NZ724372B2 - Benzimidazole derivatives as erbb tyrosine kinase inhibitors for the treatment of cancer - Google Patents

Abstract

Provided herein are benzimidazole derivatives, for example, of Formula I, and pharmaceutical compositions thereof capable of modulating ERBB tyrosine kinases. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a proliferative disease.

Description

WO 43148 IDAZOLE DERIVATIVES AS ERBB TYROSINE KINASE INHIBITORS FOR THE TREATMENT OF CANCER CROSS REFERENCE TO RELATED APPLICATION This application claims the benefit of the priority ofUS. Provisional Application No. 61/968,225, filed March 20, 2014; the disclosure of which is incorporated herein by reference in its entirety.

FIELD Provided herein are benzimidazole derivatives and ceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a erative disease.

BACKGROUND In the human receptor tyrosine kinase superfamily, the ERBB family comprises four members: ERBBl (epidermal growth factor receptor or EGFR), ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4). The ERBB receptors share an overall similar structure with a ligand-binding ectodomain, a single transmembrane domain, and an ellular kinase domain, which is active in ERBBl, HER2 and ERBB4, but defective in ERBB3. A diverse array of ligands has been identified for the ectodomains of ERBBl, ERBB3, and ERBB4, but not HER2. Ligand binding induces conformational change in receptors to form homo- and hetero-dimerization. Without ligand binding, the extracellular domain of HER2 is already fixed in a mation that resembles the other -activated ERBB members, making it a preferred dimerization partner for other ligand-bound ERBBs.

The dimerized receptors activate the intrinsic kinase activity, leading to phosphorylation of tyrosines at cytoplasmic tails. The ERBB receptors differ in kinase potency, phosphorylation sites, and substrate specificity. The phosphorylated tyrosines serve as the docking sites to recruit downstream effectors and activate multiple es of intracellular signaling pathways, including the anti-apoptotic/survival PI3K/AKT and the mitogenic RAS/RAF/MEK/ERK pathways. In normal cells, the ty of ERBB receptors is under tight control to regulate various cellular processes, such as growth, proliferation, pment and differentiation, al and apoptosis, cell shape and on, migration, and angiogenesis. Yarden et al., Nat. Rev. Mol. Cell. Biol. 2001, 2, 127-137; Hynes et al., Nat.

Rev. Cancer 2005, 5, 341—354.

As a major proliferation and survival engine for cells, constitutive activation ofERBB receptors, particularly ERBBl and HER2, is nic and can be a strong driver for genesis in cultured cells and animal models. In addition, the activated receptors accelerate cancer development by promoting tumor angiogenesis and metastasis. Persistent activation can result from overexpression of the receptors, production of excessive ligands, or generation of activating ons in the ectodomains and kinase domains of the receptors.

Yarden et al., Nat. Rev. Mol. Cell. Biol. 2001, 2, 127-137. In , genetic alterations in ERBB genes and other genes that lead to similar deregulation of ERBB receptors are frequently identified in majority of carcinomas, such as lung, breast, colon, prostate, brain, head and neck, agus, ovary, cervix, bladder, stomach, and endometrium cancer. The aberrant activation of ERBB receptors is in general an adverse prognostic indicator for higher recurrence rate and shorter survival time. Nicholson et al., Eur. J. Cancer 2001, 3 7, 9-15; Slamon et al., Science 1997, 235, 177-182.

Given the compelling association of activation of ERBB receptors with human cancers, ERBBl and HER2 are among the kinase targets for drug development, aiming to tame signaling uction pathways for cancer treatment. To reverse the abnormal activity ofERBB receptors in , monoclonal antibodies targeting the extracellular domains of ERBBl and HER2 and small molecule chemicals ting the intracellular kinase domains have been developed.

The monoclonal dy drugs attack the ERBB receptors with high specificity and attenuate ediated signaling by prevention of ligand binding and receptor dimerization, ation receptors from cell surface through endocytosis, inhibition of shedding of extracellular domain, and activation of immune system. Hudis, N. Engl. J.

Med. 2007, 35 7, 39-51. mab and panitumumab, two anti-ERBBl antibodies, have shown improvement in response rate and the rate of ssion-free survival in the treatment of metastatic colon cancer either as monotherapy or in combination with chemotherapies. In addition, cetuximab has also been approved for the treatment of locally advanced, unresectable or metastatic squamous cell carcinoma of the head and neck. ello et al., N. Engl. J. Med. 2008, 358, 1160-1174. Anti-HER2 antibody trastuzumab binds to the domain IV of the HER2 receptor at the juxtamembrane position. In clinical development, trastuzumab has demonstrated increased overall survival rate in early- and metastatic-stage breast cancer patients with tumors showing IHC 3+ HER2 overexpression or FISH gene amplification ratio of at least 2.0. Using the same criteria for patient selection, umab, which binds to a distinct epitope at the domain II of the HER2 receptor, has been found to filrther increase the complete response rate by addition to trastuzumab and docetaxel regimen as a neoadjuvant ent for patients with locally advanced, early-stage breast cancer.

Gradishar, N. Engl. J. Med. 2012, 366, 176-178.

Development of small-molecule ERBBl kinase inhibitors (ERBBlIs) has become an evolving paradigm for using cancer genomics to guide targeted drug development and treatment. Gefinitib and erlotinib, the first two ERBBlI drugs, are reversible ATP mimetic inhibitors that bind to the wild-type ERBBl catalytic domain to inhibit tyrosine kinase activity. In unselected patients of non-small cell lung cancer (NSCLC) or pancreatic cancer, only erlotinib has demonstrated clinical benefit by modestly increasing overall survival. Ciardiello et al., N. Engl. J. Med. 2008, 358, 1160-1174. In a subset C patients that harbor ting ons within ERBBl tyrosine kinase domain, both gefitinib and erlotinib ents are highly ive and can achieve lasting efficacy as monotherapy. These drug-responding mutations are mostly in-frame deletions nested around g-Glu-Ala from position 747 to 750 in ERBBl exon 19, or a leucine to arginine substitution at position 858 (L85 8R) in exon 21.

However, the initial response to nib or gefitinib relapses in 10-14 months by developing resistant mutations in tumors. Among them, a T790M gate-keeper point mutation in the exon 20 of ERBBl, which poses a steric interference to drug binding, is found in over 50% of acquired resistant tumors. To overcome the resistance from T790M mutation and confer sustained ERBBl inhibition, the second-generation ERBBlIs have been developed, some of them are irreversible ERBBl and HER2 dual inhibitors. The rsible compounds overcome the kinase binding hindrance from T790M on by better fitting into the mutated binding pocket and g covalent bond with the protein amino acid residues. Additionally, irreversible ERBBlIs appear to cause slower acquired resistance to the treatment than reversible inhibitors. Sharma et al. Nat. Rev. Cancer 2007, 7. 169-18 1.

In preclinical testing, afatinib, a second-generation , inhibited the growth ofNSCLC HCC827 cells, which harbor the sensitive exon 19 on, and is d more potent than erlotinib in inhibition of growth ofNSCLC H1975 cells, which has a T790M mutation in-cis with the L858R mutation. However, afatinib also inhibits A431 cells, whose growth is driven by a wild-type ERBB1, 100-fold more potent than H1975. The difference in ies portends that, in cancer patients, the compound could inhibit wild-type ERBB1 completely before it reaches sufficient blood level for pharmacological effect on T790M mutant ERBB1. Since wild-type ERBB1 inhibition has been reported to cause doselimiting toxicity in virtually all previously ERBB1I drugs, the preferential inhibition of pe ERBB1 over resistant mutant pose a ial challenge for afatinib to achieve high enough dose for T790M mutant inhibition. Consistent with the preclinical discovery, clinical development has found afatinib only showed equivalent efficacy to nib or gefitinib in patients with sensitive mutations, but failed to demonstrate statistically meaningful superiority to erlotinib and gefitinib in ng patients with acquired T790M resistant mutation even at the maximum tolerated dose. Langer, J. Clin. Oncol. 2013, 31, 3303-3330. Thus, there is a clear and unmet need to develop effective therapeutics for treating a proliferative disease, ally drug-resistant cancer.

SUMMARY OF THE DISCLOSURE [009a] The t invention particular relates to aspects and ments set out in the clauses below and as described further herein. However, other aspects and embodiments are also described herein for completeness. 1. A compound of Formula XIa or XIX: (XIa) (XIX) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt or solvate f; wherein each R1 is independently ed from the group consisting of: (followed by page 4A) , , , , , , , , , , , , , , , O N , , and ; R2 is C6-14 aryl, or heteroaryl; each R4, R5, and R7 is independently (a) en, cyano, halo, or nitro; (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, aryl, or heterocyclyl; or (c) –C(O)R1a, –C(O)OR1a, –C(O)NR1bR1c, –C(NR1a)NR1bR1c, –OR1a, –OC(O)R1a, –OC(O)OR1a, –OC(O)NR1bR1c, R1a)NR1bR1c, R1a, –OS(O)2R1a, –OS(O)NR1bR1c, –OS(O)2NR1bR1c, –NR1bR1c, –NR1aC(O)R1d, –NR1aC(O)OR1d, –NR1aC(O)NR1bR1c, –NR1aC(=NR1d)NR1bR1c, –NR1aS(O)R1d, –NR1aS(O)2R1d, –NR1aS(O)NR1bR1c, –NR1aS(O)2NR1bR1c, –SR1a, –S(O)R1a, –S(O)2R1a, –S(O)NR1bR1c, or –S(O)2NR1bR1c; R6a is C3-7 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; R7a is C3-7 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; (followed by page 4B) R2n is C1-6 alkyl or –OR1a; each R1a, R1b, R1c, and R1d is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or R1a and R1c together with the C and N atoms to which they are attached form heterocyclyl; or R1b and R1c together with the N atom to which they are attached form heterocyclyl; and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally tuted with one or more substituents Q, where each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C1-6 alkyl, C2-6 l, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, aryl, and heterocyclyl, each of which is r optionally substituted with one or more substituents Qa; and (c) –C(O)Ra, –C(O)ORa, –C(O)NRbRc, – C(NRa)NRbRc, –ORa, –OC(O)Ra, –OC(O)ORa, –OC(O)NRbRc, –OC(=NRa)NRbRc, – ORa)2, –OS(O)Ra, –OS(O)2Ra, –OS(O)NRbRc, –OS(O)2NRbRc, –NRbRc, – NRaC(O)Rd, –NRaC(O)ORd, –NRaC(O)NRbRc, –NRaC(=NRd)NRbRc, –NRaS(O)Rd, – )2Rd, –NRaS(O)NRbRc, –NRaS(O)2NRbRc, –SRa, –S(O)Ra, –S(O)2Ra, –S(O)NRbRc, and –S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is ally tuted with one or more substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Qa; wherein each Qa is independently selected from the group ting of (a) oxo, cyano, halo, and nitro; (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) –C(O)Rf, –C(O)ORf, –C(O)NRgRh, –C(NRf)NRgRh, –ORf, –OC(O)Rf, –OC(O)ORf, –OC(O)NRgRh, –OC(=NRf)NRgRh, (ORf)2, –OS(O)Rf, –OS(O)2Rf, –OS(O)NRgRh, –OS(O)2NRgRh, –NRgRh, –NRfC(O)Rk, –NRfC(O)ORk, –NRfC(O)NRgRh, –NRfC(=NRk)NRgRh, –NRfS(O)Rk, –NRfS(O)2Rk, –NRfS(O)NRgRh, –NRfS(O)2NRgRh, –SRf, –S(O)Rf, –S(O)2Rf, –S(O)NRgRh, and –S(O)2NRgRh; wherein each Rf, Rg, Rh, and Rk is independently (i) hydrogen; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 l, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rg and Rh together with the N atom to which they are attached form heterocyclyl. (followed by page 4C) 2. The compound of 1, having the structure of Formula XIa: (XIa) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an ic variant thereof; or a ceutically acceptable salt or solvate thereof. 3. The compound of 2, wherein R2n is methyl, uoromethyl, difluoromethyl, trifluoromethyl, –OH, or –OCH3. 4. The compound of any one of 1 to 3, wherein R7a is C3-10 cycloalkyl or heterocyclyl, each of which is optionally substituted with one or more substituents Q.

. The compound of 4, wherein R7a is heterocyclyl, optionally substituted with one or more substituents Q. 6. The compound of 4, wherein R7a is N O O N R1a , R1a , , , O N O N O N , R1a , R1a , , R1a , O N N O N O N R1b O N R1b O R1a , , R1a , R1a , , (followed by page 4D) O O N O O O O N O , O , , O R1a , R1a , , , , , , , , , , , , or ; wherein: p and q are each independently an integer of 0, 1, or 3, with the proviso that the total of p and q is no less than 1; and each r is ndently an integer of 0, 1, 2, 3, 4, 5, or 6. 7. The compound of 4, wherein R7a is , , , , , , or . (followed by page 4E) 8. The nd of 2, wherein the compound is selected from the group consisting of: O O N N N N NH NH N N O O O O N N N O N , , A1 A2 N N O O N , O , D2 , , D3 D4 N CF3 N N O O , , D5 D6 (followed by page 4F) N N O O F3C N N N NH NH N N N N O O O O O O N N O O S , and O ; D10 D11 or a single enantiomer, a racemic e, a mixture of diastereomers, or an isotopic variant thereof; or a ceutically acceptable salt or solvate thereof. 9. The compound of 1, having the structure of Formula XIX: R4 O R5 N R2 O N N R1 (XIX) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt or solvate thereof.

. The compound of 9, having the structure of a XXa: N R2n O N N N R1 (XXa) (followed by page 4G) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant f; or a pharmaceutically acceptable salt or solvate thereof. 11. The nd of 9, wherein R2n is methyl, monofluoromethyl, difluoromethyl, oromethyl, –OH, or –OCH3. 12. The compound of any one of 9 to 11, wherein R7 is chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, or –OR1a. 13. The compound of 12, wherein R7 is chloro. 14. The compound of any one of 9 to 13, wherein R6a is: N O O N R1a , R1a , , , O N O N O N , R1a , R1a , , R1a , O N N O N O N R1b O N R1b O R1a , , R1a , R1a , , O O N O O O O N O , O , , O R1a , , R1a , , , , , (followed by page 4H) , , , , , , , , , , or ; wherein: p and q are each independently an integer of 0, 1, or 3, with the proviso that the total of p and q is no less than 1; and each r is independently an integer of 0, 1, 2, 3, 4, 5, or 6.

. The nd of any one of claims 9 to 13, wherein R6a is: , , , , , , or . 16. The compound of any one of 1, 9, and 12 to 15, wherein R2 is 6- to 10-membered monocyclic or bicyclic aryl, optionally substituted with one or more substituents Q. (followed by page 4I) 17. The compound of any one of 1, 9, and 12 to 15, wherein R2 is 5- to 10-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents Q. 18. The compound of any one of 1, 9, and 12 to 15, wherein R2 is phenyl, pyridinyl, pyridazinyl, benzo[c][1,2,5]oxodiazolyl, or benzo[c][1,2,5]thiodiazolyl, each of which is optionally substituted with one or more substituents Q. 19. The nd of any one of 1, 9, and 12 to 15, wherein R2 is hydroxy-pyridinyl, methoxy-pyridinyl, methyl-pyridinyl, difluoromethyl-pyridinyl, trifluoromethyl-pyridinyl, methylaminocarbonyl-pyridinyl, or methyl-pyridazinyl.

. The nd of any one of 1, 9, and 12 to 19, wherein R4 is hydrogen. 21. The compound of any one of 1, 9, and 12 to 20 wherein R5 is hydrogen. 22. The compound of any one of 1, 9, and 12 to 21, wherein R6 is hydrogen. 23. The nd of 9, wherein the compound is selected from the group ting of: , , C1 C2 (followed by page 4J) , , C3 C4 , , C7 C8 , , C9 C10 wed by page 4K) N OCH3 N OCH3 NH NH O N N O N N Cl O O Cl O N N O O , , C11 C12 N OH N OH NH NH O N N O N N O O O Cl Cl O N N O O , , C13 C14 N CHF2 N CHF2 NH NH O N N O N N O O O Cl Cl O N N O O , , and C15 C16 N OCH3 O N N Cl O or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt or e thereof. 24. A compound selected from: (followed by page 4L and , D1 D8 or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt or solvate thereof.

. A pharmaceutical composition comprising the nd of any one of 1 to 24, or a pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable excipient. 26. The pharmaceutical composition of 25, wherein the ition is formulated as a single dosage form. 27. The pharmaceutical composition of 25 or 26, n the composition is formulated as oral, parenteral, nasal, respiratory, pulmonary, or intravenous dosage form. 28. The pharmaceutical composition of 27, wherein the pharmaceutical ition is in an oral dosage form. 29. The pharmaceutical ition of 28, wherein the oral dosage form is a tablet or . Use of the compound of any one of 1 to 24, or the pharmaceutical composition of any one of 25 to 29, in the preparation of a medicament for treating, preventing, or ameliorating a proliferative disease in a human subject. 31. The use of 30, wherein the erative disease is cancer. 32. The use of 31, wherein the cancer is drug-resistant. 33. The use of 31 or 32, wherein the cancer contains an ERBB variant. 34. The use of 33, wherein the ERBB variant is an EGFR variant. (followed by page 4M . The use of 34, wherein the EGFR variant contains one or more deletions, insertions, or substitutions at the amino acid positions of 689, 700, 709, 715, 719, 720, 9, 761- 765, 767-775, 783, 784, 790, 796, 826, 839, 846, 858, 861, and 863. 36. The use of 34, n the EGFR variant contains one or more deletions, insertions, or substitutions at the amino acid positions of 719, 746-751, 790, and 858. 37. The use of 34, wherein the EGFR variant ns one, two, or more deletions, insertions, and/or substitutions, each independently selected from G719C, G719S. G719A, ΔE746-A750, ΔE746-T751, ΔE746-A750 (ins RP), ΔD761-E762 (ins EAFQ), D770 (dup SVD), ΔV769-D770 (ins ASV), ΔD770-N771 (ins SVQ), ΔP772-H773 (ins PR), ΔH773-V774 (ins NPH), ΔH773-V774 (ins H), ΔH773-V774 (ins PH), and ΔH773-V774 (ins GNPH), T790M, and L858R. 38. The use of 34, wherein the EGFR variant contains T790M, L858R, or a combination thereof. 39. The use of 33, wherein the ERBB variant is a HER2 variant. 40. The use of 39, n the HER2 is overexpressed in the cancer. 41. The use of any one of 31 to 40, wherein the cancer is resistant to an EGFR inhibitor. 42. The use of 41, wherein the cancer is resistant to afatinib, canertinib, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, neratinib, pelitinib, varlitinib, or a combination thereof. 43. The use of any one of 31 to 42, wherein the cancer is bladder cancer, brain tumor, breast cancer, cancer of the mouth and throat, ctal cancer, lung cancer, or pancreatic cancer, prostate cancer, stomach cancer, or uterine . 44. The use of 43, wherein the cancer is lung cancer. 45. The use of 43, n the cancer is non-small cell lung cancer. (followed by page 4N 46. The use of any one of 31 to 45, wherein the cancer is relapsed or refractory. 47. A method of treating, preventing, or ameliorating a proliferative disease in a nonhuman subject, the method comprising administering a compound of any one of 1-24, or the composition according to any one of 25-29. 48. The method of 47, wherein the proliferative disease is cancer. 49. The method of 48, wherein the cancer is drug-resistant. 50. The method of 48 or 49, wherein the cancer ns an ERBB variant. 51. The method of 50, wherein the ERBB variant is an EGFR variant. 52. The method of 51, wherein the EGFR variant contains one or more ons, insertions, or tutions at the amino acid positions of 689, 700, 709, 715, 719, 720, 746- 759, 761-765, 767-775, 783, 784, 790, 796, 826, 839, 846, 858, 861, and 863. 53. The method of 51, n the EGFR variant contains one or more ons, insertions, or substitutions at the amino acid positions of 719, 746-751, 790, and 858. 54. The method of 51, n the EGFR variant contains one, two, or more deletions, insertions, and/or substitutions, each independently selected from G719C, G719S. G719A, ΔE746-A750, ΔE746-T751, ΔE746-A750 (ins RP), ΔD761-E762 (ins EAFQ), ΔS768-D770 (dup SVD), ΔV769-D770 (ins ASV), ΔD770-N771 (ins SVQ), ΔP772-H773 (ins PR), ΔH773-V774 (ins NPH), ΔH773-V774 (ins H), ΔH773-V774 (ins PH), and ΔH773-V774 (ins GNPH), T790M, and L858R. 55. The method of 51, wherein the EGFR variant contains T790M, L858R, or a combination thereof. 56. The method of 50, wherein the ERBB variant is a HER2 variant. 57. The method of 56, wherein the HER2 is overexpressed in the cancer. (followed by page 4O) 58. The method of any one of 48 to 57, wherein the cancer is resistant to an EGFR inhibitor. 59. The method of 58, wherein the cancer is resistant to afatinib, canertinib, dacomitinib, nib, nib, icotinib, lapatinib, neratinib, pelitinib, varlitinib, or a combination thereof. 60. The method of any one of 48 to 59, wherein the cancer is bladder cancer, brain tumor, breast cancer, cancer of the mouth and throat, colorectal cancer, lung cancer, or pancreatic cancer, prostate , stomach cancer, or uterine cancer. 61. The method of 60, wherein the cancer is lung cancer. 62. The method of 60, wherein the cancer is non-small cell lung cancer. 63. The method of any one of 48 to 62, wherein the cancer is ed or refractory.

More broadly, provided herein is a compound of Formula I: or a single enantiomer, a racemic mixture, a e of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; R1 is –C(O)CR1e=CR1fCR1g, , –N1aC(O)CR1e=CR1fCR1g, , – 1e=CR1fCR1g, , –S(O2)CR1e=CR1fCR1g, , – NR1aS(O)CR1e=CR1fCR1g, , –NR1aS(O2)CR1e=CR1fCR1g, or (followed by page 5) | O R g1 /N‘§’ l :le R16 R2 is C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 l, heteroaryl, or heterocyclyl; L1 is a bond, —O—, —S—, )—, or —C(R1AR1B)—, wherein each R1A and R113 is independently hydrogen, halo, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; L2 is C340 cycloalkylene, C644 arylene, C7_1 5 aralkylene, heteroarylene, or cyclylene; T is a bond, 0 s , , N—, N(R4) , C(R4)—, or C(R“)2 ; U is a bond, 0 s , , N—, N(R5) , C(R5)—, or C(R5)2 ; V is a bond, 0 s , , N—, N(R6) , C(R6)—, or C(R6)2 ; W is a bond, 0 s , , N—, N(R7) , C(R7)—, or C(R7)2 ; X and Y are each independently C or N; Z is NR2A or CRZARZB, wherein each R2A and R213 is independently hydrogen, halo, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; each R4, R5, R6, and R7 is independently (a) hydrogen, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) 1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, 2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; each R”, Rlb, R”, and R1d is independently hydrogen, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or cyclyl; or R1&1 and R10 together with the C and N atoms to which they are attached form heterocyclyl; or R1b and R10 together with the N atom to which they are attached form heterocyclyl; and each R13, R”, and ng is independently hydrogen, halo, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 lkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; with the proviso that no more than one of T, U, V, and W is a bond; and with the proviso that, when L1 is a bond, at least one of R4, R5, R6, and R7 is bromo, —OR7a, or —NR1bR1°, wherein R7&1 is C4_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 l, heteroaryl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is ally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, where each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, and heterocyclyl, each of which is filrther optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) —C(O)Ra, Ra, —C(O)NRbR°, —C(NRa)NRbR°, —0Ra, Ra, —OC(O)ORa, NRbR°, —OC(=NRa)NRbR°, —OP(O)(ORa)2, —OS(O)Ra, —OS(O)2Ra, —OS(O)NRbR°, —OS(O)2NRbR°, —NRbR°, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbR°, =NRd)NRbR°, —NRaS(O)Rd, O)2Rd, —NRaS(O)NRbR°, —NRaS(O)2NRbR°, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbR°, and —S(O)2NRbR°, wherein each Ra, Rb, RC, and Rd is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, tuents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qa is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Rf, —C(O)ORf, —C(O)NRth, —C(NRf)NRth, —ORf, —OC(O)Rf, —OC(O)ORf, —OC(O)NRth, —OC(=NRf)NRth, —OP(O)(ORf)2, —OS(O)Rf, —OS(O)2Rf, —OS(O)NRth, —OS(O)2NRth, —NRth, —NRfC(O)Rk, —NRfC(O)ORk, O)NRth, —NRfC(=NRk)NRth, O)Rk, —NRfS(O)2Rk, —NRfS(O)NRth, —NRfS(O)2NRth, —SRf, f, —S(O)2Rf, —S(O)NRth, and —S(O)2NRth; n each Rf, Rg, Rh, and Rk is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rg and Rh er with the N atom to which they are attached form heterocyclyl.

Also provided herein is a compound of Formula I: or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; R1 is (a) hydrogen, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) 1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, NR1bR1°, —OS(O)2NRle1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)ORld, (O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2Rld, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R2 is C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; L2 is C340 cycloalkylene, C644 arylene, C7_1 5 aralkylene, heteroarylene, or heterocyclylene; T is a bond, 0 s , , N—, N(R4) , C(R4)—, or C(R“)2 ; U is a bond, 0 s , , N—, N(R5) , C(R5)—, or C(R5)2 ; V is a bond, 0 s , , N—, N(R6) , C(R6)—, or C(R6)2 ; W is a bond, 0 s , , N—, N(R7) , C(R7)—, or C(R7)2 ; X and Y are each independently C or N; Z is NR2A or CRZARZB, wherein each R2A and R213 is ndently hydrogen, halo, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 lkyl, C644 aryl, C7_1 5 aralkyl, aryl, or heterocyclyl; R4, R5, R6, R7, and L1 are: (i) each R4, R5, and R6 is independently (a) en, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 l, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, R1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2Rld, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; each R7 is independently bromo, —OR7a, or 7°; R7&1 is C4_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; R7b and R70 is independently hydrogen, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or R7b and R70 together with the N atom to which they are attached form heterocyclyl; and L1 is a bond; or (ii) each R4, R5, R6, and R7 is independently (a) hydrogen, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 l, C2_6 l, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2Rld, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NRle1°, or —S(O)2NR1bR1°; with the proviso that at least one of R4, R5, R6, and R7 is not en; and L1 is —O—, —S—, —N(R1A)—, or —C(R1AR1B)—, wherein each R1A and R113 is independently hydrogen, halo, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 l, heteroaryl, or heterocyclyl; each R”, Rlb, R”, and R1d is independently hydrogen, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or R1&1 and R10 together with the C and N atoms to which they are attached form heterocyclyl; or R1b and R10 together with the N atom to which they are ed form cyclyl; with the proviso that no more than one of T, U, V, and W is a bond; wherein each alkyl, l, l, cycloalkyl, cycloalkylene, aryl, arylene, WO 43148 aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, where each Q is ndently selected from (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, and heterocyclyl, each of which is filrther optionally substituted with one or more, in one ment, one, two, three, or four, substituents Qa; and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbR°, —C(NRa)NRbR°, —0Ra, —OC(O)Ra, —OC(O)ORa, NRbR°, —OC(=NRa)NRbR°, (ORa)2, —OS(O)Ra, —OS(O)2Ra, —OS(O)NRbR°, —OS(O)2NRbR°, —NRbR°, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbR°, —NRaC(=NRd)NRbR°, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbR°, —NRaS(O)2NRbR°, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbR°, and —S(O)2NRbR°, wherein each Ra, Rb, RC, and Rd is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qa is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 l, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Rf, Rf, —C(O)NRth, —C(NRf)NRth, —ORf, —OC(O)Rf, —OC(O)ORf, NRth, —OC(=NRf)NRth, —OP(O)(ORf)2, —OS(O)Rf, —OS(O)2Rf, —OS(O)NRth, —OS(O)2NRth, —NRth, O)Rk, —NRfC(O)ORk, —NRfC(O)NRth, —NRfC(=NRk)NRth, —NRfS(O)Rk, —NRfS(O)2Rk, —NRfS(O)NRth, —NRfS(O)2NRth, —SRf, f, —S(O)2Rf, —S(O)NRth, and —S(O)2NRth; wherein each Rf, Rg, Rh, and Rk is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rg and Rh together with the N atom to which they are ed form heterocyclyl. onally, provided herein is a compound of Formula XXI: 0 N R2 R5a/ \>—z>\— R6 1‘! Cl LLLZ (XXI) or a single enantionier, a racemic mixture, a mixture of reoniers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or g thereof; 0 NE 1- C(O)CR1:32 If R CR CRlg O CR1:32 If is _ _N CR CRlg , , , Illla O ng O N O Q / W18f _§ :Rg1 0 CR e=CR CR1 1f 1 g, R61 ,—S(02)CR e=CR CR1 1f 1 g, O“ARg1 1 a | O Q —'Si R1f /N\g :ng Rle R” 0 1 1 1f 1 1 1 1f 1 ,—NR aS(O)CR e=CR CR g, Re1 ,—NR aS(Oz)CR e=CR CR g, or Rla O I o W /N\§/l <R1f (1)1 R R2 is C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; L1 is a bond, —O—, —S—, —N(R1A)—, or —C(R1AR1B)—, wherein each R1A and R113 is independently hydrogen, halo, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; L2 is C340 cycloalkylene, C644 arylene, C7_1 5 aralkylene, arylene, or heterocyclylene; Z is NR2A or CRZARZB, wherein each R2A and R213 is independently hydrogen, halo, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 l, aryl, or heterocyclyl; R4 and R6 are each independently (a) hydrogen, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 l, C340 lkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(0)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —0C(0)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(0)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(0)NR1bR1°, or —S(O)2NR1bR1°; R5&1 is C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; each R”, Rlb, R”, and R1d is independently hydrogen, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or R1&1 and R10 er with the C and N atoms to which they are attached form heterocyclyl; or R1b and R10 together with the N atom to which they are attached form heterocyclyl; and each R13, R”, and ng is independently hydrogen, halo, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, lene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, tuents Q, where each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, and heterocyclyl, each of which is r optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbR°, —C(NRa)NRbR°, —0Ra, —OC(O)Ra, ORa, —OC(O)NRbR°, —OC(=NRa)NRbR°, —OP(O)(ORa)2, Ra, —OS(O)2Ra, —OS(O)NRbR°, —OS(O)2NRbR°, —NRbR°, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbR°, —NRaC(=NRd)NRbR°, —NRaS(O)Rd, —NRaS(O)2Rd, O)NRbR°, —NRaS(O)2NRbR°, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbR°, and —S(O)2NRbR°, wherein each Ra, Rb, RC, and Rd is independently (i) en; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 l, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally tuted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qa is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Rf, —C(O)ORf, —C(O)NRth, )NRth, —ORf, —OC(O)Rf, ORf, NRth, —OC(=NRf)NRth, —OP(O)(ORf)2, —OS(O)Rf, —OS(O)2Rf, —OS(O)NRth, 2NRth, —NRth, —NRfC(O)Rk, —NRfC(O)ORk, —NRfC(O)NRth, —NRfC(=NRk)NRth, —NRfS(O)Rk, —NRfS(O)2Rk, —NRfS(O)NRth, —NRfS(O)2NRth, —SRf, —S(O)Rf, —S(O)2Rf, —S(O)NRth, and —S(O)2NRth; wherein each Rf, Rg, Rh, and Rk is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rg and Rh together with the N atom to which they are attached form heterocyclyl. ed herein are pharmaceutical compositions comprising a compound disclosed herein, e.g., a compound of Formula I or XXI, or a single omer, a racemic mixture, a mixture of diastereomers, or an isotopic t thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and optionally a pharmaceutically acceptable ent or carrier.

Provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a t, comprising administering to the subject a compound disclosed , e.g., a compound of Formula I or XXI, or a single enantiomer, a racemic mixture, a mixture of reomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Provided herein is a method for treating, preventing, or ameliorating one or more symptoms of an ERBB-mediated condition, disorder, or disease in a subject, comprising administering to the subject a compound disclosed herein, e.g., a nd of Formula I or XXI, or a single omer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug f.

Provided herein is a method for treating, preventing, or ameliorating one or more symptoms of cancer in a subject, comprising administering to the subject a compound disclosed herein, e.g., a nd of Formula I or XXI, or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof In one embodiment, the cancer is drug-resistant.

Provided herein is a method of inhibiting the growth of a cell, comprising contacting the cell with a compound provided herein, 6.g. , a nd of Formula I or XXI, or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an ic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof Provided herein is a method of inhibiting the growth of a cell in a t, comprising administering to the subject a compound disclosed herein, e.g., a compound of Formula I or XXI, or a single enantiomer, a c mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. ed herein is a method for modulating the activity of a tyrosine kinase, in one embodiment, an ERBB kinase, comprising contacting the ERBB kinase with a compound disclosed , e.g., a compound of Formula I or XXI, or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an ic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Provided herein is a method for modulating the activity of a ne kinase, in one embodiment, an ERBB , in a subject, comprising administering to the subject a compound disclosed herein, e.g., a compound of Formula I or XXI, or a single enantiomer, a racemic e, a e of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

DETAILED DESCRIPTION To facilitate understanding of the disclosure set forth , a number of terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures in biology, biochemistry, medicinal chemistry, organic chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same g as commonly understood by one of ry skill in the art to which this disclosure s.

The term “tumor,” “neoplasm,” and “neoplastic disorder or disease” are used interchangeably herein and are meant to refer to unwanted cell proliferation of one or more subset of cells in a multicellular organism resulting in harm (z'.e. discomfort or decreased life expectancy) to the multicellular organisms. In certain embodiments, a tumor can be benign (non-invasive) or malignant (invasive).

The term “cancer” is meant to refer to a malignant neoplasm, which is characterized by uncontrolled cell proliferation where cells have lost their normal regulatory controls that would otherwise govern the rate of cell growth. These unregulated, dividing cells can spread throughout the body and invade normal tissues in a process ed to as “metastasis.” The term ct” refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, and mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a WO 43148 mammalian subject, such as a human subject, in one embodiment, a human.

The terms “treat,” “treating,” and “treatment” are meant to include alleviating or abrogating a condition, disorder, or disease, or one or more of the symptoms associated with the ion, disorder, or disease; or alleviating or eradicating the cause(s) of the condition, disorder, or disease itself.

The terms “prevent,” nting,” and “prevention” are meant to e a method of delaying and/or precluding the onset of a condition, disorder, or disease, and/or its attendant symptoms; barring a subject from acquiring a condition, disorder, or disease; or reducing a subject’s risk of acquiring a condition, er, or disease.

The term “contacting” or “contact” is meant to refer to bringing together of a therapeutic agent and cell or tissue such that a physiological and/or chemical effect takes place as a result of such contact. Contacting can take place in vitro, ex vivo, or in vivo. In one embodiment, a therapeutic agent is contacted with a cell in cell culture (in vitro) to determine the effect of the therapeutic agent on the cell. In another embodiment, the ting of a therapeutic agent with a cell or tissue includes the administration of a therapeutic agent to a subject having the cell or tissue to be contacted.

The term “therapeutically effective amount” are meant to include the amount of a compound that, when administered, is sufficient to prevent pment of, or alleviate to some extent, one or more of the ms of the condition, disorder, or disease being treated. The term “therapeutically effective ” also refers to the amount of a compound that is sufficient to elicit the biological or medical se of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, l doctor, or clinician.

The term “IC50” or “EC50” refers an amount, concentration, or dosage of a compound that is required for 50% inhibition of a maximal se in an assay that measures SUCh a response.

The term “GC50” refers an amount, concentration, or dosage of a compound that is required to reduce the viability of cells treated with the compound by 50%, in comparison with cells untreated with the compound. 2015/021455 The term “CC50” refers an amount, concentration, or dosage of a compound that results in 50% reduction of the viability of a host. In certain embodiments, the CC50 of a compound is the amount, concentration, or dosage of the compound that is required to reduce the viability of cells treated with the compound by 50%, in comparison with cells untreated with the compound.

The term “relapsed” refers to a ion where a subject, who has had a remission of cancer after therapy has a return of cancer cells.

The term “refractory or resistant” refers to a circumstance where a subject, even after ive treatment, has residual cancer cells in his body.

The term “drug ance” refers to the condition when a disease does not respond to the treatment of a drug or drugs. Drug resistance can be either intrinsic, which means the disease has never been sive to the drug or drugs, or it can be acquired, which means the disease ceases responding to a drug or drugs that the disease had previously responded to. In certain embodiments, drug resistance is intrinsic. In certain embodiments, the drug resistance is acquired. [003 6] The term “pharmaceutically acceptable carrier, 33 CCpharmaceutically acceptable excipient,3, “physiologically acceptable r,” or “physiologically acceptable excipient” refers to a pharmaceutically-acceptable material, ition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is aceutically acceptable” in the sense of being compatible with the other ingredients of a ceutical formulation, and suitable for use in contact with the tissue or organ of humans and s without excessive toxicity, irritation, allergic response, genicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, Remington: The Science and Practice ofPharmacy, 2lst ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook ofPharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2012; Handbook of Pharmaceutical ves, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009. [003 7] The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ry skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or ximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% ofa given value or range.

The terms “active ingredient” and “active substance” refer to a compound, which is administered, alone or in combination with one or more ceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease. As used herein, “active ingredient” and “active substance” may be an optically active isomer or an isotopic variant of a compound described herein.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent” refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or rating one or more symptoms of a condition, disorder, or disease.

The term “naturally occurring” or “native” when used in connection with biological materials such as nucleic acid molecules, polypeptides, host cells, and the like, refers to materials which are found in nature and are not lated by man. Similarly, “non-naturally occurring” or “non-native” refers to a material that is not found in nature or that has been structurally modified or sized by man.

The term “ERBB” or “ERBB ” refers to a tyrosine kinase of the ERBB family or a variant thereof, including, but not limited to, ERBBl (EGFR or HERl), ERBB2 (HER2/c-neu), ERBB3 (HER3), and ERBB4 (HER4). ERBB variants include proteins ntially homologous to a native ERBB , z'.e. one or more , proteins having naturally or non-naturally occurring amino acid deletions, insertions or substitutions (e.g., ERBB derivatives, homologs, and fragments), as compared to the amino acid sequence of a native ERBB. The amino acid sequence of an ERBB variant is at least about 80% identical, at least about 90% identical, or at least about 95% identical to a native ERBB.

The terms “ERBB-mediated condition, disorder or disease” and “a condition, disorder, or disease mediated by ERBB” refer to a condition, er, or disease characterized by abnormal or dysregulated, e.g., greater than , ERBB activity.

Abnormal ERBB kinase fimctional activity might arise as the result of ERBB kinase overexpression in cells, expression of the ERBB kinase in cells which normally do not express ERBB, or dysregulation due to constitutive activation, caused, for example, by a mutation in ERBB. An ediated condition, disorder, or disease may be completely or partially mediated by inappropriate ERBB activity. In particular, an ERBB-mediated condition, er, or e is one in which modulation of an ERBB activity results in some effect on the underlying condition, disorder, or disease, e.g., an ERBB inhibitor results in some improvement in at least some of patients being treated.

The term “alkyl” refers to a linear or ed saturated monovalent hydrocarbon radical, n the alkyl may optionally be substituted with one or more substituents Q as described herein. For example, C1_6 alkyl refers to a linear saturated monovalent hydrocarbon radical of l to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkyl is a linear saturated lent hydrocarbon radical that has 1 to 20 (C1_20), l to 15 (C145), 1 to 10 (C1- ), or 1 to 6 (C1_6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C340), 3 to 15 (C345), 3 to 10 (C340), or 3 to 6 (C3_6) carbon atoms. As used herein, linear C1_6 and ed C3_6 alkyl groups are also referred as “lower alkyl.” Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, t—butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms).

The term “alkylene” refers to a linear or branched saturated divalent arbon radical, wherein the alkylene may optionally be substituted with one or more tuents Q as described herein. For example, C1_6 alkylene refers to a linear saturated divalent hydrocarbon radical of l to 6 carbon atoms or a ed saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkylene is a linear saturated divalent hydrocarbon l that has 1 to 20 (C1_20), l to 15 (C145), 1 to 10 (C140), or 1 to 6 (C1_6) carbon atoms, or ed saturated divalent arbon radical of 3 to 20 (C340), 3 to 15 (C345), 3 to 10 (€3-10), or 3 to 6 (C3_6) carbon atoms. As used herein, linear C1- 6 and branched C3_6 alkylene groups are also referred as “lower alkylene.” Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene ding all isomeric forms), n-propylene, isopropylene, butylene (including all isomeric forms), n- butylene, isobutylene, t—butylene, ene (including all isomeric forms), and hexylene (including all isomeric forms).

The term “heteroalkylene” refers to a linear or branched ted divalent WO 43148 hydrocarbon radical that contains one or more atoms in the hydrocarbon chain, each of which is independently selected from O, S, and N,. For example, C1_6 heteroalkylene refers to a linear ted divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent arbon radical of 3 to 6 carbon atoms. In n embodiments, the alkylene is a linear saturated divalent arbon radical that has 1 to 20 (C1_20), 1 to (C145), 1 to 10 , or 1 to 6 (C1_6) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (€3-20), 3 to 15 (C345), 3 to 10 (€3-10), or 3 to 6 (C3_6) carbon atoms. As used herein, linear C1_6 and ed C3_6 heteroalkylene groups are also referred as “lower heteroalkylene.” Examples of heteroalkylene groups include, but are not limited to, —CHzO—, —CH20CH2—, —CH2CHzO—, —CH2NH—, CH2—, —CH2CH2NH—, —CHZS—, —CHZSCH2—, and —CH2CHZS—. In certain embodiments, heteroalkylene may also be optionally substituted with one or more substituents Q as described .

The term “alkenyl” refers to a linear or branched monovalent arbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one or two, carbon-carbon double bond(s). The alkenyl may be optionally substituted with one or more substituents Q as described herein. The term “alkenyl” embraces ls having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2_6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2_20), 2 to 15 (C245), 2 to 10 (C240), or 2 to 6 (C2_6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3_20), 3 to 15 (C345), 3 to 10 (C340), or 3 to 6 (C3_6) carbon atoms. es of alkenyl groups include, but are not limited to, ethenyl, propenyl, propenyl, allyl, butenyl, and 4-methylbutenyl.

The term “alkenylene” refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one or two, carbon-carbon double bond(s). The alkenylene may be optionally substituted with one or more substituents Q as described herein. The term “alkenylene” embraces ls having a “cis” or ” configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2_6 alkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenylene is a linear divalent hydrocarbon radical of 2 to 20 (€2-20), 2 to 15 (€2-15), 2 to 10 (€2-10), or 2 to 6 (C2_6) carbon atoms, or a ed divalent hydrocarbon radical of 3 to 20 (C3_20), 3 to 15 (C345), 3 to 10 (C340), or 3 to 6 (C3_6) carbon atoms. Examples of alkenylene groups include, but are not limited to, ethenylene, allylene, propenylene, lene, and 4-methylbutenylene.

The term oalkenylene” refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one or two, carbon-carbon double bond(s), and which contains one or more atoms in the hydrocarbon chain, each of which is independently selected from O, S, and N. The heteroalkenylene may be optionally substituted with one or more substituents Q as bed . The term “heteroalkenylene” embraces radicals having a “02's” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or a mixture thereof, as iated by those of ordinary skill in the art. For example, C2_6 heteroalkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent arbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C2_20), 2 to 15 (C245), 2 to 10 , or 2 to 6 (CM) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C3_20), 3 to 15 (C345), 3 to 10 (C340), or 3 to 6 (C3_6) carbon atoms. Examples of heteroalkenylene groups include, but are not limited to, O—, —CH=CHOCH2—, —CH=CHCHzO—, —CH=CHS—, —CH=CHSCH2—, —CH=CHCHZS—, or —CH=CHCH2NH—.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbon l, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one or two, carbon-carbon triple bond(s). The alkynyl may be optionally substituted with one or more substituents Q as described herein. For example, C2_6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkynyl is a linear lent arbon radical of 2 to 20 ), 2 to (C245), 2 to 10 (C240), or 2 to 6 (C2_6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (€3-20), 3 to 15 (C345), 3 to 10 (€3-10), or 3 to 6 (C3_6) carbon atoms. Examples of alkynyl groups include, but are not d to, ethynyl (—CECH), propynyl (including all isomeric forms, e.g., l-propynyl (—CECCHg) and propargyl (—CHZCECH», butynyl (including all isomeric forms, e.g., l-butyn-l-yl and 2-butyn-l-yl), pentynyl (including all isomeric forms, 6.g. l -yl and l-methylbutyn- l -yl), and , l-pentyn- hexynyl (including all isomeric forms, e.g., l-hexyn-l-yl).

The term “alkynylene” refers to a linear or branched divalent hydrocarbon l, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one or two, carbon-carbon triple ). The alkynylene may be optionally substituted with one or more substituents Q as described herein. For example, C2_6 alkynylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched rated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkynylene is a linear divalent hydrocarbon radical of 2 to 20 (C2_20), 2 to , 2 to 10 (C240), or 2 to 6 (C2_6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C340), 3 to 15 (C345), 3 to 10 (C340), or 3 to 6 (C3_6) carbon atoms. es of alkynylene groups include, but are not limited to, ethynylene, propynylene (including all ic forms, e.g., l-propynylene and propargylene), butynylene (including all ic forms, 6.g. and 2-butyn-l-ylene), pentynylene (including all , l-butyn-l-ylene isomeric forms, e.g., l-pentyn-l-ylene and l-methylbutyn-l-ylene), and lene (including all isomeric forms, e.g., l-hexyn-l-ylene). [005 l] The term “cycloalkyl” refers to a cyclic monovalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein. In one embodiment, lkyl groups may be saturated or unsaturated but non-aromatic, and/or bridged, and/or non-bridged, and/or fused bicyclic groups. In certain embodiments, the cycloalkyl has from 3 to 20 (€3-20), from 3 to 15 (C345), from 3 to 10 (C340), or from 3 to 7 (Cs—7) carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, exyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo [2. l . l ]hexyl, bicyclo[2.2. l]heptyl, decalinyl, and adamantyl.

The term “cycloalkylene” refers to a cyclic divalent hydrocarbon radical, which may be optionally substituted with one or more tuents Q as described . In one embodiment, cycloalkyl groups may be saturated or unsaturated but non-aromatic, and/or bridged, and/or non-bridged, and/or fused bicyclic groups. In certain embodiments, the lkylene has from 3 to 20 (C3_20), from 3 to 15 (C345), from 3 to 10 (C340), or from 3 to WO 43148 7 (C34) carbon atoms. es of cycloalkylene groups include, but are not limited to, ropylene (e.g., l,l-cyclopropylene and l,2-cyclopropylene), cyclobutylene (e.g., l,l- cyclobutylene, l,2-cyclobutylene, or l,3-cyclobutylene), cyclopentylene (e.g., l,l- cyclopentylene, l,2-cyclopentylene, or l,3-cyclopentylene), cyclohexylene (e.g., l,lcyclohexylene , l,2-cyclohexylene, l,3-cyclohexylene, or clohexylene), cycloheptylene (e.g., l,l-cycloheptylene, l,2-cycloheptylene, l,3-cycloheptylene, or 1,4-cycloheptylene), decalinylene, and adamantylene.

The term “aryl” refers to a monovalent monocyclic aromatic hydrocarbon radical or monovalent polycyclic aromatic hydrocarbon l that contains at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 20 (C6_20), from 6 to 15 (C645), or from 6 to 10 (C640) ring atoms. Examples of aryl groups e, but are not d to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, thryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to bicyclic or tricyclic carbon rings, Where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, l, indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments, aryl may be optionally substituted with one or more tuents Q as described herein.

The term ne” refers to a divalent monocyclic aromatic hydrocarbon radical or divalent polycyclic aromatic hydrocarbon l that contains at least one aromatic hydrocarbon ring. In certain embodiments, the arylene has from 6 to 20 (C6_20), from 6 to 15 (C645), or from 6 to 10 (C640) ring atoms. Examples of arylene groups include, but are not limited to, phenylene, naphthylene, fluorenylene, azulenylene, anthrylene, phenanthrylene, pyrenylene, biphenylene, and terphenylene. Arylene also refers to bicyclic or tricyclic carbon rings, Where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthylene, indenylene, indanylene, or tetrahydronaphthylene (tetralinylene). In certain embodiments, arylene may be optionally substituted with one or more substituents Q as described herein.

The term “aralkyl” or “arylalkyl” refers to a lent alkyl group substituted With one or more aryl groups. In certain embodiments, the aralkyl has from 7 to (€7-30), from 7 to 20 (C740), or from 7 to 16 (€7-16) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, 2-phenylethyl, and 3-phenylpropyl. In certain embodiments, aralkyl are ally substituted with one or more substituents Q as described herein.

The term “heteroaryl” refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more atoms in the ring, each of which is independently selected from O, S, and N. Heteroaryl groups are bonded to the rest of a molecule h the aromatic ring. Each ring of a heteroaryl group can contain one or two 0 atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring ns at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. es of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, riazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, othiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridyl, pyrrolopyridyl, inyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, olyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, sazinyl, phenazinyl, hiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl may also be optionally substituted with one or more substituents Q as described herein.

The term “heteroarylene” refers to a divalent monocyclic aromatic group or divalent clic aromatic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms in the ring, each of which is independently selected from O, S, and N. A heteroarylene group has at least one linkage to the rest of a molecule via its aromatic ring(s). Each ring of a heteroarylene group can contain one or two 0 atoms, one or two S atoms, and/or one to four N atoms, ed that the total number of atoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroarylene has from 5 to 20, from 5 to 15, or from 5 to ring atoms. Examples of monocyclic heteroarylene groups include, but are not limited to, furanylene, imidazolylene, isothiazolylene, isoxazolylene, oxadiazolylene, oxadiazolylene, oxazolylene, pyrazinylene, pyrazolylene, pyridazinylene, pyridylene, pyrimidinylene, pyrrolylene, thiadiazolylene, thiazolylene, thienylene, tetrazolylene, triazinylene, and triazolylene. Examples of bicyclic heteroarylene groups include, but are not limited to, benzofuranylene, benzimidazolylene, benzoisoxazolylene, benzopyranylene, benzothiadiazolylene, benzothiazolylene, benzothienylene, benzotriazolylene, benzoxazolylene, furopyridylene, opyridinylene, imidazothiazolylene, indolizinylene, indolylene, indazolylene, isobenzofuranylene, isobenzothienylene, isoindolylene, isoquinolinylene, azolylene, naphthyridinylene, oxazolopyridinylene, phthalazinylene, pteridinylene, purinylene, pyridylene, pyrrolopyridylene, quinolinylene, quinoxalinylene, quinazolinylene, thiadiazolopyrimidylene, and thienopyridylene. Examples of tricyclic heteroarylene groups include, but are not d to, acridinylene, dolylene, carbazolylene, dibenzofuranylene, perimidinylene, phenanthrolinylene, phenanthridinylene, phenarsazinylene, phenazinylene, phenothiazinylene, phenoxazinylene, and xanthenylene. In certain embodiments, heteroarylene may also be optionally substituted with one or more substituents Q as described herein.

The term “heterocyclyl” or “heterocyclic” refers to a monovalent monocyclic non-aromatic ring system or monovalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. Heterocyclyl groups are bonded to the rest of a molecule through the non-aromatic ring. In certain embodiments, the heterocyclyl is a monocyclic, ic, lic, or yclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be ally oxidized, nitrogen atoms may be optionally quatemized, and some rings may be partially or fillly saturated, or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which s in the on of a stable compound. Examples of such heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, yranyl, benzotetrahydrofiaranyl, benzotetrahydrothienyl, hiopyranyl, azinyl, B-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, opyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, opyrimidinyl, dihydropyrrolyl, anyl, 1,4- dithianyl, furanonyl, olidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, zotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, lidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and l,3,5-trithianyl. In certain ments, heterocyclic may also be ally tuted with one or more substituents Q as described herein.

The term “heterocyclylene” refers to a divalent monocyclic non-aromatic ring system or divalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. Heterocyclylene groups are bonded to the rest of a molecule through the non-aromatic ring. In certain embodiments, the heterocyclylene group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclylene is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally ized, and some rings may be partially or fully saturated, or ic. The heterocyclylene may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclylene groups include, but are not d to, azepinylene, benzodioxanylene, benzodioxolylene, benzofuranonylene, yranonylene, benzopyranylene, benzotetrahydrofuranylene, benzotetrahydrothienylene, benzothiopyranylene, benzoxazinylene, B-carbolinylene, chromanylene, chromonylene, cinnolinylene, coumarinylene, decahydroisoquinolinylene, dihydrobenzisothiazinylene, dihydrobenzisoxazinylene, dihydrofurylene, dihydroisoindolylene, dihydropyranylene, dihydropyrazolylene, dihydropyrazinylene, dihydropyridinylene, dihydropyrimidinylene, dihydropyrrolylene, dioxolanylene, 1,4- dithianylene, furanonylene, imidazolidinylene, imidazolinylene, indolinylene, isobenzotetrahydrofuranylene, isobenzotetrahydrothienylene, isochromanylene, isocoumarinylene, isoindolinylene, isothiazolidinylene, isoxazolidinylene, morpholinylene, octahydroindolylene, octahydroisoindolylene, oxazolidinonylene, oxazolidinylene, oxiranylene, piperazinylene, dinylene, 4-piperidonylene, pyrazolidinylene, pyrazolinylene, pyrrolidinylene, pyrrolinylene, quinuclidinylene, ydrofurylene, tetrahydroisoquinolinylene, ydropyranylene, tetrahydrothienylene, thiamorpholinylene, thiazolidinylene, tetrahydroquinolinylene, and l,3,5-trithianylene. In certain embodiments, heterocyclic may also be optionally substituted with one or more substituents Q as described The term “halogen”, “halide” or “halo” refers to fluorine, chlorine, bromine, and/or iodine.

The term “optionally substituted” is ed to mean that a group or substituent, such as an alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene group, may be substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, each of which is independently selected from, e.g., (a) oxo (=0), cyano (—CN), halo, and nitro (—N02); (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally tuted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbR°, )NRbR°, —0Ra, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbR°, Ra)NRbR°, —OP(O)(ORa)2, Ra, —OS(O)2Ra, —OS(O)NRbR°, —OS(O)2NRbR°, —NRbR°, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbR°, —NRaC(=NRd)NRbR°, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbR°, —NRaS(O)2NRbR°, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbR°, and —S(O)2NRbR°, wherein each Ra, Rb, RC, and Rd is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 lkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa. As used herein, all groups that can be substituted are “optionally tuted,” unless otherwise specified.

In one embodiment, each Qa is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, aryl, and heterocyclyl; and (c) —C(O)Rf, —C(O)ORf, —C(O)NRth, —C(NRf)NRth, —ORf, Rf, —OC(O)ORf, NRth, —OC(=NRf)NRth, —OP(O)(ORf)2, —OS(O)Rf, —OS(O)2Rf, —OS(O)NRth, —OS(O)2NRth, —NRth, —NRfC(O)Rk, —NRfC(O)ORk, —NRfC(O)NRth, —NRfC(=NRk)NRth, —NRfS(O)Rk, —NRfS(O)2Rk, —NRfS(O)NRth, —NRfS(O)2NRth, —SRf, —S(O)Rf, Rf, —S(O)NRth, and —S(O)2NRth; wherein each Rf, Rg, Rh, and Rk is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rg and Rh together with the N atom to which they are attached form heterocyclyl.

The terms “optically active” and ”enantiomerically active” refer to a collection of les, which has an enantiomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. In certain embodiments, the compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer based on the total weight of the te in question.

In bing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that the nd is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation, (+) and (-), is not d to the absolute configuration of the molecule, R and S.

The term “isotopic variant” refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), tritium (3H), carbon-ll (11C), -12 (12C), carbon-l3 (13C), carbon-l4 (14C), nitrogen-l3 (EN), nitrogen- 1 4 (MN), nitrogen-15 (UN), - 1 4 (140), oxygen- 1 5 (150), oxygen- 1 6 (160), oxygen- 1 7 (170), oxygen-18 (180), fiuorine- l 7 (17F), fiuorine- l 8 (18F), phosphorus-31 (3 1P), orus-32 (32F), phosphorus-33 (33P), sulfur-32 (328), -33 (33 S), sulfur-34 (34S), sulfur-35 (35$), sulfur-36 (36S), chlorine-35 (”Cl), chlorine-36 (36C1), chlorine-37 (”0), 2015/021455 bromine-79 (79130, bromine-81 (81130, -123 (1231), -125 (1251), -127 (1271), iodine-129 (1291), and iodine-l3l (1311). In certain embodiments, an “isotopic variant” of a compound is in a stable form, that is, non-radioactive. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), ium (2H), carbon-12 (12C), carbon-l3 (13C), nitrogen- 14 (MN), nitrogen-15 (UN), oxygen-l6 (160), oxygen-l7 (170), oxygen-18 (180), fluorine-l7 (17F), phosphorus-31 (31F), sulfur-32 (32$), -33 (33S), sulfur—34 (34S), sulfur-36 (36S), chlorine-35 (35Cl), ne-37 (37Cl), bromine-79 (79Br), bromine-81 , and iodine-127 (1271). In certain embodiments, an pic variant” of a nd is in an unstable form, that is, radioactive. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not d to, tritium (3H), carbon-ll (11C), carbon-l4 (14C), nitrogen-l3 (EN), oxygen-l4 (140), oxygen-15 (150), fluorine-l8 (18F), phosphorus-32 (32F), phosphorus-33 (33P), sulfiJr-35 (358), chlorine-36 (36c1), iodine-123 (1231), iodine-125 (1251), iodine-129 (1291), and iodine-131 (1311). It will be understood that, in a nd as provided , any hydrogen can be 2H, for example, or any carbon can be 13C, as example, or any nitrogen can be 15N, as example, and any oxygen can be 180, Where feasible according to the judgment of one of skill. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of ium.

The term “solvate” refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which present in stoichiometric or non-stoichiometric amount. Suitable ts include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, drate, dihydrate, trihydrate, tetrahydrate, and ydrate.

The phrase “a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a ceutically acceptable salt, solvate, or prodrug thereof” has the same meaning as the phrase “(i) a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant of the compound referenced therein; (ii) a pharmaceutically acceptable salt, solvate, or prodrug of the compound referenced therein; or (iii) a pharmaceutically acceptable salt, solvate, or prodrug of a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant of the compound nced therein.” As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage or recognized abbreviations including abbreviations found in J. Org. Chem. 2007, 72, A or abbreviations established by the IUPAC-IUB Commission on Biochemical Nomenclature (Biochem. 1972, I], 942-944).

Compounds In one ment, provided herein is a compound of a I: or a single omer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug f; WR”NER l 16 1f lg 0 la 16 1f 1 R 1s—C(O)CR =CR CR- , ,—N C(O)CR =CR CR g, Rla O A R1? 0 R1e _g ‘40) le 0 ,—S(O)CR13=CR1fCR1g, R16 ,—S(02)CR13=CR1fCR1g, O Rg1 Ra1 0 II A I 0 W —fi le Rle /N\g/P<R1f 0 ,—NR1aS(O)CRle=CR1fCR1g, R” ,—NR1aS(Oz)CRle=CR1fCR1g, or I o W /N‘§ RIf bl R R2 is C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; L1 is a bond, —O—, —S—, —N(R1A)—, or —C(R1AR1B)—, wherein each R1A and R113 is independently hydrogen, halo, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; L2 is C340 cycloalkylene, C644 arylene, C7_1 5 lene, heteroarylene, or heterocyclylene; nd, o s , , N—, N(R4), C(R4)—, or C(R“)2 ; Uisabond, o, s , N—, N(R5), C(R5)—, or C(R5)2; Visabond, o s , , N—, N(R6) , C(R6)—, or C(R6)2; Wisabond, o s , , N—, N(R7) , C(R7)—, or C(R7)2; X and Y are each independently C or N; Z is NR2A or CRZARZB, wherein each R2A and R213 is independently en, halo, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; each R4, R5, R6, and R7 is independently (a) hydrogen, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0Rla, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, 2R1a, —OS(O)NR1bR1°, 2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; each R”, Rlb, R”, and R1d is independently hydrogen, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 lkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or R1&1 and R10 er with the C and N atoms to which they are attached form cyclyl; or R1b and R10 together with the N atom to which they are attached form cyclyl; and each R13, R”, and ng is independently hydrogen, halo, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C745 aralkyl, aryl, or heterocyclyl; with the proviso that no more than one of T, U, V, and W is a bond; and with the o that, when L1 is a bond, at least one of R4, R5, R6, and R7 is bromo, —OR1a, or —NR1bR1°, wherein R1&1 is C4_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 l, heteroaryl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, where each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, and heterocyclyl, each of which is filrther optionally tuted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) —C(O)Ra, —C(O)ORa, RbR°, —C(NRa)NRbR°, —0Ra, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbR°, —OC(=NRa)NRbR°, —OP(O)(ORa)2, Ra, —OS(O)2Ra, —OS(O)NRbR°, —OS(O)2NRbR°, —NRbR°, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbR°, —NRaC(=NRd)NRbR°, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbR°, —NRaS(O)2NRbR°, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbR°, and —S(O)2NRbR°, wherein each Ra, Rb, RC, and Rd is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 l, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally tuted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qa is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Rf, —C(O)ORf, —C(O)NRth, —C(NRf)NRth, —ORf, —OC(O)Rf, —OC(O)ORf, —OC(O)NRth, —OC(=NRf)NRth, —OP(O)(ORf)2, —OS(O)Rf, —OS(O)2Rf, —OS(O)NRth, 2NRth, —NRth, —NRfC(O)Rk, —NRfC(O)ORk, —NRfC(O)NRth, —NRfC(=NRk)NRth, —NRfS(O)Rk, —NRfS(O)2Rk, —NRfS(O)NRth, —NRfS(O)2NRth, —SRf, —S(O)Rf, —S(O)2Rf, —S(O)NRth, and —S(O)2NRth; wherein each Rf, Rg, Rh, and Rk is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or cyclyl; or (iii) Rg and Rh together with the N atom to which they are attached form heterocyclyl.

In another embodiment, provided herein is a compound of Formula I: Uf—RY’N >_R2 H ,'| \>—z V\ ~ ’ X\N LLLZ or a single enantiomer, a racemic mixture, a mixture of reomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or g thereof; R1 is (a) hydrogen, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 l, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or cyclyl; or (c) —C(O)R1a WO 43148 —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, R1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, NR1bR1°, —OS(O)2NRle1°, —NR1bR1°, (O)R1d, —NR1aC(O)ORld, (O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2Rld, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R2 is C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; L2 is C340 cycloalkylene, C644 arylene, C7_1 5 lene, heteroarylene, or heterocyclylene; T is a bond, 0 s , , N—, N(R4) , C(R4)—, or C(R“)2 ; U is a bond, 0 s , , N—, N(R5) , C(R5)—, or C(R5)2 ; V is a bond, 0 s , , N—, N(R6) , C(R6)—, or C(R6)2 ; W is a bond, 0 s , , N—, N(R7) , C(R7)—, or C(R7)2 ; X and Y are each independently C or N; Z is NR2A or CRZARZB, wherein each R2A and R213 is independently hydrogen, halo, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; R4, R5, R6, R7, and L1 are: (i) each R4, R5, and R6 is independently (a) hydrogen, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 l, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, — C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, R1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, 1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)Rld, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; each R7 is independently bromo, —OR7a, or —NR7bR7°; R7&1 is C4_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; R7b and R70 is independently hydrogen, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or WO 43148 heterocyclyl; or R7b and R70 together with the N atom to which they are attached form heterocyclyl; and Idisabond; (ii) each R4, R5, R6, and R7 is independently (a) hydrogen, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, (=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2Rld, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, 1a, —S(O)2R1a, —S(O)NRle1°, or —S(O)2NR1bR1°; with the proviso that at least one of R4, R5, R6, and R7 is not hydrogen; and L1 is —O—, —S—, )—, or —C(R1AR1B)—, wherein each R1A and R113 is independently hydrogen, halo, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 l, aryl, or heterocyclyl; each R”, Rlb, R”, and R1d is independently hydrogen, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or R1&1 and R10 er with the C and N atoms to which they are attached form heterocyclyl; or R1b and R10 together with the N atom to which they are attached form heterocyclyl; with the o that no more than one of T, U, V, and W is a bond; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, lkylene, aryl, arylene, l, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, where each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 l, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, and heterocyclyl, each of which is filrther optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbR°, —C(NRa)NRbR°, —0Ra, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbR°, —OC(=NRa)NRbR°, —OP(O)(ORa)2, Ra, —OS(O)2Ra, —OS(O)NRbR°, —OS(O)2NRbR°, —NRbR°, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbR°, —NRaC(=NRd)NRbR°, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbR°, —NRaS(O)2NRbR°, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbR°, and —S(O)2NRbR°, wherein each Ra, Rb, RC, and Rd is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 l, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc er with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, tuents Qa; wherein each Qa is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Rf, —C(O)ORf, —C(O)NRth, —C(NRf)NRth, —ORf, —OC(O)Rf, ORf, —OC(O)NRth, —OC(=NRf)NRth, —OP(O)(ORf)2, —OS(O)Rf, —OS(O)2Rf, —OS(O)NRth, —OS(O)2NRth, —NRth, —NRfC(O)Rk, —NRfC(O)ORk, —NRfC(O)NRth, —NRfC(=NRk)NRth, O)Rk, —NRfS(O)2Rk, —NRfS(O)NRth, —NRfS(O)2NRth, —SRf, —S(O)Rf, —S(O)2Rf, —S(O)NRth, and —S(O)2NRth; wherein each Rf, Rg, Rh, and Rk is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 lkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rg and Rh together with the N atom to which they are attached form heterocyclyl.

In yet another embodiment, provided herein is a compound of Formula II: (11) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic t thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R2, L1, L2, T, U, V, W, X Y, and Z are each as defined herein.

In yet r embodiment, provided herein is a compound of Formula 111: WO 43148 or a single omer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R2, R4, R5, R6, R7, L1, L2, and Z are each as defined .

In yet another embodiment, provided herein is a com ound of Formula IV:p R5 N R2 \>—z R6 N R7 LLLz (IV) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a ceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R2, R4, R5, R6, R7, L1, L2, and Z are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula V: o wN R2 R6 N R7 LLLz or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R2, R4, R5, R6, R7, L1, L2, and Z are each as defined herein, and the symbol represents that the 6-membered ring contains one N atom in the ring.

In yet r embodiment, ed herein is a com ound of Formula VI:p o wN R2 R6 N R7 LLLZ (V1) or a single enantiomer, a racemic e, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R2, R4, R5, R6, R7, L1, L2, and Z are each as defined ; and the symbol represents that the 6-membered ring contains one N atom in the ring.

In yet r embodiment, provided herein is a compound of Formula V11: (V11) or a single omer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a ceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R2, R4, R5, R7, L1, L2, and Z are each as defined herein.

In yet another ment, provided herein is a compound of Formula VIII: R5 1% >—R2 O LLLZ (VIII) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or g thereof; wherein: R7a lS (l) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, €3-10 cycloalkyl, C6—14 aryl, €7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (ii) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, 1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)Rld, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; and R1, R2, R4, R5, R6, R”, Rlb, R”, R“, L1, L2, Q, and z are each as defined herein. 2015/021455 In yet r embodiment, provided herein is a compound of Formula IX: R6 N /0 2m R7a ‘N (RL)n \ (1X) or a single enantiomer, a racemic e, a mixture of diastereomers, or an isotopic variant thereof; or a ceutically acceptable salt, solvate, or prodrug thereof; wherein: m is an integer ofO, l, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is an integer ofO, l, 2, 3, 4, 5, or 6; each RL is independently (i) hydrogen; or (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°,—OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°,—NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, (O)Rld, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; or two RL together, when there are two or more RL attached to the same ring, are linked together to form (i) a bond, —O—, —NRN—, or —S—; or (ii) C1_6 alkylene, C1_6 heteroalkylene, C2_6 alkenylene, or C2_6 heteroalkenylene, each of which is optionally substituted with one or more substituents Q; RN is (a) hydrogen; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or cyclyl, each of which is optionally substituted with one or more substituents Q; (c) —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, 2R1a, NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NRle1°, —NR1aS(O)2NR1bR1°, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; and R1, R2, R4, R5, R6, Rla, Rlb, R”, R“, R”, and Q are each as defined herein. 2015/021455 In yet another embodiment, provided herein is a compound of Formula X: or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R2, R4, R5 and R781 are each as defined herein.

, R6, In yet another embodiment, ed herein is a compound of Formula XI: (X1) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; n R1 and R7&1 are each as defined herein.

In yet another ment, provided herein is a compound of Formula XIa: $»—NHN RZn o \ /N (XIa) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a ceutically acceptable salt, solvate, or prodrug thereof; wherein R2n is C1_6 alkyl optionally substituted with one or more substituents Q or —OR1a, and R1, R”, R”, and Q are each as defined herein; in one embodiment, R2n is methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, —OH, or —OCH3.

In certain embodiments, in Formula VIII, IX, X, X1, or XIa, R7&1 is: h ”i? 29> W Ed3}o l 2}) O O 1F 1.“ N r Rla j: Rla ’ Rla ’ ’ Rla O ’ I? UK I? EliN’0 x): O N O N O N 0 O N’0 Rla 1|{13 fila ’ ’ ’ fila fila o o o o o N\ E gm O O Egp N\ X \ , q q q ’ ’ as; W saw q, q 01' q a ; each R1&1 and R1b is as defined herein; in one embodiment, R1&1 is hydrogen, methyl, ethyl, difluoromethyl, or romethyl; in another embodiment, R1b is hydrogen, methyl, methyl, ethyl, difluoromethyl, trifluoromethyl, 2-hydroxyethyl, or ethenyl; 2015/021455 p and q are each independently an r of 0, l, or 3, with the proviso that the total of p and q is no less than 1; each r is independently an integer of 0, l, 2, 3, 4, 5, or 6.

In certain embodiments, in a VIII, IX, X, XI, or XIa, R7&1 is: N N , J , F3CJ A k0 9 9 A S ’ or 0” Q0, In one embodiment, provided herein is a compound of Formula XIb: (XIb) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a ceutically acceptable salt, solvate, or prodrug thereof; Wherein u and v are each independently an integer of 0, l, 2, or 3; and R1 and R2n are each as defined herein.

In another embodiment, provided herein is a compound of Formula XIc: @N @N\>—NH _ AWE}?Oo ( Gil/8’’ (XIc) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein u and v are each as defined herein.

In yet r embodiment, provided herein is a compound of Formula XId: (XId) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically able salt, solvate, or prodrug thereof; wherein R1, R2“, u, and V are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula XIe: g\>—NHN _ \ /N O O <(U), N u 4: (XIe) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein u and v are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula XIf: g\>—NHN RZn \ /N (X10 or a single enantiomer, a racemic e, a mixture of diastereomers, or an isotopic t thereof; or a ceutically acceptable salt, solvate, or g thereof; wherein R1, R2“, u, and v are each as defined herein.

In yet another embodiment, ed herein is a compound of Formula XIg: @‘HWNN o o\ /N mO N4; (Xlg) or an isotopic t thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein u and V are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula XIh: Q: \>—NHN RZn \ /N (XIh) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug f; wherein R1, R2“, u, and v are each as defined herein.

In yet r ment, ed herein is a compound of Formula XIi: E1”idNN o o\ /N :U0 N4: (XIi) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein u and v are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula XII: R5 N9—)—R2 N L\L2 or a single enantiomer, a racemic mixture, a mixture of reomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein: R7b is (i) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (ii) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, R1a)NR1bR1°, —OS(O)R1a, 2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, (O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, 1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R70 is (i) hydrogen; or (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or cyclyl, each of which is ally substituted with one or more substituents Q; or (iii) —C(O)R1a, R1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; or R7b and R70 together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q; and R1, R2, R4, R5, R6, R”, Rlb, R”, R“, L1, L2, Q, and z are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula XIII: R6 N R7b/ \ N’Rl (x111) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R2, R4, R5, R6, R7b, and R70 are each as d herein.

In yet another ment, provided herein is a compound of Formula XIV: (XIV) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R71), and R70 are each as defined herein.

In yet r ment, provided herein is a compound of Formula XIVa: (XIVa) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R71), and R70 are each as defined herein.

In certain embodiments, in Formula XII, XIII, XIV, or XIVa, R7b is: h ‘21 2; m Ed3}o A db O O 1'“ 1'“ N r Rla Rla 9 Rla ’ ’ Rla3;O ’ If“ 13’2”“ if“ #17 lb 0 1y 0 N o N o N") o N’0 Rla fila fila ’ ’ ’ fila fila ’ ’ ii; 4442,. 04 :N’0 :9: if: o N'N‘Rlb o N’N‘R1b o N’N‘R1b ?~\O fila fila fila o Rla \J ’ ’ 9 R13, Rla O) O 0 O E Fixi—</ g 11% g liq—s?) HE p E COOH Rla Rla R13 HN\ ,NH q q q q , , , O”S\\O wherein: each R1&1 and R1b is as defined herein; in one embodiment, R1&1 is hydrogen, methyl, ethyl, difluoromethyl, or trifluoromethyl; in another embodiment, R1b is hydrogen, , , ethyl, difluoromethyl, trifluoromethyl, 2-hydroxyethyl, or ethenyl; each p and q is independently an integer of 0, l, 2, or 3, with the proviso that the total of p and q is no less than 1; and each r is independently an integer of 0, l, 2, 3, 4, 5, or 6.

In certain embodiments, in Formula XII, XIII, XIV, or XIVa, R70 is hydrogen, methyl, ethyl, difluoromethyl, or trifluoromethyl.

In certain embodiment, in a XII, XIII, XIV, or XIVa, the moiety —NR7aR7b is: W “T" | | HNO % N X A a O, 9 o, | “T” W WIW MIN N 111 EN1 N1 N X ll” Rla’ Rla’gO, /O or O\; wherein each R1&1 is as defined herein; in one embodiment, R1&1 is hydrogen, methyl, ethyl, omethyl, or trifluoromethyl.

In yet another embodiment, provided herein is a compound of Formula XV: (XV) or a single enantiomer, a racemic mixture, a mixture of reomers, or an isotopic variant f; or a ceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R2, R4, R5, R6, L1, and L2, and Z are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula XVI: (XVI) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R2, R4, R5, and R6 are each as d herein.

In yet another embodiment, provided herein is a compound of Formula XVII: 0 _N R5 N\>—N\I>i—<\:<\N R6 N N’RI (XVII) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R4, R5, and R6 are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula XVIIa: 0 _N R5 Ny—Nii—Q‘N R6 N R3n N’RI (XVIIa) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an ic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; n R3n is C1_6 alkyl ally substituted with one or more substituents Q or —OR1a, and R1, R4, R5, R6, R”, and Q are each as d herein; in one embodiment, R3n is methyl, monofluoromethyl, omethyl, trifluoromethyl, —OH, or —OCH3.

] In yet another embodiment, provided herein is a compound of Formula XVIII: R5 N >—R2 R63 \>—Z \O N R7 LLLz (XVIII) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein: R6a18 (1) C1_6 alkyl, C2_6 l, C2_6 alkynyl, €3-10 cycloalkyl, C6—14 aryl, €7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (ii) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)Rld, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; and R1, R2, R4, R5, R7, R”, Rlb, R”, R“, L1, L2, Q, and z are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula XIX: R5 N >~R2 6a \>—NH R\O N N’RI (XIX) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R2, R4, R5, R681, and R7 are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula XX: R63 \>—NH _ \O N \ N O / (XX) or an isotopic variant thereof; or a pharmaceutically able salt, solvate, or prodrug thereof; n R1, R7, and R6&1 are each as defined herein; in one ment, R7 is methyl, omethyl, trifluoromethyl, or —OR1a, where R181 is as defined herein.

In still another embodiment, provided herein is a compound of Formula XXa: N RZn R6a \>—NH — \O N \ N O / 09(3) or a single enantiomer, a c e, a e of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R2n is C1_6 alkyl optionally substituted with one or more substituents Q or —OR1a, and R1, R7, Rla, R681, and Q are each as defined herein; in one embodiment, R7 is chloro, methyl, oromethyl, difluoromethyl, trifluoromethyl, or —OR1a, where R181 is as defined ; in another embodiment, R2n is methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, —OH, or —OCH3.

In certain embodiments, in a XVIII, XIX, XX, or XXa, R6&1 is: h “in 9; m Rla Rla R13 ’ ’ Rla 0 ’ it 13/3 I?“ if]? E 0 N O N o N’0 o N’0 Rla fila Rla ’ fila £113. 9:; x x: xi, w 04 :N’0 o u’N‘RIb NR“) 0 N’N‘R1b O fiia o\J Rla Rla fiia , O O NJ O O O 0 RNNK fl OW 0w ’ \/<Rla \/<R1a 0, gfigN—SFOp 9 A 1" HE Rla HN\ /NH §{}COOH o 0 o q S\ ’ 0” \O 7< ’ ’ O)‘N O O p 5 p p - N5 5 0 O \ \ X O 0 q q wherein R- 1 a, R1b and r are each as defined herein.. , p, q, In certain embodiments, in Formula XVIII, XIX, XX, or XXa, R6&1 is: X O2h ”b ““23 “b- , E O O O 9 9 9 JVVV :1 5,?S a O O 9 1 ¢ In one embodiment, provided herein is a nd of Formula XXb: [TwoN RZn O N o \ /N )Cl N’Rl (XXb) or a single enantiomer, a c mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug f; wherein R1, R2“, u, and V are each as defined herein.

In another embodiment, provided herein is a compound of Formula XXc: (XXc) or an isotopic variant thereof; or a pharmaceutically acceptable salt, e, or prodrug thereof; wherein u and V are each as defined herein.

In yet r embodiment, provided herein is a compound of Formula XXd: N RZn 0£1W6 N N o \ / (XXd) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant f; or a pharmaceutically acceptable salt, e, or prodrug thereof; wherein R1, R2“, u, and v are each as defined herein.

In still another embodiment, provided herein is a compound of Formula XXe: Cy[:;I:N>—§§—<:i§N‘g OCH3 0 / )V N (_11: / /Nf0 C€X® or an isotopic variant thereof; or a pharmaceutically able salt, solvate, or prodrug thereof; wherein u and v are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula XXf: WO 43148 N R2n fir—NH __ O N \ /N L N’Rl ( uO (BCKD or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R2“, u, and V are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula XXg: N OCH3 fir—NH C) N ::N__ V N (110 J; (XXg) or an isotopic variant thereof; or a ceutically acceptable salt, solvate, or prodrug thereof; wherein u and v are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula XXh: N R2n sf—NH __ O N \ /N ) t N’Rl (XXh) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically able salt, solvate, or prodrug thereof; wherein R1, R2“, u, and v are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula XXi: 1?“idN OCH3 0 N \ N o / )5“ N (. / (XXi) or an ic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein s andt are each as defined herein.

In yet another embodiment, provided herein is a compound of a XXj: (XXi) or a single enantiomer, a racemic e, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R2“, u, and v are each as defined herein.

In yet r embodiment, provided herein is a compound of Formula XXk: 1?“idN OCH3 0 N \ N o O (XXk) or an isotopic variant thereof; or a ceutically acceptable salt, solvate, or prodrug thereof; wherein u and v are each as defined .

In yet another embodiment, provided herein is a compound of Formula XXI: R6 N (XXI) or a single enantionier, a racemic mixture, a e of diastereoniers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; WR”NERe 1- 1:32 If lg 0 laC(O)CR1:32 If R lg is _ CR CR _N CR CR , , , E1a O W / file (o) —§ :ng 0 ,—S(O)CR e=CR CR1 1f 1 g, Re1 ,—S(02)CR e=CR CR1 1f 1 g, 0 Rg1 R1a “A 0 I 0 Q _fi le :ng R1e /N\§ RH 0 ,—NR1aS(O)CRle=CR1fCR1g, Re1 ,—NR1aS(Oz)CRle=CR1fCR1g, or R13 0 IO W /N‘§ RIf RIe (1)1 R2 is C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; L1 is a bond, —O—, —S—, —N(R1A)—, or —C(R1AR1B)—, wherein each R1A and R113 is independently hydrogen, halo, C1_6 alkyl, C2_6 l, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; L2 is C340 lkylene, C644 arylene, C7_1 5 aralkylene, heteroarylene, or heterocyclylene; Z is NR2A or CRZARZB, wherein each R2A and R213 is independently hydrogen, halo, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; R4 and R6 are each independently (a) hydrogen, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°,—OR1a, —OC(O)R1a, OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, (O)R1d, —NR1aC(O)OR1d, 2015/021455 —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, (O)2R1d, —NR1aS(O)NRle1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R5&1 is C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; each R”, Rlb, R”, and R1d is independently hydrogen, C1_6 alkyl, C2_6 alkenyl, C2_6 l, C3_7 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or R1&1 and R10 together with the C and N atoms to which they are attached form heterocyclyl; or R1b and R10 together with the N atom to which they are attached form heterocyclyl; and each R13, R”, and ng is independently hydrogen, halo, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; n each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, where each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, and heterocyclyl, each of which is filrther optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbR°, —C(NRa)NRbR°, —0Ra, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbR°, —OC(=NRa)NRbR°, —OP(O)(ORa)2, —OS(O)Ra, —OS(O)2Ra, —OS(O)NRbR°, —OS(O)2NRbR°, —NRbR°, —NRaC(O)Rd, —NRaC(O)ORd, O)NRbR°, —NRaC(=NRd)NRbR°, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbR°, —NRaS(O)2NRbR°, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbR°, and —S(O)2NRbR°, wherein each Ra, Rb, RC, and Rd is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 l, C3_7 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally tuted with one or more, in one embodiment, one, two, three, or four, substituents Qa; n each Qa is ndently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 lkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Rf, —C(O)ORf, —C(O)NRth, —C(NRf)NRth, —ORf, —OC(O)Rf, —OC(O)ORf, —OC(O)NRth, —OC(=NRf)NRth, —OP(O)(ORf)2, Rf, —OS(O)2Rf, —OS(O)NRth, 2NRth, —NRth, —NRfC(O)Rk, —NRfC(O)ORk, —NRfC(O)NRth, =NRk)NRth, —NRfS(O)Rk, —NRfS(O)2Rk, —NRfS(O)NRth, —NRfS(O)2NRth, —SRf, f, —S(O)2Rf, Rth, and —S(O)2NRth; wherein each Rf, Rg, Rh, and Rk is ndently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rg and Rh together with the N atom to which they are attached form heterocyclyl.

In yet another embodiment, provided herein is a compound of Formula XXII: (XXII) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R2, R4, R6, and R581 are each as defined herein.

In yet another embodiment, ed herein is a compound of a XXIII: \>—Nii—<\:<0 —N 0 N N Rsa/ R6 N N’RI (XXIII) or a single enantiomer, a racemic mixture, a mixture of reomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R4, R6, and R581 are each as defined .

In still another embodiment, provided herein is a compound of Formula XXIII: 2015/021455 0 N N RSa/ \ \>_NH / R6 N N’RI (XXIV) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R4, R6, R2“, and R581 are each as defined herein.

In certain embodiments, in any of Formulae XXI to XXIV, R5&1 is: O O P >— P 5 E N/ E ... N/ E N\ E' N\ \ \ q or q q q a 3 wherein p and q are each as defined herein.

In one embodiment, provided herein is a compound of Formula XXIVa: l N W\ N 0 / )L U HH N v N I Cl N’Rl (XXIVa) or a single enantiomer, a racemic mixture, a mixture of reomers, or an ic variant thereof; or a pharmaceutically acceptable salt, solvate, or g thereof; wherein R1, R2“, u, and v are each as defined herein.

In another embodiment, provided herein is a nd of Formula XXIVb: O _ AME}?UM0o < Ti H3“/ | 0 (XXIVb) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein u and V are each as defined herein.

In yet antoher embodiment, provided herein is a compound of Formula XXIVc: R211 0 _ (UO N \ N \>_ / u NH 0 )v N N’Rl (XXIVc) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a ceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R2“, u, and v are each as defined .

In yet another embodiment, provided herein is a compound of Formula XXIVd: C1 NJE’ or an isotopic variant thereof; or a pharmaceutically able salt, solvate, or prodrug thereof; wherein u and v are each as defined herein.

] In yet antoher embodiment, provided herein is a compound of Formula XXIVe: oO N WvN )V N N’Rl (XXIVe) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R1, R2“, u, and V are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula XXIVf: o __ (WWW\ /N V N C1 N’éLZ (XXIVf) or an isotopic variant thereof; or a pharmaceutically able salt, solvate, or prodrug f; wherein u and v are each as defined herein.

In yet antoher ment, provided herein is a compound of Formula XXIVg: O _ ( N N u N>_\ \ / 0§ )V N’Rl (XXIVg) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, e, or prodrug f; wherein R1, R2“, u, and v are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula XXIVh: O _ (g0 N\ @ 02s )V UN>—NH or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein u and V are each as defined herein.

The groups, R1, R2, R4, R5, R6, R7, R2“, R3“, R52 R“, R72 R7b, R7 , L1, L2, T, U, V, W, X, Y, Z, m, n, p, q, r, u and V in formulae described herein, including Formulae I to XXIV, XIa to XIi, XVIIa, XXa to XXk, and XXIVa to XXIVh, are further defined .

All combinations of the embodiments ed herein for such groups are within the scope of this disclosure.

In certain embodiments, R1 is hydrogen. In certain embodiments, R1 is cyano.

In certain embodiments, R1 is halo. In certain embodiments, R1 is fiuoro, chloro, bromo, or iodo. In certain embodiments, R1 is fiuoro or chloro. In certain embodiments, R1 is nitro. In n embodiments, R1 is C1_6 alkyl, optionally substituted with one or more tuents Q.

In certain embodiments, R1 is C2_6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R1 is C2_6 l, optionally substituted with one or more substituents Q. In certain embodiments, R1 is C3_7 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R1 is €6-14 aryl, ally substituted with one or more substituents Q. In certain embodiments, R1 is C7_1 5 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R1 is heteroaryl, ally tuted with one or more substituents Q. In certain ments, R1 is heterocyclyl, optionally substituted with one or more substituents Q.

In certain embodiments, R1 is —C(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R1 is —C(O)OR1a, wherein R1&1 is as defined herein. In certain embodiments, R1 is —C(O)NR1bR1°, n R1b and R10 are each as defined herein. In certain ments, R1 is —C(NR1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R is —OR1a, wherein R1&1 is as defined herein. In certain embodiments, R1 is —OC(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R1 is —OC(O)OR1a, n R1&1 is as defined herein. In certain embodiments, R1 is —OC(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In n embodiments, R1 is —OC(=NR1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R1 is —OS(O)R1a, wherein R1&1 is as defined herein. In certain ments, R1 is —OS(O)2R1a, wherein R1&1 is as defined herein. In certain ments, R1 is —OS(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In n embodiments, R1 is —OS(O)2NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R1 is —NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R1 is —NR1aC(O)R1d, wherein R1&1 and R1d are each as defined herein. In n embodiments, R1 is —NR1aC(O)OR1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R1 is —NR1aC(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein.

In certain embodiments, R1 is —NR1aC(=NR1d)NR1bR1°, wherein R”, Rlb, R”, and R1d are each as defined . In certain embodiments, R1 is —NR1aS(O)R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R1 is —NR1aS(O)2R1d, wherein R1&1 and R1d are each as defined herein. In n embodiments, R1 is —NR1aS(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R1 is (O)2NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R1 is —SR1a, wherein R1&1 is as defined herein. In certain embodiments, R1 is —S(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R1 is —S(O)2R1a, wherein R1&1 is as defined herein. In certain embodiments, R1 is —S(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R1 is —S(O)2NRle1°, wherein R1b and R10 are each as defined herein.

In certain embodiments, R1 is —C(O)CR13=CR1fCR1g, wherein R”, R”, and ng WK”R1 g are each as defined herein. In certain ments, R1 is 0 wherein R13, R”, and ng are each as defined herein. In certain ments, R1 is O)CRle=CR1fCR1g, where1n R. 1 a, R 1e, R1f and R g are each as defined here1n.1 . In certa1n ments, R1 1s. . .

Ii 1a O W 0 wherein R”, R13, R”, and ng are each as defined herein. In certain embodiments, R1 is —S(O)CRle=CR1fCR1g, wherein R13, R”, and ng are each as defined O 1 _IS| :R g herein.. In certain embodiments, R. . 1 . where1n R13, R”, and ng are each as. is R16 defined . In certain embodiments, R1 is —NR1aS(O)CRle=CR1fCR1g, wherein R”, R13, Rla O I o 5 E /N‘§ .ng II R 1 e R”, and ng are each as defined herein. In certain ments, R1 is 0 wherein R”, R13, R”, and ng are each as defined herein. In certain embodiments, R1 is certain embodiments, R1 is —NR1aS(02)CRle=CR1fCR1g, wherein R”, R13, R”, and ng are Rla O I o 5 E .ng /N\% le each as defined herein. In certain embodiments, R1 is 0 wherein R”, R13, R”, and ng are each as defined herein. In certain embodiments, Rla, R13, R”, and ng are all hydrogen.

In certain embodiments, R1 is selected from: O O / 39V ammo0 / N / ,MEO O l/\ O /N o o o l/ ‘ 2M1“? O O 0 O 1/\I=N\ gMMN/go H 3M EMNKN 0 AN, or EMNAO In certain embodiments, R1 is selected from: @iNJK/ ;\NJJ\/\/N\/O AN / N / H H , H a OYo O l/\O O N 0 f\ /\/N\) ;\I}\IIJJ\/\/N\« H 0 r‘é\1}\IIJ\/\/N\<N In certain embodiments, R2 is C1_6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R2 is C2_6 alkenyl, optionally tuted with one or more substituents Q. In certain embodiments, R2 is C2_6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R2 is C3_7 lkyl, optionally substituted with one or more substituents Q. In certain embodiments, R2 is €6-14 aryl, optionally substituted with one or more tuents Q. In certain embodiments, R2 is 6- to bered monocyclic or bicyclic aryl, optionally substituted with one or more substituents Q. In certain embodiments, R2 is phenyl, optionally tuted with one or more substituents Q. In certain embodiments, R2 is phenyl or methyl-phenyl. In n embodiments, R2 is phenyl, 3-methyl-phenyl, or 4-((2-(methylcarbamoyl)pyridin yl)oxy)phenyl. In certain embodiments, R2 is C7_1 5 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R2 is heteroaryl, ally substituted with one or more substituents Q. In certain ments, R2 is 5- to lO-membered aryl, optionally substituted with one or more substituents Q. In certain embodiments, R2 is 5- to lO-membered heteroaryl comprising 1 to 4 hetereoatoms selected from N, O, and S, which is optionally tuted with one or more substituents Q. In certain embodiments, R2 is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R2 is 5-membered heteroaryl, optionally tuted with one or more substituents Q. In certain embodiments, R2 is 6-membered aryl, optionally substituted with one or more substituents Q. In n embodiments, R2 is pyridinyl or pyridazinyl, optionally substituted with one or more substituents Q. In certain embodiments, R2 is hydroxy-pyridinyl, methoxy-pyridinyl, methyl-pyridinyl, difluoromethyl-pyridinyl, trifluoromethyl-pyridinyl, methylaminocarbonyl-pyridinyl, or methyl-pyridazinyl. In certain embodiments, R2 is 2—hydroxy-pyridinyl, 2-methoxy-pyridinyl, 2-methyl-pyridinyl, 2-monofluoromethyl-pyridinyl, 2-difluoromethyl-pyridinyl, 2-trifluoromethyl-pyridin- 4-yl, 2-methylaminocarbonyl-pyridinyl, or 3-methyl-pyridazinyl. In certain embodiments, R2 is bicyclic heteroaryl, optionally tuted with one or more substituents Q. In certain embodiments, R2 is 5,6-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R2 is benzo[c][l,2,5]oxodiazolyl or benzo[c][l,2,5]thiodiazolyl, each optionally substituted with one or more substituents Q. In certain embodiments, R2 is benzo[c][l,2,5]oxodiazolyl or benzo[c][l,2,5]thiodiazolyl, each optionally tuted with one or more substituents Q. In certain embodiments, R2 is heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R2 is 4- to lZ-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, which is optionally substituted with one or more substituents Q.

In n embodiments, R4 is hydrogen. In n ments, R4 is cyano. . . 4 In certain embodiments, R . . . . is halo. In certain embodiments, R4 is fluoro, chloro, bromo, or iodo. In certain embodiments, R4 is nitro. In certain embodiments, R4 is C1_6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R4 is C2_6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R4 is C2_6 l, optionally substituted with one or more substituents Q. In n embodiments, R4 is C3_7 cycloalkyl, optionally substituted with one or more substituents Q.

In certain embodiments, R4 is €6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R4 is C7_1 5 aralkyl, optionally substituted with one or more tuents Q. In certain embodiments, R4 is aryl, optionally substituted with one or more substituents Q. In certain embodiments, R4 is heterocyclyl, optionally substituted with one or more substituents Q.

In certain embodiments, R4 is —C(O)R1a, where R181 is as defined herein. In n embodiments, R4 is —C(O)OR1a, where R181 is as defined herein. In certain ments, R4 is R1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, R4 is —C(NR1a)NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain embodiments, R4 is —OR1a, where R181 is as defined herein. In certain embodiments, R4 is —OC(O)R1a, where R181 is as defined herein. In certain embodiments, R4 is —OC(O)OR1a, where R181 is as defined herein. In certain ments, R4 is —OC(O)NR1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, R4 is —OC(=NR1a)NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain embodiments, R4 is —OS(O)R1a, where R181 is as defined herein. In certain embodiments, R4 is —OS(O)2R1a, where R181 is as defined herein. In certain embodiments, R4 is —OS(O)NR1bR1°, where R1b and R10 are each as defined herein. In n ments, R4 is —OS(O)2NR1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, R4 is —NRle1°, where R1b and R10 are each as defined herein. In n embodiments, R4 is —NR1aC(O)R1d, where R181 and R1d are each as defined herein. In certain embodiments, R4 is —NR1aC(O)OR1d, where R181 and R1d are each as defined herein. In n embodiments, R4 is —NR1aC(O)NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain embodiments, R4 is —NR1aC(=NR1d)NR1bR1°, where R”, Rlb, R”, and R1d are each as defined herein. In certain embodiments, R4 is —NR1aS(O)R1d, where R181 and R1d are each as defined herein. In certain embodiments, R4 is —NR1aS(O)2R1d, where R181 and R1d are each defined . In certain embodiments, R4 is —NR1aS(O)NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain embodiments, R4 is —NR1aS(O)2NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain embodiments, R4 is —SR1a, where R181 is as defined . In certain embodiments, R4 is WO 43148 —S(O)R1a, where R181 is as defined herein. In certain embodiments, R4 is —S(O)2R1a, where R181 is as defined herein. In certain ments, R4 is —S(O)NR1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, R4 is —S(O)2NR1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, two R4 are linked together to form =0.

In certain embodiments, R5 is hydrogen. In certain ments, R5 is cyano.

In certain embodiments, R5 is halo. In certain embodiments, R5 is fiuoro, chloro, bromo, or iodo. In n embodiments, R5 is nitro. In certain embodiments, R5 is C1_6 alkyl, optionally substituted with one or more substituents Q. In n embodiments, R5 is C2_6 alkenyl, ally substituted with one or more substituents Q. In certain embodiments, R5 is C2_6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R5 is C3_7 cycloalkyl, optionally substituted with one or more substituents Q.

In certain embodiments, R5 is C644 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R5 is C7_1 5 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R5 is aryl, optionally substituted with one or more substituents Q. In n embodiments, R5 is heterocyclyl, optionally substituted with one or more substituents Q. In n embodiments, R5 is zinyl, optionally substituted with one or more substituents Q. In certain embodiments, R5 is 4-acetylpiperazinyl.

In certain embodiments, R5 is —C(O)R1a, where R181 is as defined herein. In certain embodiments, R5 is —C(O)OR1a, where R181 is as defined herein. In certain embodiments, R5 is —C(O)NR1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, R5 is —C(NR1a)NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5 is —OR1a, where R181 is as defined herein. In certain embodiments, R5 is —OC1_6 alkyl, ally substituted with one or more substituents Q. In certain embodiments, R5 is —OCH3, optionally substituted with one or more substituents Q. In certain embodiments, R5 is trifluoromethoxy. In certain embodiments, R5 is —O-heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R5 is —O- piperidyl, optionally substituted with one or more substituents Q. In n embodiments, R5 is piperidyloxy, optionally substituted with one or more substituents Q. In certain embodiments, R5 is 1-ethyl-piperidyloxy. In certain embodiments, R5 is —OC(O)R1a, where R181 is as defined . In certain embodiments, R5 is —OC(O)OR1a, where R181 is as defined herein. In certain ments, R5 is —OC(O)NR1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, R5 is —OC(=NR1a)NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5 is —OS(O)R1a, where R181 is as defined herein. In certain embodiments, R5 is —OS(O)2R1a, where R181 is as defined . In certain embodiments, R5 is NR1bR1°, where R1b and R10 are each as defined . In certain embodiments, R5 is —OS(O)2NR1bR1°, where R1b and R10 are each as defined herein.

In certain embodiments, R5 is —NR1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, R5 is —NR1aC(O)R1d, where R181 and R1d are each as defined herein. In certain embodiments, R5 is —NHC(O)—C1_6 alkyl, optionally tuted with one or more substituents Q. In certain embodiments, R5 is )—methyl, optionally substituted with one or more substituents Q. In certain ments, R5 is acetamido. In certain embodiments, R5 is —NR1aC(O)OR1d, where R181 and R1d are each as defined herein. In certain embodiments, R5 is —NR1aC(O)NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5 is —NR1aC(=NR1d)NR1bR1°, where R”, Rlb, R”, and R1d are each as defined herein. In certain embodiments, R5 is —NR1aS(O)R1d, where R181 and R1d are each as defined herein. In certain embodiments, R5 is —NR1aS(O)2R1d, where R181 and R1d are each defined herein. In certain ments, R5 is —NR1aS(O)NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain ments, R5 is —NR1aS(O)2NR1bR1°, where R”, Rlb, and R10 are each as defined . In certain embodiments, R5 is —SR1a, where R181 is as defined herein. In certain embodiments, R5 is —S(O)R1a, where R181 is as defined herein.

In certain ments, R5 is —S(O)2R1a, where R181 is as defined herein. In certain embodiments, R5 is —S(O)NR1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, R5 is —S(O)2NR1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, two R5 are linked together to form =0.

In certain embodiments, R6 is hydrogen. In certain embodiments, R6 is cyano.

In n embodiments, R6 is halo. In certain embodiments, R6 is fluoro, chloro, bromo, or iodo. In certain ments, R6 is nitro. In certain embodiments, R6 is C1_6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R6 is C2_6 alkenyl, optionally substituted with one or more tuents Q. In certain embodiments, R6 is C2_6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R6 is C3_7 cycloalkyl, optionally substituted with one or more substituents Q.

In certain embodiments, R6 is €6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R6 is C7_1 5 aralkyl, optionally substituted with one or more substituents Q. In certain ments, R6 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R6 is heterocyclyl, optionally substituted with one or more substituents Q.

In certain embodiments, R6 is —C(O)R1a, where R181 is as defined herein. In certain embodiments, R6 is —C(O)OR1a, where R181 is as defined herein. In certain embodiments, R6 is R1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, R6 is —C(NR1a)NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain embodiments, R6 is —OR1a, where R181 is as defined herein. In certain embodiments, R6 is —O-C1_6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R6 is —O-ethyl, optionally substituted with one or more substituents Q. In certain embodiments, R6 is 2-methoxy-ethoxy. In certain embodiments, R6 is —O- heterocyclyl, optionally substituted with one or more substituents Q. In n embodiments, R6 is —O-piperidyl, optionally substituted with one or more substituents Q. In certain embodiments, R6 is piperidyloxy, optionally substituted with one or more substituents Q.

In certain embodiments, R6 is l-piperidyloxy. In certain embodiments, R6 is —OC(O)R1a, where R181 is as defined herein. In certain embodiments, R6 is OR1a, where R181 is as defined herein. In certain embodiments, R6 is —OC(O)NR1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, R6 is R1a)NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In n ments, R6 is —OS(O)R1a, where R181 is as defined herein. In certain ments, R6 is —OS(O)2R1a, where R181 is as defined herein. In n embodiments, R6 is —OS(O)NR1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, R6 is —OS(O)2NR1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, R6 is —NRle1°, where R1b and R10 are each as defined herein. In n ments, R6 is —NR1aC(O)R1d, where R181 and R1d are each as defined herein. In certain embodiments, R6 is —NR1aC(O)OR1d, where R181 and R1d are each as defined herein. In certain embodiments, R6 is (O)NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain embodiments, R6 is —NR1aC(=NR1d)NR1bR1°, where R”, Rlb, R”, and R1d are each as defined herein. In certain embodiments, R6 is (O)R1d, where R181 and R1d are each as defined herein. In certain embodiments, R6 is —NR1aS(O)2R1d, where R181 and R1d are each defined herein. In certain embodiments, R6 is —NR1aS(O)NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain embodiments, R6 is —NR1aS(O)2NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain embodiments, R6 is —SR1a, where R181 is as defined herein. In certain embodiments, R6 is —S(O)R1a, where R181 is as defined herein. In certain embodiments, R6 is —S(O)2R1a, where R181 is as defined . In certain embodiments, R6 is —S(O)NR1bR1°, where R1b and R10 are each as defined herein. In certain ments, R6 is —S(O)2NR1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, two R6 are linked er to form =0.

] In n embodiments, R7 is en. In certain embodiments, R7 is cyano.

In certain embodiments, R7 is halo. In certain embodiments, R7 is fiuoro, chloro, bromo, or iodo. In certain embodiments, R7 is chloro. In certain embodiments, R7 is bromo. In certain ments, R7 is nitro. In certain embodiments, R7 is C1_6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R7 is C2_6 alkenyl, ally substituted with one or more substituents Q. In certain embodiments, R7 is C2_6 alkynyl, optionally substituted with one or more substituents Q. In n embodiments, R7 is C3_7 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R7 is C644 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R7 is C7_1 5 aralkyl, ally substituted with one or more substituents Q. In certain embodiments, R7 is heteroaryl, optionally substituted with one or more substituents Q.

In certain embodiments, R7 is heterocyclyl, optionally substituted with one or more substituents Q.

In certain embodiments, R7 is 1a, where R181 is as defined herein. In certain embodiments, R7 is —C(O)OR1a, where R181 is as defined herein. In certain embodiments, R7 is —C(O)NR1bR1°, where R1b and R10 are each as defined herein. In certain ments, R7 is —C(NR1a)NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain embodiments, R7 is —OR1a, where R181 is as defined herein. In certain embodiments, R7 is —O-C1_6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R7 is —O-ethyl, optionally substituted with one or more substituents Q. In certain embodiments, R7 is 2-methoxy-ethoxy. In n embodiments, R7 is —O- heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R7 is eridyl, optionally substituted with one or more substituents Q. In certain embodiments, R7 is piperidyloxy, optionally substituted with one or more substituents Q.

In certain embodiments, R6 is l-ethyl-piperidyloxy, l-acetyl-piperidyloxy, or 1- acryloyl-piperidyloxy. In certain embodiments, R7 is —OC(O)R1a, where R181 is as defined . In certain ments, R7 is —OC(O)OR1a, where R181 is as defined herein. In certain embodiments, R7 is —OC(O)NR1bR1°, where R1b and R10 are each as defined herein.

In certain embodiments, R7 is —OC(=NR1a)NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain embodiments, R7 is —OS(O)R1a, where R181 is as defined herein. In 2015/021455 certain embodiments, R7 is —OS(O)2R1a, where R181 is as defined . In certain embodiments, R7 is —OS(O)NR1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, R7 is —OS(O)2NR1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, R7 is —NR1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, R7 is —NR1aC(O)R1d, where R181 and R1d are each as defined herein. In certain embodiments, R7 is —NR1aC(O)OR1d, where R181 and R1d are each as defined herein.

In certain embodiments, R7 is (O)NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain ments, R7 is (=NR1d)NR1bR1°, where R”, Rlb, R”, and R1d are each as defined herein. In certain embodiments, R7 is —NR1aS(O)R1d, where R181 and R1d are each as defined herein. In n embodiments, R7 is —NR1aS(O)2R1d, where R181 and R1d are each defined herein. In certain embodiments, R7 is (O)NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain embodiments, R7 is —NR1aS(O)2NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain embodiments, R7 is —SR1a, where R181 is as defined herein. In certain embodiments, R7 is —S(O)R1a, where R181 is as defined herein. In certain embodiments, R7 is —S(O)2R1a, where R181 is as defined herein. In certain embodiments, R7 is —S(O)NR1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, R7 is —S(O)2NR1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, two R7 are linked er to form =0.

In certain embodiments, R2n is C1_6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R211 is methyl or ethyl, each optionally tuted with one or more substituents Q. In certain embodiments, R211 is methyl, monofluoromethyl, difluoromethyl, or trifluoromethyl. In certain embodiments, R2n is —OR1a, where R181 is as defined herein. In certain embodiments, R2n is —OH. In certain embodiments, R2n is —O-C1_6 alkyl, optionally substituted with one or more substituents Q. In n embodiments, R2n is methoxy.

In certain embodiments, R3n is C1_6 alkyl, ally substituted with one or more substituents Q. In certain embodiments, R311 is methyl or ethyl, each optionally substituted with one or more substituents Q. In certain embodiments, R311 is methyl, monofluoromethyl, omethyl, or trifluoromethyl. In certain embodiments, R3n is —OR1a, where R181 is as defined . In certain embodiments, R3n is —OH. In certain embodiments, R3n is —O-C1_6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R3n is methoxy.

In certain embodiments, R5&1 is C1_6 alkyl, optionally substituted with one or more tuents Q. In certain embodiments, R5&1 is methyl or ethyl, each optionally substituted with one or more substituents Q. In certain embodiments, R581 is romethyl or 2-methoxyethyl. In certain embodiments, R5&1 is C2_6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R581 is C2_6 alkynyl, optionally substituted with one or more tuents Q. In certain embodiments, R581 is C3_7 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R5&1 is €6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R5&1 is €7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R5&1 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R581 is cyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R581 is piperidyl, optionally substituted with one or more substituents Q.

In certain embodiments, R5&1 is piperidyl, optionally tuted with one or more substituents Q. In certain ments, R5&1 is 1-ethyl-piperidyl.

In certain embodiments, R6&1 is C1_6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R6&1 is methyl or ethyl, each optionally substituted with one or more substituents Q. In certain embodiments, R681 is romethyl or 2-methoxyethyl. In certain embodiments, R6&1 is C2_6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R681 is C2_6 alkynyl, ally substituted with one or more tuents Q. In n embodiments, R681 is C3_7 cycloalkyl, optionally substituted with one or more substituents Q. In certain ments, R6&1 is €6-14 aryl, ally substituted with one or more substituents Q. In certain embodiments, R6&1 is €7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R6&1 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R681 is heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R681 is piperidyl, optionally substituted with one or more substituents Q.

In certain embodiments, R6&1 is piperidyl, optionally substituted with one or more substituents Q. In certain embodiments, R6&1 is 1-ethyl-piperidyl.

In n embodiments, R6&1 is —C(O)R1a, where R181 is as defined herein. In certain embodiments, R681 is —C(O)OR1a, where R181 is as defined herein. In certain embodiments, R6&1 is R1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, R6&1 is —C(NR1a)NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain ments, R6&1 is —NRle1°, where R1b and R10 are each as defined herein. In certain ments, R6&1 is —NR1aC(O)R1d, where R181 and R1d are each as defined herein. In n embodiments, R6&1 is (O)OR1d, where R181 and R1d are each as defined herein.

In certain embodiments, R6&1 is —NR1aC(O)NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain embodiments, R6&1 is (=NR1d)NR1bR1°, where R”, Rlb, R”, and R1d are each as defined . In certain embodiments, R6&1 is —NR1aS(O)R1d, where R181 and R1d are each as defined herein. In certain embodiments, R6&1 is —NR1aS(O)2R1d, where R181 and R1d are each defined herein. In certain embodiments, R6&1 is —NR1aS(O)NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain embodiments, R6&1 is —NR1aS(O)2NR1bR1°, where R”, Rlb, and R10 are each as defined herein. In certain embodiments, R6&1 is —S(O)R1a, where R181 is as defined herein. In certain embodiments, R681 is R1a, where R181 is as defined herein. In certain embodiments, R681 is —S(O)NR1bR1°, where R1b and R10 are each as defined herein. In certain embodiments, R6&1 is —S(O)2NR1bR1°, where R1b and R10 are each as defined herein.

In certain embodiments, R7&1 is C4_6 alkyl, optionally substituted with one or more tuents Q. In certain embodiments, R7&1 is C2_6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R781 is C2_6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R781 is C3_7 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R7&1 is €6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R7&1 is C745 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R7&1 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R781 is cyclyl, optionally substituted with one or more substituents Q.

In certain embodiments, R7b is C4_6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R7b is C2_6 alkenyl, optionally tuted with one or more substituents Q. In certain embodiments, R7b is C2_6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R7b is C3_7 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R7b is €6-14 aryl, optionally substituted with one or more substituents Q. In n embodiments, R7b is €7-15 aralkyl, optionally substituted with one or more substituents Q. In n embodiments, R7b is aryl, optionally substituted with one or more substituents Q. In n embodiments, R7b is heterocyclyl, optionally substituted with one or more substituents Q.

In certain embodiments, R70 is hydrogen. In n embodiments, R70 is C4_6 alkyl, optionally substituted with one or more substituents Q. In certain ments, R70 is C2_6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R70 is C2_6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R70 is C3_7 cycloalkyl, optionally substituted with one or more substituents Q.

In n embodiments, R70 is €6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R70 is C7_1 5 l, optionally substituted with one or more substituents Q. In certain embodiments, R70 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R70 is cyclyl, optionally substituted with one or more substituents Q.

In certain embodiments, R7b and R70 together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q.

In certain embodiments, L1 is a bond. In certain embodiments, L1 is —O—. In certain ments, L1 is —S—. In n embodiments, L1 is —N(R1A)—, wherein R1A is as defined herein. In certain ments, L1 is —N(R1A)—, wherein R1A is hydrogen or methyl.

In certain embodiments, L1 is —C(R1AR1B)—, wherein R1A and R1B are each as defined herein.

In certain embodiments, L1 is —CH2—.

In certain embodiments, L2 is €3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L2 is €6-14 arylene, optionally substituted with one or more tuents Q. In n embodiments, L2 is €7-15 aralkylene, optionally substituted with one or more tuents Q. In certain embodiments, L2 is heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, L2 is heterocyclylene, optionally substituted with one or more substituents Q.

In certain embodiments, L2 is: "1% ”1% ”‘31, (ES/({()(E/%()RL RL r r (Rig)RrL N N N \ \ \ * * * ’ ’01- wherein: sis an r of0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and RL and r are each as defined herein.

In certain embodiments, L2 is: "we "but "ya ‘ ré ‘ $9 ‘ 13 N N N \ \ \ * * or * 9 9 9 wherein s is as defined .

In certain embodiments, L2 is: "I’LL ‘ E 4N, (RL)r where1n R. L and s are each as defined here1n.. , r, In certain embodiments, L2 is: "74, ( [11> wherein s is as defined .

In certain embodiments, L2 is: tis an integer of0, 1, 2, 3, 4, 5, or 6; and RL and r are each as defined herein.

In certain embodiments, L2 is: HN ‘ wherein t is as defined herein.

In certain embodiments, L2 is: N—>X< (R)rL/\MtJ whereln R. L and t are each as defined here1n.. , r, ] In certain embodiments, L2 is: N—>x< wherein t is as defined herein.

In certain embodiments, Ll—L2 is: ,«w w w: Cw Cw 9 a HN\* /N' NH|— \ \* 171 N\* * a N N [i\N 08; \* es; \* es; \* O O O O O O WO 43148 /N /N /* / O N ,>I< \AN/>x< V\* N/* N N m It "LN is“ 45L %N E 3 Sr?“ 5% d | HN HN a * \>X< \* 9 9 wherein the symbol ents that the 6-membered ring contains one to three N atoms in the ring, and each sulfur is optionally oxidized as sulfoxide or sulfone.

In certain embodiments, Ll-L2 is: s‘\_ f N N ON i ii E is N\* ©\* 1?] ©5q\$ 9 9 * 9 N\ N\* .. m\w ’ , CO 8 Q 9 W “T” a“ *‘N/fi“ *0 X0 K/0 O N\ 9 * In certain ments, T is a bond. In certain embodiments, T is —O—. In certain embodiments, T is —S—. In certain embodiments, T is —N=. In certain embodiments, T is —N(R4)—, wherein R4 is as defined herein. In certain embodiments, T is —C(R4)=, wherein R4 is as defined herein. In certain embodiments, T is —C(R4)2—, wherein R4 is as defined herein.

In certain embodiments, U is a bond. In certain embodiments, U is —O—. In certain embodiments, U is —S—. In certain ments, U is —N=. In certain embodiments, U is —N(R5)—, wherein R5 is as defined . In n embodiments, U is —C(R5)=, wherein R5 is as defined herein. In certain embodiments, U is —C(R5)2—, wherein R5 is as defined herein.

In certain embodiments, V is a bond. In certain embodiments, V is —O—. In n embodiments, V is —S—. In certain embodiments, V is —N=. In n embodiments, V is —N(R6)—, wherein R6 is as defined herein. In certain embodiments, V is —C(R6)=, wherein R6 is as defined herein. In certain embodiments, V is —C(R6)2—, wherein R6 is as defined herein.

In certain embodiments, W is a bond. In certain embodiments, W is —O—. In certain embodiments, W is —S—. In certain embodiments, W is —N=. In certain embodiments, W is —N(R7)—, n R7 is as defined herein. In n embodiments, W is —C(R7)=, wherein R7 is as defined herein. In certain embodiments, W is 2—, wherein R7 is as defined herein.

In certain embodiments, X is C. In certain embodiments, X is N.

In certain embodiments, Y is C. In certain ments, Y is N.

] In certain embodiments, Z is NRZA, wherein R2A is as defined herein. In certain embodiments, Z is NH. In certain embodiments, Z is CRZARZB, wherein R2A and R2B are each as defined herein. In certain embodiments, Z is CH2.

In certain embodiments, m is 0. In certain ments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6. In certain embodiments, m is 7.

In certain embodiments, m is 8. In certain embodiments, m is 9. In certain embodiments, m is 10.

In certain embodiments, n is 0. In n embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain ments, n is 6.

In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain ments, p is 3.

In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3.

In certain embodiments, r is 0. In certain embodiments, r is 1. In certain embodiments, r is 2. In certain embodiments, r is 3. In n embodiments, r is 4. In certain ments, r is 5. In certain ments, r is 6.

] In certain embodiments, u is 0. In certain embodiments, u is 1. In certain embodiments, u is 2. In certain embodiments, u is 3.

In certain embodiments, V is 0. In certain embodiments, V is 1. In certain embodiments, V is 2. In certain embodiments, V is 3.

] In one embodiment, provided herein is a nd selected from the group consisting of: WO 43148 N \ N \>—NH0%/ 0 0 N4; \ /\/O 0 N4, A7 A8 0 N @ N y—NH W5C}0 \/N N ”U O N 0 0 C1 C1 N4: N4; A9 A10 and 3 and isotopic variants thereof; and pharmaceutically able salts, solvates, and prodrugs thereof.

In another embodiment, ed herein is a compound selected from the group consisting of: Blow B2 <E::}>—NH F3COgQ—NHN 0% \ / HNO/OQC“ C1 0% O 0 N N \ N \>_NH / \ @ o g \/N N>—NH / \/\O N \O/\/O CNH NH B7 BS 0 O _N Cl Br NH LNH B9 310 o o _N N @ N \ N \>—NH \>—NH / N N BI‘ \N\ Br \N\ HbNH NH , and 3 Bll BIZ and isotopic variants thereof; and pharmaceutically acceptable salts, es, and prodrugs thereof.

In yet another embodiment, provided herein is a compound selected from the group consisting of: WO 43148 C11 C12 2015/021455 C17 C18 and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

In still another embodiment, provided herein is a compound selected from the group consisting of: 2015/021455 and 0 ; and isotopic ts thereof; and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

The compounds provided herein are intended to encompass all possible stereoisomers, unless a particular stereochemistry is specified. Where the compound ed herein contains an alkenyl or alkenylene group, the compound may exist as one or mixture of geometric cis/trans (or Z/E) isomers. Where structural isomers are onvertible, the compound may exist as a single tautomer or a mixture of tautomers.

This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so-called valence tautomerism in the compound that contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

] For example, the compound of Formula I, when Z is —NH—, may exist in any of the following tautomeric forms as shown below.

U7"\\Y’N sz ’N R2 Uf—RY’N >/'_R2 H\ "I \>—NH ll\ ,1: N |\ 1| \>—N V\~' X\N V\~’_X\N V\~’ X\N LL11} LL11} LL11} R1 R1 R1 (i) (ii) (iii) ] The compounds provided herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, e.g. a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form. Conventional techniques for the preparation/isolation of individual enantiomers e sis from a suitable optically pure sor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric s followed by separation.

When the compound ed herein contains an acidic or basic moiety, it may also be provided as a pharmaceutically acceptable salt. See, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and Handbook ofPharmaceutical Salts, Properties, and Use; Stahl and Wermuth, Ed.; Wiley-VCH and VHCA: Zurich, Switzerland, 2002.

Suitable acids for use in the ation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)- camphorsulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, ic acid, exanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, amic acid, 0L- oxoglutaric acid, ic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (::)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)—L-malic acid, malonic acid, (::)-DL-mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, alene-1,5-disulfonic acid, 1-hydroxynaphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

Suitable bases for use in the preparation of ceutically acceptable salts, including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc ide, or sodium hydroxide; and organic bases, such as y, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, amine, benzathine, choline, deanol, diethanolamine, diethylamine, ylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, amine, 1H—imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, anolamine, trimethylamine, triethylamine, N—methyl-D-glucamine, o(hydroxymethyl)-1,3-propanediol, and tromethamine.

The compound provided herein may also be provided as a g, which is a onal derivative of the compound, for example, of Formula 1, IA, or 1B and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have enhanced solubility in pharmaceutical itions over the parent compound. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See, Harper, Progress in Drug Research 1962, 4, 221-294; Morozowich et al. in Design ofBiopharmaceutical Properties through Prodrugs and Analogs; Roche Ed., APHA Acad. Pharm. Sci.: 1977; r et al., Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Bundgaard, Arch. Pharm. Chem. 2015/021455 1979, 86, 1-39; Farquhar et al., J. Pharm. Sci. 1983, 72, 324-325; Wernuth in Drug Design.‘ Fact or Fantasy; Jolles et al. Eds.; Academic Press: London, 1984; pp 47-72; Design of Prodrugs; Bundgaard et al. Eds.; Elsevier: 1985; Fleisher et al., Methods l. 1985, 112, 360-381; Stella et al., Drugs 1985, 29, 455-473; Bioreversible Carriers in Drug in Drug Design, Theory and Application; Roche Ed.; APHA Acad. Pharm. Sci.: 1987; Bundgaard, Controlled Drug Delivery 1987, 17, ; Waller et al., Br. J. Clin. Pharmac. 1989, 28, 7; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15, 143-53; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Nathwani and Wood, Drugs 1993, 45, 866-94; Friis and ard, Eur. J. Pharm. Sci. 1996, 4, 49-59; er et al., Adv. Drug Delivery Rev. 1996, 19, 115-130; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Gaignault et al., Pract. Med. Chem. 1996, 671-696; Browne, Clin.

Neuropharmacol. 1997, 20, 1-12; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155; Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 6; Mizen et al., Pharm.

Biotech. 1998, 11, 345-365; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39, 63-80; Tan et al., Adv. Drug Delivery Rev. 1999, 39, 1; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209; Wang et al., Curr. Pharm. Design 1999, 5, 265-287; Han et al., AAPS Pharmsci. 2000, 2, l-l l; Asgharnejad in Transport Processes in Pharmaceutical Systems; Amidon et al., Eds.; Marcell Dekker: 2000; pp 185-218; Sinha et al., Pharm. Res. 2001, 18, 557-564; Anand et al., Expert Opin. Biol. Ther. 2002, 2, 0; Rao, Resonace 2003, 19-27; Sloan et al., Med. Res. Rev. 2003, 23, 763-793; Patterson et al., Curr. Pharm.

Des. 2003, 9, 2131-2154; Hu, [Drugs 2004, 7, 736-742; Robinson et al., Proc. Natl. Acad. Sci.

USA. 2004, 101, 14532; Erion et al., J. Pharmacol. Exp. Ther. 2005, 312, 554-560; Fang et al., Curr. Drug Discov. Technol. 2006, 3, 211-224; Stanczak et al., Pharmacol. Rep. 2006, 58, 599-613; Sloan et al., Pharm. Res. 2006, 23, 2729-2747; Stella et al., Adv. Drug Deliv. Rev. 2007, 59, 677-694; Gomes et al., Molecules 2007, 12, 2484-2506; Krafz et al., dChem 2008, 3, 20-53; Rautio et al., AAPSJ. 2008, 10, 92-102; Rautio et al., Nat.

Rev. Drug. Discov. 2008, 7, 255-270; Pavan et al., Molecules, 2008, 13, 1035-1065; Sandros et al., Molecules 2008, 13, 1156-1178; Singh et al., Curr. Med. Chem. 2008, 15, 1802-1826; Onishi et al., Molecules, 2008, 13, 2136-2155; Huttunen et al., Curr. Med. Chem. 2008, 15, 2346-2365; and Serafin et al., Mini Rev. Med. Chem. 2009, 9, 481-497.

Methods of Synthesis The compounds provided herein can be prepared, isolated, or obtained by any method known to one of skill in the art. For an example, a nd of Formula I can be prepared as shown in Scheme 1.

Scheme 1 L1~L2 UF~?Y’N02 1-2 FT? ’N02 UFT‘TY’NHZ I1\ I‘ll —> H‘ ’II —> '1‘ "1| V\~v X\X1 V\ X\I\{H V\§i] X‘NH L $121 L if1 1—3 R 1—4 R1 A ,N RZCOOH 41 ,N R2 U’ \Y UI —> \ \Y 11‘“; I >—ZH —> |1\ \ 1.. >—Z V\ .X\N V\~' X\N ‘ ‘ L ~L21 L —L21 \ \ R1 R1 1—5 1 Compound 1-1 is treated with nucleophilic amine 1-2 to form compound 1-3, wherein X1 is a leaving group, including, but not limited to fluoro, chloro, bromo, methoxy, ethoxy, and nitro. The nitro group of compound 1-3 is reduced with a reducing agent, e.g., zinc, FeC12,NiC12, or Na2S203, to form nd 1-4. The reduction can also be accomplished via hydrogenation using, e.g, ammonium formate or hydrogen in the ce of Pd/C. Compound 1-5 is then cyclized to form compound 1-5 with the Z group led simultaneously. When Z is NH, compound 1-5 is then coupled with an acid (RZCOOH) using a coupling reagent, e.g., HATU, HBTU, , PyBOP, or EDCI, to form compound of Formula 1.

Pharmaceutical Compositions Provided herein are pharmaceutical compositions comprising a compound provided herein, e.g., a compound of Formula I or XXI, as an active ient, including a single enantiomer, a racemic e, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically able vehicle, carrier, diluent, or excipient, or a mixture thereof. le excipients are well known to those skilled in the art, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the method of administration. For example, oral dosage forms such as tablets may n excipients not suited for use in eral dosage forms. The suitability of a particular ent may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines are particularly susceptible to such accelerated decomposition. Consequently, provided herein are pharmaceutical compositions and dosage forms that contain little, if any, lactose, or other mono- or di-saccharides. As used herein, the term “lactose-free” means that the amount of lactose present, if any, is insufficient to ntially se the degradation rate of an active ingredient.

The compound provided herein may be administered alone, or in combination with one or more other compounds provided herein. The pharmaceutical compositions that comprise a compound ed herein, e.g., a compound of Formula I or XXI, or a single enantiomer, a racemic e, a mixture of diastereomers, or an isotopic variant thereof; or a ceutically able salt, solvate, or g thereof, can be formulated in various dosage forms for oral, parenteral, and topical administration. The pharmaceutical itions can also be formulated as modified e dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-release, and c retention dosage forms. These dosage forms can be prepared ing to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice ofPharmacy, supra; Modified-Release Drug Delivery Technology, 2nd ed.; ne et al., Eds.; Marcel Dekker, Inc.: New York, NY, 2008).

In one embodiment, the pharmaceutical compositions are provided in a dosage form for oral administration, which comprise a compound provided herein, e.g., a compound of Formula I or XXI, or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable salt, solvate, or prodrug thereof 2015/021455 In another embodiment, the pharmaceutical compositions are provided in a dosage form for parenteral administration, which comprise a compound provided herein, e.g., a compound of Formula I or XXI, or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant f; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In yet another embodiment, the pharmaceutical compositions are ed in a dosage form for topical administration, which se a compound provided herein, e.g., a nd of Formula I or XXI, or a single enantiomer, a c e, a mixture of diastereomers, or an ic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable salt, solvate, or prodrug thereof.

The pharmaceutical compositions provided herein can be provided in a unit- dosage form or multiple-dosage form. A unit-dosage form, as used herein, refers to physically discrete a unit le for administration to a human and animal subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of a unitdosage form include an ampoule, syringe, and individually packaged tablet and capsule. For example, a 100 mg unit dose ns about 100 mg of an active ingredient in a packaged tablet or capsule. A unit-dosage form may be administered in fractions or multiples thereof A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of a multiple-dosage form include a vial, bottle of tablets or capsules, or bottle of pints or gallons.

The ceutical compositions provided herein can be administered at once, or le times at intervals of time. It is tood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage ns should be adjusted over time ing to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.

A. Oral Administration The ceutical compositions provided herein for oral stration can be provided in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration.

Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, es, pastilles, cachets, pellets, medicated g gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, sions, , les, elixirs, and syrups. In addition to the active ient(s), the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, ning agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.

Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators e, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); n; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered anth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose ; microcrystalline celluloses, such as AVICEL-PH- l 0 l, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-lOS (FMC Corp., Marcus Hook, PA); and mixtures thereof Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre- gelatinized starch, and es thereof. The amount of a binder or filler in the ceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ry skill in the art. The binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, , mannitol, sodium chloride, dry starch, and powdered sugar. n diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets. The amount of a diluent in the pharmaceutical itions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.

Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; m carbonate; microcrystalline cellulose, such as sodium starch ate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof. The amount of a disintegrant in the pharmaceutical compositions ed herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical compositions ed herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; l oil; light l oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co. of Boston, MA); and mixtures thereof. The pharmaceutical compositions ed herein may contain about 0.1 to about 5% by weight of a lubricant.

Suitable glidants include, but are not limited to, dal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, MA), and os-free talc. Suitable coloring agents include, but are not limited to, any of the approved, certif1ed, water soluble FD&C dyes, and water ble FD&C dyes suspended on alumina e, and color lakes and mixtures 2015/021455 thereof. A color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, ing in an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which e a pleasant taste sensation, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan eate 80 (TWEEN® 80), and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, anth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and yethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Suitable non-aqueous s utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids e, but are not d to, citric and tartaric acid. le sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

It should be tood that many carriers and ents may serve a plurality of ons, even within the same ation.

The pharmaceutical compositions provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with nces that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic nment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up ionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, hylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.

The tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients bed herein, ing binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.

The pharmaceutical compositions ed herein for oral stration can be provided as soft or hard capsules, which can be made from n, cellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC), consists of two sections, one slipping over the other, thus tely enclosing the active ingredient. The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be ulated in a capsule. Suitable liquid and semisolid dosage forms include ons and suspensions in propylene carbonate, vegetable oils, or triglycerides. es containing such solutions can be prepared as bed in US. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.

The pharmaceutical compositions provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which one liquid is dispersed in the form of small es throughout another liquid, which can be -water or water-in-oil. Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative. Suspensions may include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic ons may include a pharmaceutically acceptable , such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl ; and a miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.

Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ient(s) provided , and a dialkylated mono- or poly- alkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme, lyme, polyethylene glycoldimethyl ether, polyethylene glycoldimethyl ether, hylene glycoldimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene . These formulations can r comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as bed in US. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein for oral stration can be provided as non-effervescent or effervescent, granules and s, to be tituted into a liquid dosage form. Pharmaceutically acceptable carriers and ents used in the non-effervescent granules or powders may include diluents, sweeteners, and g agents.

Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosage forms.

The pharmaceutical compositions provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.

B. Parenteral Administration ] The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration.

Parenteral administration, as used herein, include intravenous, rterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous stration.

The pharmaceutical compositions provided herein for parenteral stration can be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, pheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see, Remington: The Science and Practice ofPharmacy, supra).

The pharmaceutical itions intended for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not d to, s vehicles, miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, ic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting , and inert gases.

Suitable aqueous vehicles include, but are not d to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers ion, isotonic dextrose injection, sterile water ion, dextrose and lactated Ringers injection. Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, tanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N- methylpyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl l, chlorobutanol, methyl and propyl p- hydroxybenzoates, thimerosal, benzalkonium chloride (6.g. , honium chloride), methyl- and propyl-parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. le ing agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are those as described herein, including te and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable ding and dispersing agents are those as described herein, including sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents are those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan eate 80, and anolamine oleate. Suitable sequestering or chelating agents include, but are not limited to EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including lodextrin, B-cyclodextrin, hydroxypropyl-B- cyclodextrin, utylether-B-cyclodextrin, and sulfobutylether 7-B-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).

When the pharmaceutical compositions provided herein are formulated for multiple dosage administration, the le dosage parenteral formulations must n an antimicrobial agent at bacteriostatic or fiangistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.

] In one embodiment, the pharmaceutical compositions for eral administration are provided as ready-to-use sterile solutions. In another embodiment, the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be tituted with a vehicle prior to use.

In yet another embodiment, the pharmaceutical compositions are provided as ready-to-use sterile suspensions. In yet another embodiment, the pharmaceutical itions are provided as sterile dry insoluble products to be tituted with a vehicle prior to use. In still another embodiment, the pharmaceutical compositions are provided as ready-to-use sterile emulsions.

The pharmaceutical compositions provided herein for parenteral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, ed-, and programmed-release forms.

The pharmaceutical compositions provided herein for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic , for administration as an implanted depot. In one embodiment, the ceutical compositions provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the ceutical compositions diffilse through.

Suitable inner matrixes include, but are not limited to, polymethylmethacrylate, polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, obutylene, polybutadiene, polyethylene, ethylene-vinyl acetate mers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

] Suitable outer polymeric membranes include but are not limited to, polyethylene, polypropylene, ne/propylene copolymers, ethylene/ethyl acrylate mers, ethylene/vinyl acetate mers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and ene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl l copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.

C. Topical Administration The ceutical compositions provided herein can be administered topically to the skin, orifices, or mucosa. The topical administration, as used herein, includes (intra)dermal, conjunctival, intracomeal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal stration.

The ceutical compositions provided herein can be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointrnents, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches. The topical formulation of the ceutical compositions provided herein can also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use in the topical ations provided herein e, but are not limited to, s es, water- miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of rganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, idants, local anesthetics, suspending and dispersing agents, g or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical itions can also be administered topically by oporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECTTM (Chiron Corp., Emeryville, CA), and BIOJECTTM (Bioject Medical Technologies Inc., Tualatin, OR).

The pharmaceutical compositions ed herein can be provided in the forms of ointments, creams, and gels. Suitable ointment vehicles include oleaginous or hydrocarbon es, including lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsif1able or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable es, such as hydrophilic ointment; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, including cetyl alcohol, yl monostearate, lanolin, and stearic acid (see, Remington: The e and Practice ofPharmacy, supra). These vehicles are emollient but generally require addition of antioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Suitable cream vehicles may be water-washable, and contain an oil phase, an fier, and an aqueous phase. The oil phase is also called the "internal" phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in , and generally contains a humectant. The emulsifier in a cream formulation may be a ic, anionic, cationic, or amphoteric surfactant. 2015/021455 Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier.

Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and OL®; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl ose, hydroxyethyl cellulose, ypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and n gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.

The pharmaceutical compositions provided herein can be administered rectally, ally, vaginally, or ginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, ons, suspensions, tampons, gels, foams, sprays, or .

These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body ature to release the active ingredient(s) inside the orifices. Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which e a melting point in the ity of body temperature, when formulated with the pharmaceutical compositions provided herein; and antioxidants as described herein, including bisulfite and sodium sulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, and els, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid;. Combinations of the various vehicles can also be used.

Rectal and vaginal suppositories may be prepared by compressing or molding. The l weight of a rectal and vaginal suppository is about 2 to about 3 g. [0023 9] The pharmaceutical compositions provided herein can be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, s for solutions, gels, ocular inserts, and implants.

The ceutical compositions provided herein can be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical compositions can be provided in the form of an l or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as l, l ,l,2- tetrafluoroethane or l,l,l,2,3,3,3-heptafluoropropane. The pharmaceutical compositions can also be ed as a dry powder for insufflation, alone or in combination with an inert r such as e or phospholipids; and nasal drops. For intranasal use, the powder can comprise a bioadhesive agent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient provided herein; a propellant as solvent; and/or a tant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

The ceutical compositions provided herein can be micronized to a size suitable for ry by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such sizes can be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form rticles, high pressure homogenization, or spray drying.

Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as [- leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, l, fructose, sucrose, and trehalose. The pharmaceutical compositions provided herein for inhaled/intranasal administration can further se a le flavor, such as menthol and levomenthol; and/or sweeteners, such as saccharin and saccharin sodium.

The pharmaceutical itions provided herein for topical stration can be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and mmed release. -lOl- 2015/021455 D. Modified Release The pharmaceutical compositions provided herein can be formulated as a modified release dosage form. As used herein, the term “modified release” refers to a dosage form in which the rate or place of release of the active ingredient(s) is ent from that of an ate dosage form when administered by the same route. Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, ned-, pulsatile-, controlled-, accelerated- and fast-, targeted-, mmed-release, and gastric retention dosage forms. The pharmaceutical compositions in modified e dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic lled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric gs, multilayered coatings, microspheres, liposomes, and ations thereof. The release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphorism of the active ingredient(s).

Examples ofmodified release include, but are not limited to, those bed in US. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 533; ,059,595; 767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; ,739,108; 5,891,474; 356; 5,958,458; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,270,798; 6,375,987; 6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,623,756; 6,699,500; 6,793,936; 6,827,947; 6,902,742; 6,958,161; 7,255,876; 7,416,738; 414; 322; Bussemer et al., Crit.

Rev. Ther. Drug Carrier Syst. 2001, 18, 433-458; Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et al., Eds.; Marcel Dekker AG: 2005; Maroni et al., Expert.

Opin. Drug Deliv. 2005, 2, 855-871; Shi et al., Expert Opin. Drug Deliv. 2005, 2, 1039-1058; Polymers in Drug Delivery; Ijeoma et al., Eds.; CRC Press LLC: Boca Raton, FL, 2006; Badawy et al., J. Pharm. Sci. 2007, 9, 948-959; Modified-Release Drug Delivery Technology, supra; Conway, Recent Pat. Drug Deliv. Formul. 2008, 2, 1-8; Gazzaniga et al., Eur. J.

Pharm. Biopharm. 2008, 68, 11-18; Nagarwal et al., Curr. Drug Deliv. 2008, 5, 282-289; Gallardo et al., Pharm. Dev. l. 2008, 13, 413-423; Chrzanowski, AAPS PharmSciTech. 2008, 9, 635-638; Chrzanowski, AAPS PharmSciTech. 2008, 9, 639-645; Kalantzi et al., Recent Pat. Drug Deliv. Formul. 2009, 3, 49-63; Saigal et al., Recent Pat.

Drug Deliv. Formul. 2009, 3, 64-70; and Roy et al., J. Control Release 2009, 134, 74-80. 1. Matrix Controlled Release Devices The pharmaceutical compositions provided herein in a modified release dosage form can be fabricated using a matrix controlled release device known to those skilled in the art. See, Takada et al. in Encyclopedia ofControlled Drug Delivery; Mathiowitz Ed.; Wiley: 1999; Vol 2.

In certain embodiments, the pharmaceutical compositions provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and ns.

Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, n gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic ds, such as ; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, yethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose nate (CP), cellulose te (CB), cellulose acetate butyrate (CAB), CAP, CAT, ypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or rylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); -hydroxyethyl-methacrylate); polylactides; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acidglycolic acid copolymers; poly-D-(-)hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and mers of butylmethacrylate, methyl methacrylate, ethyl rylate, ethylacrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate de.

In certain embodiments, the pharmaceutical compositions provided herein are formulated with a non-erodible matrix device. The active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffilsion through the inert matrix once administered. als suitable for use as a odible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, obutylene, tadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl rylate copolymers, ethylene- vinyl acetate copolymers, ethylene/propylene copolymers, ne/ethyl te copolymers, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubbers, epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol ymer, ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, ne rubbers, polydimethylsiloxanes, and silicone carbonate copolymers; hydrophilic polymers, such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds, such as camauba wax, microcrystalline wax, and triglycerides. [0025 1] In a matrix controlled release system, the desired release kinetics can be controlled, for example, via the polymer type employed, the r viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other ents or carriers in the compositions.

The pharmaceutical compositions ed herein in a modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet ation followed by compression, and melt-granulation followed by compression. 2. Osmotic Controlled Release Devices The pharmaceutical compositions provided herein in a ed release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric ne technology (AMT), and extruding core system (ECS). In l, such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core. The semipermeable membrane controls the influx of water to the core from an s environment of use so as to cause drug release by extrusion through the delivery port(s).

] In addition to the active ingredient(s), the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water —104— from the environment of use into the core of the device. One class of osmotic agents is water-swellable hydrophilic polymers, which are also referred to as “osmopolymers” and “hydrogels.” Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and c polymers, polysaccharides such as calcium alginate, hylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), -hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP mers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, eenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating. le osmogens include, but are not limited to, inorganic salts, such as magnesium e, magnesium chloride, calcium chloride, sodium chloride, m chloride, ium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, ol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fiJmaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures f. c agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form. For example, amorphous sugars, such as MANNOGEMTM EZ (SPI Pharma, Lewes, DE) can be used to provide faster ry during the first couple of hours to ly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.

The core can also include a wide variety of other excipients and carriers as described herein to enhance the mance of the dosage form or to promote stability or sing.

Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are permeable and water-insoluble at logically nt pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking. Examples of suitable polymers useful in forming the coating, include cized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl ate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG mers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly- (methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, hersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

] Semipermeable membrane can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in US. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, nyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

The delivery ) on the semipermeable membrane can be formed post- coating by mechanical or laser drilling. ry port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In on, delivery ports can be formed during g process, as in the case of asymmetric ne coatings of the type disclosed in US. Pat. Nos. ,612,059 and 5,698,220.

WO 43148 The total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.

The pharmaceutical itions in an osmotic controlled-release dosage form can fiarther comprise onal tional excipients or carriers as described herein to promote performance or sing of the formulation.

The c controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, Remington: The Science and Practice ofPharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35, l-2l; Verma et al. , Drug Development and Industrial Pharmacy 2000, 26, 8; and Verma et al., J. Controlled Release 2002, 79, 7-27.

] In certain embodiments, the pharmaceutical compositions provided herein are formulated as AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core sing the active ingredient(s) and other pharmaceutically acceptable excipients or carriers. See, US. Pat. No. 5,612,059 and International Pat. Appl.

Publ. No. . The AMT controlled-release dosage forms can be prepared according to tional s and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.

In certain embodiments, the pharmaceutical itions provided herein are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxylethyl cellulose, and other ceutically acceptable excipients or carriers. 3. Multiparticulate Controlled Release Devices The pharmaceutical compositions provided herein in a modified release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 um to about 3 mm, about 50 um to about 2.5 mm, or from about 100 um to about 1 mm in diameter. Such multiparticulates can be made by the processes known to those skilled in the art, including wet-and dry-granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, for example, Multiparticulate Oral Drug Delivery; Ghebre- Sellassie Ed.; Marcel Dekker: 1994; and Pharmaceutical Pelletz'zatz'on Technology; Ghebre- sie Ed.; Marcel Dekker: 1989.

Other excipients or carriers as described herein can be blended with the pharmaceutical compositions to aid in processing and forming the multiparticulates. The resulting particles can themselves constitute the multiparticulate device or can be coated by various film-forming als, such as enteric rs, water-swellable, and water-soluble polymers. The multiparticulates can be r processed as a capsule or a tablet. 4. Targeted Delivery The pharmaceutical compositions provided herein can also be formulated to be targeted to a particular tissue, or, or other area of the body of the subject to be treated, including liposome-, resealed ocyte-, and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in US. Pat. Nos. 5,709,874; 5,759,542; ,840,674; 5,900,252; 5,972,366; 5,985,307; 6,004,534; 6,039,975; 6,048,736; 6,060,082; 6,071,495; 6,120,751; 6,131,570; 6,139,865; 6,253,872; 6,271,359; 6,274,552; 6,316,652; and 7,169,410.

Methods ofUse In one embodiment, provided herein is a method for treating, preventing, or ameliorating one or more symptoms of an ERBB-mediated condition, disorder, or disease in a t, comprising administering to the t a compound disclosed herein, e.g, a compound of Formula I or XXI, or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or g thereof.

In certain embodiments, the ERBB is a Wild-type ERBB. In certain ments, the ERBB is an ERBB variant.

In certain ments, the ERBB is an EGFR. In certain embodiments, the ERBB is a wild-type EGFR. In certain embodiments, the ERBB is an EGFR t. In certain embodiments, the EGFR variant contains a deletion, insertion, or substitution. In certain embodiments, the EGFR t contains one or more deletions, insertions, or substitutions at the amino acid ons of 689, 700, 709, 715, 719, 720, 746-759, 761-765, 767-775, 783, 784, 790, 796, 826, 839, 846, 858, 861, and 863. In certain embodiments, the EGFR variant contains one, two, or more deletions, insertions, and/or substitutions, each independently selected from V689M, N700D, E709K, E709Q, E709V, E709A, E709G, I715S, G7l9C, G719S, G719A, S720P, AE746-A750, AE746-T751, AE746-A750 (ins RP), AE746-T751 (ins A/I), AE746-T751 (ins VA), AE746-S752 (ins A/V), L747S, AL747-E749 (A750P), AL747-A750 (ins P), T751, T751 (ins P/S), AL747-S752, AL747- 752 (E746V), AL747-752 (P753S), AL747-S752 (ins Q), AL747-P753, AL747-P753 (ins S), AS752-I759, D76lY, AD761-E762 (ins EAFQ), AA763-Y764 (ins FQEA), V765A, AM766- A767 (ins AI), AA767-S768 (ins TLA), S768 (ins SVA), S7681, D770 (dup SVD), V769L, AV769-D770 (ins ASV), AD770-N771 (ins NPG), AD770-N771 (ins SVQ), AD770-N771 (ins SVD), AD770-N771 (ins G), AD770-P772 (ins ASV),N771T, AP772- H773 (ins PR), AP772-H773 (ins YNP), AH773-V774 (ins NPH), AH773-V774 (ins NP), AH773-V774 (ins H), AH773-V774 (ins PH), AH773-V774 (ins GNPH), AV774-C775 (ins HV), H775Y, P782R, T783A, T784A, T790M, G796A, N826S, A839T, K846R, L858R, L86lQ, and G863D, provided that there is only one deletion and/or insertion, or substitution at a given amino acid position in the EGFR variant. In certain embodiments, the EGFR variant contains one, two, or more deletions, ions, and/or substitutions, each ndently selected from G7l9C, G719S. G719A, AE746-A750, AE746-T751, AE746- A750 (ins RP), T790M, and L85 8R. In certain embodiments, the EGFR variant contains T790M and/or L85 8R. In n embodiments, the EGFR variant contains one, two, or more deletions, insertions, and/or substitutions, each independently selected from AD761-E762 (ins EAFQ), AS768-D770 (dup SVD), AV769-D770 (ins ASV), AD770-N771 (ins SVQ), AP772- H773 (ins PR), AH773-V774 (ins NPH), AH773-V774 (ins H), AH773-V774 (ins PH), and AH773-V774 (ins GNPH). In certain embodiments, the EGFR t contains a on, insertion, or substitution in exon 19. In certain embodiments, the EGFR variant contains a deletion, insertion, or substitution in exon 20.

In certain embodiments, the ERBB is a HER2. In certain embodiments, the ERBB is a wild-type HER2. In certain embodiments, the ERBB is a HER2 variant. In certain embodiments, the HER2 variant contains a on, ion, or substitution. In certain embodiments, the HER2 variant contains one or more deletions, insertions, or substitutions at the amino acid positions of 309, 310, 630, 717, 719, 726, 733, 755-759, 767, 769, 775-778, 780, 781, 783, 785, 798, 803, 812, 821, 835, 839, 842, 896, and 915. In certain embodiments, the HER2 variant contains one, two, or more deletions, insertions, and/or substitutions, each independently selected from G309A, G309E, S310F, C630Y, E717K, E719G, E719K, L726F, T7331, L755S, L755W, AL755-T759, I767M, D769H, D769Y, AA775-G776 (ins YVMA), , G776LC, AV777-G778 (ins CG), V777L, P780L, AP780-Y781 (ins GSP), S783P, L785F, T7981, Y803N, E812K, D821N, Y835F, V839G, V842I, R896C, and L915M, provided that there is only one deletion and/or insertion, or substitution at a given amino acid position in the HER2 variant. In certain ments, the HER2 t contains one, two, or more deletions, insertions, and/or substitutions, each independently selected from G309A, L755S, AL755-T759, AA775-G776 (ins YVMA), V777L, AP780-Y781 (ins GSP), V8421, and R896C.

In certain embodiments, the ERBB is a HER3. In certain ments, the ERBB is a wild-type HER3. In certain embodiments, the ERBB is a HER3 variant. In certain embodiments, the HER3 variant contains a deletion, insertion, or substitution.

] In certain embodiments, the ERBB is a HER4. In certain embodiments, the ERBB is a wild-type HER4. In certain embodiments, the ERBB is a HER4 variant. In certain embodiments, the HER4 t contains a on, insertion, or substitution.

In certain embodiments, the ERBB is a dimer. In n ments, the ERBB is a homodimer. In certain embodiments, the ERBB is a heterodimer. In certain embodiments, the ERBB is a heterodimer of EGFR, HER2, HER3, HER4, and variants thereof.

] In certain embodiments, the compound provided herein is a selective inhibitor of a mutant ERBB. In certain embodiments, the compound provided herein has a selectivity against a mutant ERBB over a Wild-type ERBB ranging from about 2 fold, about 4 fold, about 8 fold, about 20 fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, or about 1000 fold.

In certain ments, the compound provided herein is a selective inhibitor of a mutant EGFR. In certain embodiments, the compound provided herein has a selectivity against a mutant EGFR over a wild-type EGFR ranging from about 2 fold, about 4 fold, about 8 fold, about 20 fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, or about 1000 fold.

In certain embodiments, the compound provided herein is a selective inhibitor of a mutant HER2. In certain embodiments, the compound provided herein has a selectivity against a mutant HER2 over a wild-type HER2 ranging from about 2 fold, about 4 fold, about 8 fold, about 20 fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, or about 1000 fold.

In certain embodiments, the nd ed herein is a selective inhibitor of a mutant HER3. In certain embodiments, the compound provided herein has a selectivity against a mutant HER3 over a wild-type HER3 ranging from about 2 fold, about 4 fold, about 8 fold, about 20 fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, or about 1000 fold.

In certain ments, the compound provided herein is a selective inhibitor of a mutant HER4. In certain ments, the compound provided herein has a selectivity against a mutant HER4 over a Wild HER4 ranging from about 2 fold, about 4 fold, about 8 fold, about 20 fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, or about 1000 fold.

In another embodiments, ed herein is a method for treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula I or XXI, or an enantiomer, a mixture of enantiomers, a e of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

] In certain embodiments, the subject is a . In certain embodiments, the subject is a human. In certain embodiments, the subject is a primate other than a human, a farm animal such as cattle, a sport animal, or a pet such as a horse, dog, or cat.

In certain embodiments, the ERBB-mediated condition, er, or disease is a proliferative disease. In certain embodiments, the ERBB-mediated condition, disorder, or disease is cancer. In certain embodiments, the ediated ion, disorder, or disease is a drug-resistant cancer. In certain embodiments, the ERBB-mediated condition, disorder, or disease is rug-resistant cancer. In certain embodiments, the ERBB- mediated condition, disorder, or disease is relapsed rug-resistant cancer. In certain embodiments, the ERBB-mediated condition, disorder, or disease is an inflammatory disease.

In certain embodiments, the ERBB-mediated condition, disorder, or disease is an immune -lll- disorder.

In certain embodiments, the erative disease is cancer. In certain ments, the cancer is relapsed . In certain embodiments, the cancer is drug- resistant cancer. In certain embodiments, the cancer is relapsed esistant cancer. In certain embodiments, the cancer is multidrug-resistant cancer. In certain embodiments, the cancer is ed multidrug-resistant cancer.

In certain embodiments, the cancer is ERBB inhibitor- resistant cancer. In certain embodiments, the cancer is reversible ERBB tor— resistant cancer. In certain embodiments, the cancer is irreversible ERBB tor- resistant cancer. In certain embodiments, the cancer is relapsed ERBB inhibitor- resistant . In certain embodiments, the cancer is relapsed reversible ERBB inhibitor- resistant cancer. In certain embodiments, the cancer is relapsed irreversible ERBB tor- resistant cancer. In certain embodiments, the cancer is resistant to afatinib, canertinib, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, neratinib, pelitinib, varlitinib, or a combination thereof.

In certain embodiments, the cancer is EGFR inhibitor- resistant cancer. In n embodiments, the cancer is reversible EGFR inhibitor— resistant cancer. In certain embodiments, the cancer is irreversible EGFR inhibitor- resistant cancer. In certain embodiments, the cancer is relapsed EGFR inhibitor— resistant cancer. In certain embodiments, the cancer is relapsed reversible EGFR inhibitor- ant cancer. In certain embodiments, the cancer is relapsed irreversible EGFR inhibitor— resistant .

In certain ments, the cancer is HER2 inhibitor- resistant cancer. In certain embodiments, the cancer is reversible HER2 tor- resistant cancer. In certain ments, the cancer is irreversible HER2 inhibitor— resistant cancer. In certain embodiments, the cancer is relapsed HER2 inhibitor- resistant . In certain embodiments, the cancer is relapsed reversible HER2 inhibitor- resistant cancer. In certain embodiments, the cancer is relapsed irreversible HER2 tor- resistant cancer.

In certain embodiments, the cancer is HER3 inhibitor- resistant cancer. In certain embodiments, the cancer is ible HER3 inhibitor- resistant cancer. In certain embodiments, the cancer is irreversible HER3 inhibitor— resistant cancer. In certain embodiments, the cancer is relapsed HER3 inhibitor- resistant cancer. In certain embodiments, the cancer is relapsed reversible HER3 inhibitor- resistant cancer. In certain -ll2- embodiments, the cancer is relapsed irreversible HER3 inhibitor- resistant cancer.

In certain embodiments, the cancer is HER4 inhibitor- resistant . In certain embodiments, the cancer is reversible HER4 inhibitor- resistant cancer. In certain embodiments, the cancer is irreversible HER4 inhibitor— resistant cancer. In certain embodiments, the cancer is relapsed HER4 tor- resistant cancer. In n embodiments, the cancer is ed reversible HER4 inhibitor- resistant cancer. In certain embodiments, the cancer is relapsed irreversible HER4 inhibitor- ant cancer.

In certain embodiments, the proliferative disease is an inflammatory disease.

In certain ments, the proliferative disease is an immune disorder.

The conditions, disorders, or diseases treatable with a compound provided herein include, but are not limited to, (l) inflammatory or allergic diseases, including systemic anaphylaxis and hypersensitivity disorders, atopic dermatitis, urticaria, drug allergies, insect sting allergies, food allergies (including celiac disease and the like), and mastocytosis; (2) atory bowel diseases, including Crohn's e, ulcerative colitis, ileitis, and enteritis; (3) vasculitis, and Behcet's syndrome; (4) psoriasis and inflammatory dermatoses, including dermatitis, eczema, atopic itis, allergic contact dermatitis, urticaria, viral cutaneous pathologies including those derived from human papillomavirus, HIV or RLV infection, bacterial, flugal, and other parasital cutaneous pathologies, and cutaneous lupus matosus; (5) asthma and respiratory allergic diseases, including ic asthma, exercise induced asthma, allergic rhinitis, otitis media, allergic conjunctivitis, hypersensitivity lung diseases, and chronic obstructive pulmonary disease; (6) mune diseases, including arthritis (including rheumatoid and psoriatic), systemic lupus matosus, type I diabetes, myasthenia gravis, multiple sclerosis, ' disease, and glomerulonephritis; (7) graft rejection (including allograft ion and graft-v-host disease), e.g., skin graft rejection, solid organ transplant rejection, bone marrow transplant rejection; (8) fever; (9) cardiovascular disorders, including acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, ry artery disease, restenosis, and vascular stenosis; (10) cerebrovascular disorders, including traumatic brain injury, , ischemic reperfiasion injury and aneurysm; (11) cancers of the breast, skin, prostate, , uterus, ovary, testes, r, lung, liver, larynx, oral cavity, colon and gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain, thyroid, blood, and lymphatic system; (12) f1brosis, connective -ll3- 2015/021455 tissue disease, and sarcoidosis, (13) genital and reproductive conditions, including erectile dysfunction; (14) gastrointestinal disorders, including gastritis, ulcers, nausea, pancreatitis, and ng; (15) neurologic disorders, including Alzheimer's disease; (16) sleep ers, including insomnia, narcolepsy, sleep apnea syndrome, and Pickwick Syndrome; (17) pain; (18) renal disorders; (19) ocular disorders, including glaucoma,; and (20) infectious diseases, including HIV.

In n ments, the cancer treatable with a nd provided herein includes, but is not limited to, (1) leukemias, including, but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, locytic, myelomonocytic, monocytic, oleukemia leukemias and myelodysplastic syndrome or a symptom thereof (such as , thrombocytopenia, neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), preleukemia, and chronic myelomonocytic leukemia (CMML), (2) chronic leukemias, including, but not d to, c myelocytic locytic) leukemia, chronic lymphocytic leukemia, and hairy cell leukemia; (3) polycythemia vera; (4) lymphomas, including, but not limited to, Hodgkin's disease and non-Hodgkin's disease; (5) multiple myelomas, including, but not limited to, smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary cytoma, and extramedullary plasmacytoma; (6) Waldenstrom's macroglobulinemia; (7) monoclonal gammopathy of rmined significance; (8) benign monoclonal gammopathy; (9) heavy chain disease; (10) bone and connective tissue sarcomas, including, but not limited to, bone sarcoma, osteosarcoma, chondrosarcoma, s sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue as, angiosarcoma (hemangiosarcoma), f1brosarcoma, Kaposi’s sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; (11) brain tumors, including, but not limited to, glioma, ytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; (12) breast cancer, including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, ary breast , primary cancers, Paget’s disease, and inflammatory breast cancer; (13) adrenal cancer, including, but not limited to, romocytom and adrenocortical carcinoma; (14) thyroid cancer, —114— including, but not limited to, papillary or follicular thyroid cancer, medullary thyroid cancer, and anaplastic d cancer; (15) pancreatic cancer, including, but not d to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; (16) pituitary cancer, including, but limited to, Cushing’s disease, prolactin-secreting tumor, acromegaly, and diabetes insipius; (l7) eye cancer, including, but not limited, to ocular melanoma such as iris melanoma, choroidal melanoma, and ry body ma, and retinoblastoma; (l 8) vaginal cancer, including, but not limited to, us cell carcinoma, adenocarcinoma, and melanoma; (l9) vulvar cancer, including, but not limited to, squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget’s disease; (20) cervical cancers, including, but not limited to, squamous cell oma, and adenocarcinoma; (21) uterine cancer, including, but not limited to, endometrial carcinoma and uterine sarcoma; (22) ovarian cancer, including, but not limited to, n epithelial carcinoma, borderline tumor, germ cell tumor, and l tumor; (23) esophageal cancer, including, but not d to, squamous cancer, arcinoma, d cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; (24) stomach cancer, including, but not limited to, adenocarcinoma, fiangating (polypoid), ulcerating, superficial spreading, diffusely spreading, ant lymphoma, liposarcoma, f1brosarcoma, and carcinosarcoma; (25) colon cancer; (26) rectal cancer; (27) liver cancer, including, but not limited to, hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer but not limited to, adenocarcinoma; (29) cholangiocarcinomas, including, , including, but not limited to, pappillary, nodular, and e; (30) lung cancer, including, but not limited to, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma, and small-cell lung cancer; (3 l) testicular cancer, including, but not limited to, germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal oma, teratoma carcinoma, and choriocarcinoma (yolk-sac tumor); (32) te cancer, including, but not limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; (33) penal cancer; (34) oral cancer, ing, but not limited to, squamous cell oma; (35) basal cancer; (36) salivary gland cancer, including, but not limited to, adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; (37) pharynx cancer, ing, but not limited to, squamous cell cancer and verrucous; (38) skin cancer, including, but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo ant melanoma, and acral lentiginous melanoma; (3 9) -ll5- WO 43148 kidney , including, but not limited to, renal cell cancer, adenocarcinoma, hypemephroma, fibrosarcoma, and transitional cell cancer (renal pelvis and/or ); (40) Wilms’ tumor; (41) bladder cancer, including, but not limited to, transitional cell oma, squamous cell cancer, adenocarcinoma, and carcinosarcoma; and other , including, not limited to, myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangio- endotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, lial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, ary carcinoma, and papillary adenocarcinomas (See n et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia and Murphy et al., 1997, Informed Decisions: The Complete Book ofCancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books U.S.A., Inc., United States of America).

In certain embodiments, the proliferative disease is bladder cancer, brain tumor, breast cancer, cancer of the mouth and throat, colorectal cancer, lung cancer, or pancreatic cancer, prostate cancer, h cancer, or c cancer.

In certain embodiments, the proliferative disease is lung cancer. In certain embodiments, the proliferative disease is drug-resistant lung cancer. In certain embodiments, the erative disease is multidrug-resistant lung cancer. In certain embodiments, the proliferative e is relapsed lung cancer. In certain embodiments, the proliferative disease is relapsed drug-resistant lung cancer. In certain ments, the proliferative disease is relapsed multidrug-resistant lung cancer. In certain embodiments, the proliferative disease is non-small cell lung cancer. In certain ments, the proliferative disease is drug resistant non-small cell lung cancer. In certain embodiments, the proliferative disease is multidrug resistant non-small cell lung cancer. In certain embodiments, the proliferative disease is relapsed all cell lung cancer. In n embodiments, the proliferative disease is relapsed drug resistant non-small cell lung cancer. In certain embodiments, the proliferative disease is relapsed multidrug resistant non-small cell lung cancer.

Depending on the disorder, disease, or condition to be treated, and the subject’s condition, the compounds or ceutical compositions provided herein can be administered by oral, parenteral (e.g, intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration and can be formulated, alone or together, in suitable dosage unit with ceutically acceptable -ll6- WO 43148 excipients, carriers, adjuvants, and vehicles appropriate for each route of administration.

Also provided is stration of the compounds or pharmaceutical compositions provided herein in a depot formulation, in which the active ingredient is released over a predefined time period.

In the treatment, prevention, or amelioration of one or more symptoms of the disorders, es, or conditions described herein, an appropriate dosage level generally is ranging from about 0.001 to 100 mg per kg subject body weight per day (mg/kg per day), from about 0.01 to about 75 mg/kg per day, from about 0.1 to about 50 mg/kg per day, from about 0.5 to about 25 mg/kg per day, or from about 1 to about 20 mg/kg per day, which can be administered in single or multiple doses. Within this range, the dosage can be ranging from about 0.005 to about 0.05, from about 0.05 to about 0.5, from about 0.5 to about 5.0, from about 1 to about 15, from about 1 to about 20, or from about 1 to about 50 mg/kg per day.

For oral administration, the ceutical compositions provided herein can be formulated in the form of tablets containing from about 1.0 to about 1,000 mg of the active ingredient, in one ment, about 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900, and about 1,000 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The pharmaceutical compositions can be administered on a regimen of l to 4 times per day, including once, twice, three times, and four times per day.

It will be understood, however, that the specific dose level and frequency of dosage for any particular patient can be varied and will depend upon a variety of s including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

In one embodiment, provided herein is a method of inhibiting the growth of a cell, sing ting the cell with a compound provided herein, e.g., a compound of Formula I or XXI, or a single enantiomer, a racemic mixture, a mixture of reomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. -ll7- In another embodiment, provided herein is a method of inhibiting the growth of a cell in a subject, comprising administering to the subject a compound disclosed herein, e.g., a compound of Formula I or XXI, or a single enantiomer, a racemic e, a mixture of diastereomers, or an ic variant thereof; or a pharmaceutically acceptable salt, solvate, or g thereof.

In certain embodiments, the cell is a cancer cell. In n embodiments, the cell contains an ERBB variant.

In one embodiment, provided herein is a method for modulating the activity of a tyrosine kinase, in one embodiment, an ERBB , comprising contacting the ERBB kinase with a compound disclosed herein, e.g., a compound of Formula I or XXI, or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant f; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

] In another embodiment, ed herein is a method for modulating the activity of a tyrosine kinase, in one embodiment, an ERBB kinase, in a subject, comprising administering to the subject a compound disclosed herein, e.g., a compound of Formula I or XXI, or a single enantiomer, a c e, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In certain embodiments, the ERBB is a wild-type ERBB. In certain embodiments, the ERBB is an ERBB variant. In certain embodiments, the ERBB is an EGFR. In certain embodiments, the ERBB is a wild-type EGFR. In certain embodiments, the ERBB is an EGFR variant. In certain embodiments, the ERBB is a HER2. In certain embodiments, the ERBB is a wild-type HER2. In certain embodiments, the ERBB is a HER2 variant. In certain embodiments, the ERBB is a HER3. In certain embodiments, the ERBB is a wild-type HER3. In certain ments, the ERBB is a HER3 variant. In certain embodiments, the ERBB is a HER4. In certain embodiments, the ERBB is a wild-type HER4.

In certain embodiments, the ERBB is a HER4 variant.

The compound ed herein, e.g., a compound of Formula I or XXI, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a ceutically acceptable salt, solvate, hydrate, or g thereof; can also be combined or used in combination with other agents or therapies useful in the treatment, prevention, or amelioration of one or more symptoms of the conditions, disorders, WO 43148 or diseases for which the compounds provided herein are useful.

Suitable other therapeutic agents can also include, but are not limited to, (1) alpha-adrenergic agents; (2) antiarrhythmic agents; (3) anti-atherosclerotic agents, such as ACAT tors; (4) antibiotics, such as anthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin; (5) ncer agents and cytotoxic agents, e.g., alkylating agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes; (6) anticoagulants, such as acenocoumarol, argatroban, rudin, din, fondaparinux, heparin, phenindione, warfarin, and Ximelagatran; (7) anti-diabetic agents, such as ides (e.g., metformin), idase inhibitors (e.g., acarbose), insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiozolidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), and PPAR-gamma agonists; (8) antifungal agents, such as amorolfine, amphotericin B, anidulafungin, bifonazole, butenafine, butoconazole, caspofiangin, ciclopirox, clotrimazole, econazole, fenticonazole, filipin, azole, isoconazole, itraconazole, ketoconazole, micafungin, miconazole, ne, natamycin, nystatin, oxyconazole, nazole, posaconazole, din, sertaconazole, sulconazole, terbinafine, terconazole, tioconazole, and voriconazole; (9) antiinflammatories, e.g., non-steroidal anti-inflammatory agents, such as aceclofenac, acemetacin, amoxiprin, aspirin, azapropazone, benorilate, nac, carprofen, celecoxib, e magnesium salicylate, diclofenac, diflunisal, ac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, lomoxicam, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicyl salicylate, sulindac, yrazone, suprofen, tenoxicam, tiaprofenic acid, and tolmetin; (10) antimetabolites, such as folate antagonists, purine ues, and pyrimidine analogues; (11) anti-platelet agents, such as GPIIb/IIIa blockers (e.g., abciximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine and CS-747), azol, dipyridamole, and aspirin; (12) antiproliferatives, such as methotrexate, FK506 (tacrolimus), and mycophenolate mofetil; (13) anti-TNF antibodies or soluble TNF receptor, such as etanercept, rapamycin, and leflunimide; (14) aP2 inhibitors; (15) drenergic agents, such as carvedilol and metoprolol; (l6) bile acid sequestrants, such as questran; (l7) calcium channel blockers, such as amlodipine te; (18) chemotherapeutic agents; (19) cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib; (20) cyclosporins; (21) xic drugs, such as azathioprine and cyclophosphamide; (22) diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, umethiazide, flumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzothiazide, ynic acid, ticrynafen, chlorthalidone, furosenide, muzolimine, bumetanide, triamterene, amiloride, and spironolactone; (23) endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; (24) enzymes, such as L- asparaginase; (25) Factor VIIa Inhibitors and Factor Xa Inhibitors; (26) famesyl-protein transferase inhibitors; (27) fibrates; (28) growth factor inhibitors, such as modulators of PDGF activity; (29) growth e secretagogues; (30) HMG CoA ase inhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known as rosuvastatin, atavastatin, or visastatin); neutral ptidase (NEP) inhibitors; (3 l) hormonal agents, such as glucocorticoids (e.g., one), estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; (32) immunosuppressants; (33) mineralocorticoid receptor antagonists, such as spironolactone and eplerenone; (34) ubule-disruptor agents, such as ecteinascidins; (35) ubule-stabilizing agents, such as pacitaxel, docetaxel, and epothilones A-F; (36) MTP Inhibitors; (37) niacin; (38) phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, and vardenafil); (39) plant-derived products, such as vinca alkaloids, epipodophyllotoxins, and taxanes; (40) platelet activating factor (PAF) antagonists; (41) um coordination complexes, such as cisplatin, satraplatin, and carboplatin; (42) potassium channel openers; (43) prenyl-protein transferase inhibitors; (44) protein ne kinase inhibitors; (45) renin inhibitors; (46) squalene synthetase inhibitors; (47) steroids, such as erone, beclometasone, betamethasone, deoxycorticosterone acetate, ortisone, hydrocortisone (cortisol), prednisolone, prednisone, methylprednisolone, dexamethasone, and triamcinolone; (48) TNF-alpha inhibitors, such as tenidap; (49) thrombin inhibitors, such as hirudin; (50) thrombolytic agents, such as anistreplase, reteplase, tenecteplase, tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and lated plasminogen streptokinase activator complex (APSAC); (5 l) thromboxane receptor antagonists, such as ban; (52) topoisomerase inhibitors; (53) vasopeptidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilat and gemopatrilat; and (54) other miscellaneous agents, such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, and gold nds.

] In certain embodiments, the other therapies that may be used in combination -l20- with the compounds provided herein include, but are not limited to, surgery, endocrine therapy, biologic response modifiers (e.g. , interferons, interleukins, and tumor necrosis factor (TNF)), hyperthermia and cryotherapy, and agents to attenuate any adverse effects (e.g., antiemetics).

In certain embodiments, the other therapeutic agents that may be used in combination with the compounds provided herein include, but are not limited to, alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, and ifosfamide), antimetabolites (cytarabine (also known as cytosine arabinoside or Ara-C), HDAC (high dose cytarabine), and rexate), purine nists and pyrimidine antagonists (6- mercaptopurine, 5-fluorouracil, cytarbine, and abine), e s (vinblastine, vincristine, and vinorelbine), podophyllotoxins (etoposide, irinotecan, and can), antibiotics (daunorubicin, doxorubicin, bleomycin, and mitomycin), nitrosoureas (carmustine and ine), enzymes (asparaginase), and hormones (tamoxifen, leuprolide, flutamide, and megestrol), imatinib, adriamycin, dexamethasone, and cyclophosphamide. For a more comprehensive discussion of updated cancer therapies; See, /www.nci.nih.gov/, a list of the FDA approved oncology drugs at http://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck Manual, Seventeenth Ed. 1999, the entire contents of which are hereby incorporated by reference.

In another embodiment, the method provided herein comprises administration of a compound provided herein, e.g., a compound of Formula I or XXI, or an enantiomer, a mixture of enantiomers, a e of two or more diastereomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, together with administering one or more chemotherapeutic agents and/or therapies selected from: alkylation agents (e.g., cisplatin, carboplatin); antimetabolites (e.g., methotrexate and S-FU); antitumour antibiotics (e.g., adriamymycin and bleomycin); antitumour ble alkaloids (e.g., taxol and ide); antitumor hormones (e.g., dexamethasone and tamoxifen); mour immunological agents (e.g., interferon 0t, [3, and y); radiation therapy; and surgery.

In certain embodiments, the one or more chemotherapeutic agents and/or therapies are administered to the t before, during, or after the administration of the compound provided .

Such other agents, or drugs, can be administered, by a route and in an amount commonly used therefor, aneously or sequentially with the compound provided herein, -lZl- e.g., a compound of Formula I or XXI, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic t thereof; or a ceutically acceptable salt, solvate, hydrate, or prodrug thereof. When a compound provided herein is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound ed herein can be utilized, but is not required. Accordingly, the pharmaceutical compositions provided herein include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound provided herein.

] The weight ratio of a compound provided herein to the second active ingredient can be , and will depend upon the ive dose of each ingredient.

Generally, an effective dose of each will be used. Thus, for example, when a compound provided herein is combined with a NSAID, the weight ratio of the compound to the NSAID can range from about l,000:l to about l:l,000, or about 200:1 to about 1:200. Combinations of a compound provided herein and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

] The compounds provided herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, 6.g. , US.

Pat. Nos. 5,323,907; 558; and 5,033,252. Examples ofpharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.

Provided herein also are kits which, when used by the l practitioner, can fy the stration of appropriate amounts of active ingredients to a subject. In certain embodiments, the kit provided herein includes a container and a dosage form of a compound provided herein, e.g., a compound of Formula I or XXI, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

In n embodiments, the kit includes a container comprising a dosage form of the compound ed herein, e.g., a compound of Formula I or XXI, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant -l22- thereof; or a pharmaceutically acceptable salt, solvate, e, or g thereof; in a container comprising one or more other therapeutic agent(s) described herein.

Kits provided herein can further include devices that are used to administer the active ingredients. es of such devices include, but are not limited to, syringes, needle- less injectors drip bags, patches, and inhalers. The kits ed herein can also include condoms for administration of the active ingredients.

Kits provided herein can further e pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a le e in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable es include, but are not limited to: aqueous vehicles, including, but not limited to, Water for Injection USP, Sodium Chloride ion, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and ueous es, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, pyl myristate, and benzyl benzoate.

The disclosure will be fiarther understood by the following non-limiting examples.

EXAMPLES As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is cally defined, are consistent with those used in the porary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and hout the specification: g (grams); mg (milligrams); mL (milliliters); uL (microliters); L, (liter); mM (millimolar); uM molar); Hz (Hertz); MHz (megahertz); mmol (millimoles); eq. (equivalent); hr or hrs (hours); min (minutes); MS (mass spectrometry); NMR (nuclear magnetic resonance); ESI (electrospray ionization); HPLC (high-performance liquid chromatography or high pressure liquid chromatography); ACN, (acetonitrile); CDC13 (deuterated chloroform); DCM (dichloromethane); DMA (N,N-dimethylacetamide); DME (dimethoxyethane); DMF (N,N—dimethylformamide); DMSO (dimethylsulfoxide); DMSO-d6 (deuterated dimethylsulfoxide); EtOAc (ethyl acetate); EtzO (diethyl ether); EtOH (ethanol); MeOH (methanol); PE leum ether); THF (tetrahydrofuran); DIPEA (N,N- diisopropylethylamine); TEA (triethylamine); TFA (trifluoroacetic acid); BOP (benzotriazole- l -yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate); HATU (2-(7-aza- 1H-benzotriazole- l -yl)-l , l ,3 ,3 -tetramethyluronium hexafluorophosphate); TBTU nzotriazol- l -yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate); DIPC (l ,3- diisopropylcarbodiimide); MszO (methanesulfonic anhydride); Me (methyl); Et (ethyl); z'Pr, opyl); tBu (tert-butyl); Boc (tert—butoxylcarbony); Bn (benzyl); Ph (phenyl); Ms (mesylate); and AcO (acetate).

HPLC-MS analyses were performed on Waters HPLC 2790 coupled with Waters ass ZQ 4000 (Model MAA050) as a mass detector and with Waters 2487 UV as a UV-visible detector, using a KINETEXTM reversed phase column (5 uM XB-Cl 8- 100 A, 50 x 4.6 mm; Phenomenex, 00BE0). The mobile phase were eluent A (water, 0.05% TFA) and eluent B , 0.05% TFA). The HPLC was run at 1 mL/min with a linear gradient from 10% B to 90% B for 8 min, followed by 90% B isocratic for 2 min, with the total run time of 10 min.

For all of the following examples, standard p and cation methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in 0C (degrees Centigrade). All reactions conducted at room temperature unless otherwise noted. Synthetic methodologies herein are intended to exemplify the applicable chemistry through the use of ic examples and are not indicative of the scope of the sure.

Example lA Cell Proliferation Assay The biological activity of a test compound was determined using cell proliferation assays. The activity against wild-type ERBBl was ined using A43l human epidermoid carcinoma cells (ATCC) and human epidermal keratinocytes, neonatal, or HEKn cells . The ty against mutant ERBBl was determined using HCC827 human NSCLC adenocarcinoma cells (ATCC), which has a deletion of E746-A759 in exon —124— 19. The activity against a drug-resistant mutant ERBBl was ined using H1975 human NSCLC adenocarcinoma cells (ATCC), which has the T790M mutation in-cz’s with the L858R mutation.

A431 cells were grown in DMEM (Invitrogen) supplemented with 10% FBS ), 1% llin-streptomycin, and 2 mM glutamine (Invitrogen). HEKn cells were grown in EPILIFE® rogen) supplemented with HKGS (Invitrogen). HCC827 and H1975 were cultured in RPM11640 supplemented with 10% FBS ), 1% penicillin- streptomycin, and 2 mM glutamine (Invitrogen). Cells were maintained and propagated at 37 0C and 5% C02 in a humidified cell e incubator. Aliquots of cells from early passages were preserved for liquid nitrogen e. Frozen vials of cells were thawed at 37 0C water bath. Cells were spun to remove freezing medium. The newly revived frozen cells were adapted in e for 10 days before used for compound testing. Cells used in the assay were less than 20 subculture passages or 3 months in culture.

The test compounds were dissolved in dimethylsulfoxide (DMSO) and stored at -20 0C before testing. For the cell proliferation assays, cells were seeded in 96-well plates (Costar, 3917) at various numbers: A431 cells at 2,000 cells per well, HEKn, HCC827, and H1975 at 1,000 cells per well. The cells were placed in a culture incubator overnight. Next day, test compounds in DMSO were added to the cells and placed back in the culture incubator for 72 hrs. In the meantime, the cell numbers at time zero of the compound treatment (T0) was ed by ENERCOUNT® (Codex BioSolutions). At the end of the compound treatment, the cell numbers were again measured by EnerCount as T72 values.

The untreated controls (Ctrl) were cell numbers recorded from the 0.1% DMSO treatment.

The percent growth inhibition by the test compound was calculated by the formula: (1- (T72- T0)/(Ctrl-T0)) x 100. The G150, the compound concentration at which 50% of cell growth is inhibited, was determined from the 10-point dose-response growth inhibition using non-linear sigmoidal curve fitting using ad Prism.

The results are summarized in Tables 1 and 2, wherein A represents a value no greater than 500 nM, B represents a value greater than 500 nM but no greater than 1 uM, C represents a value greater than 1 uM but no greater than 5 uM, and D ents a value greater than 5 uM; and wherein A’ represents a ratio of greater than 10, B’ represents a ratio of no greater than 10 but no less than 5, C’ represents a ratio of no greater than 5 but no less than 2, and D’ ents a ratio of no greater than 2.

TABLE 1. Inhibition of Cell Proliferation G150 Cmpd.

HCC827 H1975 HEKn A431 A1 —A C A A2 —A D A3 —A C A4 —A C A5 C Erlotinib 7.0 4381 2200 Afatinib 1.0 —120 21 1.

C0—1686 32 109 2500 TABLE 2. Selectivity Ratio ild-t e ERBBl/Mutant ERBBl cmpd° HEKn/H1975 A431/H1975 A1 A3 A3 A2 A3 D3 A3 A3 D3 A4 c3 D3 As A3 c3 DrDDnD—— D3 ADDnD—-_ D3 D3 co-msa—— A3 Example 1 sis of benzyl uoronitrophenoxy)piperidine-l-carboxylate 8 The synthesis of benzyl 4-(2-fluoronitrophenoxy)piperidine-l-carboxylate 8 is shown in Scheme 1.

Scheme 1 NYC OH M320 013 F O N\ EtsN Cbz K2C03 00N\ Step I Cbz -l26- 2015/021455 ] Step I: Dry benzyl 4-hydroxypiperidinecarboxylate (50 mmol, 11.8 g) was dissolved in dry DCM (100 mL) at 0 0C. Methanesulfonic anhydride (50 mmol, 8.74 g) was added, followed by addition of triethylamine (62.5 mmol, 8.70 mL). The on was stirred for 30 min at room temperature. DCM was stripped. The residue obtained was dried under high vacuum for 5 min to afford benzyl 4-((methylsulfonyl)oxy)piperidinecarboxylate 8, which was directly used in the next step without fiarther treatment.

Step II: Benzyl 4-((methylsulfonyl)oxy)piperidinecarboxylate (estimated to be 25 mmol) in DMF (25 mL) was added to a sion of 2-fluoronitrophenol (25 mmol, 4.33 g) and K2C03 (100 mmol, 13.8 g) in DMF (50 mL). The reaction was heated and stirred at 80 0C for 4 hrs, then another equivalent of benzyl 4-((methylsulfonyl)oxy)- piperidine-l-carboxylate (25 mmol estimated) in DMF (25 mL) was added. The mixture was stirred at 70 0C overnight. DMF was stripped under reduced pressure. The residue obtained was diluted with 250 mL of EtOAc. The EtOAc solution was washed with saturated NaHCOg (40 mL), water (40 mL), and brine (40 mL), dried with Na2S04, and concentrated.

The residue obtained was ted to silica gel chromatography purification (0-40% EtOAc) to afford benzyl 4-(2-fluoronitrophenoxy)piperidinecarboxylate 8 as brownish foam in 40% yield (3.8 g).

Example 2 Synthesis of tert—butyl (R)(7-((1-((benzyloxy)carbonyl)piperidinyl)oxy)(2- methylisonicotinamido)- 1H—benzo[d]imidazolyl)azepanecarboxylate 4 The synthesis of utyl (R)-3 -(7-((1-((benzyloxy)carbonyl)piperidin yl)oxy)(2-methylisonicotinamido)-1H—benzo[d]imidazolyl)azepanecarboxylate 4 is shown in Scheme 2.

Step I: To benzyl 4-(2-fluoronitrophenoxy)piperidinecarboxylate 8 (10.1 mmol, 3.80 g) in DMF (20 mL) was added DIPEA (11.1 mmol, 1.94 mL) and tert—butyl (R)- 3-aminoazepane-l-carboxylate (10.1 mmol, 2.16 g). The reaction was stirred at 100 0C for 4 hrs, then ved in 150 mL of EtOAc, washed with water (20 mL), 0.1N HCl aq. (20 mL), brine (20 mL), saturated NaHC03 (30 mL), and water, and dried over Na2S04. Then, the solvent was stripped off under d pressure. The residue obtained was purified by silica gel flash-chromatography (25% to 40% EtOAc in hexane) to afford tert—butyl (R)((2-((l- ((benzyloxy)carbonyl)piperidinyl)oxy)nitrophenyl)amino)azepanecarboxylate 7 as yellow solid in 57.9% yield (3.3 g).

Scheme 2 N02 CN‘BOC N02 Zn/AcOH NH2 F —, —> NH NH step I 0 step H O N—Boc N—Boc \Cbz N Cbz/ O/ CK 7 Cbz’ 6 N \)—NH _ >—NH2 HO —N N \ /N BrCN N \ o I O O —> N—Boc g5 N_Boc N HATU O/ Step m Cbz/ 4 Cbz/ Step II: To a mixture of tert—butyl (R)((2-((l-((benzyloxy)carbonyl)- piperidinyl)oxy)nitrophenyl)amino)azepane-l-carboxylate 7 (3.30 g, 5.80 mmol) in acetic acid (20 mL) was added zinc powder (5.57 g, 87 mmol) in batches under en at 0 0C. The reaction was stirred at 25 0C for 20 min. Then the reaction was filtered and the cake was washed with DCM. The combined organic solution was stripped off solvents. The residue obtained was stirred in 16 mL of 0.2 N NaOH aq. (130 mL) for 3 min, and then extracted with EtOAc (200 mL x 3). The combined organic phase was washed with sodium potassium tartrate solution (1 g in 30 mL of water), and brine, dried with NaZSO4 and concentrated. The e obtained, containing tert—butyl (R)((2-amino((l- ((benzyloxy)carbonyl)piperidinyl)oxy)phenyl)amino)azepane- l -carboxylate 6, was ly used in the next step of reaction without further ation. [0033 1] Step III: A mixture of utyl ((2-amino((l-((benzyloxy)- carbonyl)piperidinyl)oxy)phenyl)amino)azepane-l-carboxylate 6 (3. 12 g, 5.8 mmol) and cyanogen bromide (9.7 mmol, 3.2 mL of 3M DCM on) dissolved in MeOH (30 mL) and water (10 mL) was stirred at 52 0C for 2.5 hrs in a sealed tube. The solvents were stripped and the residue obtained was basified with saturated sodium carbonate solution. The reaction was then extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine and water, dried over sodium sulfate, and evaporated to dryness. The residue obtained was purified by silica gel chromatography (Eth/EtOAc, 5 to 20%), yielding tert—butyl (R) (2-amino(( l -((benzyloxy)carbonyl)piperidinyl)oxy)- l H-benzo [d]imidazol- l - -l28- yl)azepanecarboxylate 5 as tanish powder in 76% yield (2.50 g).

Step IV: 2-Methylisonicotinic acid (0.392 g, 2.858 mmol) and HATU (1.09 g, 2.858 mmol) were dissolved in a DCM/DMF mixture (total 10 mL, 1:1). DIPEA (0.671 mL, 4.083 mmol) was added and the reaction was stirred for 10 min before adding to a solution of tert-butyl (R)-3 -(2-amino(( 1 -((benzyloxy)carbonyl)piperidinyl)oxy)- 1H- benzo[d]imidazolyl)azepanecarboxylate (1 . 15 g, 2.04 mmol) in F (10 mL, 1:1). After one hour of stirring, the on was stripped off ts. The residue was dissolved in EtOAc (200 mL). The c solution was washed with NaOH aq. (1N, 40 mL x 3), brine (40 mL), dried with Na2S04, and concentrated. The residue obtained was purified on a silica gel column (0-2% methanol in DCM) to afford 1.2 g (86%) of tert—butyl (R)(7- ((1 -((benzyloxy)carbonyl)piperidinyl)oxy)(2-methylisonicotinamido)- 1H- benzo[d]imidazolyl)azepanecarboxylate 4.

Example 3 Synthesis of utyl (R)-3 -(7-(( 1 -ethylpiperidinyl)oxy)(2-methylisonicotinamido)- 1H-benzo[d]imidazolyl)azepanecarboxylate 2 and tert—butyl (R)-3 -(7-((l - acetylpiperidinyl)oxy)(2-methylisonicotinamido)- 1H-benzo[d]imidazolyl)azepane carboxylate 2’ [003 3 3] The synthesis of tert—butyl (R)-3 -(7-((1-ethylpiperidinyl)oxy)(2- methylisonicotinamido)-1H-benzo[d]imidazolyl)azepanecarboxylate 2 and tert—butyl (R)-3 -(7-(( 1 -acetylpiperidinyl)oxy)(2-methylisonicotinamido)- 1H-benzo [d]imidazol yl)azepanecarboxylate 2’ is shown in Scheme 3.

Step I: Tert—butyl (R)(7-((1-((benzyloxy)carbonyl)piperidinyl)oxy)(2- methylisonicotinamido)-1H—benzo[d]imidazolyl)azepanecarboxylate 4 (1.2 g, 1.757 mmol) and Pd/C (0.1 g, 10% Pd on carbon) were stirred in EtOAc/methanol e (1 :1, 20 mL) under hydrogen atmosphere for 3 hrs. The reaction was filtered through celite and the filtrate was concentrated to give tert—butyl (R)(2-(2-methylisonicotinamido)(piperidin- 4-yloxy)-1H—benzo[d]imidazolyl)azepanecarboxylate 3 in 78% yield (0.96 g).

] Step II: Ethyl iodide (30.66 uL) was dissolved in 1 mL ofDMA and 0.1 mL of this on was added to a suspension of tert—butyl (R)(2-(2-methy1isonicotinamido) (piperidin—4-yloxy)-1H—benzo[d]imidazolyl)azepanecarboxylate 3 (20 mg, 0.0365 mmol) and N32C03 (6.8 mg, 0.064 mmol) in 1 mL of DMA. The reaction was stirred at room ature for 2 days, filtered through celite, and washed with ethanol. Then the filtrate was stripped off solvents to afford tert—butyl (R)(7-((1-ethylpiperidinyl)oxy) (2-methylisonicotinamido)-1H—benzo[d]imidazolyl)azepanecarboxylate 2 (21 mg).

LC/MS showed retention time of 0.43 min (HPLC column: 2.1 x 30 mm, 1.7 um c18; Eluent: 1-99% ACN in water with 5 mM HCl; 1 min run; t flow rate: 12 mL/min) and correct mass ( M+1 calculated for Chemical Formula C32H44N6O4 is , observed 577.6). The compound was directly used in the next step of reaction without purification.

Scheme 3 Step III: Acetic acid (0.185 mmol, 11.1 mg) and HATU (0.185 mmol, 70.3 mg) were mixed in DMA (1 mL), followed by addition of DIPEA (47.7 mg, 0.37 mmol).

After five minutes of stirring, the reaction was transferred to a solution of tert-butyl (2- (2-methylisonicotinamido)(piperidinyloxy)-1H-benzo[d]imidazolyl)azepane carboxylate 3 (94.2 mg, 0.1718 mmol) in DMA (1 mL). The reaction was filrther stirred for 1 hr, then filtered, and purified by HPLC (column 75 X 30 mm, 5 um c18, 1-99% ACN in water with 5 mM HCl, mass triggered collection) to yield tert—butyl (7-((1- acetylpiperidinyl)oxy)(2-methylisonicotinamido)-1H-benzo[d]imidazolyl)azepane carboxylate 2’ in 51 mg.

Example 4 sis of (R)-N—(l-(azepanyl)(piperidinyloxy)-lH—benzo[d]imidazol- 2-yl) methylisonicotinamide 1” The synthesis of (R)-N—(l-(azepanyl)(piperidinyloxy)-1H- benzo[d]imidazol- 2-yl)methylisonicotinamide 1” is shown in Scheme 4.

Scheme 4 QNOE>— N \ NH \ HCl in e ©N>_NH — —» \ / CW O N—Boc 1" C [003 3 8] Tert—butyl (R)-3 -(2-(2-methylisonicotinamido)(piperidinyloxy)- 1H- benzo[d]imidazol-l-yl)azepane-l-carboxylate (50 mg, 0.091 mmol) was dissolved in 1 mL of MeOH. A solution of4M HCl in dioxane (3 mL, 12 mmol) was added. The reaction was stirred at room temperature for 5 hrs and then HCl and solvents were stripped. The residue obtained, a HCl salt of (R)-N—(l-(azepanyl)((l-ethylpiperidinyl)oxy)-1H- benzo[d]imidazolyl)methylisonicotinamide, was directly used in the next step of reaction without further treatment. sis of (R)-N—(7-(( l -acetylpiperidinyl)oxy)- l -(azepan-3 -yl)- lH—benzo [d]imidazol yl)methylisonicotinamide 1 ’ [003 3 9] The synthesis of (R)-N—(7-((l -acetylpiperidinyl)oxy)- l -(azepanyl)-1H- benzo[d]imidazolyl)methylisonicotinamide 1’ is shown in Scheme 5.

Scheme 5 (DO/Q:WW— N \ \ NH ©:N>_ IoNH _ TFA, DCM \ / N’Boc NH N . 2' \n/ 1 Tert—butyl (R)-3 -(7-(( l -acetylpiperidinyl)oxy)(2- -l3l- isonicotinamido)-lH-benzo[d]imidazolyl)azepane-l-carboxylate 2’ (51 mg, 0.086 mmol) was dissolved in DCM. Trifluoroacetic acid (0.5 mL) was added and the reaction was stirred at room temperature for 1 hr. The solvents were stripped. The residue obtained was dissolved in 150 mL of a solvent (1 :2 volume ratio of IPA:DCM) and washed with aq.

NaHCOg (15 mL), brine (20 mL), dried with NazSO4, filtered, and concentrated to yield (R)- N—(7-((1-acetylpiperidinyl)oxy)(azepanyl)-1H—benzo[d]imidazolyl) methylisonicotinamide 1’ in 52 mg.

Example 6 Synthesis of (R)-N-( 1 -(azepan-3 -yl)((l piperidinyl)oxy)- 1H—benzo [d]imidazol yl)methylisonicotinamide 1 The synthesis of (R)-N-(1-(azepanyl)((1-ethylpiperidinyl)oxy)-1H- benzo[d]imidazolyl)methylisonicotinamide 1 is shown in Scheme 6.

Scheme 6 ©N>—N\ N NH _ HCl in dioxane \ NH N _ A HCl salt of (1-(azepanyl)((1-ethylpiperidinyl)oxy)-1H- benzo[d]imidazolyl)methylisonicotinamide 1 (23 mg) was prepared from compound 2, following the synthetic procedures of compound 1”. LC/MS showed retention time of 0.45 min (HPLC column: 2.1 x 30 mm, 1.7 um c18; Eluent: 1-99% ACN in water with 5 mM HCl; 1 min run; t flow rate: 12 mL/min) and correct mass ( M+l expected: 477.29, observed 477.6).

Example 7 sis of (R)-N-(7-((1-acetylpiperidinyl)oxy)(1-acryloylazepan-3 -yl)- 1H- benzo[d]imidazolyl)methylisonicotinamide A2 ] The synthesis of (R)-N-(7-((1-acetylpiperidinyl)oxy)(1-acryloylazepan- 3-yl)-1H—benzo[d]imidazolyl)methylisonicotinamide A2 is shown in Scheme 7.

Scheme 7 @flidN\ N\>—NH me“ E1 @ OH\ / O\ / HATU o a Acrylic acid (0.127 mmol, 9.1 mg) and HATU (48.4 mg, 0.127 mmol) were mixed in DMA (1 mL), followed by addition of DIPEA (0.212 mmol, 27.4 mg). After 5 minutes of stirring, the mixture was transferred into a solution of (R)-N-(7-((1-acetyl- piperidinyl)oxy)(azepan-3 -yl)- 1H-benzo[d]imidazolyl)methylisonicotinamide 1 ’ (52 mg, 0.106 mmol) in DMA (1 mL). The reaction was further d for 1 hr and then was stripped off DMA, directly dry-loaded onto a silica gel column, and eluted with 1-10% MeOH in DCM. The expected t was isolated in 33 mg. LC/MS showed the correct mass of M+1 = 545.5 (calculated to be 545.28 for C30H36N6O4) with Rt = 0.42 min (HPLC : 2.1 x 30 mm, 1.7 um c18; Eluent: 1-99% ACN in water with 5 mM HCl; 1 min run; solvent flow rate: 12 mL/min). 1H NMR (400 MHz, chloroform-d) 5 12.59 (s, 1H), 8.68 (dd, J: 15.1, 4.7 Hz, 1H), 7.96 (d, J: 13.2 Hz, 1H), 7.88 (dd, J: 12.1, 5.3 Hz, 1H), 7.27 — 7.11 (m, 1H), 6.99 (dd, J: 19.6, 8.1 Hz, 1H), 6.93 — 6.74 (m, 1H), 6.65 (dt, .1: 16.5, 11.4 Hz, 1H), 6.53 — 6.21 (m, 1H), 5.83 — 5.64 (m, 1H), 5.55 (q, .1: 10.6, 8.5 Hz, 1H), 4.81 (d, J: 7.4 Hz, 2H), 4.63 — 4.33 (m, 2H), 4.04 (t, J: 15.4 Hz, 1H), 3.91 (h, J: 8.6, 7.8 Hz, 2H), 3.85 — 3.59 (m, 3H), 3.59 — 3.10 (m, 5H), 2.69 (d, J: 3.7 Hz, 5H), 2.35 — 1.68 (m, 13H), 1.37 (t, J: 13.0 Hz, 1H).

Example 8 Synthesis of (R)-N-(1-(1-acryloylazepan-3 -((1 -acryloylpiperidinyl)oxy)- 1H- benzo[d]imidazolyl)methylisonicotinamide A3 The synthesis of (R)-N-(1-(1-acryloylazepanyl)((1-acryloylpiperidin yl)oxy)-1H—benzo[d]imidazolyl)methylisonicotinamide A3 is shown in Scheme 8.

Acrylic acid (0.2 mmol, 14.4 mg) and HATU (76.1 mg, 0.20 mmol) were mixed in DMA (1 mL), followed by addition of DIPEA (0.575 mmol, 74.2 mg). After 5 s of stirring, the mixture was transferred into a solution of (R)-N-(1-(azepan-3 -yl) (piperidin—4-yloxy)-1H—benzo[d]imidazolyl)methylisonicotinamide (0.091 mmol) in DMA (1 mL). The reaction was further stirred for 1 hr and then was stripped off DMA, directly dry-loaded onto silica gel column, and eluted with 1-10% MeOH in DCM. The expected product was isolated in 17 mg. LC/MS showed the t mass of M+1 = 557.5 lated to be 557.28 for C31H36N6O4) with Rt = 0.45 min (HPLC column: 2.1 x 30 mm, 1.7 mm cl8; Eluent: 1-99% ACN in water with 5 mM HCl; 1 min run; t flow rate: 12 mL/min). 1H NMR (400 MHZ. cthroformwd) 6 12.57 (s, 1H), 8.70 (t. J: 4.9 Hz, 1H). 8.66 ((81,144, 1.4112, 1H), 8.31 (dd,.1===~ 8.4, , 1H), 8.10 7.91 (m, 1H), 7.33 (dd, J==== 8.4, 4.4 Hz, 1H), 7.27 — 7.15 (m. 1H), 7.03 (m, 03H), 6.99 (d, J: 8.0 Hz. 0.71%), 6.88 - 6.82 (m, 03H), 6.78 (d, .1 8.4 Hz, 0.711), 669 ~ 6.58 (m. 11:1), 647 — 6.194161, 11%),584 - 5.63 (111,211), 5.62 — 5.45 (m, 1H}, 4.86 (131‘ s, 1H), 4.66 4.33 (in, 1H), 4.29 3.29 (m, 7H}, 3.18 (q, .1 7.4 Hz, 1H), 2.75 (s, 2.11%), 12.73 (.0961). 1.57 — 1.99(D'1,7H).

Scheme 8 Example 9 Synthesis of (R)-N-(1-(1-Acryloylazepan-3 -yl)chloro(trifluoromethoxy)- 1H- benzo[d]imidazolyl)methylisonicotinamide A4 The synthesis of (R)-N-(1-(1-Acryloylazepanyl)chloro (trifluoromethoxy)-1H—benzo[d]imidazolyl)methylisonicotinamide A4 is shown in Scheme 9.

] A solution of 2-nitrotrifluoromethoxy-aniline 21 (40.0 g, 0.180 mol) and N- chlorosuccinimide (30.0 g, 0.225 mol) in ACN (300 mL) was heated at 70 0C for 4 hrs. The mixture was then cooled down to room temperature and diluted with saturated NH4Cl on (600 mL) and ethyl acetate (600 mL). The organic layer was washed with water (200 mL) and dried over Na2S04. Evaporation of solvent under reduced pressure gave a dark orange solid, which on trituration with hexane gave 2-chloronitro(trifluoromethoxy)- aniline 22 as an orange solid in 50% yield (23.0 g). 1H NMR (400 MHZ, chloroform-d) 5 8.03 (dq, J: 2.7, 0.9 Hz, 1H), 7.52 — 7.46 (m, 1H), 6.60 (s, 2H). —134— Scheme 9 F3CO N02 F3CO(112: —» F3CO CuClz Cl [Bu-ONO Cl N-Cl 22 23 HC ’BOC F3CO F3CO NHZ Zn/AcOH C1 DIPEA NzBoc N/Boc 24 25 F3CO :\>—NH2 F3CO N HOOC \— N \>—NH _ —> N N BICN C10\ / HATU C1 N,Boc N’B00 DIPEA 26 27 F3CO F3CO \quNH\>—NH HOOC/\ N\>_NH — N N HATU C1 DIPEA A4 N’é/ To a suspension of copper (II) chloride (12.6 g, 93.5 mmol) and t—butyl nitrite (13.9 mL, 117 mmol) in anhydrous ACN (100 mL) at 61 0C was added a solution of ro- 6-nitro(trifluoromethoxy)aniline 22 (20.0 g, 78.0 mmol) in acetonitrile (100 mL) dropwise.

The mixture was stirred at 61 0C for 1 hr after the addition. The solvent was removed, and the residue was treated with 4N HCl (350 mL) and extracted with EtOAc (150 mL x 3). The extracts were combined, dried over NaZSO4, and purified by silica gel chromatography e: EtOAc from 20:1 to 10: 1) to give nd 23 in 67% yield (14.5 g) as orange oil. 1H NMR (400 MHz, Chloroform—d) 7.61 (dq, J: 1.7, 0.8 Hz, 1H), 7.60 (dq, J = 2.7, 0.9 Hz, 1H). nd 24 was prepared following the procedures in step I of Example 2. 1H NMR (400 MHz, chloroform-d) a 7.98 — 7.77 (m, 1H), 7.46 (d, .1: 21.0 Hz, 1H), 7.11 (d, .1: 9.6 Hz, 0.5H), 6.61 (d, .1: 10.3 Hz, 0.5H), 4.28 (m, 0.5H), 4.08 (br s, 0.5H), 3.85 — 3.42 (m, 2.7H), 3.26-3.00 (m, 1.3H), 2.01-1.76 (m, 1.7H), 1.78 — 1.59 (m, 2.8H), 1.54—1.30 (m, 1.54H), 1.45 (s, 5.3H), 1.39 (s, 3.7H).

] Compound 25 was prepared following the procedures in step 11 of Example 2.

Compound 26 was prepared following the procedures in step 111 of Example 2.

MS ated for titled compound (M+1+) 449.15; ed 449.4 with HPLC retention time 0.59 min.

Compound 27 was prepared following the procedures in step IV of Example 2.

Compound 28 was prepared following the procedures in Example 5. [003 5 5] (R)-N—(1-(1-Acryloylazepanyl)—7-chloro(trifluoromethoxy)-1H- benzo[d]imidazolyl)methylisonicotinamide A4 was prepared following the procedures in Example 7 or 8.: MS observed for C24H23C1F3N503 (M+H+): 522.3; HPLC retention time: 0.55 min. 1H NMR (400 MHz, acetonitrile-d3) 512.65 (s, 1H), 8.62 (t, J: 5.8 Hz, 1H), 8.49- 8.42 (m, 1H), 8.40-8.33 (m, 1H), .49 (m, 1H), .28 (m, 1H), 6.78 (ddd, J: 16.7, 13.2, 10.4 Hz, 1H), 6.27 (ddd, J: 16.7, 10.0, 2.3 Hz, 1H), 5.78-5.47 (m, 2H), 4.65 (ddd, J: 19.1, 14.0, 10.4 Hz, 1H), 4.29-3.89 (m, 2H), 3.84-3.67 (m, 1H), 2.95 (two singlets, total 3H), 2.73-2.60 (m, 2H), 2.19-2.00 (m, 2H), 1.55-1.46 (m, 2H).

Example 10 Synthesis of nds A1 and A5 Compounds A1 and A5 were prepared following the procedures as described in Examples 7 and 8. [003 5 7] (R)-N—(1-(1-Acryloylazepan-3 -yl)(( 1 -ethylpiperidinyl)oxy)- 1H- benzo[d]imidazolyl)methylisonicotinamide A1: MS observed for C30H38N603 (M+H+): 531.4; HPLC retention time: 0.33 min. [003 5 8] (R,E)-N—(7-Chloro(1-(4-(dimethylamino)butenoyl)azepan-3 -yl) (trifluoromethoxy)-1H—benzo[d]imidazo1yl)methylisonicotinamide A5: MS observed for C27H30ClF3N603 (M+H+): 579.3; HPLC retention time: 0.44 min. 1H NMR (400 MHz, methanol-d4) 58.85 (dd, J: 6.1, 2.0 Hz, 1H), 8.56-8.43 (m, 2H), 7.60-7.51 (m, 1H), 7.43- 7.35 (m, 1H), 7.12-6.99 (m, 1H), 6.80 (dtd, J: 14.8, 7.2, 3.2 Hz, 1H), 5.78-5.51 (m, 1H), 4.79-4.68 (m, 1H), 4.38-4.15 (m, 2H), 4.02 (d, J: 7.2 Hz, 2H), 3.97-3.77 (m, 2H), 2.96 and 2.91 (two singlets, total 9H), 2.28-1.94 (m, 5H), 1.59-1.46 (m, 1H).

Example 11 Synthesis ofN—(l-((R)acryloylazepanyl)chloro((2-oxopyrrolidin-3 -yl)oxy)- 1H- benzo[d]imidazolyl)methylisonicotinamide C1 The synthesis ofN—( 1 -((R)acryloylazepanyl)chloro((2- oxopyrrolidinyl)oxy)-1H—benzo[d]imidazolyl)methylisonicotinamide C1 is shown in Scheme 10.

Scheme 10 g\>—NHN N _ 1. TFA _ O N N O N N o \ / g\>—NHo O\ / 0 2. Hooc/\ C1 N’BOC N HATU “N “N DIPEA / ] Step I: A mixture of tert-butyl (R)(6-(benzyloxy)chloro(2- methylisonicotinamido)-1H—benzo[d]imidazolyl)azepanecarboxylate 31 (1.1 g) and % Pd/C (0.194 g) in MeOH (5 mL) was purged by vacuume and then filled with hydrogen from a balloon. The reaction mixture was stirred under hydrogen at room ature for 4 hrs. The catalyst Pd/C was filtered through a pad of celite and the pad was washed with MeOH. The combined solution was concentrated to give nd 32 in a tative yield (932 mg).

Step II: To a solution of 3-hydroxy-pyrrolidinone (200 mg, 1.97 mmol) in DCM (5 mL) was added MszO (539 mg, 3.1 mmol) and pyridine (2 mL) at 0 0C. The reaction mixture was stirred at 0 0C for 20 min and then overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in isopropanol/CHC13 (1 :3; 40 mL),washed with saturated NaHCOg, dried over ous Na2S04, and evaporated to dryness under reduced pressure to give 2-oxopyrrolidin-3 -yl methanesulfonate 33 in 38% yield (137 mg).

To a solution of compound 32 (200 mg, 0.4 mmol) in DMF (2 mL) under N2 was added C82C03 (98 mg, 0.6 mmol) and compound 33 (108 mg, 0.6 mmol). The reaction mixture was stirred at 55 0C overnight. After the mixture was cooled down to room temperature, saturated NH4Cl (10 mL) was added. The reaction mixture was extracted with isopropanol/CHClg (1 :3; 3 x 30 mL). The organic phase was washed with brine, dried over anhydrous Na2S04, concentrated under reduced pressure, and purf1ed by column chromatography on silica gel with DCM:MeOH (100:0 to 90: 10) to give tert—butyl (3R)(7- (2-methylisonicotinamido)((2-oxopyrrolidin-3 -yl)oxy)-1H-benzo[d]imidazol yl)azepane-l-carboxylate 34. MS observed for C29H35C1N605: 583.2 (M+H+); HPLC retention time: 7.72 min.

Step III: To a solution of acrylic acid (20.4 mg, 0.28 mmol) in DMA (1 mL) under N2 at -20 0C was added HATU (107 mg, 0.28 mmol) and DIPEA (61 mg, 0.47 mmol).

After stirred at 0 0C for 20 min, the mixture was added to a solution of compound 34 (120 mg, 0.25 mmol) in DMA (1 mL). After d at room temperature for 2 hrs, the reaction mixture was diluted with isopropanol/CHClg (1 :3; 60 mL), washed with 1N NaOH (2 x 20 mL), dried over anhydrous Na2S04, concentrated under reduced pressure, and purified by column tography on silica gel with DCM;MeOH (100:0 to 90:10) to give ofN—(l- ((R)acryloylazepanyl)chloro((2-oxopyrrolidin-3 y)- 1H-benzo dazol yl)methylisonicotinamide C1 in 15.5% yield (20 mg) for the last 2 steps. 1H NMR (400 MHz,CDC13): 5 12.7 (bs, 1H), 8.64 (m, 1H), 7.90-7.93 (m, 1H), 7.81-7.84 (m, 1H), 7.34-7.40 (m, 1H), 7.17-7.23 (m, 1H), 6.64 (m, 1H), 6.37-6.43 (m, 1H), 5.96 (s, 1H), .75 (m, 1H), 4.74-4.88 (m, 2H), 4.41-4.58 (m, 1H), 3.83-4.23 (m, 2H), 3.40-3.64 (m, 4H), 1.45-2.79 (m, 10H); MS observed for C27H29C1N6O4: 537.7 (M+H+); HPLC retention time: 4.92 min.

Compounds 31 was prepared according to Scheme 11 and Example 17.

Scheme 11 N/Boc N02 N02 PhCHZONa —,F NH —’ F F C1 C1 N/Boc NO2 NH2 Zn/AcOH BrCN BnO NH BnO NH _, C1 C1 N/Boc N/Boc 30a 30b \ _ N\ >_NH2 _ HOOC \ N N>_NH B110 N / B110 N 0 \ / Example 12 Synthesis ofN—(1-((R)acryloy1azepany1)chloro(((tetrahydrofi1ran-3 -y1)oxy)-1H- benzo[d]imidazoly1)methy1isonicotinamide C2 The synthesis ofN—(1-((R)acryloy1azepan-3 -chloro (((tetrahydrofi1rany1)oxy)-1H—benzo[d]imidazo1y1)methy1isonicotinamide C2 is shown in Scheme 12.

Step I: To a solution of 3-hydroxytetrahydrofuran (200 mg, 1.55 mmol) in DCM (5 mL) was added MszO (539 mg, 3.10 mmol) and pyridine (367 mg, 4.65 mmol) at -10 0C. After stirred at room temperature overnight, the reaction e was diluted with DCM (10 mL), washed with saturated NaHCOg, dried over anhydrous Na2S04, and evaporated to dryness under d pressure to give tetrahydrofurany1methanesulfonate in 89% yield (285 mg).

Scheme 12 OMS N \>_N N H o _ 6 I?“HiN o 35 o \ / HO N \ N Cl 0 / —> C1 CsZCO3 N/Boc O 1. TFA \>—NH _ —> O N \ /N O 0 2. Hooc/\ C1 HATU DIPEA / The conversion from compound 32 to compound 36 was performed according to the procedures as described in Example ll. (3R)-Tert—butyl 3-(7-chloro(2- methylisonicotinamido)((tetrahydrofuran-3 -yl)oxy)- lH-benzo dazol- l -yl)azepane- l - carboxylate 36: MS calculated for C29H36ClN505: 570.6 (M+H+); HPLC retention time: 8.39 min.

Step II: The coversion from compound 36 to compound C2 was performed according to the procedures as described in Example 11. N—(l-((R)-l-Acryloylazepanyl)— 7-chloro(((tetrahydrofuran-3 -yl)oxy)- lH-benzo[d]imidazolyl)methylisonicotinamide C2: 1H NMR(400 MHz, CDClg): 5 12.7 (m, 1H), 8.64 (m, 1H), 7.90-7.93 (m, 1H), 7.81-7.83 (m, 1H), 7.14-7.21 (m, 1H), .66 (m, 1H), 6.36-6.43 (m,lH), .88 (m, 2H), 4.96- 4.99 (m, 1H), 4.41-4.58 (m, 1H), 3.84-4.08 (m, 6H), .68 (m, 1H), 1.49-2.79 (m, (m, 13H); MS observed for C27H30C1N504: 524.1 ; HPLC retention time: 7.14 min.

Example 13 Synthesis of (R)-N—(l -( l oylazepan-3 -yl)chloro((tetrahydro-2H-pyranyl)oxy)— lH—benzo[d]imidazolyl)methylisonicotinamide C3 ogkmedN \ /N 6 00 O in —140— Compound C3 was prepared according to the procedures as described in Example 12. MS observed for C28H32C1N504: 538.6 (M+H+); HPLC retention time: 2.09 min.

Example 14 Synthesis of (R)-N—(1-(1-acryloylazepanyl)chloro((tetrahydro-2H-pyranyl)oxy)— 1H—benzo[d]imidazolyl)(trifluoromethyl)isonicotinamide C4 £1”deN CF3 O N o O\ /N Compound C4 was prepared according to the procedures as described in Example 12. MS observed for C28H29C1F3N504: 592.1 (M+H+); HPLC retention time: 2.14 min. e 1 5 Synthesis of (R)-N—(1-(1-acryloylazepan-3 -yl)chloro((1 , 1 -dioxidotetrahydro-2H- thiopyranyl)oxy)- 1H-benzo[d]imidazolyl)methylisonicotinamide C5 nd CS was prepared according to the procedures as described in e 12. MS observed for eOsS: 586.0 (M+H+); HPLC retention time: 1.94 min. —141— Example 1 6 Synthesis of (R)-N—(1-(1-acryloylazepanyl)chloro(pyrimidinyloxy)- 1H- benzo[d]imidazolyl)methylisonicotinamide C6 The synthesis of (R)-N—(1-(1-acryloylazepanyl)chloro(pyrimidin yloxy)-1H—benzo[d]imidazolyl)methylisonicotinamide C6 is shown in Scheme 13.

Scheme 13 £1vaN 1- —> O N \ N O / 2. Hooc/\ C1 HATU J DIPEA \N / Step I: To a solution of compound 32 (200 mg, 0.4 mmol) in DMF (2 mL) was added C82C03 (99 mg, 0.6 mmol) and 2-chloropyrazine (90 mg, 0.6 mmol). After stirred at 55 0C overnight, the reaction mixture was cooled down to room temperature and saturated NH4C1 (10 mL) was added. The mixture was extracted with isopropanol/CHClg (1:3; 3 x 30 mL). The organic phase was washed with brine, dried over anhydrous , concentrated under reduced pressure, and purfied by column chromatography on silica gel using DCM:MeOH (100:0 to 90: 10) to give nd 37 in 30% yield (70 mg) HPLC retention time: 8.15 min.

Step II: The sion from compound 37 to nd C6 was performed according to the procedures as described in Example 11. MS observed for C27H26C1N703: 532.27 (M+H+); HPLC retention time: 7.01 min. —142— e 1 7 Synthesis of (R)-tert—butyl 3 inochloro(((R)-tetrahydrofuran-3 -yl)oxy)- 1H- benzo[d]imidazol- l -yl)azepane- l -carboxylate 45 The synthesis of ((R)-tert—butyl 3-(2-aminochloro(((R)-tetrahydrofuran- 3-yl)oxy)-lH-benzo[d]imidazol-l-yl)azepane-l-carboxylate 45 is shown in Scheme 14.

Scheme 14 N /Boc N02 N02 —>F NH fl 0 NH F F C1 C1 C1 N/Boc N/Boc OQNHNH2 BrCN N Zn/ACOH \>—NH2 C1 0 N N’Boc 6C] O N/Boc 44 O Step I: A on of 2-chloro-l,3-difluoronitrobenzene 41 (3.29 g, 16.99 mmol) and tert—butyl (R)aminoazepane-l-carboxylate (4.0 g, 18.69 mmol) in DME (80 mL) was stirred at 85 0C for 4 hrs. The reaction was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The organic layers were combined and dried over anhydrous Na2S04. The t was removed under reduced pressure and the residue was purified by flash chromatography on silica (eluent PE/EtOAc = 10: l~5 : l) to give compound 42 in 85% yield (5.6 g). TLC Rf = 0.5 (PE/EtOAc = 5:1, UV 254 nm).

Step II: To a solution of (R)hydroxyltetrahedrofiJran (1.82 g, 20.63 mmol) in DME (100 mL) at 0 0C was added NaHMDS (10.83 mL, 2 M in THF, 21.66 mmol) dropwise. After stirred at 0 0C for 15 min, the e was then added dropwise to a solution of tert—butyl (R)((2-chlorofluoronitrophenyl)amino)azepane-l-carboxylate 42 (4.0 g, .31 mmol) in DME (50 mL) at 0 0C. The reaction mixture was heated at 50 0C for 2 hrs.

After the mixture was cooled to 0 0C, ice water (100 mL) was added and extracted with EtOAc (3 x 200 mL). The organic layers were combined and dried over anhydrous Na2S04. —143— The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica (eluent PE/EtOAc = 10: 1~2: 1) to give tert—butyl (R)((2-chloro nitro(((R)-tetrahydrofuranyl)oxy)phenyl)amino)azepanecarboxylate 43 in 61% yield (2.88 g). TLC Rf = 0.35 (PE/EtOAc = 2:1, UV 254 nm).

] Step III: The conversion from compound 43 to compound 45 was carried out ing to the procedures as described in Example 2 and Scheme 2.

Example 1 8 Synthesis ofN-( 1 -((R)acryloylazepan-3 -chloro(((R)-tetrahydrofuran-3 y)- zo[d]imidazolyl)methylisonicotinamide C7 The synthesis ofN—( 1 -((R)acryloylazepanyl)chloro(((R)- tetrahydrofi1ranyl)oxy)-1H—benzo[d]imidazolyl)methylisonicotinamide C7 is shown in Scheme 15.

Scheme 15 N —> OQuid\ N 0 / 2. Hooc/\ C1 HATU DIPEA / [003 80] The conversion from compound 45 to compound 46 was performed according to the procedures as described Example 2 and Scheme 2. The conversion from compound 46 to compound C7 were performed according to the procedures as described in Example 11.

N—( 1 -((R)Acryloylazepan-3 -yl)chloro(((R)-tetrahydrofi1ran-3 -yl)oxy)-1H- benzo[d]imidazolyl)methylisonicotinamide C7. MS observed for C27H30C1N504: 524.6 (M+H+); HPLC retention time: 2.14 min. —144— Example 1 9 Synthesis ofN-( l -((R)- l -acryloylazepan-3 -yl)chloro(((R)—tetrahydrofuran-3 -yl)oxy)- 1H-benzo[d]imidazolyl)(trifluoromethyl)isonicotinamide C8 [003 8 l] N—( l -((R)- l -Acryloylazepan-3 -yl)chloro(((R)-tetrahydrofi1ran-3 -yl)oxy)- lH—benzo[d]imidazolyl)(trifluoromethyl)isonicotinamide C8 was sized according to the procedures as described in e 18. MS observed for ClF3N504: 576.4 (M+H'), 578.2 (M+H+); HPLC retention time: 1.85 min.

Example 20 Synthesis ofN—( l -((R)- l -acryloylazepan-3 -chloro(((S)—tetrahydrofi1ran-3 -yl)oxy)- lH—benzo[d]imidazolyl)methylisonicotinamide C9 01?:*2:de\ / [003 82] N—( l -((R)- l -Acryloylazepan-3 -yl)chloro(((S)-tetrahydrofuran-3 -yl)oxy)- lH—benzo[d]imidazolyl)methylisonicotinamide C9 was synthesized according to the procedures as described in Example 18. MS observed for C27H30ClN504: 522.5 (M-H'); HPLC retention time: 2.05 min. —145— Example 21 Synthesis ofN—( 1 -((R)acryloylazepan-3 -yl)chloro(((S)—tetrahydrofi1ran-3 -yl)oxy)- 1H-benzo[d]imidazolyl)(trifluoromethyl)isonicotinamide C 10 0);:[E>—NHO\_CN QC1 NJ; [003 83] N—( 1 -((R)Acryloylazepan-3 -chloro(((S)-tetrahydrofuran-3 -yl)oxy)- 1H-benzo[d]imidazolyl)(trifluoromethyl)isonicotinamide C 10 was synthesized according to the procedures as described in Example 18. MS observed for C27H27C1F3N504: 576.5 (M-H'); HPLC retention time: 1.85 min.

Example 22 Synthesis of (R)-N—(1-(1-(3-chloropropanoyl)azepanyl)((1-methylpiperidinyl)oxy)- 1H-benzo [d]imidazolyl)methylisonicotinamide D 1 and (R)-N—(1-(1-acryloylazepan-3 - yl)((1 -methylpiperidinyl)oxy)-1H-benzo[d]imidazolyl)methylisonicotinamide D2 [003 84] The synthesis of (1-(1-(3-chloropropanoyl)azepan-3 -yl)((1- methylpiperidinyl)oxy)- zo [d]imidazolyl)methylisonicotinamide D1 and (R)- N—( 1 -( 1 -acryloylazepan-3 -(( 1 -methylpiperidinyl)oxy)- 1H-benzo [d]imidazolyl)—2- methylisonicotinamide D2 is shown in Scheme 16.

Scheme 16 :>—\ NH \—/N _2, 1. TFA HCOH \—/N 0/o NCN’BOC NaBH(0Ac)3 /UO C:,BOC 2. C1CH2CH2CZOH HN HATU 3 51 DIPEA W0 2015/143148 Step I: To a solution of compound 3 (510 mg, 0.929 mmol) in 1.2- dichloroethane (3 mL) at 0 0C was added HCOOH (120 mg, 1.39 mmol) and NaBH(OAc)3 (256 mg). After the reaction mixture was d at room ature for 3 hrs, water (10 mL) was added and the mixture was extracted with CHClg/isoporpanol (3:1, 30 mL x 3). The organic phase was dried with anhydrous Na2SO4 and concentrated under reduced pressure.

The resulting residue was used directly in the next step without further purification.

Step II: The conversion from compound 51 to compound D1 was performed according to the ures as described in Example 11. First, compound 51 was d with TFA to form a free amine. To a solution of the free amine (400 mg, 0.865 mmol) in anhydrous THF under N2 at -30 0C was added 3-chloropropanyl acid (113 mg), DIPEA (223 mg), and HATU (390 mg). The reaction mixture was d to slowly warm up to room temperature. After stirred at room ature for 1 hr, the LC-MS showed no starting material left. Isopropanol/CHC13 (1 :3; 60 mL) and H20 (30 mL) was added. The organic phase was washed with NaHCOg, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified via Combi-Flash (1-10% MeOH in DCM) to give compound D1. MS observed for C29H37C1N603: 553.1 (M+H+); HPLC retention time: 6.81 min. [003 87] Step III: To a solution of compound D1 (514 mg) in dioxane (5 mL) was added NaOH (104 mg) in H20 (2 mL). After the reaction e was stirred at 50 0C for 1 hr, LC-MS showed no ng material left. The reaction mixture was extracted with isopropanol and CHC13(1 :3) (60 mL). The organic phase was concentrated and purified via Combi-Flash (1-10% MeOH in DCM) to give compound D2 in 31% yield (149 mg) for the last three steps. MS ed for C29H36N603: 517.6 (M+H+); HPLC retention time: 6.92 min.

Example 23 Synthesis of (R)-N-(1-(1-acryloylazepan-3 -yl)(( 1 -cyclopropylpiperidinyl)oxy)- 1H- benzo[d]imidazolyl)(trifluoromethyl)isonicotinamide D3 mmCF3 V10 02 —147— [003 8 8] (R)-N—(l -( l -Acryloylazepan-3 -yl)((l -cyclopropylpiperidinyl)oxy)- lH- benzo[d]imidazolyl)(trifluoromethyl)isonicotinamide D3 was synthesized according to the procedures as described in Example 22. MS observed for C31H35F3N603: 597.5 (M+H+); HPLC retention time: 2.10 min. e 24 Synthesis of (R)-N—( l -( l -acryloylazepan-3 -yl)(( l propylpiperidin—4-yl)oxy)- lH- benzo[d]imidazolyl)methylisonicotinamide D4 [003 89] (R)-N—(l -( l -Acryloylazepan-3 -yl)((l -cyclopropylpiperidinyl)oxy)- lH- benzo[d]imidazolyl)methylisonicotinamide D4 was synthesized according to the procedures as described in Example 22. MS observed for C31H38N603: 543.6 (M+H+); HPLC retention time: 1.99 min.

Example 25 Synthesis of (R)-N—( l -( l -acryloylazepan-3 -yl)(( l -isopropylpiperidinyl)oxy)- lH- benzo[d]imidazolyl)(trifluoromethyl)isonicotinamide D5 98%N CF3 YO N2 (R)-N—(l -( l -Acryloylazepan-3 -(( l -isopropylpiperidinyl)oxy)- lH- d]imidazolyl)(trifluoromethyl)isonicotinamide D5 was synthesized according to the ures as described in Example 22. MS observed for C31H37F3N603: 599.5 (M+H+); HPLC retention time: 2.11 min.

Example 26 Synthesis of (R)-N—( l -( l -acryloylazepan-3 -yl)(( l -isopropylpiperidinyl)oxy)- 1H- benzo[d]imidazolyl)methylisonicotinamide D6 YCr Cw [0039 l] (R)-N—(l -( l -Acryloylazepan-3 -yl)(( l -isopropylpiperidinyl)oxy)- 1H- benzo[d]imidazolyl)methylisonicotinamide D6 was synthesized ing to the procedures as described in Example 22. MS observed for N603: 545.5 (M+H+); HPLC retention time: 1.98 min.

Example 27 Synthesis of (R)-N—( l -(l -acryloylazepan-3 -yl)(( l -(2,2,2-trifluoroethyl)piperidinyl)oxy)- 1H-benzo[d]imidazolyl)methylisonicotinamide D7 The synthesis of (l -( l -acryloylazepan-3 -(( 1 -(2,2,2- trifluoroethyl)piperidinyl)oxy)-1H-benzo[d]imidazolyl)methylisonicotinamide D7 is shown in Scheme 17.

Scheme 17 N\>—NH _ \ N CF3CHZSO3CF3 :\>_NH\ o / 30/052 N/Boc :rifidCVN 1. TFA O\ N 2. C1CH3CH3C30H HATU CNV DIPEA 3. NaOH —149— Step I: To a solution of compound 3 (120 mg, 0.2 mmol) in DME (2 mL) at 0 0C was added CF3CH20802CF3 (95 mg) and DIPEA (103 mg). After the reaction mixture was d at room temperature overnight, a second batch of CF3CH20802CF3 (95 mg) and K2C03 (30 mg) were added. The reaction mixture was stirred at room temperature for 3 days and then purified with flash column chromatograph with 0-30% EtOAc in hexanes to give nd 52 in 53% yield (66 mg). MS: 531.7 (M+H+).

Step II: The sion from compound 52 to compound D7 was performed ing to the procedures as described in Example 22. MS observed for C30H35F3N603: 585.7 (M+H+); HPLC retention time: 7.01 min.

Example 28 sis of (R)-N-(7-(( l -acetylpiperidinyl)oxy)- l -(l -(3 -chloropropanoyl)azepan-3 -yl)- lH-benzo[d]imidazolyl)—2-(trifluoromethyl)isonicotinamide D8 and (R)-N-(7-(( l - acetylpiperidinyl)oxy)- l -(l -acryloylazepan-3 -yl)- lH-benzo [d]imidazolyl) (trifluoromethyl)isonicotinamide D9 The synthesis of (R)-N-(7-((l -acetylpiperidinyl)oxy)-l-(l-(3- chloropropanoyl)azepan-3 -yl)- lH-benzo [d]imidazolyl)(trifluoromethyl)isonicotinamide D8 and (R)-N-(7-((l -acetylpiperidinyl)oxy)- l -(l -acryloylazepan-3 -yl)- lH- benzo[d]imidazolyl)(trifluoromethyl)isonicotinamide D9 is shown in Scheme 18, and was sized according to the procedures as described in Example 22..

Scheme 18 2Y2zE Ioo /\Iz zfz02I 20J” /\l |> .—] ’Tl —> O O/O N/BOC 2.C1CH2CH2CZOH N’BOC O N HATU j“ Y 54 DIPEA -l50- (7-((1-Acetylpiperidinyl)oxy)(1-(3-chloropropanoyl)azepan-3 -yl)- 1H—benzo[d]imidazolyl)(trifluoromethyl)isonicotinamide D8. MS observed for C30H37ClN6O4: 635.1 (M+H+); HPLC retention time: 2.03 min.

(R)-N—(7-((1-Acetylpiperidinyl)oxy)(1-acryloylazepan-3 -yl)- 1H- benzo[d]imidazolyl)(trifluoromethyl)isonicotinamide D9. MS observed for C30H36N6O4: 599.1 (M+H+); HPLC retention time: 2.09 min.

Example 29 Synthesis of (R)-N—(1-(1-acryloylazepanyl)((tetrahydro-2H-pyranyl)oxy)- 1H- benzo[d]imidazolyl)methylisonicotinamide D 10 (R)-N—(1-(1-Acryloylazepanyl)((tetrahydro-2H-pyranyl)oxy)- 1H- benzo[d]imidazolyl)methylisonicotinamide D10 was sized according to the procedures as bed in Examples 2, 3, and 18. MS observed for N504: 504.10 (M+H+); HPLC retention time: 2.21 min.

Example 30 Synthesis of (1-(1-acryloylazepan-3 -yl)((1 , 1 -dioxidotetrahydro-2H-thiopyran yl)oxy)- 1H-benzo[d]imidazolyl)methylisonicotinamide D 1 1 (R)-N—(1-(1-Acryloylazepan-3 -yl)((1 ,1-dioxidotetrahydro-2H—thiopyran yl)oxy)-1H—benzo[d]imidazolyl)methylisonicotinamide D11 was synthesized according to the procedures as described in Examples 2, 3, and 18. MS observed for C28H33N505S: 552.5 (M+H+); HPLC ion time: 2. ll min.

***** The examples set forth above are provided to give those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of what is sed herein.

Modifications that are s to persons of skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference. -l52-

Claims (67)

WHAT WE CLAIM IS:

1. A compound of Formula XIa or XIX: (XIa) (XIX) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt or solvate thereof; n each R1 is independently selected from the group consisting of: , , , , , , , , , , , , , , , O N , , and ; R2 is C6-14 aryl or heteroaryl; each R4, R5, and R7 is independently (a) hydrogen, cyano, halo, or nitro; (b) C1- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 lkyl, C6-14 aryl, C7-15 l, heteroaryl, or heterocyclyl; or (c) 1a, –C(O)OR1a, –C(O)NR1bR1c, –C(NR1a)NR1bR1c, –OR1a, –OC(O)R1a, –OC(O)OR1a, –OC(O)NR1bR1c, –OC(=NR1a)NR1bR1c, –OS(O)R1a, –OS(O)2R1a, –OS(O)NR1bR1c, –OS(O)2NR1bR1c, –NR1bR1c, –NR1aC(O)R1d, –NR1aC(O)OR1d, –NR1aC(O)NR1bR1c, –NR1aC(=NR1d)NR1bR1c, –NR1aS(O)R1d, –NR1aS(O)2R1d, –NR1aS(O)NR1bR1c, –NR1aS(O)2NR1bR1c, –SR1a, –S(O)R1a, –S(O)2R1a, –S(O)NR1bR1c, or –S(O)2NR1bR1c; R6a is C3-7 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; R7a is C3-7 cycloalkyl, C6-14 aryl, aryl, or heterocyclyl; R2n is C1-6 alkyl or –OR1a; each R1a, R1b, R1c, and R1d is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 l, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or R1a and R1c together with the C and N atoms to which they are attached form heterocyclyl; or R1b and R1c together with the N atom to which they are attached form heterocyclyl; and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more tuents Q, where each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C1-6 alkyl, C2-6 l, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further ally substituted with one or more substituents Qa; and (c) –C(O)Ra, –C(O)ORa, –C(O)NRbRc, –C(NRa)NRbRc, –ORa, –OC(O)Ra, –OC(O)ORa, –OC(O)NRbRc, –OC(=NRa)NRbRc, –OP(O)(ORa)2, –OS(O)Ra, –OS(O)2Ra, –OS(O)NRbRc, –OS(O)2NRbRc, –NRbRc, O)Rd, –NRaC(O)ORd, –NRaC(O)NRbRc, –NRaC(=NRd)NRbRc, –NRaS(O)Rd, –NRaS(O)2Rd, –NRaS(O)NRbRc, –NRaS(O)2NRbRc, –SRa, –S(O)Ra, –S(O)2Ra, –S(O)NRbRc, and –S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or cyclyl, each of which is optionally substituted with one or more substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Qa; wherein each Qa is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) f, –C(O)ORf, –C(O)NRgRh, –C(NRf)NRgRh, –ORf, –OC(O)Rf, –OC(O)ORf, NRgRh, Rf)NRgRh, –OP(O)(ORf)2, –OS(O)Rf, –OS(O)2Rf, –OS(O)NRgRh, –OS(O)2NRgRh, –NRgRh, –NRfC(O)Rk, –NRfC(O)ORk, –NRfC(O)NRgRh, –NRfC(=NRk)NRgRh, –NRfS(O)Rk, –NRfS(O)2Rk, –NRfS(O)NRgRh, –NRfS(O)2NRgRh, –SRf, –S(O)Rf, –S(O)2Rf, –S(O)NRgRh, and –S(O)2NRgRh; wherein each Rf, Rg, Rh, and Rk is independently (i) en; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 l, heteroaryl, or heterocyclyl; or (iii) Rg and Rh together with the N atom to which they are attached form heterocyclyl.

2. The compound of claim 1, having the structure of Formula XIa: (XIa) or a single enantiomer, a c mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 2, wherein R2n is methyl, uoromethyl, difluoromethyl, trifluoromethyl, –OH, or –OCH3.

4. The compound of any one of claims 1 to 3, wherein R7a is C3-10 cycloalkyl or heterocyclyl, each of which is optionally substituted with one or more substituents Q.

5. The compound of claim 4, wherein R7a is heterocyclyl, optionally tuted with one or more substituents Q.

6. The compound of claim 4, wherein R7a is N O O N R1a , R1a , , , O N O N O N , R1a , R1a , , R1a , O N N O N O N R1b O N R1b O R1a , , R1a , R1a , , O O N O O O O N O , O , R1a, R1a , , , , , , , , , , , , or ; p and q are each independently an integer of 0, 1, or 3, with the proviso that the total of p and q is no less than 1; and each r is independently an integer of 0, 1, 2, 3, 4, 5, or 6.

7. The compound of claim 4, wherein R7a is , , , , , , or .

8. The compound of claim 2, wherein the nd is selected from the group consisting of: O O N N N N NH NH N N O O O O N N N O N , , A1 A2 N N O O N , O , D2 , , D3 D4 N CF3 N NH NH N N N N O O O O O O N N N N , , D5 D6 N N O O F3C N N N NH NH N N N N O O O O O N N O O S , and O ; D10 D11 or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt or solvate f.

9. The compound of claim 1, having the structure of Formula XIX: R4 O R5 N R2 O N N R1 (XIX) or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant f; or a pharmaceutically able salt or solvate thereof.

10. The compound of claim 9, having the structure of Formula XXa: (XXa) or a single enantiomer, a racemic mixture, a mixture of reomers, or an isotopic t thereof; or a pharmaceutically acceptable salt or solvate f.

11. The compound of claim 9, wherein R2n is methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, –OH, or –OCH3.

12. The compound of any one of claims 9 to 11, wherein R7 is chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, or –OR1a.

13. The compound of claim 12, wherein R7 is chloro.

14. The compound of any one of claims 9 to 13, wherein R6a is: N O O N , R1a , R1a , , , O N O N O N , R1a , R1a , , R1a , O N N O N O N R1b O N R1b O R1a , , R1a , R1a , , O O N O O O O N O , O , R1a, R1a , , , , , , , , , , , , , , , , or ; wherein: p and q are each independently an integer of 0, 1, or 3, with the proviso that the total of p and q is no less than 1; and each r is independently an integer of 0, 1, 2, 3, 4, 5, or 6.

15. The compound of any one of claims 9 to 13, n R6a is: , , , , , , or .

16. The compound of any one of claims 1, 9, and 12 to 15, wherein R2 is 6- to 10- membered monocyclic or bicyclic aryl, optionally substituted with one or more substituents Q.

17. The compound of any one of claims 1, 9, and 12 to 15, wherein R2 is 5- to 10- membered monocyclic or bicyclic heteroaryl comprising 1 to 4 atoms selected from N, O, and S, optionally substituted with one or more substituents Q.

18. The nd of any one of claims 1, 9, and 12 to 15, wherein R2 is phenyl, pyridinyl, pyridazinyl, benzo[c][1,2,5]oxodiazolyl, or benzo[c][1,2,5]thiodiazolyl, each of which is optionally substituted with one or more tuents Q.

19. The compound of any one of claims 1, 9, and 12 to 15, wherein R2 is hydroxypyridinyl , methoxy-pyridinyl, methyl-pyridinyl, difluoromethyl-pyridinyl, trifluoromethyl-pyridinyl, methylaminocarbonyl-pyridinyl, or methyl-pyridazinyl.

20. The nd of any one of claims 1, 9, and 12 to 19, wherein R4 is hydrogen.

21. The compound of any one of claims 1, 9, and 12 to 20 wherein R5 is hydrogen.

22. The compound of any one of claims 1, 9, and 12 to 21, wherein R6 is hydrogen.

23. The compound of claim 9, wherein the compound is selected from the group consisting of: O N N Cl O , , C1 C2 , , C3 C4 , , C7 C8 , , C9 C10 , , C11 C12 , , C13 C14 N CHF2 N CHF2 NH NH O N N O N N O O O Cl Cl O N N O O , , and C15 C16 N OCH3 O N N Cl O or a single enantiomer, a racemic mixture, a mixture of reomers, or an ic variant thereof; or a pharmaceutically acceptable salt or solvate thereof.

24. A compound selected from: N N NH NH N N N N O O O O O O N N N O N Cl and Cl , D1 D8 or a single enantiomer, a racemic mixture, a e of diastereomers, or an isotopic variant thereof; or pharmaceutically acceptable salt or solvate thereof.

25. A pharmaceutical composition comprising the compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt or solvate f; and a ceutically acceptable excipient.

26. The pharmaceutical composition of claim 25, wherein the composition is formulated as a single dosage form.

27. The pharmaceutical composition of claim 25 or 26, wherein the composition is formulated as oral, parenteral, nasal, respiratory, pulmonary, or intravenous dosage form.

28. The pharmaceutical ition of claim 27, wherein the pharmaceutical composition is in an oral dosage form.

29. The pharmaceutical composition of claim 28, wherein the oral dosage form is a tablet or capsule.

30. Use of the compound of any one of claims 1 to 24, or the pharmaceutical composition of any one of claims 25 to 29, in the preparation of a medicament for treating, preventing, or ameliorating a proliferative disease in a human subject.

31. The use of claim 30, wherein the proliferative disease is cancer.

32. The use of claim 31, wherein the cancer is drug-resistant.

33. The use of claim 31 or 32, wherein the cancer ns an ERBB variant.

34. The use of claim 33, wherein the ERBB variant is an EGFR variant.

35. The use of claim 34, wherein the EGFR variant contains one or more deletions, insertions, or tutions at the amino acid positions of 689, 700, 709, 715, 719, 720, 746-759, 761-765, 767-775, 783, 784, 790, 796, 826, 839, 846, 858, 861, and 863.

36. The use of claim 35, n the EGFR variant contains one or more deletions, insertions, or substitutions at the amino acid positions of 719, 746-751, 790, and 858.

37. The use of claim 35, wherein the EGFR variant contains one, two, or more deletions, insertions, and/or substitutions, each independently selected from G719C, G719S. G719A, ΔE746-A750, ΔE746-T751, A750 (ins RP), ΔD761-E762 (ins EAFQ), D770 (dup SVD), ΔV769-D770 (ins ASV), ΔD770-N771 (ins SVQ), ΔP772-H773 (ins PR), ΔH773-V774 (ins NPH), ΔH773-V774 (ins H), ΔH773-V774 (ins PH), and ΔH773-V774 (ins GNPH), T790M, and L858R.

38. The use of claim 34, wherein the EGFR variant contains T790M, L858R, or a ation thereof.

39. The use of claim 33, wherein the ERBB variant is a HER2 variant.

40. The use of claim 39, wherein the HER2 is overexpressed in the cancer.

41. The use of any one of claims 31 to 40, wherein the cancer is resistant to an EGFR inhibitor.

42. The use of claim 41, wherein the cancer is resistant to afatinib, canertinib, dacomitinib, nib, gefitinib, icotinib, lapatinib, neratinib, pelitinib, varlitinib, or a combination thereof.

43. The use of any one of claims 31 to 42, wherein the cancer is bladder cancer, brain tumor, breast , cancer of the mouth and throat, colorectal cancer, lung cancer, or pancreatic cancer, prostate cancer, stomach cancer, or uterine cancer.

44. The use of claim 43, wherein the cancer is lung cancer.

45. The use of claim 43, wherein the cancer is non-small cell lung cancer.

46. The use of any one of claims 31 to 45, wherein the cancer is ed or refractory.

47. A method of treating, preventing, or ameliorating a erative disease in a non-human subject, the method comprising administering a compound of any one of claims 1-24, or the composition according to any one of claims 25-29.

48. The method of claim 47, wherein the erative disease is cancer.

49. The method of claim 48, wherein the cancer is drug-resistant.

50. The method of claim 48 or 49, wherein the cancer contains an ERBB variant.

51. The method of claim 50, wherein the ERBB t is an EGFR variant.

52. The method of claim 51, wherein the EGFR variant contains one or more deletions, insertions, or substitutions at the amino acid positions of 689, 700, 709, 715, 719, 720, 746-759, 761-765, 767-775, 783, 784, 790, 796, 826, 839, 846, 858, 861, and 863.

53. The method of claim 51, wherein the EGFR variant contains one or more deletions, insertions, or tutions at the amino acid positions of 719, 746-751, 790, and 858.

54. The method of claim 51, wherein the EGFR variant contains one, two, or more deletions, insertions, and/or substitutions, each independently selected from G719C, G719S. G719A, ΔE746-A750, ΔE746-T751, ΔE746-A750 (ins RP), E762 (ins EAFQ), ΔS768-D770 (dup SVD), ΔV769-D770 (ins ASV), ΔD770-N771 (ins SVQ), ΔP772-H773 (ins PR), ΔH773-V774 (ins NPH), ΔH773-V774 (ins H), V774 (ins PH), and ΔH773-V774 (ins GNPH), T790M, and L858R.

55. The method of claim 51, wherein the EGFR t contains T790M, L858R, or a combination thereof.

56. The method of claim 50, wherein the ERBB variant is a HER2 t.

57. The method of claim 56, n the HER2 is overexpressed in the cancer.

58. The method of any one of claims 48 to 57, wherein the cancer is resistant to an EGFR inhibitor.

59. The method of claim 58, n the cancer is resistant to afatinib, canertinib, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, neratinib, pelitinib, varlitinib, or a combination thereof.

60. The method of any one of claims 48 to 59, wherein the cancer is bladder cancer, brain tumor, breast cancer, cancer of the mouth and throat, colorectal cancer, lung cancer, or pancreatic cancer, prostate cancer, stomach cancer, or uterine cancer.

61. The method of claim 60, n the cancer is lung cancer.

62. The method of claim 60, wherein the cancer is non-small cell lung cancer.

63. The method of any one of claims 48 to 62, wherein the cancer is relapsed or refractory.

64. A compound according to claim 1 substantially as herein described or exemplified.

65. A pharmaceutical ition according to claim 25 substantially as herein described or exemplified.

66. A use according to claim 30 ntially as herein described or exemplified.

67. A method according to claim 47 substantially as herein described or exemplified.