, I655V, V659E / D, L674F, G660D, R678Q / C, L755R / S / P / Y / M, I767M, D769H / N / Y, V777L / M, V842I, R868W , H878Y, E930K / D, E1021Q, F1030C, V1128I, N1219S, G222C, A1057V, V842I, G776S / C / V / A, V773M, L869R, Y803F, H878Y, R896G, and E1195G, or (b) an amino acid substitution selected from the group consisting of A1232, H878Y, E930K / D, E1021Q, F1030C, V1128I, N1219S, G222C, A1057V, V842I, G776S / C / V / A, V773M, L869R, Y803F, H878Y, R896G, and E1195G, or (b) a frameshift at A1232. In certain variations, the one or more point mutations introduce certain amino acid substitutions selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y, H470Q, I655V, V659E, G660D, R678Q / C, L755R / S / P, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, N1219S, and A1232fs. In other embodiments, the one or more point mutations introduce (a) an amino acid substitution selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y, H470Q, I655V, V659E, G660D, R678Q / C, L755R / S / P, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, and N1219S, or (b) a frameshift at A1232. In other embodiments, the refractory disease or disorder in an individual with increased activation of ErbB2 kinase activity is associated with expression or overexpression of amino-terminally truncated carboxyl-terminal fragments of HER2, collectively referred to as p95HER2.

[0139] In some embodiments, a method for treating cancer in an individual in need thereof is provided, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I') or Formula (I) or any variation thereof described herein, or a therapeutically effective amount of a composition described herein. In some embodiments, the cancer comprises cells or cell tissues with increased ErbB2 kinase activity, for example, compared to the ErbB2 kinase activity of a corresponding cell type or cell tissue from a healthy individual. In some embodiments, the cancer comprises cells or cell tissues with one or more mutations in exon 20 of ErbB2. In certain embodiments, the one or more mutations in exon 20 of ErbB2 are A775_A776insYVMA, A775_A776insAYVM, A775_A776insYVMS, A775_A776insVVMA, A775_A776insMMAY, A775_A776insYVMA-R678Q, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G776delinsLV, G776d Deletion and / or insertion of certain amino acids selected from the group consisting of: V777_G778insVV, G776insIC, G776delinsCVC, G776delinsAVGS, G776delinsAVGA, G776delinsAVGCG776_V777insLeu, G776_V777insVGS, G778_S779insCPG; V777_G778insGSP, V777_G778insGC, V777_G778insCG, V777_G778insQ, V777_G778insG, G778_S779insLPS, and G778_S779insAVG is introduced.In certain embodiments, the one or more mutations in exon 20 of ErbB2 introduce a deletion and / or insertion of certain amino acids selected from the group consisting of A775_A776insYVMA, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G778_S779InsCPG, and V777_G778insGSP. In some embodiments, the cancer comprises cells or cell tissues containing one or more disease-associated point mutations. In certain embodiments, the cancer is characterized by (a) P122L, R217C, I263T, A293T, S305C, S310F / Y / P, H470Q, I655V, V659E / D, L674F, G660D, R678Q / C, L755R / S / P / Y / M, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, or (b) one or more point mutations introducing an amino acid substitution selected from the group consisting of E1021Q, F1030C, V1128I, N1219S, G222C, A1057V, V842I, G776S / C / V / A, V773M, L869R, Y803F, H878Y, R896G, and E1195G, or a frameshift at A1232. In certain embodiments, the one or more point mutations introduce certain amino acid substitutions selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y, H470Q, I655V, V659E, G660D, R678Q / C, L755R / S / P, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, N1219S, and A1232fs.In certain other embodiments, the cancer comprises cells or cell tissues with (a) an amino acid substitution selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y, H470Q, I655V, V659E, G660D, R678Q / C, L755R / S / P, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, and N1219S, or (b) one or more point mutations introducing a frameshift at A1232. In other embodiments, the cancer comprises cells or cell tissues with or associated with expression or overexpression of amino-terminally truncated carboxyl-terminal fragments of HER2, collectively referred to as p95HER2. In some embodiments, the disease or disorder is lung cancer, glioma, head and / or neck cancer, salivary gland cancer, breast cancer, esophageal cancer, liver cancer, gastric cancer, uterine cancer, cervical cancer, biliary tract cancer, pancreatic cancer, colorectal cancer, kidney cancer, bladder cancer, or prostate cancer. In some embodiments, the cancer is non-small cell lung cancer.

[0140] In one aspect, provided herein is a method of treating cancer in an individual in need thereof, wherein modulation of ErbB2 kinase activity inhibits or ameliorates cancer pathology and / or symptomology, comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein. In one embodiment, provided herein is a method of treating cancer, wherein modulation of ErbB2 kinase activity inhibits cancer pathology and / or symptomology in the individual, comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein. In one embodiment, provided herein is a method of treating cancer, wherein modulation of ErbB2 kinase activity ameliorates cancer pathology and / or symptomology in the individual, comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein.

[0141] In another aspect, provided herein are methods of treating cancer, wherein modulation of ErbB2 kinase activity prevents cancer pathology and / or symptomology in an individual, comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein. In another aspect, provided herein are methods of delaying the onset and / or development of cancer in an individual (such as a human) at risk of developing cancer, e.g., an individual having cells or tissues with increased ErbB2 kinase activity. It is understood that delaying development can include prevention in cases where the individual has not developed cancer.

[0142] In one aspect, provided herein is a method of delaying the onset and / or development of cancer in an individual having a cell or tissue with increased ErbB2 kinase activity in need thereof, comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein. In some embodiments, the cancer is lung cancer, glioma, head and / or neck cancer, salivary gland cancer, breast cancer, esophageal cancer, liver cancer, gastric cancer, uterine cancer, cervical cancer, biliary tract cancer, pancreatic cancer, colorectal cancer, kidney cancer, bladder cancer, or prostate cancer. In some embodiments, the cancer is non-small cell lung cancer.

[0143] In one aspect, provided herein is a compound of Formula (F) or Formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, for use in therapy. In some embodiments, provided herein is a compound of Formula (F) or Formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, for use in the treatment of cancer, or a pharmaceutical composition comprising such a compound. In some embodiments, provided is a compound of Formula (F) or Formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising such a compound, for use in the treatment of cancer. In some embodiments, there is provided a compound of Formula (F) or Formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising such a compound, for use in treating cancer, wherein the cancer comprises cells or cell tissue with increased activation of ErbB2 kinase activity. In some embodiments, there is provided a compound of Formula (F) or Formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising such a compound, for use in treating cancer, wherein the cancer comprises cells or cell tissue with one or more mutations in exon 20 of ErbB2.In some embodiments, there is provided a compound of Formula (F) or Formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising such a compound, for use in treating cancer, wherein the cancer cells are selected from the group consisting of A775_A776insYVMA, A775_A776insAYVM, A775_A776insYVMS, A775_A776insVVMA, A775_A776insMMAY, A775_A776insYVMA-R678Q, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G ...YVMA-R678Q, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776ins insI, G776delinsLC, G776delinsLV, G776delinsVV, G776insIC, G776delinsCVC, G776delinsAVGS, G776delinsAVGA, G776delinsAVGCG776_V777insLeu, G776_V777insVGS, G778_S779InsCPG; V777_G778insGSP, V777_G778insGC, V777_G778insCG, V777_G778insQ, V777_G778insG, G778_S779insLPS, and G778_S779insAVG.In some embodiments, there is provided a compound of Formula (F) or Formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising such a compound, for use in treating cancer, wherein the cancer cells comprise one or more genetic modifications in exon 20 of ErbB2 introducing a deletion and / or insertion of certain amino acids selected from the group consisting of A775_A776insYVMA, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G778_S779InsCPG, and V777_G778insGSP. In some embodiments, there is provided a compound of Formula (F) or Formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising such a compound, for use in treating cancer, wherein the cancer comprises cells or cell tissues with one or more disease-associated point mutations in ErbB2. In certain other embodiments, there is provided a compound of Formula (F) or Formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising such a compound, for use in treating cancer, wherein the cancer is characterized by (a) P122L, R217C, I263T, A293T, S305C, S310F / Y / P, H470Q, I655V, V659E / D, L674F, G660D, R678Q / C, L7 or (b) one or more point mutations introducing a frameshift at A1232; or (c) an amino acid substitution selected from the group consisting of 55R / S / P / Y / M, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, N1219S, G222C, A1057V, V842I, G776S / C / V / A, V773M, L869R, Y803F, H878Y, R896G, and E1195G.In certain embodiments, the cancer comprises cells or cell tissues with one or more point mutations introducing certain amino acid substitutions selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y, H470Q, I655V, V659E, G660D, R678Q / C, L755R / S / P, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, N1219S, and A1232fs. In certain other embodiments, the cancer comprises cells or cell tissues with one or more point mutations introducing (a) an amino acid substitution selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y, H470Q, I655V, V659E, G660D, R678Q / C, L755R / S / P, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, and N1219S, or (b) a frameshift at A1232. In some embodiments, a compound of Formula (I') or Formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising such a compound, is provided for use in treating cancer, wherein the cancer comprises cells or cell tissues that express or overexpress an amino-terminally truncated carboxyl-terminal fragment of HER2, collectively referred to as p95HER2. In some embodiments, a compound of Formula (I') or Formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising such a compound, is provided for use in treating lung cancer, glioma, head and / or neck cancer, salivary gland cancer, breast cancer, esophageal cancer, liver cancer, gastric cancer, uterine cancer, cervical cancer, biliary tract cancer, pancreatic cancer, colorectal cancer, kidney cancer, bladder cancer, or prostate cancer. In some embodiments, the lung cancer is non-small cell lung cancer.

[0144] In another embodiment, provided herein is a compound of Formula (I') or Formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, for use in the manufacture of a medicament for the treatment of cancer. In another embodiment, provided herein is a compound of Formula (I') or Formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, for use in the manufacture of a medicament for the treatment of cancer, wherein the cancer comprises cells or cell tissue with increased ErbB2 kinase activity. In another embodiment, provided herein is a compound of Formula (I') or Formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, for use in the manufacture of a medicament for the treatment of cancer, wherein the cancer cells or cancer cell tissue comprise one or more mutations in exon 20 of ErbB2.In some embodiments, the medicament is for the treatment of cancer, and the cancer cells are selected from the group consisting of A775_A776insYVMA, A775_A776insAYVM, A775_A776insYVMS, A775_A776insVVMA, A775_A776insMMAY, A775_A776insYVMA-R678Q, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G776delinsLV, G776delinsVV, G776ins IC, G776delinsCVC, G776delinsAVGS, G776delinsAVGA, G776delinsAVGCG776_V777insLeu, G776_V777insVGS, G778_S779InsCPG; V777_G778insGSP, V777_G778insGC, V777_G778insCG, V777_G778insQ, V777_G778insG, G778_S779insLPS, and G778_S779insAVG. In some embodiments, the medicament is for the treatment of cancer, and the cancer cells comprise one or more genetic modifications in exon 20 of ErbB2 that introduce a deletion and / or insertion of certain amino acids selected from the group consisting of A775_A776insYVMA, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G778_S779InsCPG, and V777_G778insGSP.In another embodiment, provided herein is a compound of Formula (I') or Formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, for use in the manufacture of a medicament for the treatment of cancer, wherein the cancer cells or cancer tissue contain one or more disease-associated point mutations in ErbB2. In some embodiments, the medicament is for the treatment of cancer, wherein the cancer cells or cancer tissue contain one or more disease-associated point mutations in ErbB2. In some embodiments, the medicament is for the treatment of cancer, wherein the cancer cells are selected from the group consisting of: (a) P122L, R217C, I263T, A293T, S305C, S310F / Y / P, H470Q, I655V, V659E / D, L674F, G660D, R678Q / C, L755R / S / P / Y / M, I767M, D769H / N / Y, V777L / M, V842I, R8 or (b) one or more point mutations introducing a frameshift at A1232; or (b) an amino acid substitution selected from the group consisting of 68W, H878Y, E930K / D, E1021Q, F1030C, V1128I, N1219S, G222C, A1057V, V842I, G776S / C / V / A, V773M, L869R, Y803F, H878Y, R896G, and E1195G. In some embodiments, the medicament is for the treatment of cancer, and the cancer cells comprise one or more point mutations introducing certain amino acid substitutions selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y, H470Q, I655V, V659E, G660D, R678Q / C, L755R / S / P, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, N1219S, and A1232fs.In some embodiments, the medicament is for the treatment of cancer, and the cancer cells comprise (a) an amino acid substitution selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y, H470Q, I655V, V659E, G660D, R678Q / C, L755R / S / P, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, and N1219S, or (b) one or more point mutations introducing a frameshift at A1232. In some embodiments, the medicament is for the treatment of cancer, wherein the cancer cells contain, express, or overexpress an amino-terminally truncated carboxyl-terminal fragment of HER2, collectively referred to as p95HER2. In some embodiments, the medicament is for the treatment of lung cancer, glioma, head and / or neck cancer, salivary gland cancer, breast cancer, esophageal cancer, liver cancer, gastric cancer, uterine cancer, cervical cancer, biliary tract cancer, pancreatic cancer, colorectal cancer, kidney cancer, bladder cancer, or prostate cancer. In some embodiments, the medicament is for the treatment of non-small cell lung cancer.

[0145] In some embodiments, the individual is a mammal. In some embodiments, the individual is a primate, dog, cat, rabbit, or rodent. In some embodiments, the individual is a primate. In some embodiments, the individual is a human. In some embodiments, the human is at least about 18 years old, at least about 21 years old, at least about 30 years old, at least about 50 years old, at least about 60 years old, at least about 65 years old, at least about 70 years old, at least about 75 years old, at least about 80 years old, or at least about 85 years old, or any of about 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is under about 21 years old, under about 18 years old, under about 15 years old, under about 10 years old, under about 5 years old, under about 4 years old, under about 3 years old, under about 2 years old, or under about 1 year old, or any of about 21 years old, 18 years old, 15 years old, 10 years old, 5 years old, 4 years old, 3 years old, 2 years old, or 1 year old.

[0146] In some embodiments, the method further comprises administering one or more additional agents. In some embodiments, the method further comprises administering one or more additional anti-cancer agents to the patient. In some embodiments, the method further comprises administering radiation. In some embodiments, the method further comprises administering one or more additional agents and administering radiation.

[0147] In some embodiments, the method further comprises administering an anti-HER2 antibody or anti-HER2 drug conjugate. In certain embodiments, the method further comprises administering KADCYLA® (ado-trastuzumab emtansine), ENHERTU® (fam-trastuzumab deruxtecan-nxki), or any biosimilar thereof.

[0148] V. Administration and Methods of Administration The dose of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, administered to an individual (such as a human) can vary depending on the particular compound or salt thereof, the method of administration, and the particular cancer being treated, e.g., the type and stage of cancer. In some embodiments, the amount of the compound, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, is a therapeutically effective amount.

[0149] The compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, can be administered to an individual by a variety of routes, including, for example, intravenous, intramuscular, subcutaneous, oral, and transdermal.

[0150] In one embodiment, an effective amount of a compound can be a dose of about 0.01 to about 100 mg / kg. Effective amounts or doses of compounds of the present disclosure can be confirmed by conventional methods, such as modeling, dose escalation, or clinical trials, taking into account conventional factors, such as the mode or route of administration or drug delivery, the pharmacokinetics of the drug, the severity and course of the disease being treated, and the subject's health, physical condition, and weight. Exemplary doses range from about 0.7 mg to 7 g per day, or about 7 mg to 350 mg per day, or about 350 mg to 1.75 g per day, or about 1.75 to 7 g per day.

[0151] In one aspect, any of the methods provided herein comprises administering to an individual a pharmaceutical composition containing an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable excipient.

[0152] The compounds or compositions provided herein can be administered to an individual for a desired time or period, for example, at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more, according to an effective dosing regimen, and in some variations, can be administered for the duration of the individual's life. In one variation, the compound is administered daily or on an intermittent schedule. The compound can be administered to an individual continuously (e.g., at least once daily) for a period of time. The dosing frequency can be less than once daily, for example, about once a week. The dosing frequency can be more than once a day, for example, twice or three times a day. The dosing frequency can be intermittent, including "drug holidays" (e.g., 7 days of single daily administration followed by 7 days of no administration, repeated for any 14-day period, for example, about 2 months, about 4 months, about 6 months, or more). Any of these dosing frequencies can be used with any of the compounds described herein and any of the dosages described herein.

[0153] VI. Manufactured Articles and Kits The present disclosure further provides an article of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, a composition described herein, or one or more unit doses described herein, in suitable packaging. In certain embodiments, the article of manufacture is intended for use in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, jars, flexible packaging, etc. The article of manufacture may further be sterilized and / or sealed.

[0154] The present disclosure further provides kits for carrying out the methods of the present disclosure, comprising one or more compounds described herein or compositions comprising the compounds described herein. The kits may use any of the compounds disclosed herein. In one variation, the kits use the compounds described herein, or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals, or any mixtures thereof. The kits may be used for any one or more of the uses described herein, and accordingly may contain instructions for treating any or all of the diseases described herein, for example, cancer, including lung cancer, glioma, skin cancer, head and neck cancer, salivary gland cancer, breast cancer, esophageal cancer, liver cancer, gastric cancer, uterine cancer, cervical cancer, biliary tract cancer, pancreatic cancer, colorectal cancer, kidney cancer, bladder cancer, or prostate cancer. In some embodiments, the kits may contain instructions for treating non-small cell lung cancer.

[0155] In certain of the foregoing embodiments, the cancer comprises cells or cell tissues with one or more mutations in ErbB2 exon 20. In still further embodiments, the cancer cells or cancer cell tissues comprise any of A775_A776insYVMA, A775_A776insAYVM, A775_A776insYVMS, A775_A776insVVMA, A775_A776insMMAY, A775_A776insYVMA-R678Q, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G776delinsLV, G776delinsVV, G776insIC, G The gene comprises one or more mutations in exon 20 of ErbB2 that introduce deletions and / or insertions of certain amino acids selected from the group consisting of: 776delinsCVC, G776delinsAVGS, G776delinsAVGA, G776delinsAVGCG776_V777insLeu, G776_V777insVGS, G778_S779InsCPG; V777_G778insGSP, V777_G778insGC, V777_G778insCG, V777_G778insQ, V777_G778insG, G778_S779insLPS, and G778_S779insAVG. In still further embodiments, the cancer cells or cancer tissue comprise one or more mutations in exon 20 of ErbB2 that introduce deletions and / or insertions of certain amino acids selected from the group consisting of A775_A776insYVMA, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G778_S779InsCPG, and V777_G778insGSP. In certain other embodiments, the cancer comprises cells or cell tissue with one or more disease-associated point mutations in ErbB2.In other embodiments, the cancer is (a) P122L, R217C, I263T, A293T, S305C, S310F / Y / P, H470Q, I655V, V659E / D, L674F, G660D, R678Q / C, L755R / S / P / Y / M, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E or (b) one or more point mutations introducing a frameshift at A1232; or (c) an amino acid substitution selected from the group consisting of 1021Q, F1030C, V1128I, N1219S, G222C, A1057V, V842I, G776S / C / V / A, V773M, L869R, Y803F, H878Y, R896G, and E1195G. In still further embodiments, the cancer cells or cancer cell tissue comprise one or more point mutations introducing an amino acid substitution selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y, H470Q, I655V, V659E, G660D, R678Q / C, L755R / S / P, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, N1219S, and A1232fs. In other embodiments, the cancer comprises cells or cell tissues that have (a) an amino acid substitution selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y, H470Q, I655V, V659E, G660D, R678Q / C, L755R / S / P, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, and N1219S, or (b) one or more point mutations introducing a frameshift at A1232. In still yet other embodiments, the cancer comprises cells or cell tissues that have, express, or overexpress an amino-terminally truncated carboxyl-terminal fragment of HER2, collectively referred to as p95HER2.

[0156] The kit optionally further comprises a container containing one or more additional agents, and the kit further comprises instructions on or in the package insert for treating the subject with an effective amount of the one or more additional agents.

[0157] The kit generally includes suitable packaging. The kit may include one or more containers containing any of the compounds described herein. Each component (if there are two or more components) may be packaged in a separate container, or, if cross-reactivity and shelf life permit, some components may be combined in a single container.

[0158] The kit may be in unit dosage form, bulk packaging (e.g., multi-dose packaging), or divided unit doses. For example, a kit may be provided containing a sufficient dosage of the compounds disclosed herein and / or additional pharmaceutically active compounds useful for the diseases detailed herein to provide effective treatment to an individual for an extended period of time, such as 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. The kit may also include multiple unit doses of the compound and instructions for use, and may be packaged in an amount sufficient for storage and use in a pharmacy (e.g., a hospital pharmacy or a compounding pharmacy).

[0159] The kit may optionally include a set of instructions, typically written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing the instructions are also acceptable, regarding the use of the component(s) of the disclosed methods. The instructions included with the kit generally include information regarding the components and their administration to an individual.

[0160] VII. Enumerated Embodiments The embodiments listed below are representative of some aspects of the present invention. Embodiment 1. Compound of Formula (I) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: Ring A is [ka] and E is -C(=O)-R 1 and G is -O-, -C(=O)-, -S-, -S(O)-, -S(O)2-, or -CH2-; V is O, S, or NR 2 and each X 1 are independently N or CH; X 2 is O, S, or NR 3 and Y is N or CR y where R y is -H or -F, Z is -H, halogen, -C≡CH, -OCH3, or C1-C2 alkyl; R 1 is a C2-C4 alkenyl or a C2-C4 alkynyl, each of which is independently halogen, C1-C3 alkyl, a 3- to 7-membered carbon-linked N-heterocycloalkyl, or —NR 1a R 1b and optionally substituted with 1 to 4 substituents selected from the group consisting of: 1a and R 1b are independently -H, C1-C3 alkyl, or -CD3, or a geminal R 1a and R 1b each pair of can be taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered N-heterocyclyl, where the nitrogen atom of each heterocyclyl, if present, is independently optionally substituted with C-C alkyl; R 2 is C1-C6 alkyl or C1-C6 cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines; R3 is -H, C1-C6 alkyl, -CD3 or C1-C6 cycloalkyl; R 4 is -H or a halogen, R 5 is -H or a halogen, R 6 is -H or a halogen). Embodiment 2. Ring A is [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 3. Ring A is [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 4. Ring A is [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 5. Ring A is [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 6. Ring A is [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 7.R 3 is —CH3, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 8. A compound of any one of embodiments 1-7, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Z is -H, -F, -Cl, -C≡CH, -OCH3, or -CH3. Embodiment 9. A compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Z is -CH3. Embodiment 10.R 1 is C2-C4 alkenyl, and -NR 1a R 1b or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 11.R 1 is —CH═CH2, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 12.R 1 is —CH═CH—CH2—N(CH3)2, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 13.R 1 is C2-C4 alkynyl, -NR 1a R 1b or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 14.R 1is —C≡C—CH3, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 15. A compound according to any one of embodiments 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Y is N. Embodiment 16.Y is CR y 15. The compound of any one of embodiments 1-14, wherein: Embodiment 17.Y is CR y and R y is —H, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 18.Y is CR y and R y is -F, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 19. A compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein V is O. Embodiment 20. A compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein V is S. Embodiment 21. V is NR 2 or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 22. A compound according to any one of embodiments 1 to 21, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein G is -O-. Embodiment 23. A compound of any one of embodiments 1-21, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein G is -C(=O)-. Embodiment 24. A compound of any one of embodiments 1 to 21, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein G is -S-, -S(O)-, or -S(O)2-. Embodiment 25. A compound according to any one of embodiments 1 to 21, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein G is -CH2-. Embodiment 26.R 4 is —H, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 27.R 4 is halogen; or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 28.R 5 The compound of any one of embodiments 1-27, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Embodiment 29.R 5 is halogen; or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 30.R 6is —H, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 31.R 6 is halogen; or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 32. A compound selected from the group consisting of: [ka] [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 33. A compound selected from the group consisting of: [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 34. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 33, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and at least one pharmaceutically acceptable excipient. Embodiment 35. A method for inhibiting the kinase activity of human receptor tyrosine kinase ErbB2 or a mutant form of human ErbB2, comprising contacting said ErbB2 or said mutant form with a therapeutically effective amount of a compound of any one of embodiments 1 to 33 or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of embodiment 34. Embodiment 36 The method of embodiment 35, wherein the mutant human ErbB2 comprises a mutation in exon 20. Embodiment 37. The method of embodiment 35 or embodiment 36, wherein the mutant human ErbB2 comprises one or more mutations introducing a deletion and / or insertion of an amino acid selected from the group consisting of A775_A776insYVMA, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G778_S779InsCPG, and V777_G778insGSP. Embodiment 38 The method of embodiment 35, wherein the mutant human ErbB2 comprises a disease-associated point mutation in ErbB2. Embodiment 39. The mutant human ErbB2 is: (a) an amino acid substitution selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y, H470Q, I655V, V659E, G660D, R678Q / C, L755R / S / P, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, and N1219S; or (b) A1232 frameshift 39. The method of embodiment 35 or 38, comprising one or more point mutations in ErbB2 that introduce: Embodiment 40. A method of treating a patient having cancer, comprising administering to the patient a therapeutically effective amount of a compound of any one of embodiments 1 to 33 or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of embodiment 34. Embodiment 41. The method of embodiment 40, wherein the cancer comprises cells or cell tissues that have increased ErbB2 kinase activity compared to a control. Embodiment 42. The method of embodiment 40 or embodiment 41, wherein the cancer comprises cells or cell tissues with one or more mutations in exon 20 of ErbB2. Embodiment 43. The method of any one of embodiments 40 to 42, wherein the cancer comprises cells or cell tissues having one or more mutations in exon 20 of ErbB2 that introduce deletions and / or insertions of amino acids selected from the group consisting of A775_A776insYVMA, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G778_S779InsCPG, and V777_G778insGSP. Embodiment 44 The method of embodiment 40 or embodiment 41, wherein the cancer comprises cells or cell tissues that have one or more disease-associated point mutations in ErbB2. Embodiment 45. The cancer is: (a) an amino acid substitution selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y, H470Q, I655V, V659E, G660D, R678Q / C, L755R / S / P, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, V1128I, and N1219S; or (b) A1232 frameshift 45. The method of any one of embodiments 40 to 41 and 44, comprising introducing one or more point mutations into a cell or cell tissue. Embodiment 46. The method of any one of embodiments 40 to 45, wherein the cancer is lung cancer, glioma, skin cancer, head and neck cancer, salivary gland cancer, breast cancer, esophageal cancer, liver cancer, gastric cancer, uterine cancer, cervical cancer, biliary tract cancer, pancreatic cancer, colorectal cancer, kidney cancer, bladder cancer, or prostate cancer. Embodiment 47. The method of any one of embodiments 40 to 46, wherein the cancer is non-small cell lung cancer. Embodiment 48. The method of any one of embodiments 40 to 47, wherein the patient has received at least one, at least two, or at least three prior treatments for the cancer. Embodiment 49. The method of embodiment 48, wherein one or more of the prior treatments is selected from the group consisting of lapatinib, neratinib, afatinib, pyrotinib, poziotinib, TAK-788, and tucatinib. Embodiment 50. The method of any one of embodiments 40 to 49, wherein the method further comprises administering one or more additional anti-cancer agents. Embodiment 51. Compound of Formula (I') [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein ring A is [ka] and E is -C(=O)-R 1 and G is -O-, -C(=O)-, -S-, -S(O)-, -S(O)2-, or -CH2-; V is O, S, or NR 2 and each X 1 are independently N or CH; X 2 is O, S, or NR 3 and Y is N or CR y where R y is -H or -F, Z is -H, halogen, -C≡CH, -OCH3, or C1-C2 alkyl; R 1 is a C2-C4 alkenyl or a C2-C4 alkynyl, each of which is independently halogen, C1-C3 alkyl, a 3- to 7-membered carbon-linked N-heterocycloalkyl, or —NR 1a R 1b and optionally substituted with 1 to 4 substituents selected from the group consisting of: 1a and R 1bare independently -H, C1-C3 alkyl, or -CD3, or a geminal R 1a and R 1b each pair of can be taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered N-heterocyclyl, where the nitrogen atom of each heterocyclyl, if present, is independently optionally substituted with C-C alkyl; R 2 is C1-C6 alkyl or C1-C6 cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines; R 3 is -H, C1-C6 alkyl, -CD3 or C1-C6 cycloalkyl; R 4 is -H or a halogen, R 5 is -H or a halogen, R 6 is -H or a halogen, R 7 is -H, halogen, C1-C6 alkyl, -CD3 or C1-C6 cycloalkyl; n is 1 or 2, p is 0 or 1, q is 1 or 2). Embodiment 52. Ring A is: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 53. Ring A is [ka] 53. The compound of embodiment 51 or 52, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein: Embodiment 54.R 7is -F, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 55. The compound is a compound of formula (I) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: Ring A is [ka] and E is -C(=O)-R 1 and G is -O-, -C(=O)-, -S-, -S(O)-, -S(O)2-, or -CH2-; V is O, S, or NR 2 and each X 1 are independently N or CH; X 2 is O, S, or NR 3 and Y is N or CR y where R y is -H or -F, Z is -H, halogen, -C≡CH, -OCH3, or C1-C2 alkyl; R 1 is a C2-C4 alkenyl or a C2-C4 alkynyl, each of which is independently halogen, C1-C3 alkyl, a 3- to 7-membered carbon-linked N-heterocycloalkyl, or —NR 1a R 1b and optionally substituted with 1 to 4 substituents selected from the group consisting of: 1a and R 1b are independently -H, C1-C3 alkyl, or -CD3, or a geminal R 1a and R 1beach pair of can be taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered N-heterocyclyl, where the nitrogen atom of each heterocyclyl, if present, is independently optionally substituted with C-C alkyl; R 2 is C1-C6 alkyl or C1-C6 cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines; R 3 is -H, C1-C6 alkyl, -CD3 or C1-C6 cycloalkyl; R 4 is -H or a halogen, R 5 is -H or a halogen, R 6 is —H or halogen), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 56. Ring A is: [ka] 56. The compound of embodiment 51 or 55, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein: Embodiment 57. Ring A is: [ka] 57. The compound of any one of embodiments 51, 55, and 56, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Embodiment 58. Ring A is [ka] 57. The compound of any one of embodiments 51, 55, and 56, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Embodiment 59. Ring A is [ka] 59. The compound of any one of embodiments 51 and 55-58, wherein: Embodiment 60. Ring A is [ka] 56. The compound of embodiment 51 or 55, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein: Embodiment 61.R 3 is —CH3, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 62. A compound according to any one of embodiments 51-61, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Z is -H, -F, -Cl, -C≡CH, -OCH3, or -CH3. Embodiment 63. A compound according to any one of embodiments 51-62, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Z is -CH3. Embodiment 64.R 1 is C2-C4 alkenyl, and -NR 1a R 1b or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 65.R 1 is —CH═CH2, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 66.R 1is —CH═CH—CH2—N(CH3)2 or —CH═CH—CH(CH3)—N(CH3)2, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 67.R 1 is C2-C4 alkynyl, -NR 1a R 1b or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 68.R 1 is —C≡C—CH3, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 69. A compound according to any one of embodiments 51 to 68, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Y is N. Embodiment 70.Y is CR y or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 71.Y is CR y and R y The compound of any one of embodiments 51-68 and 70, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Embodiment 72.Y is CR y and R y The compound of any one of embodiments 51-68 and 70, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Embodiment 73. A compound according to any one of embodiments 51-72, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein V is O. Embodiment 74. A compound according to any one of embodiments 51-72, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein V is S. Embodiment 75. V is NR 2 or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 76. A compound according to any one of embodiments 51 to 75, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein G is -O-. Embodiment 77. A compound according to any one of embodiments 51 to 75, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein G is -C(=O)-. Embodiment 78. A compound according to any one of embodiments 51 to 75, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein G is -S-, -S(O)-, or -S(O)2-. Embodiment 79. A compound according to any one of embodiments 51 to 75, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein G is -CH2-. Embodiment 80.R 4 The compound of any one of embodiments 51-79, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Embodiment 81.R 4 The compound of any one of embodiments 51-79, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein is halogen. Embodiment 82.R 5 The compound of any one of embodiments 51-81, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Embodiment 83.R 5 The compound of any one of embodiments 51-81, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein is halogen. Embodiment 84.R 6 The compound of any one of embodiments 51-83, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Embodiment 85.R 6 The compound of any one of embodiments 51-83, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein is halogen. Embodiment 86. A compound selected from the group consisting of: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 87. A compound selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 88. A pharmaceutical composition comprising a compound according to any one of embodiments 51 to 87, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and at least one pharmaceutically acceptable excipient. Embodiment 89. A method for inhibiting the kinase activity of human receptor tyrosine kinase ErbB2 or a mutant form of human ErbB2, comprising contacting said ErbB2 or said mutant form with a therapeutically effective amount of a compound according to any one of embodiments 51 to 87 or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition according to embodiment 88. Embodiment 90. The method of embodiment 89, wherein the mutant human ErbB2 comprises a mutation in exon 20. Embodiment 91. The mutant human ErbB2 is selected from the group consisting of A775_A776insYVMA, A775_A776insAYVM, A775_A776insYVMS, A775_A776insVVMA, A775_A776insMMAY, A775_A776insYVMA-R678Q, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G776delinsLV, G776delinsVV, G776insIC, G776 91. The method of embodiment 89 or embodiment 90, comprising one or more mutations introducing a deletion and / or insertion of an amino acid selected from the group consisting of: V777_G778insGSP, V777_G778insGC, V777_G778insCG, V777_G778insQ, V777_G778insG, G778_S779insLPS, and G778_S779insAVG. Embodiment 92 The method of embodiment 89, wherein the mutant human ErbB2 comprises a disease-associated point mutation in ErbB2. Embodiment 93. The mutant human ErbB2 is: (a)P122L, R217C, I263T, A293T, S305C, S310F / Y / P, H470Q, I655V, V659E / D, L67 4F, G660D, R678Q / C, L755R / S / P / Y / M, I767M, D769H / N / Y, V777L / M, V842I, R868W, an amino acid substitution selected from the group consisting of H878Y, E930K / D, E1021Q, F1030C, V1128I, N1219S, G222C, A1057V, V842I, G776S / C / V / A, V773M, L869R, Y803F, H878Y, R896G, and E1195G; or (b) A1232 frameshift 93. The method of embodiment 89 or embodiment 92, comprising one or more point mutations in ErbB2 that introduce: Embodiment 94 The method of embodiment 90, wherein the mutant human ErbB2 comprises an amino-terminally truncated carboxyl-terminal fragment of HER2. Embodiment 95. A method for treating a patient having cancer, comprising administering to the patient a therapeutically effective amount of a compound described in any one of embodiments 51 to 87 or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition described in embodiment 88. Embodiment 96. The method of embodiment 95, wherein the cancer comprises cells or cell tissues that have increased ErbB2 kinase activity compared to a control. Embodiment 97. The method of embodiment 95 or embodiment 96, wherein the cancer comprises cells or cell tissues with one or more mutations in exon 20 of ErbB2. Embodiment 98. The cancer is selected from the group consisting of A775_A776insYVMA, A775_A776insAYVM, A775_A776insYVMS, A775_A776insVVMA, A775_A776insMMAY, A775_A776insYVMA-R678Q, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G776delinsLV, G776delinsVV, G776insIC, G776delinsCVC, G776delins 98. The method of any one of embodiments 95 to 97, comprising cells or cell tissues having one or more mutations in exon 20 of ErbB2 that introduce deletions and / or insertions of amino acids selected from the group consisting of: V777_G778insGC, V777_G778insCG, V777_G778insQ, V777_G778insG, G778_S779insLPS, and G778_S779insAVG. Embodiment 99. The method of embodiment 95 or embodiment 96, wherein the cancer comprises cells or cell tissues that have one or more disease-associated point mutations in ErbB2. Embodiment 100. The cancer is: (a)P122L, R217C, I263T, A293T, S305C, S310F / Y / P, H470Q, I655V, V659E / D, L67 4F, G660D, R678Q / C, L755R / S / P / Y / M, I767M, D769H / N / Y, V777L / M, V842I, R868W, an amino acid substitution selected from the group consisting of H878Y, E930K / D, E1021Q, F1030C, V1128I, N1219S, G222C, A1057V, V842I, G776S / C / V / A, V773M, L869R, Y803F, H878Y, R896G, and E1195G; or (b) A1232 frameshift 100. The method of any one of embodiments 95, 96, and 99, comprising a cell or cell tissue having one or more point mutations introducing: Embodiment 101. The method of embodiment 95 or 96, wherein the cancer comprises cells or cell tissues that have, express, or overexpress an amino-terminal truncated carboxyl-terminal fragment of HER2. Embodiment 102. The method of any one of embodiments 95 to 101, wherein the cancer is lung cancer, glioma, skin cancer, head and neck cancer, salivary gland cancer, breast cancer, esophageal cancer, liver cancer, gastric cancer, uterine cancer, cervical cancer, biliary tract cancer, pancreatic cancer, colorectal cancer, kidney cancer, bladder cancer, or prostate cancer. Embodiment 103. The method of any one of embodiments 95 to 102, wherein the cancer is non-small cell lung cancer. Embodiment 104. The method of any one of embodiments 95 to 103, wherein the patient has received at least one, at least two, or at least three prior treatments for the cancer. Embodiment 105. The method of embodiment 104, wherein one or more of the prior treatments is selected from the group consisting of lapatinib, neratinib, afatinib, pyrotinib, poziotinib, TAK-788, and tucatinib. Embodiment 106. The method of any one of embodiments 95 to 105, wherein the method further comprises administering one or more additional anti-cancer agents. Embodiment 107. The method of embodiment 106, wherein the method further comprises administering an anti-HER2 antibody or an anti-HER2 drug conjugate. Embodiment 108. The method of embodiment 106 or 107, wherein the method further comprises administering KADCYLA® (ado-trastuzumab emtansine), ENHERTU® (fam-trastuzumab deruxtecan-nxki), or any biosimilar thereof.

[0161] VIII. General Synthetic Methods The compounds of the present disclosure can be prepared by a number of processes, such as the schemes provided in the Examples below, which are outlined below and more specifically described in the Examples below. In describing the processes below, the symbols used in the formulae shown should be understood to represent the groups described above in connection with the formulae herein.

[0162] The intermediates described in the following preparations may contain multiple nitrogen-protecting groups, hydroxy-protecting groups, and acid-protecting groups, such as esters. The variable protecting groups may be the same or different in each occurrence, depending on the specific reaction conditions and the specific transformation being performed. Protection and deprotection conditions are well known to those skilled in the art and are described in the literature. See, for example, Greene and Wuts, Protective Groups in Organic Synthesis (T. Greene and P. Wuts, eds., 2nd ed. 1991).

[0163] Certain stereochemical centers are not specified, and certain substituents are omitted in the following schemes for clarity, but this is not intended to limit the teaching of the schemes. Furthermore, individual isomers, enantiomers, and diastereomers can be separated or resolved by methods such as selective crystallization techniques or chiral chromatography at any convenient point in the synthesis of the compounds of the invention by one of ordinary skill in the art (see, e.g., J. Jacques, et al., "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen, "Stereochemistry of Organic Compounds," Wiley-Interscience, 1994).

[0164] The compounds of the present invention or their salts can be prepared by various procedures known in the art, some of which are illustrated in the following examples. The specific synthetic steps of each route described can be combined in various ways to prepare the compounds of the present invention or their salts. The products of each step can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. The reagents and starting materials are readily available to those skilled in the art. Others can be made by the procedures described in the following examples, including standard techniques of organic and heterocyclic chemistry analogous to the synthesis of structurally similar known compounds, as well as any novel procedures.

[0165] Formula (I'), (I), (I'-a-1), (I'-a-2), (I'-a-3), (Ia-1), (Ia-2), (Ia-3), (I'-b-1), (I'-b-2), (Ib-1), (Ib-2), (I'-c-1), (I'-c-2), (I '-c-3), (I'-c-4), (I'-c-5), (I'-c-6), (Ic-1), (Ic-2), (Ic-3), (Ic-4), (Ic-5), (Ic-6), (I'-d-1), (I'-d-2), (I'-d-3), (I'-d-4 ), (I'-d-5), (I'-d-6), (I'-d-7), (Id-1), (Id-2), (Id-3), (Id-4), (Id-5), (Id-6), (Id-7), (I'-e-1), (I'-e-2), (I'-e-3), (I'-e -4), (I'-e-5), (I'-e-6), (I'-e-7), (I'-e-8), (Ie-1), (Ie-2), (Ie-3), (Ie-4), (Ie-5), (Ie-6), (Ie-7), (I'-f-1), (I'-f-2), (I'- f-3), (I'-f-4), (I'-f-5), (I'-f-6), (If-1), (If-2), (If-3), (If-4), (If-5), (If-6), (I'-g-1), (I'-g-2), (I'-g-3), (I'-g-4), (I'-g-5), (I'-g-6), (I'-g-7), (I'-g-8), (Ig-1), (Ig-2), (Ig-3), (Ig-4), (Ig-5), (Ig-6), (Ig-7), (I'-h-1), (I'-h-2), (I'-h-3 Compounds of (I'-h-4), (I'-h-5), (I'-h-6), (I'-h-7), (I'-h-8), (Ih-1), (Ih-2), (Ih-3), (Ih-4), (Ih-5), (Ih-6), (Ih-7), (I'-i-1), (I'-i-2), (I'-i-3), and (I'-i-4) can be prepared according to Scheme A, Scheme B, Scheme C, Scheme D, Scheme E, Scheme F, Scheme G, Scheme H, and Scheme I, wherein the ring A moiety, E, n, p, q, R 1 , R 2 , R 3 , R 4 , R 5, R 6 , R 7 , G, R 1a , R 1b , V, X 1 , X 2 , Y, R y and Z are as defined for formula (I'), formula (I) or any applicable variations thereof detailed herein.

[0166] [ka] As shown in Scheme A, compounds of general formula Aa can be chlorinated with, for example, N-chlorosuccinimide (NCS) and acetic acid to give compounds of general formula Ab.

[0167] [ka] As shown in Scheme B, a compound of general formula Ab is reacted with N,N-dimethylformamide-dimethylacetal (DMF-DMA) to give a compound of general formula Ba. Further reaction of a compound of general formula Ba with a compound of general formula Bb, for example, in the presence of acetic acid, gives a compound of general formula Bc.

[0168] [ka] As shown in Scheme C, a compound of general formula Bc is reacted with a compound of general formula Ca to give a compound of general formula Cb. The compound of general formula Cb is further cyclized, for example, in the presence of Brettphos Pd, Brettphos, KCO, and dioxane to give a compound of general formula Cc. The compound of general formula Cc is further deprotected, for example, in the presence of trifluoroacetic acid (TFA), to give a compound of general formula Cd.

[0169] [ka] As shown in Scheme D, a compound of formula Da is reacted with a compound of formula Ca to give a compound of formula Db, which can be further cyclized in the presence of, for example, Brettphos Pd, Brettphos, KCO, and dioxane to give a compound of formula Dc.

[0170] [ka] As shown in Scheme E, the nitrosyl group on compounds of general formula Dc is reduced (e.g., in the presence of Fe and acetic acid) to give compounds of general formula Ea. Compounds of general formula Ea are reacted with N,N-dimethylformamide-dimethylacetal (DMF-DMA) to give compounds of general formula Eb.

[0171] [ka] As shown in Scheme F, a compound of general formula Eb is reacted with a compound of general formula Bb in the presence of, for example, acetic acid to give a compound of general formula Fa. Further deprotection of the compound of general formula Fa in the presence of, for example, HCl gives a compound of general formula Fb.

[0172] [ka] As shown in Scheme G, compounds of general formula Ga (corresponding to compounds of general formula Cd and Fb) are reacted with compounds of general formula Gb to give compounds of general formula Gc. 1 Optional substituents of the group may be present in compounds of formula Gc. In some embodiments, R 1 may be present on the intermediate of formula Gb prior to reaction with formula Ga to give a compound of formula Gc, or may be present on the intermediate of formula Gb prior to reaction with formula Ga to give a compound of formula Gc, or may be present on the intermediate of formula Gb prior to reaction with formula Ga to give a compound of formula Gc 1 may be added to.

[0173] Schemes H and I further detail the synthesis of general compounds of formula Bb. [ka]

[0174] As shown in Scheme H, nucleophilic substitution reaction of a hydroxylated ring A-containing heterocycle of general formula Ha with a nitrosylated benzene of general formula Hb provides coupled ether compounds of general formula Hc.

[0175] [ka] Compounds of formula Hd, which are compounds of formula Bb where G is -O-, can be prepared according to the general synthetic scheme shown in Scheme I. Reduction of the nitrosyl group on compounds of general formula Hc (e.g., in the presence of H2 and Pd / C) provides compounds of general formula Hd. Compounds of general formula Hd can be used as compounds of formula Bb and can be reacted with compounds of general formula Ba as shown in Scheme B above. [Example]

[0176] This disclosure has been given by way of example only, and it will be understood by those skilled in the art that numerous changes in the combination and arrangement of parts may be made without departing from the spirit and scope of the disclosure.

[0177] The chemical reactions of the examples described can be easily adapted to prepare some other compounds disclosed herein, and alternative methods for preparing compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, the synthesis of compounds according to the present disclosure that are not exemplified can be successfully carried out by making modifications apparent to those skilled in the art, such as by properly protecting interfering groups, utilizing other suitable reagents known in the art other than those described, or by routinely modifying reaction conditions, reagents, and starting materials. Alternatively, it will be recognized that other reactions disclosed herein or known in the art can be applied to the preparation of compounds of the present disclosure.

[0178] Abbreviations used in the examples include: ACN: acetonitrile, AcOH: acetic acid, 4AMS: 4 Angstrom molecular sieves, BSA: bovine serum albumin, DCM: dichloromethane, DIEA: diisopropylethylamine, DMAC: dimethylacetamide, DMF: dimethylformamide, DMF-DMA: dimethylformamide-dimethylacetal, DMSO: dimethylsulfoxide, EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, ESI: electrospray ionization, EtOAc: ethyl acetate, EtOH: ethanol or ethyl alcohol, 1 HNMR: proton nuclear magnetic resonance, HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (hexafluorophosphate azabenzotriazole tetramethyluronium), LCMS: liquid chromatography-mass spectrometry, MeOH: methanol or methyl alcohol, n-BuLi: n-butyllithium, NCS: N-chlorosuccinimide, PBS: phosphate buffered saline, PBST: PBS with Tween® 20, Py: pyridine, TEA: triethylamine, TEMPO: (2,2,6,6-tetramethylpiperidin-1-yl)oxyl, TFA: trifluoroacetic acid, and THF: tetrahydrofuran.

[0179] Example S1: Synthesis of 1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (Compound 1) Step 1. Synthesis of 3-amino-5-bromo-6-chloropicolinonitrile [ka] To a solution of 3-amino-5-bromopyridine-2-carbonitrile (40.0 g, 202.0 mmol) in CHCOOH (2.0 L) was added NCS (29.7 g, 222.3 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was completed, the resulting mixture was diluted with HO and filtered. The filter cake was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to give 3-amino-5-bromo-6-chloropicolinonitrile (25.0 g, 53%) as a pale yellow solid. LCMS (ESI, m / z): [M+H] + =231.9.

[0180] Step 2. Synthesis of (Z)-N'-(5-bromo-6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimidamide [ka] To a solution of 3-amino-5-bromo-6-chloropicolinonitrile (3.0 g, 12.90 mmol) in ethyl alcohol (200.0 mL) was added DMF-DMA (2.6 g, 21.90 mmol) at room temperature. The resulting mixture was stirred at 75° C. for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was diluted with water and filtered. The solid was washed with water and dried to give (Z)-N'-(5-bromo-6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylmethanimidamide (3.3 g, crude) as a yellow solid. LCMS (ESI, m / z): [M+H] + =287.0.

[0181] Step 3: Synthesis of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-7-bromo-6-chloropyrido[3,2-d]pyrimidin-4-amine [ka] To a solution of (Z)-N'-(5-bromo-6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylmethanimidamide (3.3 g, crude) in acetic acid (100.0 mL) was added 3-methyl-4-{[1,2,4]triazolo[1,5-a]pyridin-7-yloxy}aniline (2.7 g, 11.48 mmol) at room temperature. The resulting mixture was stirred at 85°C for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water and filtered. The solid was washed with water and dried to give N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-7-bromo-6-chloropyrido[3,2-d]pyrimidin-4-amine (5.0 g, crude) as a yellow solid. LCMS (ESI, m / z): [M+H] + =482.0.

[0182] Step 4. Synthesis of (S)-tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7-bromopyrido[3,2-d]pyrimidin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate [ka] To a solution of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-7-bromo-6-chloropyrido[3,2-d]pyrimidin-4-amine (5.0 g, crude) in DMF (150.0 mL) was added (S)-tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate (3.4 g, 15.60 mmol) and K2CO3 (5.73 g, 41.40 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 hours. After the reaction was completed, the resulting mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography with HO / MeOH (1 / 7, v / v) to give (S)-tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7-bromopyrido[3,2-d]pyrimidin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (5.7 g, 83%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =662.2.

[0183] Step 5. Synthesis of tert-butyl (10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate [ka] To a solution of (S)-tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7-bromopyrido[3,2-d]pyrimidin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (4.1 g, 6.20 mmol) in dioxane (120.0 mL) was added KCO (3.4 g, 24.80 mmol), BrettPhos (1.3 g, 2.46 mmol), and BrettPhos Pd G (1.1 g, 1.23 mmol) at room temperature under N. The resulting mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the resulting mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography with HO / MeOH (1 / 7, v / v) to give tert-butyl (10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate (1.7 g, 47%) as a brown oil. LCMS (ESI, m / z): [M+H] + =582.2.

[0184] Step 6. Synthesis of (10S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine [ka] To a solution of tert-butyl (10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate (1.7 g, 2.93 mmol) in DCM (20.0 mL) was added TFA (20.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was diluted with water. The pH value of the mixture was adjusted to 7 with aqueous NaHCO3 solution. The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give (10S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine (800.0 mg, crude) as a brown oil. LCMS (ESI, m / z): [M+H] + =482.2.

[0185] Step 7. Synthesis of 1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (compound 1) [ka] To a solution of (10S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4′,5′:5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine (300.0 mg, crude) in DMF (10.0 mL) was added acrylic acid (89.6 mg, 1.24 mmol), DIEA (322.1 mg, 2.48 mmol), and HATU (564.4 mg, 1.45 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the resulting mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography with HO / ACN (1 / 8, v / v) to give 1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (compound 1) (79.9 mg, 24%) as a white solid. LCMS (ESI, m / z): [M+H] + = 536.3. 1 H NMR (400 MHz, DMSO-d6): δ 9.57 - 9.52 (m, 1H), 8.94 (d, J = 7.6 Hz, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.02 - 8.00 (m, 2H), 7.52 (s, 1H), 7.22 (d, J = 9.6 Hz, 1H), 7.04 - 7.02 (m, 1H), 6.87 - 6.79 (m, 2H), 6.18 - 6.13 (m, 1H), 5.75 - 5.72 (m, 1H), 5.13 - 4.64 (m, 3H), 4.29 - 4.08 (m, 3H), 3.87 - 3.42 (m, 1H), 3.39 - 3.32 (m, 1H), 3.30 - 3.24 (m, 1H), 2.18 (s, 3H).

[0186] Example S2: Synthesis of 1-((10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (Compound 2) Step 1. Synthesis of tert-butyl (R)-4-(4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenylamino)-7-bromopyrido[3,2-d]pyrimidin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate [ka] To a solution of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-7-bromo-6-chloropyrido[3,2-d]pyrimidin-4-amine (268.0 mg, 0.55 mmol) in DMF (10.0 mL) were added (R)-tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate (180.1 mg, 0.83 mmol) and KCO (306.9 mg, 2.22 mmol) at room temperature. The resulting mixture was stirred at 100° C. for 16 hours. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give (R)-tert-butyl 4-(4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenylamino)-7-bromopyrido[3,2-d]pyrimidin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (336.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H] + =662.2.

[0187] Step 2. Synthesis of tert-butyl (10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate [ka] To a solution of tert-butyl (R)-4-(4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenylamino)-7-bromopyrido[3,2-d]pyrimidin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (316.0 mg, crude) in dioxane (5.0 mL) was added BrettPhos (51.2 mg, 0.10 mmol), CsCO (466.2 mg, 1.43 mmol), and BrettPhos Pd G (43.2 mg, 0.05 mmol) at room temperature under N. The resulting mixture was stirred at 100 °C for 4 hours. After the reaction was complete, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash column chromatography with water / MeOH (1 / 7, v / v) to give tert-butyl (10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate (90.0 mg, 32%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =582.2.

[0188] Step 3: Synthesis of (10R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine [ka] To a solution of tert-butyl (10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate (80.0 mg, 0.03 mmol) in DCM (2.0 mL) was added TFA (2.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was diluted with water. The pH value of the mixture was adjusted to 8 with aqueous NaHCO3 solution. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give (10R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine (50.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H] + =482.2.

[0189] Step 4. Synthesis of 1-((10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (compound 2) [ka] To a solution of (10R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine (50.0 mg, crude) in DMF (2.0 mL) was added DIEA (80.5 mg, 0.62 mmol), acrylic acid (9.0 mg, 0.13 mmol), and HATU (55.3 mg, 0.15 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with MeOH / H2O (7 / 1, v / v) and then purified using the following conditions (column: XBridge Prep Phenyl Purification by preparative HPLC on an OBD column, 19 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH₄HCO₃), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 31% B to 31% B in 8 min; wavelength: 254 nm) afforded 1-((10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (compound 2) (6.6 mg, 12%) as a white solid. LCMS (ESI, m / z): [M+H] + =536.3. 1H NMR (400 MHz, DMSO-d6): δ 9.56 - 9.53 (m, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 8.02 - 8.00 (m, 2H), 7.52 (s, 1H), 7.22 (d, J = 9.2 Hz 1H), 7.04 - 7.02 (m, 1H), 6.87 - 6.79 (m, 2H), 6.18 - 6.13 (m, 1H), 5.75 - 5.72 (m, 1H), 5.15 - 4.71 (m, 3H), 4.29 - 4.23 (m, 1H), 4.20 - 4.11 (m, 1H), 3.98 - 3.60 (m,1H), 3.42 - 3.32 (m, 1H), 3.29 - 3.25 (m, 1H), 2.22 (s, 3H).

[0190] Example S3: Synthesis of 1-((10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonin-o[3,2-g]quinazolin-9-yl)prop-2-en-1-one (Compound 3) Step 1. Synthesis of tert-butyl (10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazoline-9-carboxylate [ka] A mixture of tert-butyl (3S)-9-cyano-10-(((Z)-(dimethylamino)methylene)amino)-2,3,5,6-tetrahydro-4H-3,7-methanobenzo[b][1,4,7]oxadiazonin-4-carboxylate (1.0 g, 2.59 mmol) and 3-methyl-4-[(1-methyl-1,3-benzodiazol-5-yl)oxy]aniline (0.6 g, 2.59 mmol) in acetic acid (20.0 mL) was stirred at 85° C. for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHCl / MeOH (9 / 1, v / v) to give tert-butyl (10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazoline-9-carboxylate (1.3 g, 84%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 594.1.

[0191] Step 2. Synthesis of (10S)-N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-8,9,10,11-tetrahydro-7H-6,10-methano[1,4,7]oxadiazonin-3,2-g]quinazolin-4-amine [ka] A mixture of tert-butyl (10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazoline-9-carboxylate (1.2 g, 2.02 mmol) in DCM (15.0 mL) and TFA (15.0 mL) was stirred at room temperature for 1 hour. After the reaction was complete, the resulting mixture was neutralized with saturated NaHCO3 (aq) to pH = 7. The resulting mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash column chromatography with CHCN / HO (60 / 40, v / v) to give (10S)—N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-8,9,10,11-tetrahydro-7H-6,10-methano[1,4,7]oxadiazonin-o[3,2-g]quinazolin-4-amine (600.0 mg, 60%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 494.1.

[0192] Step 3: Synthesis of 1-((10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonin-o[3,2-g]quinazolin-9-yl)prop-2-en-1-one (compound 3) [ka] To a stirred mixture of (10S)—N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-8,9,10,11-tetrahydro-7H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-4-amine (100.0 mg, 0.20 mmol) and acrylic acid (14.6 mg, 0.20 mmol) in pyridine (3.0 mL) was added EDCI (77.6 mg, 0.40 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was evaporated in vacuo. The residue was purified by reverse-phase flash column chromatography in CH3CN / HO (60 / 40, v / v) and then eluted under the following conditions: (XBridge Shield RP18 Purification by preparative HPLC on an OBD column, 19 × 250 mm, 10 μm; mobile phase A: water (10 mmol / L NH₄HCO₃), mobile phase B: MeOH; flow rate: 25 mL / min; gradient: 61% B to 71% B in 8 min; wavelength: 254 nm gave 1-((10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonin-o[3,2-g]quinazolin-9-yl)prop-2-en-1-one (compound 3) (17.6 mg, 15%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 548.2. 1H NMR (400 MHz, DMSO-d6): δ 9.50 (d, J = 4.8 Hz, 1H), 8.41 (d, J = 4.4 Hz, 1H), 8.28 - 8.24 (m, 1H), 8.17 (s, 1H), 7.74 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 6.0 Hz, 1H), 7.09 (s, 1H), 7.01 - 6.98 (m, 1H), 6.88 - 6.77 (m, 2H), 6.18 - 6.13 (m, 1H), 5.74 - 5.71 (m, 1H), 4.93 - 4.61 (m, 1H), 4.58 - 4.41 (m, 1H), 4.19 - 4.16 (m, 1.5H), 3.93 - 3.80 (m, 4.5H), 3.69 - 3.60 (m, 1H), 3.49 - 3.40 (m, 1H), 3.29 - 3.25 (m, 2H), 2.24 (s, 3H).

[0193] Example S4: Synthesis of 1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-9-yl)prop-2-en-1-one (Compound 4) Step 1. Synthesis of tert-butyl (2S)-4-(2-bromo-5-cyano-4-nitrophenyl)-2-(hydroxymethyl)piperazine-1-carboxylate [ka] To a solution of 4-bromo-5-fluoro-2-nitrobenzonitrile (3.0 g, 12.24 mmol) in ACN (50.0 mL) were added tert-butyl (2S)-2-(hydroxymethyl)piperazine-1-carboxylate (2.9 g, 13.46 mmol) and K2CO3 (5.1 g, 36.72 mmol) at room temperature. The resulting mixture was stirred at 85 °C for 16 hours. After the reaction was completed, the mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with ethyl acetate / petroleum ether (90 / 10, v / v) to give tert-butyl (2S)-4-(2-bromo-5-cyano-4-nitrophenyl)-2-(hydroxymethyl)piperazine-1-carboxylate (3.8 g, 99%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =441.1.

[0194] Step 2. Synthesis of tert-butyl (3S)-9-cyano-10-nitro-2,3,5,6-tetrahydro-4H-3,7-methanobenzo[b][1,4,7]oxadiazoline-4-carboxylate [ka] To a solution of tert-butyl (2S)-4-(2-bromo-5-cyano-4-nitrophenyl)-2-(hydroxymethyl)piperazine-1-carboxylate (1.0 g, 2.27 mmol) in dioxane (20.0 mL) was added CsCO (2.2 g, 6.80 mmol), BrettPhos (486.6 mg, 0.91 mmol), and Brettphos Pd G (410.9 mg, 0.45 mmol) at room temperature under N. The resulting mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the resulting mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with ethyl acetate / petroleum ether (50 / 50, v / v) to give tert-butyl (3S)-9-cyano-10-nitro-2,3,5,6-tetrahydro-4H-3,7-methanobenzo[b][1,4,7]oxadiazonin-4-carboxylate (470.0 mg, 54%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =361.1.

[0195] Step 3: Synthesis of tert-butyl (3S)-10-amino-9-cyano-2,3,5,6-tetrahydro-4H-3,7-methanobenzo[b][1,4,7]oxadiazoline-4-carboxylate [ka] To a solution of tert-butyl (3S)-9-cyano-10-nitro-2,3,5,6-tetrahydro-4H-3,7-methanobenzo[b][1,4,7]oxadiazonin-4-carboxylate (2.0 g, 5.5 mmol) in CHCOOH (24.0 mL) was added Fe (1.6 g, 27.07 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with CHCl / MeOH (90 / 10, v / v) to give tert-butyl (3S)-10-amino-9-cyano-2,3,5,6-tetrahydro-4H-3,7-methanobenzo[b][1,4,7]oxadiazonin-4-carboxylate (1.0 g, 44%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =331.2.

[0196] Step 4. Synthesis of tert-butyl (3S)-9-cyano-10-(((Z)-(dimethylamino)methylene)amino)-2,3,5,6-tetrahydro-4H-3,7-methanobenzo[b][1,4,7]oxadiazoline-4-carboxylate [ka] To a solution of tert-butyl (3S)-10-amino-9-cyano-2,3,5,6-tetrahydro-4H-3,7-methanobenzo[b][1,4,7]oxadiazonin-4-carboxylate (200.0 mg, 0.61 mmol) in EtOH (8.0 mL) was added DMF-DMA (66.4 mg, 0.91 mmol) at room temperature. The resulting mixture was stirred at 85° C. for 16 hours. After the reaction was completed, the resulting mixture was concentrated in vacuo to give tert-butyl (3S)-9-cyano-10-(((Z)-(dimethylamino)methylene)amino)-2,3,5,6-tetrahydro-4H-3,7-methanobenzo[b][1,4,7]oxadiazonin-4-carboxylate (200.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H] + =386.2.

[0197] Step 5. Synthesis of tert-butyl (10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazoline-9-carboxylate [ka] To a solution of tert-butyl (3S)-9-cyano-10-(((Z)-(dimethylamino)methylene)amino)-2,3,5,6-tetrahydro-4H-3,7-methanobenzo[b][1,4,7]oxadiazonin-4-carboxylate (500.0 mg, 1.30 mmol) in AcOH (8.0 mL) was added 3-methyl-4-{[1,2,4]triazolo[1,5-a]pyridin-7-yloxy}aniline (343.0 mg, 1.40 mmol) at room temperature. The resulting mixture was stirred at 85° C. for 16 hours. After the reaction was completed, the resulting mixture was concentrated in vacuo. The residue was purified by flash column chromatography with ethyl acetate / petroleum ether (80 / 20, v / v) to give tert-butyl (10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazoline-9-carboxylate (300.0 mg, 36%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =581.3.

[0198] Step 6. Synthesis of (10S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-4-amine hydrochloride [ka] A solution of tert-butyl (10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazoline-9-carboxylate (100.0 mg, 0.22 mmol) in HCl / 1,4-dioxane (4.0 mL, 4.0 mol / L) was stirred at room temperature for 1 hour. After the reaction was completed, the resulting mixture was concentrated in vacuo to give (10S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-4-amine hydrochloride (80.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H] + =481.2.

[0199] Step 7. Synthesis of 1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-9-yl)prop-2-en-1-one (compound 4) [ka] To a solution of (10S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-4-amine hydrochloride (200.0 mg, crude) in DMF (10.0 mL) was added acrylic acid (29.0 mg, 0.54 mmol), DIEA (537.9 mg, 4.2 mmol), and HATU (253.1 mg, 0.67 mmol) under N at 0° C. The resulting mixture was stirred at 0° C. under N for 1 h. After the reaction was completed, the resulting mixture was purified by reversed-phase flash chromatography in CHCN / H0 (50 / 50, v / v), and then purified under the following conditions: (Column: XBridge Prep Phenyl Purification by preparative HPLC on an OBD column, 19 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH₄HCO₃), mobile phase B: MeOH—HPLC; flow rate: 25 mL / min; gradient: 60% B to 75% B in 10 min; wavelength: 254 nm gave 1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonin-o[3,2-g]quinazolin-9-yl)prop-2-en-1-one (compound 4) (20.2 mg, 9%) as a white solid. LCMS (ESI, m / z): [M+H] + =535.3. 1H NMR (400 MHz, DMSO-d6): δ 9.59 (d, J = 5.2 Hz, 1H), 8.94 (d, J = 7.6 Hz, 1H), 8.47 (d, J = 4.8 Hz, 1H), 8.39 (s, 1H), 8.31 - 8.27 (m, 1H), 7.87 - 7.85 (m, 2H), 7.24 - 7.20 (m, 2H), 7.05 - 7.02 (m, 1H), 6.85 - 6.80 (m, 2H), 6.19 - 6.14 (m, 1H), 6.75 - 5.72 (m, 1H), 4.99 - 4.63 (m, 1H), 4.62 - 4.47 (m, 1H), 4.21 - 4.18 (m, 1H), 3.91 - 3.81 (m, 2H), 3.68 - 3.57 (m, 1H), 3.52 - 3.44 (m, 1H), 3.32 - 3.25 (m, 2H), 2.20 (s, 3H).

[0200] Example S5: Synthesis of 1-((10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-9-yl)prop-2-en-1-one (Compound 5) Step 1. Synthesis of 1-((10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-9-yl)prop-2-en-1-one (compound 5) [ka] To a solution of (10R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-4-amine (86.0 mg, 0.18 mmol) in DMF (3.0 mL) was added HATU (81.7 mg, 0.18 mmol), acrylic acid (12.9 mg, 0.18 mmol), and DIEA (115.65 mg, 1.80 mmol) under N at 0° C. The resulting mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, the mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography with ACN / H2O (70 / 30, v / v), followed by elution with the following conditions: (Column: XBridge Prep Phenyl Purification by preparative HPLC on an OBD column, 19 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 35% B to 45% B in 10 min; wavelength: 254 nm) afforded 1-((10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-9-yl)prop-2-en-1-one (compound 5) (6.0 mg, 6%) as a white solid. LCMS (ESI, m / z): [M + H] + = 535.3. 1H NMR (400 MHz, DMSO-d6): δ 9.59 (s, 1H), 8.95 (s, 1H), 8.47 (d, J = 4.8 Hz, 1H), 8.38 (s, 1H), 8.31 - 8.27 (m, 1H), 7.87 - 7.85 (m, 2H), 7.25 - 7.20 (m, 2H), 7.05 - 7.02 (m, 1H), 6.88 - 6.78 (m, 2H), 6.19 - 6.14(m, 1H), 5.75 - 5.72 (m, 1H), 4.95 - 4.68 (m, 1H), 4.62 - 4.47 (m, 1H), 4.21 - 4.18 (m, 1H), 3.93 - 3.81 (m, 2H), 3.71 - 3.62 (m, 2H), 3.55 - 3.50 (m, 1H), 3.27 - 3.25 (m, 1H), 2.20 (s, 3H).

[0201] Example S6: Synthesis of (E)-4-(dimethylamino)-1-((10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)but-2-en-1-one (Compound 6) Step 1. Synthesis of (E)-4-(dimethylamino)-1-((10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)but-2-en-1-one (compound 6) [ka] To a stirred mixture of (10S)—N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4′,5′:5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine (170.0 mg, 0.34 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid (88.8 mg, 0.69 mmol) in DMF (6.0 mL) was added DIEA (133.3 mg, 1.03 mmol) and HATU (261.4 mg, 0.69 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography in acetonitrile / water (27 / 73, v / v), and then purified under the following conditions: (Column: YMC-Actus Triart C18 Purification by preparative HPLC using an ExRS column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% B to 40% B in 8 min; wavelength: 254 nm) gave (E)-4-(dimethylamino)-1-((10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)but-2-en-1-one (compound 6) (5.1 mg, 2%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 606.4. 1H NMR (400 MHz, DMSO-d6): δ 9.45 - 9.43 (m, 1H), 8.43 (s, 1H), 8.17 (s, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.81 - 7.77 (m, 1H), 7.58 - 7.56 (m, 1H), 7.49 (s, 1H), 7.08 (d, J = 2.4 Hz, 1H), 7.01 - 6.98 (m, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.65 - 6.61 (m, 2H), 5.12 - 4.56 (m, 3H), 4.27 - 4.18 (m, 1H), 4.12 - 4.01 (m, 2H), 3.84 (s, 3H), 3.69 - 3.57 (m, 1H), 3.46 - 3.42 (m, 1H), 3.28 - 3.22 (m, 1H), 3.06 (s, 2H), 2.25 (s, 3H), 2.17 (d, J = 7.2 Hz, 6H).

[0202] Example S7: Synthesis of (E)-4-(dimethylamino)-1-((10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonin-o[3,2-g]quinazolin-9-yl)but-2-en-1-one (Compound 7) Step 1. Synthesis of (E)-4-(dimethylamino)-1-((10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazoninno[3,2-g]quinazolin-9-yl)but-2-en-1-one (compound 7) [ka] To a stirred mixture of (10S)—N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-8,9,10,11-tetrahydro-7H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-4-amine (200.0 mg, 0.40 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid (52.3 mg, 0.40 mmol) in DMF (3.0 mL) was added DIEA (209.5 mg, 1.62 mmol) and HATU (308.2 mg, 0.81 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was purified by reversed-phase flash column chromatography with CHCN / H0 (70 / 30, v / v), followed by column chromatography under the following conditions: (XBridge Prep OBD Purification by preparative HPLC on a C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 27% B to 37% B in 8 min; wavelength: 254 nm) gave (E)-4-(dimethylamino)-1-((10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonin-o[3,2-g]quinazolin-9-yl)but-2-en-1-one (compound 7) (27.6 mg, 11%) as a white solid. LCMS (ESI, m / z): [M+H] + = 605.3. 1H NMR (400 MHz, DMSO-d6): δ 9.49 (s, 1H), 8.41 (d, J = 3.6 Hz, 1H), 8.28 - 8.24 (m, 1H), 8.17 (s, 1H), 7.75 (s, 1H), 7.66 - 7.63 (m, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 4.4 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 7.02 - 6.98 (m, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.65 - 6.61 (m, 2H), 4.92 - 4.64 (m, 1H), 4.57 - 4.46 (m, 1H), 4.18 - 4.15 (m, 1H), 4.03 - 3.93 (m, 1H), 3.91 - 3.81 (m, 4H), 3.77 - 3.64 (m, 1H), 3.49 - 3.42 (m, 1H), 3.29 - 3.24 (m, 2H), 3.04 (d, J = 5.6 Hz, 2H), 2.25 (s, 3H), 2.17 - 2.15 (m, 6H).

[0203] Example S8: Synthesis of (E)-1-((10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-9-yl)-4-(dimethylamino)but-2-en-1-one (Compound 8) Step 1. Synthesis of (E)-1-((10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-9-yl)-4-(dimethylamino)but-2-en-1-one (compound 8) [ka] To a solution of (10R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-4-amine (80.0 mg, 0.17 mmol) in DMF (5.0 mL) was added (2E)-4-(dimethylamino)but-2-enoic acid (25.8 mg, 0.20 mmol), DIEA (215.2 mg, 1.67 mmol), and HATU (75.9 mg, 0.20 mmol) under N at 0°C. The resulting mixture was stirred at 0°C for 1.5 hours. After the reaction was complete, the mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: (Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 45% B in 8 min; Wavelength: 254 nm) to give (E)-1-((10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-9-yl)-4-(dimethylamino)but-2-en-1-one (Compound 8) (25.1 mg, 25%) as a white solid. LCMS (ESI, m / z): [M+H] + = 592.3. 1H NMR (400 MHz, DMSO-d6): δ 9.60 (s, 1H), 8.93 (d, J = 7.2 Hz, 1H), 8.46 (s, 1H), 8.38 (s, 1H), 8.31 - 8.27 (m, 1H), 7.87 - 7.85 (m, 2H), 7.22 - 7.20 (m, 2H), 7.04 - 7.02 (m, 1H), 6.80 (s, 1H), 6.64 - 6.57 (m, 2H), 4.98 - 4.92 (m, 0.5H), 4.75 - 4.46 (m, 1.5H), 4.20 - 4.14 (m, 2H), 3.92 - 3.79 (m, 2H), 3.70 - 3.67 (m, 1H), 3.61 - 3.54 (m, 1H), 3.27 - 3.23 (m, 1H), 3.04 (s, 2H), 2.20 - 2.15 (m, 9H).

[0204] Example S9: Synthesis of (E)-1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-9-yl)-4-(dimethylamino)but-2-en-1-one (Compound 9) Step 1. Synthesis of (E)-1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-9-yl)-4-(dimethylamino)but-2-en-1-one (Compound 9) [ka] To a solution of (10S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-4-amine hydrochloride (80.0 mg, crude) in DMF (5.0 mL) was added (2E)-4-(dimethylamino)but-2-enoic acid (25.8 mg, 0.20 mmol), DIEA (215.2 mg, 1.66 mmol), and HATU (75.9 mg, 0.20 mmol) under N at 0° C. The resulting mixture was stirred at 0° C. for 1.5 h. After the reaction was complete, the mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by phase flash chromatography with ethyl acetate / methanol (90 / 10, v / v), and then purified under the following conditions: (Column: YMC-Actus Triart C18 Purification by preparative HPLC with ExRS, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH₄HCO₃), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 35% B in 8 min; wavelength: 254 nm) gave (E)-1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonin-o[3,2-g]quinazolin-9-yl)-4-(dimethylamino)but-2-en-1-one (compound 9) (34.8 mg, 35%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 592.4. 1H NMR (400 MHz, DMSO-d6): δ 9.60 (d, J = 7.2 Hz, 1H), 8.94 (d, J = 7.6 Hz, 1H), 8.46 (d, J = 4.4 Hz, 1H), 8.39 (s, 1H), 8.31 - 8.27 (m, 1H), 7.87 - 7.85 (m, 2H), 7.23 - 7.20 (m, 2H), 7.05 - 7.02 (m, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.65 - 6.62 (m, 2H), 4.94 - 4.65 (m, 1H), 4.61 - 4.45 (m, 1H), 4.20 - 4.17 (m, 1H), 3.92 - 3.79 (m, 2H), 3.70 - 3.60 (m, 1H), 3.54 - 3.43 (m, 1H), 3.29 - 3.23 (m, 2H), 3.07 - 3.03 (m, 2H), 2.20 - 2.15 (m, 9H).

[0205] Example S10: Synthesis of (E)-1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)-4-(dimethylamino)but-2-en-1-one (Compound 10) Step 1. Synthesis of 3-amino-5-bromo-6-chloropicolinonitrile [ka] To a solution of 3-amino-5-bromopyridine-2-carbonitrile (40.0 g, 202.0 mmol) in CHCOOH (2.0 L) was added NCS (29.7 g, 222.3 mmol) at room temperature. The resulting mixture was stirred at room temperature for 72 hours. After the reaction was complete, the resulting mixture was diluted with HO and filtered. The solid was washed with water and dried to give 3-amino-5-bromo-6-chloropicolinonitrile (25.0 g, crude) as a pale yellow solid. LCMS (ESI, m / z): [M+H]+ =231.9.

[0206] Step 2. Synthesis of (Z)-N'-(5-bromo-6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimidamide [ka] To a solution of 3-amino-5-bromo-6-chloropicolinonitrile (15.0 g, 64.52 mmol) in EtOH (300.0 mL) was added DMF-DMA (9.4 g, 129.04 mmol) at room temperature. The resulting mixture was stirred at 75° C. for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to give (Z)-N′-(5-bromo-6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylmethanimidamide (18.0 g, crude) as a yellow solid. LCMS (ESI, m / z): [M+H] + =287.0.

[0207] Step 3: Synthesis of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-7-bromo-6-chloropyrido[3,2-d]pyrimidin-4-amine [ka] To a solution of (Z)-N'-(5-bromo-6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylmethanimidamide (18.0 g, crude) in acetic acid (300.0 mL) was added 3-methyl-4-{[1,2,4]triazolo[1,5-a]pyridin-7-yloxy}aniline (15.0 g, 62.59 mmol) at room temperature. The resulting mixture was stirred at 85°C for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was diluted with water and filtered. The precipitated solid was washed with water and dried to give N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-7-bromo-6-chloropyrido[3,2-d]pyrimidin-4-amine (30.0 g, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+ =482.0.

[0208] Step 4. Synthesis of (S)-tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7-bromopyrido[3,2-d]pyrimidin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate [ka] To a solution of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-7-bromo-6-chloropyrido[3,2-d]pyrimidin-4-amine (10.0 g, crude) in DMF (500.0 mL) was added tert-butyl (2S)-2-(hydroxymethyl)piperazine-1-carboxylate (6.7 g, 31.07 mmol) and KCO (14.3 g, 103.58 mmol) at room temperature. The resulting mixture was stirred at 100° C. for 16 hours. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with CHCl / CHOH (10 / 1, v / v) to give (S)-tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7-bromopyrido[3,2-d]pyrimidin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (12.0 g, 87%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =662.2.

[0209] Step 5. Synthesis of tert-butyl (10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate [ka] To a solution of (S)-tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7-bromopyrido[3,2-d]pyrimidin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (4.1 g, 6.20 mmol) in dioxane (120.0 mL) was added KCO (3.4 g, 24.80 mmol), BrettPhos (1.3 g, 2.46 mmol), and BrettPhos Pd G (1.1 g, 1.23 mmol) at room temperature under N. The resulting mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the resulting mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHCl / MeOH (12 / 1, v / v) to give tert-butyl (10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate (1.7 g, 47%) as a brown oil. LCMS (ESI, m / z): [M+H] + =582.2.

[0210] Step 6. Synthesis of (10S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine [ka] To a solution of tert-butyl (10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate (1.7 g, 2.93 mmol) in DCM (20.0 mL) was added TFA (20.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 hours. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. The residue was basified to pH = 8 with saturated NaHCO3 (aq). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give (10S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine (800.0 mg, crude) as a brown oil. LCMS (ESI, m / z): [M+H] + =482.2.

[0211] Step 7. Synthesis of (E)-1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)-4-(dimethylamino)but-2-en-1-one (Compound 10) [ka] To a solution of (10S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4′,5′:5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine (4.5 g, crude) in DMF (50.0 mL) was added (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride (7.7 g, 46.8 mmol) and DIEA (14.4 g, 112.2 mmol). Then, HATU (7.1 g, 18.70 mmol) was added to the mixture at 0° C. under N. The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash column chromatography with CHCN / HO (40 / 60, v / v) to give (E)-1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)-4-(dimethylamino)but-2-en-1-one (compound 10) (820.0 mg, 15%) as a pale yellow solid. LCMS (ESI, m / z): [M+H] + =593.5. 1H NMR (400 MHz, DMSO-d6): δ 9.52 - 9.49 (m, 1H), 8.94 (d, J = 7.6 Hz, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 8.02 - 7.95 (m, 2H), 7.51 (s, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.04 - 7.02 (m, 1H), 6.79 (d, J = 2.8 Hz, 1H), 6.67 - 6.62 (m, 2H), 5.12 - 4.63 (m, 3H), 4.28 - 4.20 (m, 2H), 4.15 - 4.03 (m, 1H), 3.88 - 3.65 (m, 1H), 3.28 - 3.22 (m, 2H), 3.06 - 3.03 (m, 2H), 2.20 - 2.15 (m, 9H).

[0212] Example S11: Synthesis of 1-((10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonin-o[3,2-g]quinazolin-9-yl)but-2-yn-1-one (compound 11) Step 1. Synthesis of 1-((10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-9-yl)but-2-yn-1-one (compound 11) [ka] To a stirred mixture of (10S)—N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-8,9,10,11-tetrahydro-7H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-4-amine (150.0 mg, 0.30 mmol) and 2-butynoic acid (25.5 mg, 0.30 mmol) in DMF (2.0 mL) was added EDCI (116.5 mg, 0.61 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography in CHCN / H0 (70 / 30, v / v), followed by column chromatography using the following conditions: XSelect CSH Prep C18 Purification by preparative HPLC on an OBD column, 19 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH₄HCO₃), mobile phase B: MeOH; flow rate: 25 mL / min; gradient: 68% B to 68% B in 10 min; wavelength: 254 nm gave 1-((10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonin-o[3,2-g]quinazolin-9-yl)but-2-yn-1-one (compound 11) (20.6 mg, 12%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 560.3. 1H NMR (400 MHz, DMSO-d6): δ 9.55 - 9.51 (m, 1H), 8.42 (d, J = 4.8 Hz, 1H), 8.31 - 8.26 (m, 1H), 8.17 (s, 1H), 7.76 - 7.74 (m, 1H), 7.66 - 7.63 (m, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 6.0 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 7.01 - 6.98 (m, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.85 - 4.83 (m, 1H), 4.59 - 4.42 (m, 1H), 4.26 - 4.19 (m, 1H), 4.09 - 3.99 (m, 1H), 3.91 - 3.84 (m, 4H), 3.80 - 3.64 (m, 2H), 3.56 - 3.39 (m, 1H), 3.28 - 3.20 (m, 1H), 2.25 (s, 3H), 2.06 (d, J = 8.4 Hz, 3H).

[0213] Example S12: Synthesis of 1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-9-yl)but-2-yn-1-one (Compound 12) Step 1. Synthesis of 1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-9-yl)but-2-yn-1-one (compound 12) [ka] To a solution of (10S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-4-amine hydrochloride (100.0 mg, crude) in DMF (2.0 mL) was added 2-butynoic acid (18.5 mg, 0.26 mmol), HATU (162.6 mg, 0.43 mmol), and DIEA (274.0 mg, 2.1 mmol) at 0° C. under N. The resulting mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 27% B to 37% B in 8 min; Wavelength: 254 nm) to give 1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-9-yl)but-2-yn-1-one (Compound 12) (23.4 mg, 40%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 547.3. 1H NMR (400 MHz, DMSO-d6): δ 9.63 - 9.59 (m, 1H), 8.94 (d, J = 7.6 Hz, 1H), 8.48 (s, 1H), 8.38 - 8.29 (m, 2H), 7.88 - 7.85 (m, 2H), 7.26 -7.20 (m, 2H), 7.04 - 7.02 (m, 1H), 6.81 (d, J = 2.4 Hz, 1H), 4.86 - 4.84 (m, 1H), 4.60 - 4.47 (m, 1H), 4.26 - 4.20 (m, 1H), 4.09 - 4.02 (m, 1H), 3.93 - 3.71 (m, 3H), 3.69 - 3.53 (m, 1H), 3.31 - 3.20 (m, 1H), 2.20 (s, 3H), 2.07 (s, 3H).

[0214] Example S13: Synthesis of 1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (Compound 13) Step 1. Synthesis of tert-butyl (S)-4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)amino)-7-bromopyrido[3,2-d]pyrimidin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate [ka] To a solution of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)-7-bromo-6-chloropyrido[3,2-d]pyrimidin-4-amine (500.0 mg, 1.04 mmol) in DMAC (12.0 mL) was added (S)-tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate (224.9 mg, 1.04 mmol), 4AMS (200.0 mg), and KCO (431.2 mg, 3.12 mmol) at room temperature. The resulting mixture was stirred at 100° C. for 16 hours. After the reaction was complete, the mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHCl / MeOH (90 / 10, v / v) to afford (S)-tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)amino)-7-bromopyrido[3,2-d]pyrimidin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (610.0 mg, 88%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 660.2.

[0215] Step 2. Synthesis of tert-butyl (10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate [ka] To a solution of (S)-tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)amino)-7-bromopyrido[3,2-d]pyrimidin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (200.0 mg, 0.30 mmol) in 1,4-dioxane (10.0 mL) was added KCO (167.4 mg, 1.21 mmol), BrettPhos Pd G (54.9 mg, 0.06 mmol), and BrettPhos (65.0 mg, 0.12 mmol) at room temperature under N. The resulting mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate / MeOH (90 / 10, v / v) to give tert-butyl (10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate (100.0 mg, 57%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 580.0.

[0216] Step 3: Synthesis of (10S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine hydrochloride [ka] A solution of tert-butyl (10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate (100.0 mg, 0.20 mmol) in HCl / 1,4-dioxane (5.0 mL, 4.0 mol / L) was stirred at room temperature for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to give (10S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine hydrochloride (90.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 480.0.

[0217] Step 4. Synthesis of 1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (compound 13) [ka] To a solution of (10S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4′,5′:5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine hydrochloride (150.0 mg, crude) in DMF (5.0 mL) was added acrylic acid (22.5 mg, 0.31 mmol), DIEA (404.3 mg, 3.13 mmol), and HATU (237.9 mg, 0.63 mmol) at 0° C. under N. The resulting mixture was stirred at 0° C. for 1.5 hours. After the reaction was complete, the mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography in CHCN / H0 (50 / 50, v / v), followed by elution with the following conditions: (Column: XBridge Prep OBD Purification by preparative HPLC on a C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 27% B to 37% B in 8 min; wavelength: 254 nm) gave 1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (compound 13) (12.6 mg, 4%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 534.3. 1H NMR (400 MHz, DMSO-d6): δ 9.41 - 9.39 (m, 1H), 8.86 - 8.84 (m, 1H), 8.44 (s, 2H), 7.85 - 7.79 (m, 2H), 7.50 - 7.49 (m, 2H), 7.27 - 7.25 (m, 1H), 7.03 - 7.00 (m, 1H), 6.85 - 6.80 (m, 1H), 6.17 - 6.13 (m, 1H), 5.74 - 5.71 (m, 1H), 5.10 - 4.61 (m, 3H), 4.20 - 4.06 (m, 5H), 3.89 - 3.62 (m, 1H), 3.59 - 3.51 (m, 1H), 3.30 - 3.23 (m, 1H), 2.32 (s, 3H).

[0218] Example S14: Synthesis of 1-((10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (Compound 14) Step 1. Synthesis of 7-bromo-6-chloro-N-{3-methyl-4-[(1-methyl-1,3-benzodiazol-5-yl)oxy]phenyl}pyrido[3,2-d]pyrimidin-4-amine [ka] To a stirred mixture of (Z)-N'-(5-bromo-6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylmethanimidamide (3.4 g, 11.82 mmol) in acetic acid (45.3 mL) was added 3-methyl-4-[(1-methyl-1,3-benzodiazol-5-yl)oxy]aniline (3.0 g, 11.82 mmol) at room temperature. The resulting mixture was stirred at 85 °C for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHCl / MeOH (6 / 1, v / v) to give 7-bromo-6-chloro-N-{3-methyl-4-[(1-methyl-1,3-benzodiazol-5-yl)oxy]phenyl}pyrido[3,2-d]pyrimidin-4-amine (4.8 g, 81%) as a brown solid. LCMS (ESI, m / z): [M+H] + = 495.0.

[0219] Step 2. Synthesis of tert-butyl (2S)-4-[7-bromo-4-({3-methyl-4-[(1-methyl-1,3-benzodiazol-5-yl)oxy]phenyl}amino)pyrido[3,2-d]pyrimidin-6-yl]-2-(hydroxymethyl)piperazine-1-carboxylate [ka] To a stirred mixture of 7-bromo-6-chloro-N-{3-methyl-4-[(1-methyl-1,3-benzodiazol-5-yl)oxy]phenyl}pyrido[3,2-d]pyrimidin-4-amine (4.2 g, 8.47 mmol) and tert-butyl (2S)-2-(hydroxymethyl)piperazine-1-carboxylate (14.7 g, 67.78 mmol) in ACN (40.0 mL) was added KCO (5.9 g, 42.36 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHCl / MeOH (6 / 1, v / v) to give tert-butyl (2S)-4-[7-bromo-4-({3-methyl-4-[(1-methyl-1,3-benzodiazol-5-yl)oxy]phenyl}amino)pyrido[3,2-d]pyrimidin-6-yl]-2-(hydroxymethyl)piperazine-1-carboxylate (3.0 g, 52%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 675.2.

[0220] Step 3: Synthesis of tert-butyl (10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazoline-9-carboxylate [ka] To a stirred mixture of tert-butyl (2S)-4-[7-bromo-4-({3-methyl-4-[(1-methyl-1,3-benzodiazol-5-yl)oxy]phenyl}amino)pyrido[3,2-d]pyrimidin-6-yl]-2-(hydroxymethyl)piperazine-1-carboxylate (3.5 g, 5.18 mmol) and KCO (2.1 g, 15.54 mmol) in dioxane (40.0 mL), BrettPhos (1.1 g, 2.07 mmol) and BrettPhos Pd G (939.3 mg, 1.04 mmol) were added at room temperature under N. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHCl / MeOH (5 / 1, v / v) to give tert-butyl (10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazoline-9-carboxylate (1.3 g, 43%) as a brown solid. LCMS (ESI, m / z): [M+H] + = 595.2.

[0221] Step 4. Synthesis of (10S)-N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine [ka] To a stirred solution of tert-butyl (10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazoline-9-carboxylate (1.3 g, 2.27 mmol) in DCM (8.0 mL) was added TFA (4.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was basified to pH = 8 with saturated NaHCO3 (aq). The resulting mixture was extracted with CHCl2. The combined organic layers were washed with brine, dried over anhydrous NaSO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash column chromatography with acetonitrile / water (43 / 57, v / v) to give (10S)—N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4′,5′:5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine (400.0 mg, 35%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 495.2.

[0222] Step 5. Synthesis of 1-((10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (compound 14) [ka] To a stirred mixture of (10S)-N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine (180.0 mg, 0.36 mmol) and acrylic acid (52.5 mg, 0.73 mmol) in pyridine (6.0 mL) was added EDCI (139.5 mg, 0.73 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash column chromatography in acetonitrile / water (39 / 61, v / v) and then purified under the following conditions: (Column: XSelect CSH Fluoro Purification by preparative HPLC using Phenyl, 30 × 150 mm, 5 μm; mobile phase A: ACN, mobile phase B: water (0.1% FA); flow rate: 60 mL / min; gradient: 5% B to 25% B in 8 min, 25% B to 25% B in 12 min; wavelength: 254 / 220 nm) gave 1-((10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (Compound 14) (52.4 mg, 26%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 549.2. 1H NMR (400 MHz, DMSO-d6): δ 9.82 - 9.75 (m, 1H), 8.78 (d, J = 6.4 Hz, 1H), 8.52 (s, 1H), 7.87 (s, 1H), 7.82 - 7.75 (m, 2H), 7.52 (s, 1H), 7.17 - 7.14 (m, 2H), 6.98 (d, J = 8.4 Hz, 1H), 6.83 - 6.80 (m, 1H), 6.18 - 6.14 (m, 1H), 5.75 - 5.72 (m, 1H), 4.81 - 4.62 (m, 3H), 4.25 - 4.08 (m, 3H), 3.94 (s, 3H), 3.42 - 3.23 (m, 3H), 2.24 (s, 3H).

[0223] Example S15: Synthesis of (E)-1-((10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)-4-(dimethylamino)but-2-en-1-one (Compound 15) Step 1. Synthesis of tert-butyl (2R)-4-{7-bromo-4-[(3-methyl-4-{[1,2,4]triazolo[1,5-a]pyridin-7-yloxy}phenyl)amino]pyrido[3,2-d]pyrimidin-6-yl}-2-(hydroxymethyl)piperazine-1-carboxylate [ka] To a solution of 7-bromo-6-chloro-N-(3-methyl-4-{[1,2,4]triazolo[1,5-a]pyridin-7-yloxy}phenyl)pyrido[3,2-d]pyrimidin-4-amine (2.8 g, 5.80 mmol) in DMF (100.0 mL) was added tert-butyl (2R)-2-(hydroxymethyl)piperazine-1-carboxylate (1.9 g, 8.70 mmol) and K2CO3 (3.2 g, 23.20 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the resulting mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash column chromatography with HO / ACN (40 / 60, v / v) to give tert-butyl (2R)-4-{7-bromo-4-[(3-methyl-4-{[1,2,4]triazolo[1,5-a]pyridin-7-yloxy}phenyl)amino]pyrido[3,2-d]pyrimidin-6-yl}-2-(hydroxymethyl)piperazine-1-carboxylate (2.0 g, 52%) as a brown solid. LCMS (ESI, m / z): [M+H] + =662.2.

[0224] Step 2. Synthesis of tert-butyl (10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate [ka] To a solution of tert-butyl (2R)-4-{7-bromo-4-[(3-methyl-4-{[1,2,4]triazolo[1,5-a]pyridin-7-yloxy}phenyl)amino]pyrido[3,2-d]pyrimidin-6-yl}-2-(hydroxymethyl)piperazine-1-carboxylate (1.2 g, 1.81 mmol) in dioxane (60.0 mL) was added BrettPhos (388.9 mg, 0.72 mmol), KCO (751.0 mg, 5.43 mmol), and BrettPhos Pd G (328.4 mg, 0.36 mmol) at room temperature under N. The resulting mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash column chromatography with HO / MeOH (10 / 90, v / v) to give tert-butyl (10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate (190.0 mg, 18%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =582.2.

[0225] Step 3: Synthesis of (10R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine [ka] To a solution of tert-butyl (10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate (190.0 mg, 0.33 mmol) in DCM (2.0 mL) was added TFA (2.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The pH value of the mixture was adjusted to 7 with aqueous NaHCO3 solution. The resulting mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give (10R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine (100.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H] + =482.2.

[0226] Step 4. Synthesis of (E)-1-((10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)-4-(dimethylamino)but-2-en-1-one (Compound 15) [ka] To a solution of (10R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine (70.0 mg, crude) in DMF (1.0 mL) was added DIEA (112.7 mg, 0.87 mmol), (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (28.9 mg, 0.18 mmol), and HATU (82.9 mg, 0.22 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. After the reaction was completed, the resulting mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography with HO / MeOH (50 / 50, v / v), and then purified under the following conditions (column: XBridge Prep OBD Purification by preparative HPLC on a C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 34% B to 44% B in 8 min; wavelength: 254 nm) gave (E)-1-((10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)-4-(dimethylamino)but-2-en-1-one (compound 15) (10.7 mg, 12%) as a white solid. LCMS (ESI, m / z): [M+H] + = 593.3. 1H NMR (400 MHz, DMSO-d6): δ 9.55 - 9.52 (m, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 8.00 (s, 2H), 7.51 (s, 1H), 7.22 (d, J = 9.2 Hz, 1H), 7.04 - 7.02 (m, 1H), 6.79 (d, J = 2.8 Hz, 1H), 6.65 - 6.60 (m, 2H), 5.12 - 4.63 (m, 3H), 4.28 - 4.05 (m, 3H), 3.89 - 3.65 (m, 1H), 3.52 - 3.38 (m, 1H), 3.23 - 3.19 (m, 1H), 3.07 - 3.03 (m, 2H), 2.25 - 2.15 (m, 9H).

[0227] Example S16: Synthesis of 1-((10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)but-2-yn-1-one (Compound 16) Step 1. Synthesis of 1-((10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)but-2-yn-1-one (compound 16) [ka] To a stirred mixture of (10S)—N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4′,5′:5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine (170.0 mg, 0.34 mmol) and 2-butynoic acid (57.8 mg, 0.69 mmol) in pyridine (6.0 mL) was added EDCI (131.8 mg, 0.69 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH2Cl2 / MeOH (5 / 1, v / v), and then purified under the following conditions: (Column: Xselect CSH OBD column Purification by preparative HPLC on a 30 × 150 mm column, 5 μm column; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 33% B to 43% B in 9 min; 254 / 220 nm) afforded 1-((10S)-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)but-2-yn-1-one (compound 16) (51.2 mg, 26%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 561.4. 1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H), 8.43 (s, 1H), 8.17 (s, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.82 - 7.78 (m, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 0.4 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 7.01 - 6.98 (m, 1H), 6.90 - 6.87 (m, 1H), 5.04 - 5.02 (m, 1H), 4.77 - 4.65 (m, 2H), 4.26 - 4.07 (m, 3H), 3.84 (s, 3H), 3.81 - 3.65 (m, 1H), 3.45 - 3.38 (m, 1H), 3.25 - 3.12 (m, 1H), 2.25 (s, 3H), 2.07 - 2.04 (m, 3H).

[0228] Example S17: Synthesis of 1-((10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-9-yl)but-2-yn-1-one (compound 17) Step 1. Synthesis of 1-((10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-9-yl)but-2-yn-1-one (compound 17) [ka] To a solution of (10R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-4-amine hydrochloride (100.0 mg, crude) in DMF (2.0 mL) was added but-2-ynoic acid (19.2 mg, 0.26 mmol), HATU (162.6 mg, 0.43 mmol), and DIEA (274.0 mg, 2.1 mmol) at 0° C. under N. The resulting mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography with CHOH / HO (55 / 45, v / v) to give 1-((10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methano[1,4,7]oxadiazonino[3,2-g]quinazolin-9-yl)but-2-yn-1-one (compound 17) (40.2 mg, 50%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 547.4. 1H NMR (400 MHz, DMSO-d6): δ 9.64 - 9.60 (m, 1H), 8.93 (d, J = 7.2 Hz, 1H), 8.47 (d, J = 4.8 Hz, 1H), 8.38 - 8.30 (m, 2H), 7.88 - 7.85 (m, 2H), 7.25 - 7.20 (m, 2H), 7.04 - 7.02 (m, 1H), 6.81 (s, 1H), 4.86 - 4.84 (m, 1H), 4.60 - 4.42 (m, 1H), 4.26 - 4.21 (m, 1H), 4.09 - 4.02 (m, 1H), 3.93 - 3.90 (m, 0.5H), 3.77 - 3.63 (m, 2H), 3.60 - 3.44 (m, 1H), 3.28 - 3.20 (m, 1H), 2.20 (s, 3H), 2.07 - 2.05 (m, 3H).

[0229] Example S18: Synthesis of 1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)but-2-yn-1-one (compound 18) Step 1. Synthesis of 1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)but-2-yn-1-one (compound 18) [ka] To a solution of (10S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4′,5′:5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine (150.0 mg, crude) in DMF (5.0 mL) was added 2-butynoic acid (78.6 mg, 0.94 mmol), DIEA (161.0 mg, 1.25 mmol), and HATU (165.8 mg, 0.44 mmol) under N at 0° C. The resulting mixture was stirred at 0° C. for 1 hour. After the reaction was complete, the resulting mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography in CHCN / H0 (40 / 60, v / v), followed by elution with the following conditions (column: XBridge Prep OBD Purification by preparative HPLC on a C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 31% B to 41% B in 8 min; wavelength: 254 nm) gave 1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)but-2-yn-1-one (compound 18) (53.7 mg, 30%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =548.4. 1H NMR (400 MHz, DMSO-d6): δ 9.54 (s, 1H), 8.94 (d, J = 7.6 Hz, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 8.02 - 8.00 (m, 2H), 7.52 (s, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 5.05 - 4.97 (m, 1H), 4.81 - 4.63 (m, 2H), 4.27 - 4.07 (m, 3H), 3.75 - 3.42 (m, 2H), 3.26 - 3.21 (m, 1H), 2.20 (s, 3H), 2.07 - 2.05 (m, 3H).

[0230] Example S19: Synthesis of 1-((10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (Compound 19) Step 1. Synthesis of (Z)-N'-(5-bromo-6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimidamide [ka] To a solution of 3-amino-5-bromo-6-chloropicolinonitrile (1.0 g, 4.30 mmol) in EtOH (20.0 mL) was added DMF-DMA (0.5 g, 4.73 mmol) at room temperature. The resulting mixture was stirred at 70° C. for 50 minutes. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to give (Z)-N′-(5-bromo-6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimidamide (1.0 g, crude) as a yellow oil. LCMS (ESI, m / z): [M+H] + =287.0.

[0231] Step 2. Synthesis of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)-7-bromo-6-chloropyrido[3,2-d]pyrimidin-4-amine [ka] To a solution of (Z)-N'-(5-bromo-6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimidamide (540.0 mg, 1.88 mmol) in CH3COOH (20.0 mL) was added 4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylaniline (671.3 mg, 2.82 mmol) at room temperature. The resulting mixture was stirred at 75 °C for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column with dichloromethane / methanol (83 / 17, v / v) to give N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)-7-bromo-6-chloropyrido[3,2-d]pyrimidin-4-amine (920.0 mg, 98%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =480.0.

[0232] Step 3: Synthesis of tert-butyl (R)-4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)amino)-7-bromopyrido[3,2-d]pyrimidin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate [ka] To a solution of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)-7-bromo-6-chloropyrido[3,2-d]pyrimidin-4-amine (360.0 mg, 0.75 mmol) in DMAc (12.0 mL) was added (R)-tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate (194.4 mg, 0.95 mmol), 4AMS (200.0 mg), and KCO (310.5 mg, 2.25 mmol) at room temperature. The resulting mixture was stirred at 100° C. for 16 hours. After the reaction was complete, the mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHCl / MeOH (87 / 13, v / v) to afford (R)-tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)amino)-7-bromopyrido[3,2-d]pyrimidin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (170.0 mg, 34%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 660.2.

[0233] Step 4. Synthesis of tert-butyl (10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate [ka] To a solution of tert-butyl (R)-4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)amino)-7-bromopyrido[3,2-d]pyrimidin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (170.0 mg, 0.26 mmol) in 1,4-dioxane (6.0 mL) was added KCO (142.3 mg, 1.03 mmol), BrettPhos Pd G (46.7 mg, 0.05 mmol), and BrettPhos (55.3 mg, 0.10 mmol) at room temperature under N. The resulting mixture was stirred at 100 °C under N for 16 hours. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate / MeOH (89 / 11, v / v) to give tert-butyl (10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate (136.0 mg, 91%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 580.0.

[0234] Step 5. Synthesis of (10R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine hydrochloride [ka] A solution of tert-butyl (10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate (120.0 mg, 0.21 mmol) in HCl / 1,4-dioxane (5.0 mL, 4.0 mol / L) was stirred at room temperature for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to give (10R)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine hydrochloride (96.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 480.0. Step 6. Synthesis of 1-((10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (compound 19) [ka] To a solution of (10R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine hydrochloride (96.0 mg, crude) in DMF (5.0 mL) was added acrylic acid (17.3 mg, 0.24 mmol), DIEA (310.5 mg, 2.40 mmol), and HATU (152.2 mg, 0.40 mmol) at 0°C under N2. The resulting mixture was stirred at 0°C under N2 for 1.5 hours. After the reaction was complete, the mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography with CHOH / H0 (80 / 20, v / v), followed by elution with the following conditions: (Column: XBridge Prep OBD Purification by preparative HPLC on a C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 29% B to 66% B in 8 min; wavelength: 254 nm) gave 1-((10R)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (compound 19) (8.6 mg, 8%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 534.2. 1H NMR (400 MHz, DMSO-d6): δ 9.40 (d, J = 8.8 Hz, 1H), 8.85 (d, J = 6.8 Hz, 1H), 8.43 (d, J = 3.2 Hz, 2H), 7.90 - 7.80 (m, 2H), 7.50 (d, J = 4.8 Hz, 2H), 7.26 (d, J = 8.0 Hz, 1H), 7.02 - 7.00 (m, 1H), 6.91 - 6.80 (m, 1H), 6.15 - 6.10 (m, 1H), 5.74 - 5.71 (m, 1H), 5.12 - 4.64 (m, 3H), 4.27 - 4.05 (m, 5H), 3.91 - 3.60 (m, 1H), 2.26 (s, 3H).

[0235] Example S20: Synthesis of 1-((10S)-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (Compound 20) Step 1. Synthesis of (10S)-N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine hydrochloride [ka] A solution of tert-butyl (10S)-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate (500.0 mg, 0.90 mmol) in HCl / 1,4-dioxane (10.0 mL, 4.0 mol / L) was stirred at room temperature for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to give (10S)—N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4′,5′:5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine hydrochloride (230.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 456.2.

[0236] Step 2. Synthesis of 1-((10S)-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (compound 20) [ka] To a solution of (10S)—N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4′,5′:5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine hydrochloride (180.0 mg, crude) in DMF (5.0 mL) was added DIEA (510.7 mg, 3.95 mmol), acrylic acid (34.2 mg, 0.47 mmol), and HATU (300.5 mg, 0.79 mmol) at 0° C. under N. The resulting mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, the mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography in CHCN / H0 (50 / 50, v / v), followed by elution with the following conditions: (Column: Xselect CSH C18 OBD column) Purification by preparative HPLC (30 × 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 25% B in 12 min; wavelength: 220 nm) afforded 1-((10S)-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (compound 20) (11.7 mg, 6%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 510.3. 1H NMR (400 MHz, DMSO-d6): δ 9.47 - 9.44 (m, 1H), 8.44 (s, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.91 - 7.87 (m, 2H), 7.50 (s, 1H), 7.25 - 7.18 (m, 2H), 6.98 (d, J = 8.4 Hz, 1H), 6.86 - 6.79 (m, 1H), 6.17 - 6.13 (m, 1H), 5.75 - 5.72 (m, 1H), 5.11 - 4.63 (m, 3H), 4.28 - 3.87 (m, 3H), 3.65 - 3.51 (m, 1H), 3.30 - 3.21 (m, 1H), 2.44 (s, 3H), 2.21 (s, 3H).

[0237] Example S21: Synthesis of (E)-4-(dimethylamino)-1-((10S)-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)but-2-en-1-one (Compound 21) Step 1. Synthesis of 7-bromo-6-chloro-N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine [ka] To a solution of (Z)-N'-(5-bromo-6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimidamide (900.0 mg, 3.13 mmol) in CHCOOH (20.0 mL) was added 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (804.7 mg, 3.76 mmol) at room temperature. The resulting mixture was stirred at 75 °C for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHCl / MeOH (90 / 10, v / v) to give 7-bromo-6-chloro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrido[3,2-d]pyrimidin-4-amine (1.3 g, 90%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 456.0.

[0238] Step 2. Synthesis of tert-butyl (S)-4-(7-bromo-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate [ka] To a solution of 7-bromo-6-chloro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrido[3,2-d]pyrimidin-4-amine (650.0 mg, 1.42 mmol) in DMAC (15.0 mL) was added tert-butyl (2S)-2-(hydroxymethyl)piperazine-1-carboxylate (307.8 mg, 1.42 mmol) and K2CO3 (786.7 mg, 5.69 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHCl / MeOH (92 / 8, v / v) to give tert-butyl (2S)-4-[7-bromo-4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)pyrido[3,2-d]pyrimidin-6-yl]-2-(hydroxymethyl)piperazine-1-carboxylate (280.0 mg, 66.9%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 636.0.

[0239] Step 3: Synthesis of tert-butyl (10S)-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazoline-9-carboxylate [ka] To a solution of tert-butyl (2S)-4-[7-bromo-4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)pyrido[3,2-d]pyrimidin-6-yl]-2-(hydroxymethyl)piperazine-1-carboxylate (300.0 mg, 0.47 mmol) in 1,4-dioxane (20.0 mL) was added BrettPhos (101.2 mg, 0.19 mmol), BrettPhos Pd G3 (50.6 mg, 0.09 mmol), and K2CO3 (130.3 mg, 0.94 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHCl / MeOH (95 / 5, v / v) to give tert-butyl (10S)-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazoline-9-carboxylate (150.0 mg, 57%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 556.3.

[0240] Step 4. Synthesis of (10S)-N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine hydrochloride [ka] A solution of tert-butyl (10S)-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate (500.0 mg, 0.90 mmol) in HCl / 1,4-dioxane (10.0 mL, 4 mol / L) was stirred at room temperature for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to give (10S)—N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4′,5′:5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine hydrochloride (230.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 456.2.

[0241] Step 5. Synthesis of (E)-4-(dimethylamino)-1-((10S)-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)but-2-en-1-one (Compound 21) [ka] To a solution of (10S)—N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4′,5′:5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine hydrochloride (50.0 mg, crude) in DMF (10.0 mL) was added DIEA (141.9 mg, 1.10 mmol), (2E)-4-(dimethylamino)but-2-enoic acid (17.0 mg, 0.13 mmol), and HATU (83.5 mg, 0.22 mmol) at 0° C. under N. The resulting mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, the mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography in CHCN / H0 (50 / 50, v / v), followed by elution with the following conditions: (Column: Xselect CSH C18 OBD column) Purification by preparative HPLC (30 × 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 7% B to 15% B in 12 min; wavelength: 220 nm) afforded (E)-4-(dimethylamino)-1-((10S)-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)but-2-en-1-one (compound 21) (14.3 mg, 23%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 567.3. 1H NMR (400 MHz, DMSO-d6): δ 9.48 - 9.46 (m, 1H), 8.43 (s, 1H), 8.17 (s, 1H), 7.90 - 7.86 (m, 2H), 7.49 (s, 1H), 7.25 - 7.18 (m, 2H), 6.98 (d, J = 8.8 Hz, 1H), 6.64 (s, 2H), 5.10 - 4.60 (m, 3H), 4.27 - 3.87 (m, 3H), 3.35 - 3.30 (m, 1H), 3.28 - 3.20 (m, 2H), 3.10 - 3.06 (m, 2H), 2.42 (s, 3H), 2.21 - 2.19 (m, 9H).

[0242] Example S22: Synthesis of 1-((10S)-4-((4-((6-ethylpyridin-3-yl)oxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (Compound 22) Step 1. Synthesis of (10S)-N-(4-((6-ethylpyridin-3-yl)oxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine hydrochloride [ka] A solution of tert-butyl (10S)-4-((4-((6-ethylpyridin-3-yl)oxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate (250.0 mg, 0.44 mmol) in HCl / 1,4-dioxane (5.0 mL, 4.0 mol / L) was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to give (10S)—N-(4-((6-ethylpyridin-3-yl)oxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine hydrochloride (200.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 470.2.

[0243] Step 2. Synthesis of 1-((10S)-4-((4-((6-ethylpyridin-3-yl)oxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (compound 22) [ka] To a solution of (10S)—N-(4-((6-ethylpyridin-3-yl)oxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4′,5′:5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine hydrochloride (200.0 mg, crude) in DMF (5.0 mL) was added DIEA (165.2 mg, 1.28 mol), acrylic acid (36.8 mg, 0.51 mmol), and HATU (485.9 mg, 1.28 mmol) at 0° C. under N. The resulting mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography with CHOH / H0 (80 / 20, v / v), followed by elution with the following conditions: (Column: XBridge Prep OBD Purification by preparative HPLC on a C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 41% B to 46% B in 8 min; wavelength: 254 nm) gave 1-((10S)-4-((4-((6-ethylpyridin-3-yl)oxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)prop-2-en-1-one (compound 22) (12.5 mg, 6%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =524.4. 1H NMR (400 MHz, DMSO-d6): δ 9.48 - 9.46 (m, 1H), 8.44 (s, 1H), 8.21 (d, J = 2.8 Hz, 1H), 7.92 - 7.87 (m, 2H), 7.50 (s, 1H), 7.27 - 7.20 (m, 2H), 6.99 (d, J = 8.8 Hz, 1H), 6.85 - 6.77 (m, 1H), 6.18 - 6.13 (m, 1H), 5.75 - 5.72 (m, 1H), 5.12 - 4.61 (m, 3H), 4.28 - 4.19 (m, 1H), 4.15 - 4.03 (m, 1H), 3.91 - 3.59 (m, 1H), 3.32 - 3.28 (m, 2H), 2.76 - 2.70 (m, 2H), 2.22 (s, 3H), 1.24 - 1.20 (m, 3H).

[0244] Example S23: Synthesis of 1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)-2-fluoroprop-2-en-1-one (Compound 23) Step 1. Synthesis of 1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)-2-fluoroprop-2-en-1-one (compound 23) [ka] To a solution of (10S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4′,5′:5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine (200.0 mg, 0.42 mmol) in DMF (2.0 mL) was added 2-fluoroacrylic acid (56.1 mg, 0.62 mmol), DIEA (214.7 mg, 1.66 mmol), and HATU (315.9 mg, 0.83 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. After the reaction was completed, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following column conditions: (XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 31% B to 41% B in 8 min; wavelength: 254 nm) to give 1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)-2-fluoroprop-2-en-1-one (compound 23) (27.8 mg, 12%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 554.2. 1H NMR (400 MHz, DMSO-d6): δ 9.54 (s, 1H), 8.93 (d, J = 7.6 Hz, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 8.00 (s, 2H), 7.54 (s, 1H), 7.22 (d, J = 9.2 Hz, 1H), 7.03 (d, J = 6.8 Hz, 1H), 6.79 (s, 1H), 5.35 - 5.30 (m, 1H), 5.17 - 4.93 (m, 1H), 4.84 - 4.62 (m, 2H), 4.26 - 4.15 (m, 2H), 3.93 - 3.68 (m, 1H), 3.51 - 3.37 (m, 1H), 2.20 (s, 3H).

[0245] Example S24: Synthesis of (E)-1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)-4-(dimethylamino)but-2-en-1-one (Compound 24) Step 1. Synthesis of [1,2,4]triazolo[1,5-a]pyridin-7-ol [ka] To a solution of 7-bromo-[1,2,4]triazolo[1,5-a]pyridine (501.0 mg, 2.53 mmol) in 1,4-dioxane (8.0 mL) / HO (2.0 mL) was added KOH (625.7 mg, 11.15 mmol), Pd(dba) (263.1 mg, 0.28 mmol), and t-BuXPhos (231.1 mg, 0.54 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 4 h. After the reaction was complete, the resulting mixture was cooled to room temperature and diluted with water. The aqueous layer was adjusted to pH 5 with 1 N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH2Cl2 / MeOH (5 / 1, v / v) to give [1,2,4]triazolo[1,5-a]pyridin-7-ol (140.0 mg, 40%) as a white solid. LCMS (ESI, m / z): [M+H] + =136.0.

[0246] Step 2. Synthesis of 7-(5-fluoro-2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine [ka] To a solution of [1,2,4]triazolo[1,5-a]pyridin-7-ol (1.3 g, 9.62 mmol) in DMF (30.0 mL) were added 1,5-difluoro-2-methyl-4-nitrobenzene (5.0 g, 28.86 mmol) and K2CO3 (8.0 g, 57.72 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 hours. After the reaction was completed, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (2 / 1, v / v) to give 7-(5-fluoro-2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (1.1 g, 39%) as a white solid. LCMS (ESI, m / z): [M+H]+ =289.1. 1 H NMR (400 MHz, DMSO-d6): δ 9.03 (d, J = 7.5 Hz, 1H), 8.48 (s, 1H), 8.29 - 8.23 ​​(m, 1H), 7.45 - 7.35 (m, 2H), 7.16 - 7.08 (m, 1H), 2.30 (s, 3H).MS (ESI, m / z): 289 (M + H) + .

[0247] Step 3. Synthesis of 2-fluoro-5-methyl-4-[[1,2,4]triazolo[1,5-a]pyridin-7-yloxy]aniline [ka] To a solution of 7-(5-fluoro-2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 1.73 mmol) in MeOH (10.0 mL) was added Pd / C (150.0 mg, dry) at room temperature. The resulting mixture was stirred under H2 at room temperature for 2 hours. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure to give 2-fluoro-5-methyl-4-[[1,2,4]triazolo[1,5-a]pyridin-7-yloxy]aniline (380.0 mg, crude) as a white solid. LCMS (ESI, m / z): [M+H] + =259.1.

[0248] Step 4. Synthesis of 7-bromo-6-chloro-N-(2-fluoro-5-methyl-4-{[1,2,4]triazolo[1,5-a]pyridin-7-yloxy}phenyl)pyrido[3,2-d]pyrimidin-4-amine [ka] To a solution of (Z)-N'-(5-bromo-6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylmethanimidamide (800.0 mg, 2.78 mmol) in CH3COOH (10.0 mL) was added 2-fluoro-5-methyl-4-{[1,2,4]triazolo[1,5-a]pyridin-7-yloxy}aniline (718.5 mg, 2.78 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 16 hours. After the reaction was completed, the resulting mixture was concentrated in vacuo. The residue was purified by flash column chromatography with CHCl / MeOH (10 / 1, v / v) to give 7-bromo-6-chloro-N-(2-fluoro-5-methyl-4-{[1,2,4]triazolo[1,5-a]pyridin-7-yloxy}phenyl)pyrido[3,2-d]pyrimidin-4-amine (1.0 g, 50%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 500.0.

[0249] Step 5. Synthesis of tert-butyl (2S)-4-{7-bromo-4-[(2-fluoro-5-methyl-4-{[1,2,4]triazolo[1,5-a]pyridin-7-yloxy}phenyl)amino]pyrido[3,2-d]pyrimidin-6-yl}-2-(hydroxymethyl)piperazine-1-carboxylate [ka] To a solution of 7-bromo-6-chloro-N-(2-fluoro-5-methyl-4-{[1,2,4]triazolo[1,5-a]pyridin-7-yloxy}phenyl)pyrido[3,2-d]pyrimidin-4-amine (1.0 g, 1.99 mmol) in DMF (10.0 mL) was added tert-butyl (2S)-2-(hydroxymethyl)piperazine-1-carboxylate (431.9 mg, 1.99 mmol) and K2CO3 (828.0 mg, 5.99 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHCl / MeOH (10 / 1, v / v) to give tert-butyl (2S)-4-{7-bromo-4-[(2-fluoro-5-methyl-4-{[1,2,4]triazolo[1,5-a]pyridin-7-yloxy}phenyl)amino]pyrido[3,2-d]pyrimidin-6-yl}-2-(hydroxymethyl)piperazine-1-carboxylate (700.0 mg, 50%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 680.2.

[0250] Step 6: Synthesis of tert-butyl (10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate [ka] To a solution of tert-butyl (2S)-4-{7-bromo-4-[(2-fluoro-5-methyl-4-{[1,2,4]triazolo[1,5-a]pyridin-7-yloxy}phenyl)amino]pyrido[3,2-d]pyrimidin-6-yl}-2-(hydroxymethyl)piperazine-1-carboxylate (680.0 mg, 0.99 mmol) in dioxane (20.0 mL) was added KCO (414.2 mg, 2.99 mmol), BrettPhos (107.2 mg, 0.20 mmol), and BrettPhos Pd G (90.5 mg, 0.10 mmol) at room temperature under N. The resulting mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHCl / MeOH (10 / 1, v / v) to give tert-butyl (10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate (400.0 mg, 66%) as a pale yellow solid. LCMS (ESI, m / z): [M+H] + = 600.2.

[0251] Step 7. Synthesis of (10S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine [ka] A solution of tert-butyl (10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate (400.0 mg, 0.66 mmol) and TFA (4.0 mL) in CHCl (8.0 mL) was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was basified to pH = 8 with saturated NaHCO (aq). The resulting mixture was extracted with CHCl. ​​The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHCl / MeOH (10 / 1, v / v) to give (10S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4′,5′:5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine (300.0 mg, 90%) as a pale yellow solid. LCMS (ESI, m / z): [M+H] + = 500.2.

[0252] Step 8. Synthesis of (E)-1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)-4-(dimethylamino)but-2-en-1-one (Compound 24) [ka] To a solution of (10S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4′,5′:5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine (150.0 mg, 0.30 mmol) in DMF (4.0 mL) was added (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride (38.7 mg, 0.30 mmol), DIEA (194.0 mg, 1.50 mmol), and HATU (228.3 mg, 0.60 mmol) under N at 0° C. The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash column chromatography in CHCN / HO (50 / 50, v / v), followed by elution with the following conditions: (Column: XSelect CSH Prep C18 Purification by preparative HPLC on an OBD column, 19 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH₄HCO₃), mobile phase B: MeOH; flow rate: 25 mL / min; gradient: 67% B to 67% B in 12 min; wavelength: 254 nm gave (E)-1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)-4-(dimethylamino)but-2-en-1-one (compound 24) (10.7 mg, 5%) as a pale yellow solid. LCMS (ESI, m / z): [M+H] + = 611.4. 1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 8.97 (d, J = 7.2 Hz, 1H), 8.42 (d, J = 5.2 Hz, 2H), 8.01 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.32 (d, J = 10.8 Hz, 1H), 7.07 - 7.05 (m, 1H), 6.92 (d, J = 2.0 Hz, 1H), 6.69 - 6.57 (m, 2H), 5.11 - 4.79 (m, 1H), 4.78 - 4.55 (m, 2H), 4.28 - 4.04 (m, 3H), 3.90 - 3.67 (m, 1H), 3.48 - 3.34 (m, 1H), 3.31 - 3.20 (m, 1H), 3.05 - 2.99 (m, 2H), 2.20 - 2.15 (m, 9H).

[0253] Example S25: Synthesis of (E)-4-(dimethylamino)-1-((10S)-4-((3-methyl-4-(pyridin-3-yloxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)but-2-en-1-one (Compound 25) Step 1. Synthesis of 7-bromo-6-chloro-N-[3-methyl-4-(pyridin-3-yloxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine [ka] To a mixture of (Z)-N'-(5-bromo-6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylmethanimidamide (1.0 g, 3.48 mmol) in acetic acid (15.0 mL) was added 3-methyl-4-(pyridin-3-yloxy)aniline (696.4 mg, 3.48 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to give 7-bromo-6-chloro-N-[3-methyl-4-(pyridin-3-yloxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (2.0 g, 90%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 442.1.

[0254] Step 2. Synthesis of tert-butyl (2S)-4-(7-bromo-4-{[3-methyl-4-(pyridin-3-yloxy)phenyl]amino}pyrido[3,2-d]pyrimidin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate [ka] To a mixture of 7-bromo-6-chloro-N-[3-methyl-4-(pyridin-3-yloxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (2.0 g, 4.52 mmol) and tert-butyl (2S)-2-(hydroxymethyl)piperazine-1-carboxylate (1.5 g, 6.80 mmol) in ACN (50.0 mL) was added KCO (3.8 g, 27.10 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane / methanol (10 / 1, v / v) to give tert-butyl (2S)-4-(7-bromo-4-{[3-methyl-4-(pyridin-3-yloxy)phenyl]amino}pyrido[3,2-d]pyrimidin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (2.4 g, 85%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 622.5.

[0255] Step 3: Synthesis of tert-butyl (10S)-4-((3-methyl-4-(pyridin-3-yloxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazoline-9-carboxylate [ka] To a mixture of (S)-tert-butyl 4-(7-bromo-4-((3-methyl-4-(pyridin-3-yloxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (2.4 g, 3.86 mmol) in dioxane (50.0 mL), CsCO (3.8 g, 11.6 mmol), Brettphos (0.8 g, 1.5 mmol), and Brettphos Pd G (0.7 g, 0.8 mmol) were added at room temperature. The resulting mixture was stirred at 100 °C under N for 16 hours. After the reaction was complete, the resulting mixture was diluted with EtOAc and filtered. The filtrate was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane / methanol (10 / 1, v / v) to give tert-butyl (10S)-4-((3-methyl-4-(pyridin-3-yloxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-carboxylate (1.7 g, 80%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 542.1.

[0256] Step 4. Synthesis of (10S)-N-(3-methyl-4-(pyridin-3-yloxy)phenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine [ka] A mixture of tert-butyl (10S)-4-((3-methyl-4-(pyridin-3-yloxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazoline-9-carboxylate (1.0 g, 1.90 mmol) in DCM (10.0 mL) and TFA (5.0 mL) was stirred at room temperature for 30 minutes. After the reaction was complete, the resulting mixture was neutralized with saturated NaHCO3 (aq) to pH = 8. The resulting mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane / methanol (10 / 1, v / v) to give (10S)—N-(3-methyl-4-(pyridin-3-yloxy)phenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine (600.0 mg, 74%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 442.2.

[0257] Step 5. Synthesis of (E)-4-(dimethylamino)-1-((10S)-4-((3-methyl-4-(pyridin-3-yloxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)but-2-en-1-one (Compound 25) [ka] To a stirred mixture of (10S)-N-(3-methyl-4-(pyridin-3-yloxy)phenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine (340.0 mg, 0.77 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid (199.5 mg, 1.54 mmol) in pyridine (5.0 mL) was added EDCI (296.1 mg, 1.54 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using dichloromethane / methanol (10 / 1, v / v) and then purified under the following conditions: (Column: XBridge Shield RP18 Purification by preparative HPLC on an OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH₄HCO₃), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 34% B to 50% B in 8 min; wavelength: 254 nm) afforded (E)-4-(dimethylamino)-1-((10S)-4-((3-methyl-4-(pyridin-3-yloxy)phenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)but-2-en-1-one (compound 25) (41.0 mg, 9%) as a pale yellow solid. LCMS (ESI, m / z): [M+H] + = 553.4. 1H NMR (400 MHz, DMSO-d6): δ 9.51 - 9.48 (m, 1H), 8.45 (s, 1H), 8.33 - 8.30 (m, 2H), 7.93 - 7.89 (m, 2H), 7.50 (s, 1H), 7.42 - 7.38 (m, 1H), 7.29 - 7.25 (m, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.66 - 6.64 (m, 2H), 5.11 - 4.60 (m, 4H), 4.27 - 4.18 (m, 2H), 4.14 - 4.03 (m, 1H), 3.88 - 3.66 (m, 2H), 3.23 - 3.15 (m, 2H), 2.25 - 2.20 (m, 9H).

[0258] Example S26: Synthesis of (E)-1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)-4-(azetidin-1-yl)but-2-en-1-one (Compound 26) Step 1. Synthesis of (E)-1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)-4-bromobut-2-en-1-one [ka] To a solution of (10S)—N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-8,9,10,11-tetrahydro-7H-6,10-methanopyrimido[4′,5′:5,6]pyrido[3,2-b][1,4,7]oxadiazonin-4-amine (200.0 mg, 0.42 mmol) in THF (5.0 mL) was added 4-bromo-trans-crotonic acid (68.5 mg, 0.42 mmol) and EDCI (159.3 mg, 0.83 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to give (E)-1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)-4-bromobut-2-en-1-one (200.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 628.1.

[0259] Step 2. Synthesis of (E)-1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)-4-(azetidin-1-yl)but-2-en-1-one (Compound 26) [ka] To a solution of (E)-1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)-4-bromobut-2-en-1-one (200.0 mg, crude) in THF (5.0 mL) was added TEA (96.6 mg, 0.95 mmol) and azetidine (18.2 mg, 0.32 mmol) at room temperature. The resulting mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH2Cl2 / MeOH (8 / 1, v / v) and then purified under the following conditions: (Column: XSelect CSH Prep C18 Purification by preparative HPLC on an OBD column, 19 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH; flow rate: 20 mL / min; gradient: 71% B to 71% B in 11 min; wavelength: 254 nm gave (E)-1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)-4-(azetidin-1-yl)but-2-en-1-one (compound 26) (4.8 mg, 2%) as a yellow solid. LCMS (ESI, m / z): [M+H] + = 605.4. 1H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 8.03 - 7.97 (m, 2H), 7.51 (s, 1H), 7.22 (d, J = 9.2 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.79 (d, J = 1.6 Hz, 1H), 6.54 - 6.48 (m, 2H), 5.10 - 4.60 (m, 3H), 4.31 - 3.62 (m, 5H), 3.18 - 3.12 (m, 5H), 2.21 (s, 3H), 2.03 - 1.92 (m, 2H).

[0260] Example S27: Synthesis of (E)-1-((10S)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7,8,10,11-tetrahydro-9H-6,10-methanopyrimido[4',5':5,6]pyrido[3,2-b][1,4,7]oxadiazonin-9-yl)-3-((S)-1-methylpyrrolidin-2-yl)prop-2-en-1-one (Compound 28) Step 1. Synthesis of (S)-pyrrolidine-2-carbaldehyde [ka] To a solution of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate (10.0 g, 50.25 mmol) in CHCl (100.0 mL) was added TFA (30.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 8.0 with saturated NaHCO (aq). The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give (S)-pyrrolidine-2-carbaldehyde (4.9 g, crude) as a brown oil. LCMS (ESI, m / z): [M+H] + =100.1.

[0261] Step 2. Synthesis of (S)-1-methylpyrrolidine-2-carbaldehyde [ka] To a solution of (S)-pyrrolidine-2-carbaldehyde (1.0 g, crude) in MeOH (30.0 mL) was added KCO (4.2 g, 30.30 mmol) and CHI (2.15 g, 15.15 mmol) at room temperature. The resulting mixture was stirred at 40 °C for 16 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (50 / 50, v / v) to give (S)-1-methylpyrrolidine-2-carbaldehyde (300.0 mg, 26%) as a yellow oil. LCMS (ESI, m / z): [M+H] + =114.1.

[0262] Step 3. Synthesis of ethyl (S,E)-3-(1-methylpyrrolidin-2-yl)acrylate [ka] To a solution of (S)-1-methylpyrrolidine-2-carbaldehyde (300.0 mg, 1.64 mmol) in CHCl (10.0 mL) was added 2-(triphenyl-λ 5 Eth...

Claims

1. Compound of formula (I') 【Chemistry 434】 or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, wherein ring A is 【Chemistry 435】 and E is -C(=O)-R １ and G is -O-, -C(=O)-, -S-, -S(O)-, -S(O) ２ - or -CH ２ - and V is O, S, or N-R ２ and each X １ is independently N or CH; X ２ is O, S, or N-R ３ and Y is N or C-R ｙ where R ｙ is -H or -F, Z is -H, halogen, -C≡CH, -OCH ３ , or C １ -C ２ is alkyl, R １ is C ２ -C ４ Alkenyl or C ２ -C ４ alkynyl, each of which is independently selected from halogen, C １ -C ３ alkyl, 3- to 7-membered carbon-linked N-heterocycloalkyl, or -NR １ａ R １ｂ wherein each R １ａ and R １ｂ are independently -H, C １ -C ３ Alkyl or -CD ３ or geminal R １ａ and R １ｂ Each pair of can be taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered N-heterocyclyl, where the nitrogen atom of each heterocyclyl, if present, is independently selected from C １ -C ３ optionally substituted with alkyl; R ２ is C １ -C ６ Alkyl or C １ -C ６ cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines; R ３ is -H, C １ -C ６ Alkyl, -CD ３ Or C １ -C ６ cycloalkyl, R ４ is —H or a halogen; R ５ is —H or a halogen; R ６ is —H or a halogen; R ７ is -H, halogen, C １ -C ６ Alkyl, -CD ３ Or C １ -C ６ is cycloalkyl, n is 1 or 2; p is 0 or 1; and q is 1 or 2.

2. The compound is a compound of formula (I) 【Chemistry 438】 or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, Ring A is 【Chemistry 439】 and E is -C(=O)-R １ and G is -O-, -C(=O)-, -S-, -S(O)-, -S(O) ２ - or -CH ２ - and V is O, S, or N-R ２ and each X １ is independently N or CH; X ２ is O, S, or N-R ３ and Y is N or C-R ｙ where R ｙ is -H or -F, Z is -H, halogen, -C≡CH, -OCH ３ , or C １ -C ２ is alkyl, R １ is C ２ -C ４ Alkenyl or C ２ -C ４ alkynyl, each of which is independently selected from halogen, C １ -C ３ alkyl, 3- to 7-membered carbon-linked N-heterocycloalkyl, or -NR １ａ R １ｂ wherein each R １ａ and R １ｂ are independently -H, C １ -C ３ Alkyl or -CD ３ or geminal R １ａ and R １ｂ Each pair of can be taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered N-heterocyclyl, where the nitrogen atom of each heterocyclyl, if present, is independently selected from C １ -C ３ optionally substituted with alkyl; R ２ is C １ -C ６ Alkyl or C １ -C ６ cycloalkyl, each of which is independently optionally substituted with 1 to 4 fluorines; R ３ is -H, C １ -C ６ Alkyl, -CD ３ Or C １ -C ６ cycloalkyl, R ４ is —H or a halogen; R ５ is —H or a halogen; R ６ is -H or a halogen), or a pharma- ceutically acceptable salt, solvate, or hydrate thereof.

3. Ring A is 【Chemistry 440】 2. The compound of claim 1, wherein:

4. Ring A is 【Chemistry 441】 2. The compound of claim 1, wherein:

5. Ring A is 【Chemical 442】 2. The compound of claim 1, wherein:

6. Ring A is 【Chemical 443】 2. The compound of claim 1, wherein:

7. Ring A is 【Chemical 444】 2. The compound of claim 1, wherein:

8. R ３ But -CH ３ 2. The compound of claim 1, wherein:

9. Z is -H, -F, -Cl, -C≡CH, -OCH ３ , or -CH ３ 2. The compound of claim 1, wherein:

10. Z is -CH ３ 2. The compound of claim 1, wherein:

11. R １ But, C ２ -C ４ alkenyl, -NR １ａ R １ｂ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, optionally substituted by:

12. R １ But -CH=CH ２ 2. The compound of claim 1, wherein:

13. R １ is -CH=CH-CH ２ -N(CH ３ ) ２ or -CH=CH-CH(CH ３ )-N(CH ３ ) ２ 2. The compound of claim 1, wherein:

14. R １ But, C ２ -C ４ alkynyl, -NR １ａ R １ｂ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, optionally substituted by:

15. R １ But -C≡C-CH ３ 2. The compound of claim 1, wherein:

16. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, wherein Y is N.

17. Y is C-R ｙ 2. The compound of claim 1, wherein:

18. Y is C-R ｙ and R ｙ The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, wherein:

19. 2. The compound of claim 1, wherein V is O, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof.

20. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, wherein G is --O--.

21. G is -CH ２ 2. The compound of claim 1, wherein: -, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof.

22. R ４ The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, wherein:

23. R ５ The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, wherein:

24. R ５ The compound of claim 1 , or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, wherein is a halogen.

25. R ６ The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, wherein:

26. 10. A pharmaceutical composition comprising a compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, and at least one pharma- ceutically acceptable excipient.

27. 【501】 【Chemistry 502】 【Chemistry 503】 【Chemistry 504】 【Chemistry 505】 【Chemistry 506】 【Chemistry 507】 【Chemistry 508】 【Chemistry 509】 【Chemistry 510】 or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, selected from the group consisting of:

28. 30. A pharmaceutical composition comprising a compound of claim 27, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, and at least one pharma- ceutically acceptable excipient.

29. 【Chemical 511】 or a pharma- ceutically acceptable salt thereof.

30. 30. The compound of claim 29, or a pharma- ceutically acceptable salt thereof, wherein the pharma- ceutically acceptable salt of the compound is a salt of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, malonic acid, benzoic acid, succinic acid, benzenesulfonic acid, p-tolylsulfonic acid, glucuronic acid, or an amino acid salt.

31. 30. A pharmaceutical composition comprising a compound of claim 29, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

32. 32. The pharmaceutical composition of claim 31, wherein the pharma- ceutically acceptable salt of the compound is a salt of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, malonic acid, benzoic acid, succinic acid, benzenesulfonic acid, p-tolylsulfonic acid, glucuronic acid, or an amino acid salt. 【Request 33】 【Chemistry 512】 or a pharma- ceutically acceptable salt thereof.

34. 34. The compound of claim 33, or a pharma- ceutically acceptable salt thereof, wherein the pharma- ceutically acceptable salt of the compound is a salt of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, malonic acid, benzoic acid, succinic acid, benzenesulfonic acid, p-tolylsulfonic acid, glucuronic acid, or an amino acid salt.

35. 34. A pharmaceutical composition comprising a compound of claim 33, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

36. 36. The pharmaceutical composition of claim 35, wherein the pharma- ceutically acceptable salt of the compound is a salt of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, malonic acid, benzoic acid, succinic acid, benzenesulfonic acid, p-tolylsulfonic acid, glucuronic acid, or an amino acid salt. 【Request 37】 【Chemical 513】 or a pharma- ceutically acceptable salt thereof.

38. 38. The compound of claim 37, or a pharma- ceutically acceptable salt thereof, wherein the pharma- ceutically acceptable salt of the compound is a salt of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, malonic acid, benzoic acid, succinic acid, benzenesulfonic acid, p-tolylsulfonic acid, glucuronic acid, or an amino acid salt.

39. 40. A pharmaceutical composition comprising a compound of claim 37, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

40. 40. The pharmaceutical composition of claim 39, wherein the pharma- ceutically acceptable salt of the compound is a salt of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, malonic acid, benzoic acid, succinic acid, benzenesulfonic acid, p-tolylsulfonic acid, glucuronic acid, or an amino acid salt.

41. 【Chemical 514】 1. A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

42. 42. The compound of claim 41, or a pharma- ceutically acceptable salt thereof, wherein the pharma- ceutically acceptable salt of the compound is a salt of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, malonic acid, benzoic acid, succinic acid, benzenesulfonic acid, p-tolylsulfonic acid, glucuronic acid, or an amino acid salt.

43. 42. A pharmaceutical composition comprising a compound of claim 41, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

44. 44. The pharmaceutical composition of claim 43, wherein the pharma- ceutically acceptable salt of the compound is a salt of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, malonic acid, benzoic acid, succinic acid, benzenesulfonic acid, p-tolylsulfonic acid, glucuronic acid, or an amino acid salt.

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