Benzimidazole derivatives as ERBB tyrosine kinase inhibitors for cancer treatment

Abstract

Provided herein are benzimidazole derivatives, such as those of Formula I, and pharmaceutical compositions thereof. Also provided herein are methods of using the same to treat, prevent, or ameliorate one or more symptoms of a proliferative disease.

Description

[0001] This application is a divisional application of the Chinese invention patent application filed on March 19, 2015, with application number 201580023803.1 and entitled “Benzimidazole derivatives as ERBB tyrosine kinase inhibitors for the treatment of cancer”.

[0002] Cross-reference to related applications

[0003] This application claims the benefit of priority to U.S. Provisional Application No. 61 / 968,225, filed on March 20, 2014, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0004] Provided herein are benzimidazole derivatives and pharmaceutical compositions thereof. Also provided herein are methods of using the same to treat, prevent, or ameliorate one or more symptoms of a proliferative disease. Background Art

[0005] Within the human receptor tyrosine kinase superfamily, the ERBB family comprises four members: ERBB1 (epidermal growth factor receptor, or EGFR), ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4). ERBB receptors share an overall similar structure, with a ligand-binding extracellular domain, a single transmembrane domain, and an intracellular kinase domain that is active in ERBB1, HER2, and ERBB4, but deficient in ERBB3. A diverse array of ligands has been identified for the extracellular domains of ERBB1, ERBB3, and ERBB4, but not HER2. Ligand binding can induce conformational changes in the receptors to form homo- and heterodimers. In the absence of ligand binding, the extracellular domain of HER2 is fixed in a conformation similar to that of other ligand-activated ERBB members, making it a preferred dimerization partner for other ligand-bound ERBBs. Dimeric receptors activate endogenous kinase activity, leading to phosphorylation of tyrosines in the cytoplasmic tail. ERBB receptors differ in kinase potency, phosphorylation sites, and substrate specificity. Phosphorylated tyrosine acts as a docking site to recruit downstream effectors and activate multiple cascades of intracellular signaling pathways, including anti-apoptosis / survival PI3K / AKT and pro-cell division RAS / RAF / MEK / ERK pathways. In normal cells, the activity of ERBB receptors is strictly controlled to regulate different cell processes, such as growth, proliferation, development and differentiation, survival and apoptosis, cell shape and adhesion, migration and angiogenesis. Yaden et al., Natural Molecular Cell Biology Review (Nat.Rev.Mol.Cell.Biol.) 2001, 2, 127-137; Hynes et al., Natural Cancer Review (Nat.Rev.Cancer) 2005, 5, 341-354.

[0006] As the main proliferation and survival engine of cells, ERBB receptors, especially the constitutive activation of ERBB1 and HER2 are carcinogenic and can be a strong driving factor for tumorigenesis in cultured cells and animal models. In addition, activated receptors accelerate cancer development by promoting tumor angiogenesis and metastasis. Persistent activation can be caused by the overexpression of receptors, the production of excessive ligands or the generation of activating mutations in the extracellular domain and kinase domain of receptors. Yaden et al., Nature Mol Cell Biology Reviews 2001, 2, 127-137. In humans, ERBB genes and other genes causing similar disorders of ERBB receptors are often found in most carcinomas (such as lung cancer, breast cancer, colon cancer, prostate cancer, brain cancer, head and neck cancer, esophageal cancer, ovarian cancer, cervical cancer, bladder cancer, gastric cancer and endometrial cancer). Abnormal activation of ERBB receptors is generally a poor prognostic indicator of higher recurrence rate and shorter survival time. Nicholson et al., Eur. J. Cancer 2001, 37, 9-15; Slamon et al., Science 1997, 235, 177-182.

[0007] Given the significant association of ERBB receptor activation with human cancers, ERBB1 and HER2 have become kinase targets for drug development aimed at controlling signal transduction pathways for cancer treatment. To reverse the aberrant activity of ERBB receptors in tumors, monoclonal antibodies targeting the extracellular domains of ERBB1 and HER2 and small molecule chemicals that inhibit the intracellular kinase domains have been developed.

[0008] Monoclonal antibody drugs attack ERBB receptors with high specificity and alleviate ERBB-mediated signal transduction by the following means: prevent ligand binding and receptor dimerization, eliminate receptors from the cell surface via endocytosis, suppress the discharge of extracellular domains and activate the immune system. Hudis, New England Journal of Medicine (N.Engl.J.Med.) 2007, 357, 39-51. Cetuximab (Cetuximab) and panitumumab (panitumumab) (two anti-ERBB1 antibodies) have been shown to improve response rate and progression-free survival in the treatment of metastatic colon cancer as monotherapy or in combination with chemotherapy. In addition, cetuximab is also approved for the treatment of locally advanced, unresectable or metastatic squamous cell carcinoma of the head and neck. Ciardiello et al., New England Journal of Medicine 2008, 358, 1160-1174. The anti-HER2 antibody trastuzumab binds to domain IV of the HER2 receptor in a juxta-membrane location. In clinical development, trastuzumab has shown increased overall survival in patients with early-stage and metastatic breast cancer whose tumors exhibit IHC3+HER2 overexpression or a FISH gene amplification ratio of at least 2.0. Using the same patient selection criteria, pertuzumab (which binds to a different epitope at domain II of the HER2 receptor) was found to further improve complete response rates by adding it to a course of trastuzumab and docetaxel as neoadjuvant therapy for patients with locally advanced, early-stage breast cancer. Gradishar, New England Journal of Medicine 2012, 366, 176-178.

[0009] The development of small molecule ERBB1 kinase inhibitors (ERBB1I) has become an evolutionary paradigm for using cancer genomics to guide targeted drug development and treatment. Gefitinib and erlotinib (the first two ERBB1I drugs) are reversible ATP analog inhibitors that bind to the wild-type ERBB1 catalytic domain to inhibit tyrosine kinase activity. In unselected patients with non-small cell lung cancer (NSCLC) or pancreatic cancer, only erlotinib showed clinical benefit by modestly improving overall survival. Ciardiello et al., New England Journal of Medicine 2008, 358, 1160-1174. In a subset of NSCLC patients with activating mutations within the ERBB1 tyrosine kinase domain, both gefitinib and erlotinib treatment were highly sensitive and sustained efficacy was achieved as monotherapy. Most of these drug-responsive mutations are in-frame deletions clustered around Leu-Arg-Glu-Ala at positions 747 to 750 in ERBB1 exon 19 or a leucine to arginine substitution at position 858 (L858R) in exon 21.

[0010] However, the initial response to erlotinib or gefitinib relapses within 10-14 months due to the development of resistance mutations in the tumor. Among them, the T790M gate-keeper point mutation in exon 20 of ERBB1 is found in more than 50% of acquired resistant tumors, which produces spatial interference with drug binding. In order to overcome resistance from the T790M mutation and provide sustained ERBB1 inhibition, second-generation ERBB1Is have been developed, some of which are irreversible ERBB1 and HER2 dual inhibitors. Irreversible compounds overcome the kinase binding steric hindrance from the T790M mutation by better adapting to the mutation binding pocket and forming covalent bonds with protein amino acid residues. In addition, compared with reversible inhibitors, irreversible ERBB1Is appear to cause slower acquired resistance to treatment. Sharma et al., Nat. Rev. Cancer 2007, 7.169-181.

[0011] In preclinical testing, afatinib (a second-generation ERBB1I) inhibited the growth of NSCLC HCC827 cells (which have a sensitive exon 19 deletion) and was 50-fold more effective than erlotinib (which has a T790M mutation that is compliant with the L858R mutation) in inhibiting the growth of NSCLC H1975 cells. However, afatinib also inhibited A431 cells (whose growth is driven by wild-type ERBB1) with 100-fold greater effectiveness than H1975. This difference in potency suggests that in cancer patients, the compound can completely inhibit wild-type ERBB1 before it reaches sufficient blood levels for pharmacological effects against the T790M mutant ERBB1. Because wild-type ERBB1 inhibition has been reported to cause dose-limiting toxicities in almost all previous ERBB1I drugs, preferential inhibition of wild-type ERBB1 over resistant mutants poses a potential challenge for achieving sufficiently high doses of afatinib for inhibition of the T790M mutant. Consistent with preclinical findings, clinical studies have found that afatinib only demonstrated equivalent efficacy to erlotinib or gefitinib in patients with sensitizing mutations, but even at the maximum tolerated dose, it failed to demonstrate statistically significant superiority over erlotinib and gefitinib in treating patients with acquired T790M resistance mutations. Langer, J. Clin. Oncol. 2013, 31, 3303-3330. Therefore, there is a clear and unmet need for the development of effective therapies for the treatment of proliferative diseases, particularly drug-resistant cancers. Summary of the Invention

[0012] Provided herein are compounds of Formula I:

[0013]

[0014] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof;

[0015] R 1 -C(O)CR 1e =CR 1f CR 1g 、 -N 1a C(O)CR 1e =CR 1f CR 1g 、 -S(O)CR 1e =CR 1f CR 1g 、 -S(O2)CR 1e =CR 1fCR 1g 、 -NR 1a S(O)CR 1e =CR 1f CR 1g 、 -NR 1a S(O2)CR 1e =CR 1f CR 1g or

[0016] R 2 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0017] L 1 For bonds, -O-, -S-, -N(R 1A )-or-C(R 1A R 1B )-, where each R 1A and R 1B are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0018] L 2 C 3-10 Cycloalkylene, C 6-14 Arylene, C 7-15 an aralkylene group, a heteroarylene group, or a heterocyclylene group;

[0019] T is a bond, -O-, -S-, -N=, -N(R 4 )-、-C(R 4 )=or-C(R 4 )2-;

[0020] U is a bond, -O-, -S-, -N=, -N(R 5 )-、-C(R 5 )=or-C(R 5 )2-;

[0021] V is a bond, -O-, -S-, -N=, -N(R 6 )-、-C(R 6 )=or-C(R6 )2-;

[0022] W is a bond, -O-, -S-, -N=, -N(R 7 )-、-C(R 7 )=or-C(R 7 )2-;

[0023] X and Y are each independently C or N;

[0024] Z is NR 2A or CR 2A R 2B , where each R 2A and R 2B are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0025] Each R 4 、R 5 、R 6 and R 7 are independently (a) hydrogen, cyano, halo or nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl; or (c)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;

[0026] Each R 1a 、R 1b 、R 1c and R 1d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic; or R 1a and R 1c Together with the C and N atoms to which they are attached, they form a heterocyclic group; or R 1b and R 1c Together with the nitrogen atom to which they are attached, they form a heterocyclic group; and

[0027] Each R 1e 、R 1f and R 1g are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15Aralkyl, heteroaryl or heterocyclic group;

[0028] with the restriction that no more than one of T, U, V, and W is a bond; and

[0029] The constraint condition is that when L 1 When R is a key, 4 、R 5 、R 6 and R 7 At least one of them is bromine, -OR 7a or -NR 1b R 1c , where R 7a C 4-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0030] 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, wherein each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three or four substituents Q a substituted; and (c)-C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-C(NR a )NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(=NR a )NR b R c 、-OP(O)(OR a )2. -OS(O)R a、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(=NR d )NR b R c 、-NR a S(O)R d 、-NR a S(O)2R d 、-NR a S(O)NR b R c 、-NR a S(O)2NR b R c 、-SR a 、-S(O)R a 、-S(O)2R a 、-S(O)NR b R c and -S(O)2NR b R c , where each R a 、R b 、R c and R d are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three or four substituents Q a or (iii) R b and R c Together with the N atom to which it is attached, it forms a heterocyclic group, optionally substituted by one or more, in one embodiment, one, two, three or four substituents Q a replace;

[0031] Each Q aare independently selected from the group consisting of: (a) oxo, cyano, halo and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; and (c)-C(O)R f 、-C(O)OR f 、-C(O)NR g R h 、-C(NR f )NR g R h 、-OR f 、-OC(O)R f 、-OC(O)OR f 、-OC(O)NR g R h 、-OC(=NR f )NR g R h 、-OP(O)(OR f )2. -OS(O)R f 、-OS(O)2R f 、-OS(O)NR g R h 、-OS(O)2NR g R h 、-NR g R h 、-NR f C(O)R k 、-NR f C(O)OR k 、-NR f C(O)NR g R h 、-NR f C(=NR k )NR g R h 、-NR f S(O)R k 、-NR f S(O)2R k 、-NR f S(O)NR g R h 、-NR f S(O)2NR g R h 、-SR f 、-S(O)R f 、-S(O)2Rf 、-S(O)NR g R h and -S(O)2NR g R h ; where each R f 、R g 、R h and R k are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) R g and R h Together with the nitrogen atom to which it is attached, it forms a heterocyclic group.

[0032] Also provided herein are compounds of formula I:

[0033]

[0034] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof;

[0035] R 1 is (a) hydrogen, cyano, halide or nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl; or (c)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;

[0036] R 2 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0037] L 2 C 3-10 Cycloalkylene, C 6-14 Arylene, C 7-15 an aralkylene group, a heteroarylene group, or a heterocyclylene group;

[0038] T is a bond, -O-, -S-, -N=, -N(R 4 )-、-C(R 4 )=or-C(R 4 )2-;

[0039] U is a bond, -O-, -S-, -N=, -N(R 5 )-、-C(R5 )=or-C(R 5 )2-;

[0040] V is a bond, -O-, -S-, -N=, -N(R 6 )-、-C(R 6 )=or-C(R 6 )2-;

[0041] W is a bond, -O-, -S-, -N=, -N(R 7 )-、-C(R 7 )=or-C(R 7 )2-;

[0042] X and Y are each independently C or N;

[0043] Z is NR 2A or CR 2A R 2B , where each R 2A and R 2B are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0044] R 4 、R 5 、R 6 、R 7 and L 1 for:

[0045] (i) Each R 4 、R 5 and R 6 are independently (a) hydrogen, cyano, halo or nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl; or (c)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;

[0046] Each R 7 are independently bromine, -OR 7a or -NR 7b R 7c ;

[0047] R 7a C 4-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0048] R 7b and R 7c are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic; or R 7b and R 7c Together with the nitrogen atom to which they are attached, they form a heterocyclic group; and

[0049] L 1 is a key; or

[0050] (ii) Each R 4 、R 5 、R 6 and R 7 are independently (a) hydrogen, cyano, halo or nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl; or (c)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1bR 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ; Its restriction condition is R 4 、R 5 、R 6 and R 7 At least one of is not hydrogen; and

[0051] L 1 -O-, -S-, -N(R 1A )-or-C(R 1A R 1B )-, where each R 1A and R 1B are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; and

[0052] Each R 1a 、R 1b 、R 1c and R 1d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic; or R 1a and R 1c Together with the C and N atoms to which they are attached, they form a heterocyclic group; or R 1b and R 1cTogether with the nitrogen atom to which it is attached, it forms a heterocyclic group;

[0053] The restriction is that no more than one of T, U, V, and W is a bond;

[0054] 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, wherein each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three or four substituents Q a substituted; and (c)-C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-C(NR a )NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(=NR a )NR b R c 、-OP(O)(OR a )2. -OS(O)R a 、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(=NR d )NR b Rc 、-NR a S(O)R d 、-NR a S(O)2R d 、-NR a S(O)NR b R c 、-NR a S(O)2NR b R c 、-SR a 、-S(O)R a 、-S(O)2R a 、-S(O)NR b R c and -S(O)2NR b R c , where each R a 、R b 、R c and R d are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three or four substituents Q a or (iii) R b and R c Together with the N atom to which it is attached, it forms a heterocyclic group, optionally substituted by one or more, in one embodiment, one, two, three or four substituents Q a replace;

[0055] Each Q a are independently selected from the group consisting of: (a) oxo, cyano, halo and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; and (c)-C(O)R f 、-C(O)OR f 、-C(O)NR g R h 、-C(NR f )NR g R h 、-OR f 、-OC(O)Rf 、-OC(O)OR f 、-OC(O)NR g R h 、-OC(=NR f )NR g R h 、-OP(O)(OR f )2. -OS(O)R f 、-OS(O)2R f 、-OS(O)NR g R h 、-OS(O)2NR g R h 、-NR g R h 、-NR f C(O)R k 、-NR f C(O)OR k 、-NR f C(O)NR g R h 、-NR f C(=NR k )NR g R h 、-NR f S(O)R k 、-NR f S(O)2R k 、-NR f S(O)NR g R h 、-NR f S(O)2NR g R h 、-SR f 、-S(O)R f 、-S(O)2R f 、-S(O)NR g R h and -S(O)2NR g R h ; where each R f 、R g 、R h and R k are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) R g and R hTogether with the nitrogen atom to which it is attached, it forms a heterocyclic group.

[0056] Additionally provided herein are compounds of formula XXI:

[0057]

[0058] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof;

[0059] R 1 -C(O)CR 1e =CR 1f CR 1g 、 -N 1a C(O)CR 1e =CR 1f CR 1g 、 -S(O)CR 1e =CR 1f CR 1g 、 -S(O2)CR 1e =CR 1f CR 1g 、 -NR 1a S(O)CR 1e =CR 1f CR 1g 、 -NR 1a S(O2)CR 1e =CR 1f CR 1g or

[0060] R 2 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0061] L 1 For bonds, -O-, -S-, -N(R 1A )-or-C(R 1A R 1B )-, where each R 1A and R 1B are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0062] L 2 C 3-10 Cycloalkylene, C 6-14 Arylene, C 7-15 an aralkylene group, a heteroarylene group, or a heterocyclylene group;

[0063] Z is NR 2A or CR 2A R 2B , where each R 2A and R 2B are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0064] R 4 and R 6 are each independently (a) hydrogen, cyano, halo or nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl; or (c)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;

[0065] R 5a C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0066] Each R 1a 、R 1b 、R 1c and R 1d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic; or R 1a and R 1c Together with the C and N atoms to which they are attached, they form a heterocyclic group; or R 1b and R 1c Together with the nitrogen atom to which they are attached, they form a heterocyclic group; and

[0067] Each R1e 、R 1f and R 1g are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0068] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, and in one embodiment one, two, three, or four, substituents Q, wherein each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted by one or more, in one embodiment one, two, three or four substituents Q a substituted; and (c)-C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-C(NR a )NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(=NR a )NR b R c 、-OP(O)(OR a )2. -OS(O)R a 、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NRa C(O)NR b R c 、-NR a C(=NR d )NR b R c 、-NR a S(O)R d 、-NR a S(O)2R d 、-NR a S(O)NR b R c 、-NR a S(O)2NR b R c 、-SR a 、-S(O)R a 、-S(O)2R a 、-S(O)NR b R c and -S(O)2NR b R c , where each R a 、R b 、R c and R d are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted by one or more, in one embodiment by one, two, three or four substituents Q a or (iii) R b and R c Together with the N atom to which it is attached, it forms a heterocyclic group, optionally substituted by one or more, in one embodiment by one, two, three or four substituents Q a replace;

[0069] Each Q a are independently selected from the group consisting of: (a) oxo, cyano, halo and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; and (c)-C(O)R f 、-C(O)OR f 、-C(O)NRg R h 、-C(NR f )NR g R h 、-OR f 、-OC(O)R f 、-OC(O)OR f 、-OC(O)NR g R h 、-OC(=NR f )NR g R h 、-OP(O)(OR f )2. -OS(O)R f 、-OS(O)2R f 、-OS(O)NR g R h 、-OS(O)2NR g R h 、-NR g R h 、-NR f C(O)R k 、-NR f C(O)OR k 、-NR f C(O)NR g R h 、-NR f C(=NR k )NR g R h 、-NR f S(O)R k 、-NR f S(O)2R k 、-NR f S(O)NR g R h 、-NR f S(O)2NR g R h 、-SR f 、-S(O)R f 、-S(O)2R f 、-S(O)NR g R h and -S(O)2NR g R h ; where each R f 、R g 、R h and R k are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) R g and R h Together with the nitrogen atom to which it is attached, it forms a heterocyclic group.

[0070] Provided herein are pharmaceutical compositions comprising a compound disclosed herein, e.g., a compound of Formula I or XXI, or a single enantiomer, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and optionally a pharmaceutically acceptable excipient or carrier.

[0071] Provided herein are methods for treating, preventing, or ameliorating one or more symptoms of a proliferative disease 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, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0072] Provided herein are methods 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 compound of Formula I or XXI, or a single enantiomer, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0073] Provided herein are methods for treating, preventing, or ameliorating one or more symptoms of cancer in a subject, comprising administering to the subject a compound disclosed herein, such as a compound of Formula I or XXI, or a single enantiomer, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In one embodiment, the cancer is drug-resistant.

[0074] Provided herein are methods of inhibiting cell growth comprising contacting the cell with a compound provided herein, e.g., a compound of Formula I or XXI, or a single enantiomer, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0075] Provided herein are methods of inhibiting cell growth 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, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0076] Provided herein are methods for modulating the activity of a tyrosine kinase, in one embodiment, an ERBB kinase, comprising contacting an ERBB kinase with a compound disclosed herein, e.g., a compound of Formula I or XXI, or a single enantiomer, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0077] Provided herein are methods of 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, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. DETAILED DESCRIPTION

[0078] To facilitate understanding of the invention described herein, a number of terms are defined below.

[0079] 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 used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0080] The terms "tumor," "neoplasm," and "neoplastic disorder or disease" are used interchangeably herein and refer to an undesirable proliferation of one or more cell subsets in a multicellular organism that causes damage to the multicellular organism (i.e., discomfort or reduced life expectancy). In certain embodiments, a tumor can be benign (non-invasive) or malignant (invasive).

[0081] The term "cancer" refers to a malignant neoplasm characterized by uncontrolled cell proliferation in which cells have lost their normal regulatory controls that would otherwise govern their growth rate. These dysregulated, compartmentalized cells can spread throughout the body and invade normal tissues in a process called metastasis.

[0082] The term "subject" refers to animals, including but not limited to primates (e.g., humans), cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. The terms "subject" and "patient" are used interchangeably herein to refer to, for example, a mammalian subject, such as a human subject, and in one embodiment, a human.

[0083] The term "treating" is meant to include alleviating or eliminating the condition, disorder or disease or one or more symptoms associated with the condition, disorder or disease; or alleviating or eradicating the cause of the condition, disorder or disease itself.

[0084] The term "preventing" is meant to include methods of delaying and / or eliminating the onset of a condition, disorder or disease and / or its attendant symptoms; preventing a subject from developing a condition, disorder or disease; or reducing a subject's risk of developing a condition, disorder or disease.

[0085] The term "contacting" means bringing a therapeutic agent into contact with a cell or tissue such that a physiological and / or chemical effect occurs as a result of such contact. Contacting can be performed in vitro, ex vivo, or in vivo. In one embodiment, a therapeutic agent is contacted with cells in cell culture (in vitro) to determine the effect of the therapeutic agent on the cells. In another embodiment, contacting a therapeutic agent with a cell or tissue comprises administering the therapeutic agent to a subject having the cell or tissue to be contacted.

[0086] The term "therapeutically effective amount" is meant to include an amount of a compound that, when administered, is sufficient to prevent the development of or alleviate to some extent one or more symptoms of the condition, disorder, or disease being treated. The term "therapeutically effective amount" also refers to an amount of a compound that is sufficient to elicit the biological or medical response of a biomolecule (e.g., protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0087] The term "IC 50 ” or “EC 50 ” refers to the amount, concentration or dose of a compound required to achieve 50% inhibition of the maximal response in the assay measuring the response.

[0088] The term "GC 50 "" refers to the amount, concentration or dose of a compound required to reduce the viability of cells treated with the compound by 50% compared to cells not treated with the compound.

[0089] The term "CC 50 " refers to the amount, concentration or dose of a compound that causes a 50% decrease in the viability of a host. In certain embodiments, the CC of a compound 50 It is the amount, concentration or dose of a compound required to reduce the viability of cells treated with the compound by 50% compared to cells not treated with the compound.

[0090] The term "relapse" refers to the return of cancer cells in an individual who has been in remission from cancer following therapy.

[0091] The term "refractory or resistant" refers to a situation in which an individual still has residual cancer cells in his or her body even after adequate treatment.

[0092] The term "drug resistance" refers to a condition when a disease does not respond to drug treatment. Drug resistance can be intrinsic, meaning the disease never responded to the drug, or it can be acquired, meaning the disease stops responding to a drug to which it previously responded. In certain embodiments, drug resistance is intrinsic. In certain embodiments, drug resistance is acquired.

[0093] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense that it is compatible with the other ingredients of the pharmaceutical formulation and is suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2012; Handbook of Pharmaceutical Additives, 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.

[0094] The term "about" or "approximately" means an acceptable error for a particular value as determined by one skilled in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" 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% of a given value or range.

[0095] The terms "active ingredient" and "active substance" refer to a compound that is administered to a subject alone or in combination with one or more pharmaceutically acceptable excipients for the treatment, prevention, or amelioration of 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 isotopic variant of a compound described herein.

[0096] The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a compound or pharmaceutical composition thereof administered to a subject to treat, prevent, or ameliorate one or more symptoms of a condition, disorder, or disease.

[0097] The terms "naturally occurring" or "native," when used in conjunction with biological substances (e.g., nucleic acid molecules, polypeptides, host cells, etc.), refer to substances that are found in nature and are not manipulated by humans. Similarly, "non-naturally occurring" or "non-native" refers to substances that are not found in nature or have been structurally modified or synthesized by humans.

[0098] The term "ERBB" or "ERBB kinase" refers to a tyrosine kinase of the ERBB family or variants thereof, including but not limited to ERBB1 (EGFR or HER1), ERBB2 (HER2 / c-neu), ERBB3 (HER3), and ERBB4 (HER4). ERBB variants include proteins that are substantially homologous to native ERBB kinases, i.e., proteins that have one or more naturally or non-naturally occurring amino acid deletions, insertions, or substitutions compared to the amino acid sequence of native ERBB (e.g., ERBB derivatives, homologs, and fragments). 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 that of native ERBB.

[0099] The terms "ERBB-mediated condition, disorder, or disease" and "condition, disorder, or disease mediated by ERBB" refer to a condition, disorder, or disease characterized by abnormal or dysregulated (e.g., above normal) ERBB activity. Abnormal ERBB kinase functional activity can be caused by overexpression of ERBB kinase in cells, expression of ERBB kinase in cells that do not normally express ERBB, or dysregulation caused by constitutive activation (e.g., caused by mutations in ERBB). ERBB-mediated conditions, disorders, or diseases can be mediated in whole or in part by inappropriate ERBB activity. Specifically, ERBB-mediated conditions, disorders, or diseases are those in which modulation of ERBB activity has some effect on the underlying condition, disorder, or disease, e.g., an ERBB inhibitor causes some improvement in at least some of the patients treated.

[0100] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl radical may be optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Alkyl refers to a linear saturated monovalent hydrocarbon group of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, an alkyl group is a group having 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ) or 1 to 6 (C 1-6 ) carbon atoms, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. As used herein, a straight chain C 1-6 and branch chain C 3-6 Alkyl groups are also referred to as "lower alkyl groups." 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, tert-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms).

[0101] The term "alkylene" refers to a straight or branched chain saturated divalent hydrocarbon radical, wherein the alkylene radical may be optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Alkylene refers to a linear saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, an alkylene group is a group having 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ) or 1 to 6 (C 1-6) carbon atoms, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. As used herein, a straight chain C 1-6 and branch chain C 3-6 Alkylene is also referred to as "lower alkylene." Examples of alkylene include, but are not limited to, methylene, ethylene, propylene glycol (including all isomeric forms), n-propylene, isopropylene, butylene (including all isomeric forms), n-butylene, isobutylene, tert-butylene, pentylene (including all isomeric forms), and hexylene (including all isomeric forms).

[0102] The term "heteroalkylene" refers to a straight or branched saturated divalent hydrocarbon group containing one or more heteroatoms in the hydrocarbon chain, each of which is independently selected from O, S and N. For example, C 1-6 Heteroalkylene refers to a linear saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, heteroalkylene is a group having 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ) or 1 to 6 (C 1-6 ) carbon atoms, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. As used herein, a straight chain C 1-6 and branch chain C 3-6 Heteroalkylene is also referred to as "lower heteroalkylene". Examples of heteroalkylene include, but are not limited to, -CH2O-, -CH2OCH2-, -CH2CH2O-, -CH2NH-, -CH2NHCH2-, -CH2CH2NH-, -CH2S-, -CH2SCH2-, and -CH2CH2S-. In certain embodiments, heteroalkylene may be optionally substituted with one or more substituents Q as described herein.

[0103] The term "alkenyl" refers to a straight or branched monovalent hydrocarbon radical containing one or more, in one embodiment, one, two, three, four or five, in another embodiment, one or two carbon-carbon double bonds. The alkenyl group may be optionally substituted with one or more substituents Q as described herein. As will be appreciated by those skilled in the art, the term "alkenyl" encompasses groups having a "cis" or "trans" configuration, or a mixture thereof, or alternatively, a "Z" or "E" configuration, or a mixture thereof. For example, C 2-6 Alkenyl refers to a linear unsaturated monovalent hydrocarbon group of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, alkenyl is 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ) or 2 to 6 (C 2-6 ) carbon atoms, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.

[0104] The term "alkenylene" refers to a straight or branched divalent hydrocarbon radical containing one or more, in one embodiment, one, two, three, four or five, in another embodiment, one or two carbon-carbon double bonds. The alkenylene radical may be optionally substituted with one or more substituents Q as described herein. As will be appreciated by those skilled in the art, the term "alkenylene" encompasses radicals having a "cis" or "trans" configuration, or a mixture thereof, or alternatively, a "Z" or "E" configuration, or a mixture thereof. For example, C 2-6 Alkenylene refers to a straight chain unsaturated divalent hydrocarbon group of 2 to 6 carbon atoms or a branched chain unsaturated divalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, alkenylene is 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ) or 2 to 6 (C 2-6 ) carbon atoms, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. Examples of alkenylene groups include, but are not limited to, vinylene, allylene, propenylene, butenylene, and 4-methylbutenylene.

[0105] The term "heteroalkenylene" refers to a straight or branched divalent hydrocarbon radical containing one or more, in one embodiment, one, two, three, four or five, in another embodiment, one or two carbon-carbon double bonds, and containing one or more heteroatoms in the hydrocarbon chain, each of the one or more heteroatoms being independently selected from O, S and N. The heteroalkenylene radical may be optionally substituted with one or more substituents Q as described herein. As will be appreciated by those skilled in the art, the term "heteroalkenylene" encompasses radicals having a "cis" or "trans" configuration, or a mixture thereof, or alternatively, a "Z" or "E" configuration, or a mixture thereof. For example, C 2-6 Heteroalkenylene refers to a straight-chain unsaturated divalent hydrocarbon group of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, heteroalkenylene is 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ) or 2 to 6 (C 2-6 ) carbon atoms, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. Examples of heteroalkenylene groups include, but are not limited to, -CH=CHO-, -CH=CHOCH2-, -CH=CHCH2O-, -CH=CHS-, -CH=CHSCH2-, -CH=CHCH2S-, or -CH=CHCH2NH-.

[0106] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon radical containing one or more, in one embodiment, one, two, three, four or five, in another embodiment, one or two carbon-carbon triple bonds. Alkynyl groups may be optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynyl refers to a linear unsaturated monovalent hydrocarbon group of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, an alkynyl group is 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ) or 2 to 6 (C 2-6 ) carbon atoms, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (—C≡CH), propynyl (including all isomeric forms such as 1-propynyl (—C≡CCH ) and propargyl (—CH C≡CH )), butynyl (including all isomeric forms such as 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including all isomeric forms such as 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomeric forms such as 1-hexyn-1-yl).

[0107] The term "alkynylene" refers to a straight or branched divalent hydrocarbon radical containing one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one or two carbon-carbon triple bonds. An alkynylene radical may be optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkyne refers to a straight chain unsaturated divalent hydrocarbon group of 2 to 6 carbon atoms or a branched chain unsaturated divalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, an alkynyl group is 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ) or 2 to 6 (C 2-6 ) carbon atoms, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. Examples of alkynylene groups include, but are not limited to, ethynylene, propynylene (including all isomeric forms such as 1-propynylene and propargylene), butynylene (including all isomeric forms such as 1-butyn-1-ylidene and 2-butyn-1-ylidene), pentynylene (including all isomeric forms such as 1-pentyn-1-ylidene and 1-methyl-2-butyn-1-ylidene), and hexynylene (including all isomeric forms such as 1-hexyn-1-ylidene).

[0108] The term "cycloalkyl" refers to a cyclic monovalent hydrocarbon group that may be optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl group may be a saturated or unsaturated but non-aromatic, and / or bridged, and / or non-bridged, and / or fused bicyclic group. In certain embodiments, the cycloalkyl group has 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 7 (C 3-7) carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decahydronaphthyl, and adamantyl.

[0109] The term "cycloalkylene" refers to a cyclic divalent hydrocarbon radical that may be optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl radical may be a saturated or unsaturated but non-aromatic, and / or bridged, and / or non-bridged, and / or fused bicyclic radical. In certain embodiments, the cycloalkylene radical has 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 7 (C 3-7 ) carbon atoms. Examples of cycloalkylene groups include, but are not limited to, cyclopropylene (e.g., 1,1-cyclopropylene and 1,2-cyclopropylene), cyclobutylene (e.g., 1,1-cyclobutylene, 1,2-cyclobutylene, or 1,3-cyclobutylene), cyclopentylene (e.g., 1,1-cyclopentylene, 1,2-cyclopentylene, or 1,3-cyclopentylene), cyclohexylene (e.g., 1,1-cyclohexylene, 1,2-cyclohexylene, 1,3-cyclohexylene, or 1,4-cyclohexylene), cycloheptylene (e.g., 1,1-cycloheptylene, 1,2-cycloheptylene, 1,3-cycloheptylene, or 1,4-cycloheptylene), decalinylene, and adamantylene.

[0110] The term "aryl" refers to a monovalent monocyclic aromatic hydrocarbon group or a monovalent polycyclic aromatic hydrocarbon group containing at least one aromatic hydrocarbon ring. In certain embodiments, an aryl group has 6 to 20 (C 6-20 ), 6 to 15 (C 6-15 ) or 6 to 10 (C 6-10 ) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to a bicyclic or tricyclic carbocyclic ring in which one of the rings is aromatic and the other rings may be saturated, partially unsaturated, or aromatic, such as dihydronaphthyl, indenyl, dihydroindenyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments, aryl groups may be optionally substituted with one or more substituents Q as described herein.

[0111] The term "arylene" refers to a divalent monocyclic aromatic hydrocarbon group or a divalent polycyclic aromatic hydrocarbon group containing at least one aromatic hydrocarbon ring. In certain embodiments, an arylene group has 6 to 20 (C 6-20 ), 6 to 15 (C 6-15 ) or 6 to 10 (C 6-10) ring atoms. Examples of arylene groups include, but are not limited to, phenylene, naphthylene, fluorenylene, azulenylene, anthrylene, phenanthrenylene, pyrenylene, biphenylene, and triphenylene. Arylene also refers to a bicyclic or tricyclic carbocyclic ring in which one of the rings is aromatic and the other ring can be saturated, partially unsaturated, or aromatic, such as dihydronaphthylene, indenylene, indanylene, or tetrahydronaphthylene (tetrahydronaphthylene). In certain embodiments, an arylene group may be optionally substituted with one or more substituents Q as described herein.

[0112] The term "aralkyl" or "arylalkyl" refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl group has 7 to 30 (C 7-30 ), 7 to 20 (C 7-20 ) or 7 to 16 (C 7-16 ) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, 2-phenylethyl, and 3-phenylpropyl. In certain embodiments, the aralkyl group is optionally substituted with one or more substituents Q as described herein.

[0113] The term "heteroaryl" refers to a monovalent monocyclic aromatic radical or a monovalent polycyclic aromatic radical containing 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. The heteroaryl group is bonded to the rest of the molecule via the aromatic ring. Each ring of the heteroaryl group may contain one or two O 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 fewer and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl group has 5 to 20, 5 to 15, or 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridinyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, and thienopyridinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, benzophenanthroline, phenanthroline, phenanthroline, phenanthroline, phenanthroline, phenanthroline, phenanthroline, phenanthroline, phenanthroline, phenanthroline, phenanthroline, phenanthroline, phenanthroline, phenanthroline, and anthenyl. In certain embodiments, the heteroaryl group may be optionally substituted with one or more substituents Q as described herein.

[0114] The term "heteroarylene" refers to a divalent monocyclic aromatic radical or a divalent polycyclic aromatic radical containing at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms in the ring, each of the one or more heteroatoms being independently selected from O, S, and N. A heteroarylene radical has at least one bond connected to the rest of the molecule via its aromatic ring. Each ring of a heteroarylene radical may contain one or two O 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 contains at least one carbon atom. In certain embodiments, a heteroarylene radical has 5 to 20, 5 to 15, or 5 to 10 ring atoms. Examples of monocyclic heteroarylene groups include, but are not limited to, furanylene, imidazolylene, isothiazolylene, isoxazolylene, oxadiazolylene, oxadiazolylene, oxazolylene, pyrazinylene, pyrazolylene, pyridazinylene, pyridinylene, pyrimidinylene, pyrrolylene, thiadiazolylene, thiazolylene, thienylene, tetrazolylene, triazinylene, and triazolylene. Examples of bicyclic heteroarylene groups include, but are not limited to, benzofuranylene, benzimidazolylene, benzisoxazolylene, benzopyranylene, benzothiadiazolylene, benzothiazolylene, benzothienylene, benzotriazolylene, benzoxazolylene, furapyridylene, imidazopyridylene, imidazothiazolylene, indolizinylene, indolylene, indazolylene, isobenzofuranylene, isobenzothiazolylene, isoindolylene, isoquinolinylene, isothiazolylene, naphthyridinylene, oxazolopyridylene, phthalazinylene, pteridinylene, purinylene, pyridopyridylene, pyrrolopyridylene, quinolinylene, quinoxalinylene, quinazolinylene, thiadiazolopyrimidylene, and thienopyridylene. Examples of tricyclic heteroarylene groups include, but are not limited to, acridinylene, benzindolylene, carbazolylene, dibenzofuranylene, pyridineylene, phenanthroline, phenanthridylene, phenanthridylene, phenanthiazinylene, phenathiazinylene, phenoxazinylene, and anthrenylene. In certain embodiments, the heteroarylene group may be optionally substituted with one or more substituents Q as described herein.

[0115] The term "heterocyclyl" or "heterocycle" refers to a monovalent monocyclic non-aromatic ring system or a monovalent polycyclic ring system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms is a heteroatom independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. The heterocyclyl is bonded to the rest of the molecule via the non-aromatic ring. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some of the rings may be partially or fully saturated, or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable compound. Examples of such heterocyclic groups include, but are not limited to, azepine, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothiophenyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolane, 1,4-dihydro- thianyl, furanyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thimorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl group may also be optionally substituted with one or more substituents Q as described herein.

[0116] The term "heterocyclylene" refers to a divalent monocyclic non-aromatic ring system or a divalent polycyclic ring system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms is a heteroatom independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. The heterocyclylene is bonded to the rest of the molecule via the non-aromatic ring. In certain embodiments, the heterocyclylene has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 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 the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some of the rings may be partially or fully saturated, or aromatic. The heterocyclylene may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable compound. Examples of such heterocyclylene groups include, but are not limited to, azepinylene, benzodioxanylene, benzodioxolylene, benzofuranonylene, benzopyranonylene, chromanylene, chromotetrahydrofuranylene, chromanylene, benzothiopyranylene, benzoxazinylene, β-carbolenylene, chromanylene, chromonylene, cinnolinylene, coumarinylene, decahydroisoquinolylene, dihydrobenzisothiazinylene, dihydrobenzisoxazinylene, dihydrofuranylene, dihydroisoindolylene, dihydropyranylene, dihydropyrazolylene, dihydropyrazinylene, dihydropyridinylene, dihydropyrimidinylene, dihydropyrrolylene, dioxolanylidene, 1,4-dithianylene 1,3,5-trithianylene, 1,4-dihydro-1,4-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2-[1,2-dihydro-2- In certain embodiments, the heterocyclyl group may also be optionally substituted with one or more substituents Q as described herein.

[0117] The term "halogen," "halide," or "halo" refers to fluorine, chlorine, bromine, and / or iodine.

[0118] The term "optionally substituted" is intended to mean that a group or substituent (e.g., alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene) may be substituted with one or more, in one embodiment, one, two, three, or four substituents Q independently selected from, for example, (a) oxo (=O), cyano (-CN), halo, and nitro (-NO); (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three or four substituents Q a substituted; and (c)-C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-C(NR a )NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(=NR a )NR b R c 、-OP(O)(OR a )2. -OS(O)R a 、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(=NR d )NR b R c 、-NR a S(O)Rd 、-NR a S(O)2R d 、-NR a S(O)NR b R c 、-NR a S(O)2NR b R c 、-SR a 、-S(O)R a 、-S(O)2R a 、-S(O)NR b R c and -S(O)2NR b R c , where each R a 、R b 、R c and R d are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three or four substituents Q a or (iii) R b and R c Together with the N atom to which it is attached, it forms a heterocyclic group, which is optionally substituted by one or more, in one embodiment, one, two, three or four substituents Q a Substitution. As used herein, unless otherwise specified, all substitutable groups are "optionally substituted."

[0119] In one embodiment, each Q a are independently selected from the group consisting of: (a) oxo, cyano, halo and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; and (c)-C(O)R f 、-C(O)OR f 、-C(O)NR g R h 、-C(NR f )NR g R h 、-OR f、-OC(O)R f 、-OC(O)OR f 、-OC(O)NR g R h 、-OC(=NR f )NR g R h 、-OP(O)(OR f )2. -OS(O)R f 、-OS(O)2R f 、-OS(O)NR g R h 、-OS(O)2NR g R h 、-NR g R h 、-NR f C(O)R k 、-NR f C(O)OR k 、-NR f C(O)NR g R h 、-NR f C(=NR k )NR g R h 、-NR f S(O)R k 、-NR f S(O)2R k 、-NR f S(O)NR g R h 、-NR f S(O)2NR g R h 、-SR f 、-S(O)R f 、-S(O)2R f 、-S(O)NR g R h and -S(O)2NR g R h ; where each R f 、R g 、R h and R k are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) R g and Rh Together with the nitrogen atom to which it is attached, it forms a heterocyclic group.

[0120] The terms "optical activity" and "enantiomeric activity" refer to a collection of molecules having an enantiomeric excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not 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 racemate.

[0121] When describing optically active compounds, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center. The signs (+) and (-) are used to indicate the compound's optical rotation, which is the direction in which the plane of polarization rotates through the optically active compound. The prefix (-) indicates that the compound is levorotatory, meaning it rotates the plane of polarization to the left, or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, meaning it rotates the plane of polarization to the right, or clockwise. However, the signs (+) and (-) of the optical rotations have nothing to do with the molecule's absolute configuration, R or S.

[0122] The term "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that make up such compound. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including but not limited to hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F) Phosphorus-31( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 (32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), chlorine-37( 37 Cl), bromine-79( 79 Br), bromine-81( 81 Br), iodine-123 ( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I) and iodine-131( 131 I). In certain embodiments, an "isotopic variant" of a compound is a stable form, i.e., 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 ( 1 H), deuterium ( 2 H), carbon-12 ( 12 C), carbon-13 ( 13 C), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), phosphorus-31 ( 31 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-37( 37 Cl), bromine-79( 79 Br), bromine-81( 81 Br) and iodine-127( 127 I). In certain embodiments, an "isotopic variant" of a compound is an unstable form, i.e., radioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including but not limited to tritium ( 3 H), carbon-11 ( 11 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), oxygen-14 ( 14 O), oxygen-15 (15 O), fluorine-18 ( 18 F), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-35( 35 S), chlorine-36 ( 36 Cl), iodine-123 ( 123 I), iodine-125( 125 I), iodine-129( 129 I) and iodine-131( 131 I) It is understood that in the compounds as provided herein, any hydrogen may be, for example, 2 H, or any carbon may be e.g. 13 C, or any nitrogen may be e.g. 15 N, and any oxygen may be 18 O. In certain embodiments, "isotopic variants" of a compound contain unnatural proportions of deuterium.

[0123] The term "solvate" refers to a complex or aggregate formed by one or more solute molecules (e.g., a compound provided herein) and one or more solvent molecules (which are present in stoichiometric or non-stoichiometric amounts). Suitable solvents 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 non-crystalline form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates, and pentahydrates.

[0124] The phrase “a single enantiomer, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof” has the same meaning as the phrase “(i) a single enantiomer, racemic mixture, mixture of diastereoisomers, or 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, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof”.

[0125] As used herein, unless otherwise indicated, abbreviations for any protecting groups, amino acids, and other compounds are consistent with their common usage or recognized abbreviations, including abbreviations found in J. Org. Chem. 2007, 72, 23A-24A or abbreviations approved by the IUPAC-IUB Commission on Biochemical Nomenclature (Biochem. 1972, 11, 942-944).

[0126] Compound

[0127] In one embodiment, provided herein is a compound of Formula I:

[0128]

[0129] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof;

[0130] R 1 -C(O)CR 1e =CR 1f CR 1g 、 -N 1a C(O)CR 1e =CR 1f CR 1g 、 -S(O)CR 1e =CR 1f CR 1g 、 -S(O2)CR 1e =CR 1f CR 1g 、 -NR 1a S(O)CR 1e =CR 1f CR 1g 、 -NR 1a S(O2)CR 1e =CR 1f CR 1g or

[0131] R 2 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C7-15 Aralkyl, heteroaryl or heterocyclic group;

[0132] L 1 For bonds, -O-, -S-, -N(R 1A )-or-C(R 1A R 1B )-, where each R 1A and R 1B are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0133] L 2 C 3-10 Cycloalkylene, C 6-14 Arylene, C 7-15 an aralkylene group, a heteroarylene group, or a heterocyclylene group;

[0134] T is a bond, -O-, -S-, -N=, -N(R 4 )-、-C(R 4 )=or-C(R 4 )2-;

[0135] U is a bond, -O-, -S-, -N=, -N(R 5 )-、-C(R 5 )=or-C(R 5 )2-;

[0136] V is a bond, -O-, -S-, -N=, -N(R 6 )-、-C(R 6 )=or-C(R 6 )2-;

[0137] W is a bond, -O-, -S-, -N=, -N(R 7 )-、-C(R 7 )=or-C(R 7 )2-;

[0138] X and Y are each independently C or N;

[0139] Z is NR 2A or CR 2A R 2B , where each R 2A and R 2B are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0140] Each R 4 、R 5 、R 6 and R 7 are independently (a) hydrogen, cyano, halo or nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl; or (c)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;

[0141] Each R 1a 、R 1b 、R 1c and R 1d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic; or R 1a and R 1c Together with the C and N atoms to which they are attached, they form a heterocyclic group; or R 1b and R 1c Together with the nitrogen atom to which they are attached, they form a heterocyclic group; and

[0142] Each R 1e 、R 1f and R 1g are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0143] with the restriction that no more than one of T, U, V, and W is a bond; and

[0144] The constraint condition is that when L 1 When R is a key, 4 、R 5 、R 6 and R 7 At least one of them is bromine, -OR 1a or -NR 1b R 1c , where R 1a C 4-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0145] 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, wherein each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three or four substituents Q a substituted; and (c)-C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-C(NR a )NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(=NR a )NR b R c 、-OP(O)(OR a )2. -OS(O)R a 、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(=NR d )NR b R c 、-NRa S(O)R d 、-NR a S(O)2R d 、-NR a S(O)NR b R c 、-NR a S(O)2NR b R c 、-SR a 、-S(O)R a 、-S(O)2R a 、-S(O)NR b R c and -S(O)2NR b R c , where each R a 、R b 、R c and R d are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three or four substituents Q a or (iii) R b and R c Together with the N atom to which it is attached, it forms a heterocyclic group, optionally substituted by one or more, in one embodiment, one, two, three or four substituents Q a replace;

[0146] Each Q a are independently selected from the group consisting of: (a) oxo, cyano, halo and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; and (c)-C(O)R f 、-C(O)OR f 、-C(O)NR g R h 、-C(NR f )NR g R h 、-OR f 、-OC(O)R f 、-OC(O)ORf 、-OC(O)NR g R h 、-OC(=NR f )NR g R h 、-OP(O)(OR f )2. -OS(O)R f 、-OS(O)2R f 、-OS(O)NR g R h 、-OS(O)2NR g R h 、-NR g R h 、-NR f C(O)R k 、-NR f C(O)OR k 、-NR f C(O)NR g R h 、-NR f C(=NR k )NR g R h 、-NR f S(O)R k 、-NR f S(O)2R k 、-NR f S(O)NR g R h 、-NR f S(O)2NR g R h 、-SR f 、-S(O)R f 、-S(O)2R f 、-S(O)NR g R h and -S(O)2NR g R h ; where each R f 、R g 、R h and R k are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) R g and R h Together with the nitrogen atom to which it is attached, it forms a heterocyclic group.

[0147] In another embodiment, provided herein is a compound of Formula I:

[0148]

[0149] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof;

[0150] R 1 is (a) hydrogen, cyano, halide or nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl; or (c)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;

[0151] R 2 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0152] L 2 C 3-10 Cycloalkylene, C 6-14 Arylene, C 7-15 an aralkylene group, a heteroarylene group, or a heterocyclylene group;

[0153] T is a bond, -O-, -S-, -N=, -N(R 4 )-、-C(R 4 )=or-C(R 4 )2-;

[0154] U is a bond, -O-, -S-, -N=, -N(R 5 )-、-C(R 5 )=or-C(R 5 )2-;

[0155] V is a bond, -O-, -S-, -N=, -N(R 6 )-、-C(R 6 )=or-C(R 6 )2-;

[0156] W is a bond, -O-, -S-, -N=, -N(R 7 )-、-C(R 7 )=or-C(R 7 )2-;

[0157] X and Y are each independently C or N;

[0158] Z is NR 2A or CR2A R 2B , where each R 2A and R 2B are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0159] R 4 、R 5 、R 6 、R 7 and L 1 for:

[0160] (i) Each R 4 、R 5 and R 6 are independently (a) hydrogen, cyano, halo or nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl; or (c)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1aC(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;

[0161] Each R 7 are independently bromine, -OR 7a or -NR 7b R 7c ;

[0162] R 7a C 4-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0163] R 7b and R 7c are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic; or R 7b and R 7c Together with the nitrogen atom to which they are attached, they form a heterocyclic group; and

[0164] L 1 is the key;

[0165] (ii) Each R 4 、R 5 、R 6 and R7 are independently (a) hydrogen, cyano, halo or nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl; or (c)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1bR 1c or -S(O)2NR 1b R 1c ; Its restriction condition is R 4 、R 5 、R 6 and R 7 At least one of is not hydrogen; and

[0166] L 1 -O-, -S-, -N(R 1A )-or-C(R 1A R 1B )-, where each R 1A and R 1B are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; and

[0167] Each R 1a 、R 1b 、R 1c and R 1d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic; or R 1a and R 1c Together with the C and N atoms to which they are attached, they form a heterocyclic group; or R 1b and R 1c Together with the nitrogen atom to which it is attached, it forms a heterocyclic group;

[0168] The restriction is that no more than one of T, U, V, and W is a bond;

[0169] 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, wherein each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three or four substituents Q a substituted; and (c)-C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-C(NR a )NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(=NR a )NR b R c 、-OP(O)(OR a )2. -OS(O)R a 、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(=NR d )NR b R c 、-NR a S(O)R d 、-NR a S(O)2R d 、-NR a S(O)NR b R c 、-NR a S(O)2NR b R c 、-SR a 、-S(O)R a 、-S(O)2R a 、-S(O)NR b R c and -S(O)2NR b R c, where each R a 、R b 、R c and R d are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three or four substituents Q a or (iii) R b and R c Together with the N atom to which it is attached, it forms a heterocyclic group, optionally substituted by one or more, in one embodiment, one, two, three or four substituents Q a replace;

[0170] Each Q a are independently selected from the group consisting of: (a) oxo, cyano, halo and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; and (c)-C(O)R f 、-C(O)OR f 、-C(O)NR g R h 、-C(NR f )NR g R h 、-OR f 、-OC(O)R f 、-OC(O)OR f 、-OC(O)NR g R h 、-OC(=NR f )NR g R h 、-OP(O)(OR f )2. -OS(O)R f 、-OS(O)2R f 、-OS(O)NR g R h 、-OS(O)2NR g R h 、-NR g R h 、-NR f C(O)Rk 、-NR f C(O)OR k 、-NR f C(O)NR g R h 、-NR f C(=NR k )NR g R h 、-NR f S(O)R k 、-NR f S(O)2R k 、-NR f S(O)NR g R h 、-NR f S(O)2NR g R h 、-SR f 、-S(O)R f 、-S(O)2R f 、-S(O)NR g R h and -S(O)2NR g R h ; where each R f 、R g 、R h and R k are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) R g and R h Together with the nitrogen atom to which it is attached, it forms a heterocyclic group.

[0171] In another embodiment, provided herein is a compound of Formula II:

[0172]

[0173] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2 、L 1 、L 2 , T, U, V, W, X, Y and Z are each as defined herein.

[0174] In another embodiment, provided herein is a compound of formula III:

[0175]

[0176] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2 、R 4 、R 5 、R 6 、R 7 、L 1 、L 2 and Z are each as defined herein.

[0177] In another embodiment, provided herein is a compound of formula IV:

[0178]

[0179] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2 、R 4 、R 5 、R 6 、R 7 、L 1 、L 2 and Z are each as defined herein.

[0180] In another embodiment, provided herein is a compound of Formula V:

[0181]

[0182] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2 、R 4 、R 5 、R 6 、R 7 、L 1 、L 2 and Z are each as defined herein, and the symbol It indicates that the 6-membered ring contains one N atom in the ring.

[0183] In another embodiment, provided herein is a compound of formula VI:

[0184]

[0185] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2 、R 4 、R 5 、R 6 、R 7 、L 1 、L 2 and Z are each as defined herein, and the symbol It indicates that the 6-membered ring contains one N atom in the ring.

[0186] In another embodiment, provided herein is a compound of formula VII:

[0187]

[0188] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2 、R 4 、R 5 、R 7 、L 1 、L 2 and Z are each as defined herein.

[0189] In another embodiment, provided herein is a compound of Formula VIII:

[0190]

[0191] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein:

[0192] R 7a (i) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (ii) -C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-NR1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;and

[0193] R 1 、R 2 、R 4 、R 5 、R 6 、R 1a 、R 1b 、R 1c 、R 1d 、L 1 、L 2 , Q and Z are each as defined herein.

[0194] In another embodiment, provided herein is a compound of formula IX:

[0195]

[0196] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein:

[0197] m is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0198] n is an integer of 0, 1, 2, 3, 4, 5 or 6;

[0199] Each RL are independently (i) hydrogen; or (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 arylalkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;or

[0200] When there are two or more R connected to the same ring L When two R L Connected together to form (i) bonds, -O-, -NR N -or-S-; or (ii)C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene or C 2-6 heteroalkenylene, each of which is optionally substituted with one or more substituents Q;

[0201] R N (a) hydrogen; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; (c)-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;and

[0202] R 1 、R 2 、R 4 、R 5 、R 6 、R 1a 、R 1b 、R 1c 、R 1d 、R 7a and Q are each as defined herein.

[0203] In another embodiment, provided herein is a compound of formula X:

[0204]

[0205] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2 、R 4 、R 5 、R 6 and R 7a Each is as defined herein.

[0206] In another embodiment, provided herein is a compound of formula XI:

[0207]

[0208] or its isotopic variant; or its pharmaceutically acceptable salt, solvate or prodrug; wherein R 1 and R 7a Each is as defined herein.

[0209] In another embodiment, provided herein is a compound of Formula XIa:

[0210]

[0211] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 2n is C optionally substituted with one or more substituents Q 1-6 Alkyl or -OR 1a , and R 1 、R 1a 、R 7a and Q are each as defined herein; in one embodiment, R 2n is methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -OH or -OCH3.

[0212] In certain embodiments, in Formula VIII, IX, X, XI, or XIa, R 7a for:

[0213]

[0214]

[0215] in:

[0216] Each R 1a and R 1b As defined herein, in one embodiment, R 1a is hydrogen, methyl, ethyl, difluoromethyl or trifluoromethyl; in another embodiment, R 1b is hydrogen, methyl, methyl, ethyl, difluoromethyl, trifluoromethyl, 2-hydroxyethyl or vinyl;

[0217] p and q are each independently an integer of 0, 1 or 3, with the constraint that the sum of p and q is not less than 1;

[0218] Each r is independently an integer of 0, 1, 2, 3, 4, 5 or 6.

[0219] In certain embodiments, in Formula VIII, IX, X, XI, or XIa, R 7a for:

[0220]

[0221]

[0222] In one embodiment, provided herein is a compound of Formula XIb:

[0223]

[0224] or a single enantiomer, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein u and v are each independently an integer of 0, 1, 2, or 3; and R 1 and R 2n Each is as defined herein.

[0225] In another embodiment, provided herein is a compound of Formula XIc:

[0226]

[0227] or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein u and v are each as defined herein.

[0228] In another embodiment, provided herein is a compound of Formula XId:

[0229]

[0230] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2n , u and v are each as defined herein.

[0231] In another embodiment, provided herein is a compound of Formula XIe:

[0232]

[0233] or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein u and v are each as defined herein.

[0234] In another embodiment, provided herein is a compound of Formula XIf:

[0235]

[0236] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2n , u and v are each as defined herein.

[0237] In another embodiment, provided herein is a compound of Formula XIg:

[0238]

[0239] or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein u and v are each as defined herein.

[0240] In another embodiment, provided herein is a compound of Formula XIh:

[0241]

[0242] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2n , u and v are each as defined herein.

[0243] In another embodiment, provided herein is a compound of Formula XIi:

[0244]

[0245] or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein u and v are each as defined herein.

[0246] In another embodiment, provided herein is a compound of Formula XII:

[0247]

[0248] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein:

[0249] R 7b (i) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (ii) -C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a)NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;

[0250] R 7c is (i) hydrogen; or (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 arylalkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;or

[0251] R 7b and R 7c Together with the N atom to which it is attached, it forms a heterocyclic group, optionally substituted with one or more substituents Q; and

[0252] R 1 、R 2 、R 4 、R 5 、R 6 、R 1a 、R 1b 、R 1c 、R 1d 、L 1 、L2 , Q and Z are each as defined herein.

[0253] In another embodiment, provided herein is a compound of Formula XIII:

[0254]

[0255] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2 、R 4 、R 5 、R 6 、R 7b and R 7c Each is as defined herein.

[0256] In another embodiment, provided herein is a compound of Formula XIV:

[0257]

[0258] or its isotopic variant; or its pharmaceutically acceptable salt, solvate or prodrug; wherein R 1 、R 7b and R 7c Each is as defined herein.

[0259] In another embodiment, provided herein is a compound of Formula XIVa:

[0260]

[0261] or its isotopic variant; or its pharmaceutically acceptable salt, solvate or prodrug; wherein R 1 、R 7b and R 7c Each is as defined herein.

[0262] In certain embodiments, in Formula XII, XIII, XIV, or XIVa, R 7b for:

[0263]

[0264] in:

[0265] Each R 1a and R 1b As defined herein, in one embodiment, R 1a is hydrogen, methyl, ethyl, difluoromethyl or trifluoromethyl; in another embodiment, R 1b is hydrogen, methyl, methyl, ethyl, difluoromethyl, trifluoromethyl, 2-hydroxyethyl or vinyl;

[0266] p and q are each independently an integer of 0, 1, 2 or 3, with the proviso that the sum of p and q is not less than 1; and

[0267] Each r is independently an integer of 0, 1, 2, 3, 4, 5 or 6.

[0268] In certain embodiments, in Formula XII, XIII, XIV, or XIVa, R 7c is hydrogen, methyl, ethyl, difluoromethyl or trifluoromethyl.

[0269] In a specific embodiment, in Formula XII, XIII, XIV or XIVa, the moiety -NR 7a R 7b for:

[0270]

[0271] Each R 1a As defined herein; in one embodiment, R 1a is hydrogen, methyl, ethyl, difluoromethyl or trifluoromethyl.

[0272] In another embodiment, provided herein is a compound of Formula XV:

[0273]

[0274] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2 、R 4 、R 5 、R 6 、L 1 、L 2 and Z are each as defined herein.

[0275] In another embodiment, provided herein is a compound of Formula XVI:

[0276]

[0277] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2 、R 4 、R 5 and R 6 Each is as defined herein.

[0278] In another embodiment, provided herein is a compound of Formula XVII:

[0279]

[0280] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 4 、R 5 and R 6 Each is as defined herein.

[0281] In another embodiment, provided herein is a compound of Formula XVIIa:

[0282]

[0283] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein

[0284] R 3n is C optionally substituted with one or more substituents Q 1-6 Alkyl or -OR 1a , and R 1 、R 4 、R 5 、R 6 、R 1a and Q are each as defined herein; in one embodiment, R 3n is methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -OH or -OCH3.

[0285] In another embodiment, provided herein is a compound of Formula XVIII:

[0286]

[0287] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein:

[0288] R 6a (i) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (ii) -C(O)R 1a 、-C(O)OR 1a、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;and

[0289] R 1 、R 2 、R 4 、R 5 、R 7 、R 1a 、R 1b 、R 1c 、R 1d 、L 1 、L 2 , Q and Z are each as defined herein.

[0290] In another embodiment, provided herein is a compound of Formula XIX:

[0291]

[0292] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2 、R 4、R 5 、R 6a and R 7 Each is as defined herein.

[0293] In another embodiment, provided herein is a compound of formula XX:

[0294]

[0295] or its isotopic variant; or its pharmaceutically acceptable salt, solvate or prodrug; wherein R 1 、R 7 and R 6a Each is as defined herein; in one embodiment, R 7 is methyl, difluoromethyl, trifluoromethyl or -OR 1a , where R 1a As defined herein.

[0296] In another embodiment, provided herein is a compound of formula XXa:

[0297]

[0298] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 2n is C optionally substituted with one or more substituents Q 1-6 Alkyl or -OR 1a , and R 1 、R 7 、R 1a 、R 6a and Q are each as defined herein; in one embodiment, R 7 is chlorine, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl or -OR 1a , where R 1a As defined herein; in another embodiment, R 2n is methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -OH or -OCH3.

[0299] In certain embodiments, in Formula XVIII, XIX, XX, or XXa, R 6a for:

[0300]

[0301] where R 1a 、R 1b , p, q and r are each as defined herein.

[0302] In certain embodiments, in Formula XVIII, XIX, XX, or XXa, R6a for:

[0303]

[0304]

[0305] In one embodiment, provided herein is a compound of formula XXb:

[0306]

[0307] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2n , u and v are each as defined herein.

[0308] In another embodiment, provided herein is a compound of formula XXc:

[0309]

[0310] or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein u and v are each as defined herein.

[0311] In another embodiment, provided herein is a compound of formula XXd:

[0312]

[0313] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2n , u and v are each as defined herein.

[0314] In another embodiment, provided herein is a compound of formula XXe:

[0315]

[0316] or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein u and v are each as defined herein.

[0317] In another embodiment, provided herein is a compound of formula XXf:

[0318]

[0319] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R1 、R 2n , u and v are each as defined herein.

[0320] In another embodiment, provided herein is a compound of formula XXg:

[0321]

[0322] or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein u and v are each as defined herein.

[0323] In another embodiment, provided herein is a compound of formula XXh:

[0324]

[0325] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2n , u and v are each as defined herein.

[0326] In another embodiment, provided herein is a compound of formula XXi:

[0327]

[0328] or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein s and t are each as defined herein.

[0329] In another embodiment, provided herein is a compound of formula XXj:

[0330]

[0331] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2n , u and v are each as defined herein.

[0332] In another embodiment, provided herein is a compound of formula XXk:

[0333]

[0334] or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein u and v are each as defined herein.

[0335] In another embodiment, provided herein is a compound of formula XXI:

[0336]

[0337] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof;

[0338] R 1 -C(O)CR 1e =CR 1f CR 1g 、 -N 1a C(O)CR 1e =CR 1f CR 1g 、 -S(O)CR 1e =CR 1f CR 1g 、 -S(O2)CR 1e =CR 1f CR 1g 、 -NR 1a S(O)CR 1e =CR 1f CR 1g 、 -NR 1a S(O2)CR 1e =CR 1f CR 1g or

[0339] R 2 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0340] L 1 For bonds, -O-, -S-, -N(R 1A )-or-C(R 1A R 1B )-, where each R 1A and R 1B are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0341] L 2 C 3-10 Cycloalkylene, C 6-14 Arylene, C 7-15 an aralkylene group, a heteroarylene group, or a heterocyclylene group;

[0342] Z is NR 2A or CR 2A R 2B , where each R 2A and R 2B are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0343] R 4 and R 6 are each independently (a) hydrogen, cyano, halo or nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl; or (c)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;

[0344] R 5a C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0345] Each R 1a 、R 1b 、R 1c and R 1d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic; or R 1a and R 1c Together with the C and N atoms to which they are attached, they form a heterocyclic group; or R 1b and R 1c Together with the nitrogen atom to which they are attached, they form a heterocyclic group; and

[0346] Each R 1e 、R 1f and R 1g are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0347] 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, wherein each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each further optionally substituted with one or more, in one embodiment one, two, three or four substituents Q a substituted; and (c)-C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-C(NR a )NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(=NR a )NR b R c 、-OP(O)(OR a )2. -OS(O)R a 、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(=NR d )NR b Rc 、-NR a S(O)R d 、-NR a S(O)2R d 、-NR a S(O)NR b R c 、-NR a S(O)2NR b R c 、-SR a 、-S(O)R a 、-S(O)2R a 、-S(O)NR b R c and -S(O)2NR b R c , where each R a 、R b 、R c and R d are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each optionally substituted with one or more, in one embodiment one, two, three or four, substituents Q a or (iii) R b and R c Together with the N atom to which it is attached, it forms a heterocyclic group, optionally substituted by one or more, in one embodiment by one, two, three or four substituents Q a replace;

[0348] Each Q a are independently selected from the group consisting of: (a) oxo, cyano, halo and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; and (c)-C(O)R f 、-C(O)OR f 、-C(O)NR g R h 、-C(NR f )NR g R h 、-OR f 、-OC(O)Rf 、-OC(O)OR f 、-OC(O)NR g R h 、-OC(=NR f )NR g R h 、-OP(O)(OR f )2. -OS(O)R f 、-OS(O)2R f 、-OS(O)NR g R h 、-OS(O)2NR g R h 、-NR g R h 、-NR f C(O)R k 、-NR f C(O)OR k 、-NR f C(O)NR g R h 、-NR f C(=NR k )NR g R h 、-NR f S(O)R k 、-NR f S(O)2R k 、-NR f S(O)NR g R h 、-NR f S(O)2NR g R h 、-SR f 、-S(O)R f 、-S(O)2R f 、-S(O)NR g R h and -S(O)2NR g R h ; where each R f 、R g 、R h and R k are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) R g and R hTogether with the nitrogen atom to which it is attached, it forms a heterocyclic group.

[0349] In another embodiment, provided herein is a compound of formula XXII:

[0350]

[0351] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2 、R 4 、R 6 and R 5a Each is as defined herein.

[0352] In another embodiment, provided herein is a compound of formula XXIII:

[0353]

[0354] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 4 、R 6 and R 5a Each is as defined herein.

[0355] In another embodiment, provided herein is a compound of formula XXIII:

[0356]

[0357] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 4 、R 6 、R 2n and R 5a Each is as defined herein.

[0358] In certain embodiments, in any one of Formulas XXI to XXIV, R 5a for:

[0359]

[0360] wherein p and q are each as defined herein.

[0361] In one embodiment, provided herein is a compound of Formula XXIVa:

[0362]

[0363] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2n , u and v are each as defined herein.

[0364] In another embodiment, provided herein is a compound of Formula XXIVb:

[0365]

[0366] or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein u and v are each as defined herein.

[0367] In another embodiment, provided herein is a compound of Formula XXIVc:

[0368]

[0369] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2n , u and v are each as defined herein.

[0370] In another embodiment, provided herein is a compound of Formula XXIVd:

[0371]

[0372] or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein u and v are each as defined herein.

[0373] In another embodiment, provided herein is a compound of Formula XXIVe:

[0374]

[0375] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2n , u and v are each as defined herein.

[0376] In another embodiment, provided herein is a compound of Formula XXIVf:

[0377]

[0378] or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein u and v are each as defined herein.

[0379] In another embodiment, provided herein is a compound of Formula XXIVg:

[0380]

[0381] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 1 、R 2n , u and v are each as defined herein.

[0382] In another embodiment, provided herein is a compound of Formula XXIVh:

[0383]

[0384] or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein u and v are each as defined herein.

[0385] The group R in the formulae described herein (including Formulae I to XXIV, XIa to XIi, XVIIa, XXa to XXk, and XXIVa to XXIVh) 1 、R 2 、R 4 、R 5 、R 6 、R 7 、R 2n 、R 3n 、R 5a 、R 6a 、R 7a 、R 7b 、R 7c 、L 1 、L 2 , T, U, V, W, X, Y, Z, m, n, p, q, r, u, and v are further defined herein. All combinations of the examples of such groups provided herein are within the scope of the present invention.

[0386] In certain embodiments, R 1 In certain embodiments, R 1 In certain embodiments, R 1 In certain embodiments, R 1 is fluorine, chlorine, bromine or iodine. In certain embodiments, R 1 is fluorine or chlorine. In certain embodiments, R 1 In certain embodiments, R 1 C1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 1 C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 1 C 2-6 Alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R 1 C 3-7 Cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 1 C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 1 C 7-15 Aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 1 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 1 is a heterocyclic group, optionally substituted with one or more substituents Q.

[0387] In certain embodiments, R 1 -C(O)R 1a , where R 1a As defined herein. In certain embodiments, R 1 -C(O)OR 1a , where R 1a As defined herein. In certain embodiments, R 1 -C(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 1 -C(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 1 For-OR 1a , where R 1a As defined herein. In certain embodiments, R 1 -OC(O)R 1a , where R 1a As defined herein. In certain embodiments, R 1 -OC(O)OR 1a , where R 1a As defined herein. In certain embodiments, R 1-OC(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 1 =NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 1 -OS(O)R 1a , where R 1a As defined herein. In certain embodiments, R 1 -OS(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 1 -OS(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 1 -OS(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 1 -NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 1 -NR 1a C(O)R 1d , where R 1a and R 1d Each is as defined herein. In certain embodiments, R 1 -NR 1a C(O)OR 1d , where R 1a and R 1d Each is as defined herein. In certain embodiments, R 1 -NR 1a C(O)NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 1 -NR 1aC(=NR 1d )NR 1b R 1c , where R 1a 、R 1b 、R 1c and R 1d Each is as defined herein. In certain embodiments, R 1 -NR 1a S(O)R 1d , where R 1a and R 1d Each is as defined herein. In certain embodiments, R 1 -NR 1a S(O)2R 1d , where R 1a and R 1d Each is as defined herein. In certain embodiments, R 1 -NR 1a S(O)NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 1 -NR 1a S(O)2NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 1 For-SR 1a , where R 1a As defined herein. In certain embodiments, R 1 -S(O)R 1a , where R 1a As defined herein. In certain embodiments, R 1 is -S(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 1 -S(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 1 -S(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined herein.

[0388] In certain embodiments, R1 -C(O)CR 1e =CR 1f CR 1g , where R 1e 、R 1f and R 1g Each is as defined herein. In certain embodiments, R 1 for where R 1e 、R 1f and R 1g Each is as defined herein. In certain embodiments, R 1 -N 1a C(O)CR 1e =CR 1f CR 1g , where R 1a 、R 1e 、R 1f and R 1g Each is as defined herein. In certain embodiments, R 1 for where R 1a 、R 1e 、R 1f and R 1g Each is as defined herein. In certain embodiments, R 1 -S(O)CR 1e =CR 1f CR 1g , where R 1e 、R 1f and R 1g Each is as defined herein. In certain embodiments, R 1 for where R 1e 、R 1f and R 1g Each is as defined herein. In certain embodiments, R 1 -NR 1a S(O)CR 1e =CR 1f CR 1g , where R 1a 、R 1e 、R 1f and R 1g Each is as defined herein. In certain embodiments, R 1 for where R 1a 、R 1e 、R 1f and R 1g Each is as defined herein. In certain embodiments, R 1 -NR 1aS(O2)CR 1e =CR 1f CR 1g , where R 1a 、R 1e 、R 1f and R 1g Each is as defined herein. In certain embodiments, R 1 for where R 1a 、R 1e 、R 1f and R 1g Each is as defined herein. In certain embodiments, R 1a 、R 1e 、R 1f and R 1g All are hydrogen.

[0389] In certain embodiments, R 1 Selected from:

[0390]

[0391]

[0392] In certain embodiments, R 1 Selected from:

[0393]

[0394] In certain embodiments, R 2 C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 2 C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 2 C 2-6 Alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R 2 C 3-7 Cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 2 C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 6- to 10-membered monocyclic or bicyclic aromatic group, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is phenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is phenyl or methyl-phenyl. In certain embodiments, R 2is phenyl, 3-methyl-phenyl or 4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl. In certain embodiments, R 2 C 7-15 Aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 5- to 10-membered heteroaryl group, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 5- to 10-membered heteroaryl group comprising 1 to 4 heteroatoms selected from N, O, and S, which is optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a monocyclic heteroaryl group, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 5-membered heteroaryl group, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 6-membered heteroaryl group, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is pyridyl or pyridazinyl, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is hydroxy-pyridyl, methoxy-pyridyl, methyl-pyridyl, difluoromethyl-pyridyl, trifluoromethyl-pyridyl, methylaminocarbonyl, pyridyl or methyl-pyridazinyl. In certain embodiments, R 2 is 2-hydroxy-pyridin-4-yl, 2-methoxy-pyridin-4-yl, 2-methyl-pyridin-4-yl, 2-monofluoromethyl-pyridin-4-yl, 2-difluoromethyl-pyridin-4-yl, 2-trifluoromethyl-pyridin-4-yl, 2-methylaminocarbonyl-pyridin-4-yl or 3-methyl-pyridazin-5-yl. In certain embodiments, R 2 is a bicyclic heteroaryl group, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 5,6-fused heteroaryl group, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is benzo[c][1,2,5]oxadiazolyl or benzo[c][1,2,5]thiadiazolyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 2 is benzo[c][1,2,5]oxadiazol-5-yl or benzo[c][1,2,5]thiadiazol-5-yl, each optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a heterocyclyl group, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 4- to 12-membered monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected from N, O and S, which is optionally substituted with one or more substituents Q.

[0395] In certain embodiments, R 4 In certain embodiments, R 4 In certain embodiments, R 4 In certain embodiments, R 4 is fluorine, chlorine, bromine or iodine. In certain embodiments, R 4 In certain embodiments, R 4 C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 4 C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 4 C 2-6 Alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R 4 C 3-7 Cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 4 C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 4 C 7-15 Aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 4 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 4 is a heterocyclic group, optionally substituted with one or more substituents Q.

[0396] In certain embodiments, R 4 -C(O)R 1a , where R 1a As defined herein. In certain embodiments, R 4 -C(O)OR 1a , where R 1a As defined herein. In certain embodiments, R 4 -C(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 4 -C(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 4 For-OR 1a , where R1a As defined herein. In certain embodiments, R 4 -OC(O)R 1a , where R 1a As defined herein. In certain embodiments, R 4 -OC(O)OR 1a , where R 1a As defined herein. In certain embodiments, R 4 -OC(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 4 =NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 4 -OS(O)R 1a , where R 1a As defined herein. In certain embodiments, R 4 -OS(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 4 -OS(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 4 -OS(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 4 -NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 4 -NR 1a C(O)R 1d , where R 1a and R 1d Each is as defined herein. In certain embodiments, R 4 -NR 1a C(O)OR 1d , where R 1a and R 1dEach is as defined herein. In certain embodiments, R 4 -NR 1a C(O)NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 4 -NR 1a C(=NR 1d )NR 1b R 1c , where R 1a 、R 1b 、R 1c and R 1d Each is as defined herein. In certain embodiments, R 4 -NR 1a S(O)R 1d , where R 1a and R 1d Each is as defined herein. In certain embodiments, R 4 -NR 1a S(O)2R 1d , where R 1a and R 1d Each is as defined herein. In certain embodiments, R 4 -NR 1a S(O)NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 4 -NR 1a S(O)2NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 4 For-SR 1a , where R 1a As defined herein. In certain embodiments, R 4 -S(O)R 1a , where R 1a As defined herein. In certain embodiments, R 4 is -S(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 4 -S(O)NR 1b R 1c, where R 1b and R 1c Each is as defined herein. In certain embodiments, R 4 -S(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, two R 4 Joined together to form =O.

[0397] In certain embodiments, R 5 In certain embodiments, R 5 In certain embodiments, R 5 In certain embodiments, R 5 is fluorine, chlorine, bromine or iodine. In certain embodiments, R 5 In certain embodiments, R 5 C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 5 C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 5 C 2-6 Alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R 5 C 3-7 Cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 5 C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 5 C 7-15 Aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 5 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 5 is a heterocyclyl group, optionally substituted with one or more substituents Q. In certain embodiments, R 5 is piperazinyl, optionally substituted with one or more substituents Q. In certain embodiments, R 5 It is 4-acetylpiperazinyl.

[0398] In certain embodiments, R 5 -C(O)R 1a , where R 1a As defined herein. In certain embodiments, R 5 -C(O)OR 1a , where R 1a As defined herein. In certain embodiments, R5 -C(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 5 -C(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 5 For-OR 1a , where R 1a As defined herein. In certain embodiments, R 5 For-OC 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 5 is -OCH3, optionally substituted with one or more substituents Q. In certain embodiments, R 5 In certain embodiments, R 5 is -O-heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R 5 is -O-piperidinyl, optionally substituted with one or more substituents Q. In certain embodiments, R 5 is piperidin-4-yloxy, optionally substituted with one or more substituents Q. In certain embodiments, R 5 In certain embodiments, R 5 -OC(O)R 1a , where R 1a As defined herein. In certain embodiments, R 5 -OC(O)OR 1a , where R 1a As defined herein. In certain embodiments, R 5 -OC(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 5 =NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 5 -OS(O)R 1a , where R1a As defined herein. In certain embodiments, R 5 -OS(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 5 -OS(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 5 -OS(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 5 -NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 5 -NR 1a C(O)R 1d , where R 1a and R 1d Each is as defined herein. In certain embodiments, R 5 -NHC(O)-C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 5 is -NHC(O)-methyl, optionally substituted with one or more substituents Q. In certain embodiments, R 5 In certain embodiments, R 5 -NR 1a C(O)OR 1d , where R 1a and R 1d Each is as defined herein. In certain embodiments, R 5 -NR 1a C(O)NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 5 -NR 1a C(=NR 1d )NR 1b R 1c , where R 1a 、R 1b 、R 1c and R 1dEach is as defined herein. In certain embodiments, R 5 -NR 1a S(O)R 1d , where R 1a and R 1d Each is as defined herein. In certain embodiments, R 5 -NR 1a S(O)2R 1d , where R 1a and R 1d Each is defined herein. In certain embodiments, R 5 -NR 1a S(O)NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 5 -NR 1a S(O)2NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 5 For-SR 1a , where R 1a As defined herein. In certain embodiments, R 5 -S(O)R 1a , where R 1a As defined herein. In certain embodiments, R 5 is -S(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 5 -S(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 5 -S(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, two R 5 Joined together to form =O.

[0399] In certain embodiments, R 6 In certain embodiments, R 6 In certain embodiments, R 6In certain embodiments, R 6 is fluorine, chlorine, bromine or iodine. In certain embodiments, R 6 In certain embodiments, R 6 C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 C 2-6 Alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 C 3-7 Cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 C 7-15 Aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 is a heterocyclic group, optionally substituted with one or more substituents Q.

[0400] In certain embodiments, R 6 -C(O)R 1a , where R 1a As defined herein. In certain embodiments, R 6 -C(O)OR 1a , where R 1a As defined herein. In certain embodiments, R 6 -C(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 6 -C(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 6 For-OR 1a , where R 1a As defined herein. In certain embodiments, R 6 For-OC 1-6 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, R 6 In certain embodiments, R 6 is -O-heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 is -O-piperidinyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 is piperidin-4-yloxy, optionally substituted with one or more substituents Q. In certain embodiments, R 6 In certain embodiments, R 6 -OC(O)R 1a , where R 1a As defined herein. In certain embodiments, R 6 -OC(O)OR 1a , where R 1a As defined herein. In certain embodiments, R 6 -OC(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 6 =NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 6 -OS(O)R 1a , where R 1a As defined herein. In certain embodiments, R 6 -OS(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 6 -OS(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 6 -OS(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 6 -NR 1b R 1c , where R1b and R 1c Each is as defined herein. In certain embodiments, R 6 -NR 1a C(O)R 1d , where R 1a and R 1d Each is as defined herein. In certain embodiments, R 6 -NR 1a C(O)OR 1d , where R 1a and R 1d Each is as defined herein. In certain embodiments, R 6 -NR 1a C(O)NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 6 -NR 1a C(=NR 1d )NR 1b R 1c , where R 1a 、R 1b 、R 1c and R 1d Each is as defined herein. In certain embodiments, R 6 -NR 1a S(O)R 1d , where R 1a and R 1d Each is as defined herein. In certain embodiments, R 6 -NR 1a S(O)2R 1d , where R 1a and R 1d Each is defined herein. In certain embodiments, R 6 -NR 1a S(O)NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 6 -NR 1a S(O)2NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 6 For-SR1a , where R 1a As defined herein. In certain embodiments, R 6 -S(O)R 1a , where R 1a As defined herein. In certain embodiments, R 6 is -S(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 6 -S(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 6 -S(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, two R 6 Joined together to form =O.

[0401] In certain embodiments, R 7 In certain embodiments, R 7 In certain embodiments, R 7 In certain embodiments, R 7 is fluorine, chlorine, bromine or iodine. In certain embodiments, R 7 In certain embodiments, R 7 In certain embodiments, R 7 In certain embodiments, R 7 C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7 C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7 C 2-6 Alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7 C 3-7 Cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7 C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 7 C 7-15 Aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R7 is a heterocyclic group, optionally substituted with one or more substituents Q.

[0402] In certain embodiments, R 7 -C(O)R 1a , where R 1a As defined herein. In certain embodiments, R 7 -C(O)OR 1a , where R 1a As defined herein. In certain embodiments, R 7 -C(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 7 -C(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 7 For-OR 1a , where R 1a As defined herein. In certain embodiments, R 7 For-OC 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7 is -O-ethyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7 In certain embodiments, R 7 is -O-heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7 is -O-piperidinyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7 is piperidin-4-yloxy, optionally substituted with one or more substituents Q. In certain embodiments, R 6 In certain embodiments, R 7 -OC(O)R 1a , where R 1a As defined herein. In certain embodiments, R 7 -OC(O)OR 1a , where R 1a As defined herein. In certain embodiments, R 7 -OC(O)NR 1b R1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 7 =NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 7 -OS(O)R 1a , where R 1a As defined herein. In certain embodiments, R 7 -OS(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 7 -OS(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 7 -OS(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 7 -NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 7 -NR 1a C(O)R 1d , where R 1a and R 1d Each is as defined herein. In certain embodiments, R 7 -NR 1a C(O)OR 1d , where R 1a and R 1d Each is as defined herein. In certain embodiments, R 7 -NR 1a C(O)NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 7 -NR 1a C(=NR 1d )NR1b R 1c , where R 1a 、R 1b 、R 1c and R 1d Each is as defined herein. In certain embodiments, R 7 -NR 1a S(O)R 1d , where R 1a and R 1d Each is as defined herein. In certain embodiments, R 7 -NR 1a S(O)2R 1d , where R 1a and R 1d Each is defined herein. In certain embodiments, R 7 -NR 1a S(O)NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 7 -NR 1a S(O)2NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 7 For-SR 1a , where R 1a As defined herein. In certain embodiments, R 7 -S(O)R 1a , where R 1a As defined herein. In certain embodiments, R 7 is -S(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 7 -S(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 7 -S(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, two R 7 Joined together to form =O.

[0403] In certain embodiments, R 2n C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 2n is methyl or ethyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 2n is methyl, monofluoromethyl, difluoromethyl or trifluoromethyl. In certain embodiments, R 2n For-OR 1a , where R 1a As defined herein. In certain embodiments, R 2n In certain embodiments, R 2n For-OC 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 2n It is a methoxy group.

[0404] In certain embodiments, R 3n C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 3n is methyl or ethyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 3n is methyl, monofluoromethyl, difluoromethyl or trifluoromethyl. In certain embodiments, R 3n For-OR 1a , where R 1a As defined herein. In certain embodiments, R 3n In certain embodiments, R 3n For-OC 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 3n It is a methoxy group.

[0405] In certain embodiments, R 5a C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 5a is methyl or ethyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 5a is trifluoromethyl or 2-methoxyethyl. In certain embodiments, R 5a C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 5a C 2-6 Alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R 5a C 3-7Cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 5a C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 5a C 7-15 Aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 5a is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 5a is a heterocyclyl group, optionally substituted with one or more substituents Q. In certain embodiments, R 5a is piperidinyl, optionally substituted with one or more substituents Q. In certain embodiments, R 5a is piperidin-4-yl, optionally substituted with one or more substituents Q. In certain embodiments, R 5a It is 1-ethyl-piperidin-4-yl.

[0406] In certain embodiments, R 6a C 1-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6a is methyl or ethyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 6a is trifluoromethyl or 2-methoxyethyl. In certain embodiments, R 6a C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6a C 2-6 Alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6a C 3-7 Cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6a C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 6a C 7-15 Aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6a is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 6a is a heterocyclyl group, optionally substituted with one or more substituents Q. In certain embodiments, R 6a is piperidinyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6a is piperidin-4-yl, optionally substituted with one or more substituents Q. In certain embodiments, R 6a It is 1-ethyl-piperidin-4-yl.

[0407] In certain embodiments, R 6a -C(O)R 1a , where R 1a As defined herein. In certain embodiments, R 6a -C(O)OR 1a , where R 1a As defined herein. In certain embodiments, R 6a -C(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 6a -C(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 6a -NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 6a -NR 1a C(O)R 1d , where R 1a and R 1d Each is as defined herein. In certain embodiments, R 6a -NR 1a C(O)OR 1d , where R 1a and R 1d Each is as defined herein. In certain embodiments, R 6a -NR 1a C(O)NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 6a -NR 1a C(=NR 1d )NR 1b R 1c , where R 1a 、R 1b 、R 1c and R 1d Each is as defined herein. In certain embodiments, R 6a -NR 1a S(O)R 1d, where R 1a and R 1d Each is as defined herein. In certain embodiments, R 6a -NR 1a S(O)2R 1d , where R 1a and R 1d Each is defined herein. In certain embodiments, R 6a -NR 1a S(O)NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 6a -NR 1a S(O)2NR 1b R 1c , where R 1a 、R 1b and R 1c Each is as defined herein. In certain embodiments, R 6a -S(O)R 1a , where R 1a As defined herein. In certain embodiments, R 6a is -S(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 6a -S(O)NR 1b R 1c , where R 1b and R 1c Each is as defined herein. In certain embodiments, R 6a -S(O)2NR 1b R 1c , where R 1b and R 1c Each is as defined herein.

[0408] In certain embodiments, R 7a C 4-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7a C 2-6 alkenyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7a C 2-6 Alkynyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7a C 3-7 Cycloalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7a C6-14 Aryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7a C 7-15 Aralkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7a is heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7a is a heterocyclic group, which is optionally substituted with one or more substituents Q.

[0409] In certain embodiments, R 7b C 4-6 Alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7b C 2-6 alkenyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7b C 2-6 Alkynyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7b C 3-7 Cycloalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7b C 6-14 Aryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7b C 7-15 Aralkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7b is heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7b is a heterocyclic group, which is optionally substituted with one or more substituents Q.

[0410] In certain embodiments, R 7c In certain embodiments, R 7c C 4-6 Alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7c C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7c C 2-6 Alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7c C 3-7 Cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7c C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 7c C 7-15Aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 7c is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 7c is a heterocyclic group, optionally substituted with one or more substituents Q.

[0411] In certain embodiments, R 7b and R 7c Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, which is optionally substituted with one or more substituents Q.

[0412] In certain embodiments, L 1 In certain embodiments, L 1 In certain embodiments, L 1 In certain embodiments, L 1 -N(R 1A )-, where R 1A As defined herein. In certain embodiments, L 1 -N(R 1A )-, where R 1A In certain embodiments, L 1 -C(R 1A R 1B )-, where R 1A and R 1B Each is as defined herein. In certain embodiments, L 1 It is -CH2-.

[0413] In certain embodiments, L 2 C 3-10 Cycloalkylene is optionally substituted with one or more substituents Q. In certain embodiments, L 2 C 6-14 Arylene is optionally substituted with one or more substituents Q. In certain embodiments, L 2 C 7-15 arylalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L 2 is heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, L 2 is a heterocyclylene group, optionally substituted by one or more substituents Q.

[0414] In certain embodiments, L 2 for:

[0415]

[0416] in:

[0417] s is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[0418] R L and r are each as defined herein.

[0419] In certain embodiments, L 2 for:

[0420]

[0421] wherein s is as defined herein.

[0422] In certain embodiments, L 2 for:

[0423]

[0424] where R L , r and s are each as defined herein.

[0425] In certain embodiments, L 2 for:

[0426]

[0427] wherein s is as defined herein.

[0428] In certain embodiments, L 2 for:

[0429]

[0430] in:

[0431] t is an integer of 0, 1, 2, 3, 4, 5 or 6; and

[0432] R L and r are each as defined herein.

[0433] In certain embodiments, L 2 for:

[0434]

[0435] wherein t is as defined herein.

[0436] In certain embodiments, L 2 for:

[0437]

[0438] where R L , r and t are each as defined herein.

[0439] In certain embodiments, L2 for:

[0440]

[0441] wherein t is as defined herein.

[0442] In certain embodiments, L 1 -L 2 for:

[0443]

[0444]

[0445]

[0446] The symbols

[0066] It indicates that the 6-membered ring contains one to three N atoms in the ring, and each sulfur is optionally oxidized to a sulfoxide or sulfone.

[0447] In certain embodiments, L 1 -L 2 for:

[0448]

[0449]

[0450] In certain embodiments, 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(R 4 )-, where R 4 As defined herein. In certain embodiments, T is -C(R 4 )=, where R 4 As defined herein. In certain embodiments, T is -C(R 4 )2-, where R 4 As defined herein.

[0451] In certain embodiments, U is a bond. In certain embodiments, U is -O-. In certain embodiments, U is -S-. In certain embodiments, U is -N=. In certain embodiments, U is -N(R 5 )-, where R 5 As defined herein. In certain embodiments, U is -C(R 5 )=, where R 5 As defined herein. In certain embodiments, U is -C(R 5 )2-, where R 5 As defined herein.

[0452] In certain embodiments, V is a bond. In certain embodiments, V is -O-. In certain embodiments, V is -S-. In certain embodiments, V is -N=. In certain embodiments, V is -N(R 6 )-, where R 6 As defined herein. In certain embodiments, V is -C(R 6 )=, where R 6 As defined herein. In certain embodiments, V is -C(R 6 )2-, where R 6 As defined herein.

[0453] 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(R 7 )-, where R 7 As defined herein. In certain embodiments, W is -C(R 7 )=, where R 7 As defined herein. In certain embodiments, W is -C(R 7 )2-, where R 7 As defined herein.

[0454] In certain embodiments, X is C. In certain embodiments, X is N.

[0455] In certain embodiments, Y is C. In certain embodiments, Y is N.

[0456] In certain embodiments, Z is NR 2A , where R 2A As defined herein. In certain embodiments, Z is NH. In certain embodiments, Z is CR 2A R 2B , where R 2A and R 2B Each is as defined herein. In certain embodiments, Z is CH2.

[0457] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

[0458] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.

[0459] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0460] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3.

[0461] 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 certain embodiments, r is 4. In certain embodiments, r is 5. In certain embodiments, r is 6.

[0462] In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3.

[0463] In some embodiments, v is 0. In some embodiments, v is 1. In some embodiments, v is 2. In some embodiments, v is 3.

[0464] In one embodiment, provided herein is a compound selected from the group consisting of:

[0465]

[0466]

[0467] and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

[0468] In another embodiment, provided herein is a compound selected from the group consisting of:

[0469]

[0470]

[0471] and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

[0472] In another embodiment, provided herein is a compound selected from the group consisting of:

[0473]

[0474]

[0475] and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

[0476] In another embodiment, provided herein is a compound selected from the group consisting of:

[0477]

[0478]

[0479] and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

[0480] Unless a specific stereochemistry is specified, the compounds provided herein are intended to encompass all possible stereoisomers. When the compounds provided herein contain alkenyl or alkenylene groups, the compounds can exist as a geometric cis / trans (or Z / E) isomer or a mixture thereof. When structural isomers are interconvertible, the compounds can exist as a single tautomer or a mixture of tautomers. Tautomerism can be in the form of proton tautomerism in compounds containing, for example, imino, keto or oxime groups; or in the form of so-called valence tautomerism in compounds containing aromatic moieties. Therefore, a single compound can present more than one type of isomerism.

[0481] For example, when Z is -NH-, compounds of Formula I may exist in any one of the following tautomeric forms as shown below.

[0482]

[0483] The compounds provided herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or may be stereoisomeric mixtures, such as a mixture of enantiomers, for example, a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. Thus, one skilled in the art will recognize that, for compounds that undergo epimerization in vivo, administration of the compound in its (R) form is equivalent to administration of the compound in its (S) form. Conventional techniques for preparing / isolating individual enantiomers include synthesis from suitable optically pure precursors, asymmetric synthesis from achiral starting materials, or resolution of enantiomeric mixtures, such as chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.

[0484] When the compounds provided herein contain an acidic or basic moiety, they can also be provided in the form of pharmaceutically acceptable salts. See Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and Handbook of Pharmaceutical Salts, Properties, and Use; Stahl and Wermuth, eds.; Wiley-VCH and VHCA: Zurich, Switzerland, 2002.

[0485] Suitable acids for preparing 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)-camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclamic acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptanoic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid. , α-oxoglutaric acid, glycolic 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, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, glucaric acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

[0486] Suitable bases for preparing pharmaceutically acceptable salts include, but are not limited to, inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases such as primary, secondary, tertiary, and quaternary, aliphatic, and aromatic amines including L-arginine, benzylphenethylamine, benzathine, choline, dimethylaminoethanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylamine, diamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

[0487] The compounds provided herein can also be provided in the form of prodrugs, which are functional derivatives of compounds such as Formula I, IA or IB, and can be easily converted into the parent compound in vivo. Prodrugs are generally useful because, in some cases, they may be easier to administer than the parent compound. They can be, for example, bioavailable by oral administration, whereas the parent compound cannot. Prodrugs can also have enhanced solubility in pharmaceutical compositions compared to the parent compound. Prodrugs can be converted into parent drugs by various mechanisms, including enzymatic methods and metabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4, 221-294; Morozowich et al., Design of Biopharmaceutical Properties through Prodrugs and Analogs; Roche, ed., APHA Acad. Pharm. Sci.: 1977; Gangwar et al., Design of Biopharmaceutical Properties through Prodrugs and Analogs. Analogs, 1977, 409-421; Bundgaard, Arch. Pharm. Chem., 1979, 86, 1-39; Farquhar et al., J. Pharm. Sci., 1983, 72, 324-325; Wernuth, 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 Enzymol.) 1985, 112, 360-381; Stella et al., Drugs 1985, 29, 455-473; Bioreversible Carriers in Drug in Drug Design, Theory and Application; Roach ed.; APHA Journal of Pharmaceutical Sciences: 1987; Bandegra, Controlled Drug Delivery 1987, 17, 179-96; Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15, 143-53; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877; Bandegra, Adv. Drug Delivery Rev. 1992, 8, 1-38; Nathwani and Wood, Drugs 1993, 45, 866-94; Friis and Bandegra, Eur. J. Pharm. Sci. 1996, 4, 49-59; Fleischer et al., Adv. Drug Delivery 1996, 19, 115-130; Sinhababu and Thakker, Adv. Drug Delivery 1996, 19, 2 41-273; Taylor, Advances in Drug Delivery, 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., Advances in Drug Delivery, 1997, 27, 235-256; Mizen et al., Pharm. Biotech.) 1998, 11, 345-365; Wiebe and Knaus, Progress in Drug Delivery 1999, 39, 63-80; Tan et al., Progress in Drug Delivery 1999, 39, 117-151; Balimane and Sinko, Progress in Drug Delivery 1999, 39, 183-209; Wang et al., Curr. Pharm. Design 1999, 5, 265-287; Han et al., AAPS Pharmsci. 2000, 2, 1-11; Asgharnejad, Transport Processes in Pharmaceutical Systems; Amidon et al., eds.; Marcel Dekker, J.D., et al. ... Dekker: 2000; pp. 185-218; Sinha et al., Pharm. Res. 2001, 18, 557-564; Anand et al., Expert Opin. Biol. Ther. 2002, 2, 607-620; 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, ID Rugs 2004, 7, 736-742; Robinson et al., Proc. Natl. Acad. Sci. USA 2004, 101, 14527-14532; 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., Advances in Drug Delivery 2007, 59, 677-694; Gomes et al., Molecules 2007, 12, 2484-2506; Krafz et al., ChemMedChem 2008, 3, 20-53; Rautio et al., AAPS Journal J. 2008, 10, 92-102; Laudio et al., Nat. Rev. Drug. Discov. 2008, 7, 255-270; Pavan et al., Mol. Sci. 2008, 13, 1035-1065; Sandros et al., Mol. Sci. 2008, 13, 1156-1178; Singh et al., Curr. Med. Chem. 2008, 15, 1802-1826; Onishi et al., Mol. Sci. 2008, 13, 2136-2155; Huttunen et al., Curr. Med. Chem. 2008, 15, 2346-2365; and Serafin et al., Mini-Reviews in Medicinal Chemistry. Rev. Med. Chem.) 2009, 9, 481-497. .

[0488] Synthesis method

[0489] The compounds provided herein can be prepared, isolated or obtained by any method known to those skilled in the art. For example, compounds of formula I can be prepared as shown in Scheme 1.

[0490] Plan I

[0491]

[0492] Compound I-1 is treated with a nucleophilic amine I-2 to form compound I-3, wherein X 1 is a leaving group, including but not limited to fluorine, chlorine, bromine, methoxy, ethoxy and nitro. The nitro group of compound I-3 is reduced with a reducing agent (e.g., zinc, FeCl2, NiCl2 or Na2S2O3) to form compound I-4. Reduction can also be achieved via hydrogenation using, for example, ammonium formate or hydrogen in the presence of Pd / C. Compound I-5 is then cyclized to form compound I-5 while simultaneously installing the Z group. When Z is NH, compound I-5 is then reacted with an acid (R) using a coupling agent (e.g., HATU, HBTU, PyBroP, PyBOP or EDCI) to form compound I-5. 2 COOH) coupling to form a compound of formula I.

[0493] Pharmaceutical compositions

[0494] Provided herein are pharmaceutical compositions comprising, as an active ingredient, a compound provided herein, e.g., a compound of Formula I or XXI, including single enantiomers, racemic mixtures, mixtures of diastereoisomers, or isotopic variants thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture thereof.

[0495] Suitable 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, an oral dosage form such as a tablet may contain excipients that are not suitable for parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredient in the dosage form. For example, the decomposition of some active ingredients may be accelerated by certain excipients (such as lactose) or when exposed to water. Active ingredients containing primary or secondary amines are particularly sensitive to this type of accelerated decomposition. Therefore, pharmaceutical compositions and dosage forms are provided herein that contain very little (if any) lactose or other monosaccharides or disaccharides. As used herein, the term "lactose-free" means that the amount of lactose present (if any) is insufficient to substantially increase the degradation rate of the active ingredient.

[0496] The compounds provided herein can be administered alone or in combination with one or more other compounds provided herein. Pharmaceutical compositions comprising a compound provided herein (e.g., a compound of Formula I or XXI) or a single enantiomer, racemic mixture, mixture of diastereomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, can be formulated in different dosage forms for oral, parenteral, and topical administration. Pharmaceutical compositions can also be formulated as modified release formulations, including delayed release, sustained release, extended release, sustained release, pulsed release, controlled release, accelerated release, rapid release, targeted release, programmed release, and gastric retention formulations. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et al., eds.; Marcel Dekker, Inc.: New York, NY, 2008).

[0497] In one embodiment, the pharmaceutical composition is provided in a dosage form for oral administration, comprising a compound provided herein, e.g., a compound of Formula I or XXI, or a single enantiomer, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0498] In another embodiment, a pharmaceutical composition is provided in a dosage form for parenteral administration, comprising a compound provided herein, e.g., a compound of Formula I or XXI, or a single enantiomer, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0499] In another embodiment, a pharmaceutical composition is provided in a dosage form for topical administration, comprising a compound provided herein, e.g., a compound of Formula I or XXI, or a single enantiomer, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0500] The pharmaceutical compositions provided herein can be provided in unit dosage form or multiple dosage form. As used herein, unit dosage form refers to physically discrete units suitable for administration to human and animal subjects, and is individually packaged as known in the art. Each unit dose contains a predetermined amount of active ingredient, which is combined with the required pharmaceutical carrier or excipient to produce the desired therapeutic effect. Examples of unit dosage forms include ampoules, syringes, and individually packaged tablets and capsules. For example, a 100 mg unit dose contains approximately 100 mg of active ingredient in a packaged tablet or capsule. Unit dosage forms can be administered in part or multiple times thereof. Multiple dosage forms are a plurality of identical unit dosage forms packaged in a single container to be administered in the form of separated unit dosage forms. Examples of multiple dosage forms include vials, bottles of tablets or capsules, or pint or gallon bottles.

[0501] The pharmaceutical compositions provided herein can be administered once or multiple times at intervals. It will be understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It will also be understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the individual administering or supervising the administration of the formulation.

[0502] A. Oral administration

[0503] The pharmaceutical compositions for oral administration provided herein can be provided in solid, semisolid or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, tongue and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fast-dissolving tablets, chewable tablets, capsules, pills, strips, dragees, lozenges, tablets, cachets, pills, medicinal chewable tablets, bulk powders, effervescent or non-effervescent powders or granules, oral sprays, solutions, emulsions, suspensions, wafers, sprinkles, elixirs and syrups. In addition to the active ingredient, the pharmaceutical composition may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, slip agents, colorants, dye migration inhibitors, sweeteners, flavorings, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids and sources of carbon dioxide.

[0504] Binders or granulating agents impart cohesion to the tablet to ensure that the tablet remains intact after compression. Suitable binders or granulating agents include, but are not limited to, starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, extracts of Irish moss, panwar gum, ghatti gum, mucilage from psyllium husk, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabinogalactan, ... Examples of fillers include arabogalactan, powdered tragacanth, and guar gum; celluloses such as ethylcellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC); microcrystalline cellulose such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, and AVICEL-PH-105 (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, pregelatinized starch, and mixtures thereof. The amount of binder or filler in the pharmaceutical compositions provided herein varies depending on the type of formulation and can be readily discerned by one skilled in the art. A binder or filler may be present in the pharmaceutical compositions provided herein in an amount of about 50% to about 99% by weight.

[0505] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, anhydrous starch, and powdered sugar. When present in sufficient amounts, certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, can impart to some compressed tablets the property of disintegrating in the mouth by chewing. Such compressed tablets can be used as chewable tablets. The amount of diluent in the pharmaceutical compositions provided herein varies depending on the type of formulation and can be easily discerned by those skilled in the art.

[0506] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and Wigham HV; citrus pulp; cross-linked celluloses such as cross-linked carboxymethylcellulose; cross-linked polymers such as cross-linked polyvinylpyrrolidone; cross-linked starch; calcium carbonate; microcrystalline cellulose such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clays; aligners; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and can be readily discerned by one skilled in the art. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and can be readily discerned by one skilled in the art. The pharmaceutical compositions provided herein may contain about 0.5 to about 15% by weight or about 1 to about 5% by weight of a disintegrant.

[0507] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerol; sorbitol; mannitol; glycols such as glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium; silica or silica gel, such as 200 (WR Grace Co., Baltimore, MD) and (Cabot Co., Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein can contain from about 0.1 to about 5% by weight of a lubricant.

[0508] Suitable slip agents include, but are not limited to, colloidal silicon dioxide, (Cabot Corporation, Boston, Massachusetts), and asbestos-free talc. Suitable coloring agents include, but are not limited to, any approved, certified, water-soluble FD&C dyes, and water-insoluble FD&C dyes suspended on alumina hydrate, and lakes and mixtures thereof. Lakes are combinations formed by the adsorption of water-soluble dyes onto hydrous oxides of heavy metals, resulting in an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural flavorings extracted from plants, such as fruits, and synthetic blends of compounds that produce a pleasant mouthfeel, such as peppermint and methyl salicylate. Suitable sweeteners include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerol, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifiers include, but are not limited to, gelatin, gum arabic, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate ( 20), Polyoxyethylene sorbitan monooleate 80 ( 80) and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, wigamom, gum arabic, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerol, methyl and propyl parabens, benzoic acid additives, sodium benzoate, and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, monolauryl glycol, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerol, sorbitol, ethanol, and syrup. Suitable non-aqueous liquids for use in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric acid and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

[0509] It will be appreciated that many carriers and excipients may serve multiple functions, even within the same formulation.

[0510] The pharmaceutical compositions provided herein for oral administration can be compressed tablets, triturated tablets, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of gastric acid but dissolves or disintegrates in the intestine, thereby protecting the active ingredients from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets coated with a sugar coating, which can advantageously mask unpleasant tastes or odors and protect the tablets from oxidation. Film-coated tablets are compressed tablets coated with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings provide the same general characteristics as sugar coatings. Multiple compressed tablets are compressed tablets prepared by more than one compression cycle and include layered tablets and compression-coated or dry-coated tablets.

[0511] Tablet dosage forms can be prepared from the active ingredient alone in powder, crystal or granular form or in combination with one or more carriers or excipients described herein (including binders, disintegrants, controlled release polymers, lubricants, diluents and / or colorants). Flavorings and sweeteners are particularly suitable for forming chewable tablets and lozenges.

[0512] The pharmaceutical composition for oral administration provided herein can be provided in soft or hard capsule form, which can be prepared by gelatin, methylcellulose, starch or calcium alginate. Hard gelatin capsules, also known as dry fill capsules (DFCs), are composed of two parts, one part sliding on the other part, thus fully wrapping the active ingredient. Soft elastic capsules (SECs) are soft spherical shells, such as gelatin shells, which are plasticized by adding glycerol, sorbitol or similar polyols. Soft gelatin shells can contain preservatives to prevent microbial growth. Suitable preservatives such as these described herein include methylparaben and propylparaben, sorbic acid. Liquids, semisolids and solid dosage forms provided herein can be encapsulated in capsules. Suitable liquids and semisolid dosage forms are included in solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in US Patent Nos. 4,328,245; 4,409,239; and 4,410,545. As known to those skilled in the art, capsules may also be coated to improve or sustain dissolution of the active ingredient.

[0513] The pharmaceutical compositions for oral administration provided herein can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems in which one liquid is dispersed throughout another liquid in the form of small spheres, which can be oil-in-water or water-in-oil. Emulsions can include pharmaceutically acceptable non-aqueous liquids or solvents, emulsifiers, and preservatives. Suspensions can include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions can include pharmaceutically acceptable acetals, such as di(low alkyl) acetals of low-carbon alkyl aldehydes, such as acetaldehyde diethanol acetal; and water-miscible solvents 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 sugars (e.g., sucrose) and can also contain preservatives. For liquid dosage forms, such as solutions in polyethylene glycol, dilution with a sufficient amount of a conveniently measured pharmaceutically acceptable liquid carrier (e.g., water) for administration can be used.

[0514] Other suitable liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredients provided herein and dialkylated monoalkylene glycols or polyalkylene glycols, including 1,2-dimethoxymethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further 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 dithiocarbamic acid.

[0515] The pharmaceutical compositions provided herein for oral administration can also be provided in the form of liposomes, micelles, microparticles, or nanosystems. Micellar dosage forms can be prepared as described in US Pat. No. 6,350,458.

[0516] The pharmaceutical compositions for oral administration provided herein can be provided in non-foaming or foaming, granular and powder forms to be reconstituted into liquid dosage forms. Pharmaceutically acceptable carriers and excipients for non-foaming granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients for foaming granules or powders may include organic acids and a source of carbon dioxide.

[0517] Coloring and flavoring agents can be used in all of the above dosage forms.

[0518] The pharmaceutical compositions provided herein for oral administration can be formulated in immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0519] B. Parenteral administration

[0520] The pharmaceutical compositions provided herein can be administered by injection, infusion or implantation rather than parenteral administration for local or systemic administration. As used herein, parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, intravesical and subcutaneous administration.

[0521] The pharmaceutical compositions provided herein for parenteral administration can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microparticles, nanosystems, and solid forms suitable for dissolution or suspension in a 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 of Pharmacy, supra).

[0522] Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including but not limited to aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to combat the growth of microorganisms, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusters, and inert gases.

[0523] Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate-buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose, and lactated Ringer's injection. Suitable non-aqueous vehicles include, but are not limited to, fixed oils of plant origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, medium- and long-chain triglycerides of hydrogenated soybean and coconut oils, and palm kernel oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butylene glycol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0524] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol, and dextrose. Suitable buffers include, but are not limited to, phosphates and citrates. Suitable antioxidants are those described herein, including bisulfites and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those described herein, including sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers are those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable barrier or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters 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 α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether 7-β-cyclodextrin ( CyDex, Lenexa, KS.

[0525] When the pharmaceutical compositions provided herein are formulated for multiple-dose administration, the multiple-dose parenteral formulations must contain bacteriostatic or fungistatic concentrations of an antibacterial agent.All parenteral formulations must be sterile, as known and practiced in the art.

[0526] In one embodiment, pharmaceutical compositions for parenteral administration are provided as ready-to-use sterile solutions. In another embodiment, pharmaceutical compositions are provided as sterile dry soluble products to be reconstituted with a vehicle prior to use, including lyophilized powders and subcutaneous tablets. In another embodiment, pharmaceutical compositions are provided as ready-to-use sterile suspensions. In another embodiment, pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle prior to use. In another embodiment, pharmaceutical compositions are provided as ready-to-use sterile emulsions.

[0527] The pharmaceutical compositions provided herein for parenteral administration can be formulated in immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0528] The pharmaceutical compositions provided herein for parenteral administration can be formulated as suspensions, solids, semisolids, or thixotropic liquids for administration as implantable depots. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid inner matrix that is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical composition to diffuse through.

[0529] Suitable inner matrices include, but are not limited to, polymethyl methacrylate, polybutyl methacrylate, plasticized or non-plasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, polysiloxane carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic acid and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

[0530] Suitable outer polymeric films include, but are not limited to, polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers.

[0531] C. Local administration

[0532] The pharmaceutical compositions provided herein can be administered topically to the skin, orifices, or mucous membranes. As used herein, topical administration includes (internal) transdermal, transconjunctival, intracorneal, intraocular, ocular, otic, transdermal, nasal, vaginal, urethral, ​​respiratory, and rectal administration.

[0533] The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, rinses, sprays, suppositories, bandages, and transdermal patches. Topical formulations of the pharmaceutical compositions provided herein can also comprise liposomes, micelles, microparticles, nanosystems, and mixtures thereof.

[0534] Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to combat the growth of microorganisms, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.

[0535] The pharmaceutical composition can also be administered topically by electroporation, iontophoresis, sonotrode, or microneedle or needle-free injection, such as POWDERJECT TM (Chiron Corp., Emeryville, CA) and BIOJECT TM (Bioject Medical Technologies Inc., Tualatin, OR).

[0536] The pharmaceutical compositions provided herein can be provided in the form of ointments, creams, and gels. Suitable ointment vehicles include oily or hydrocarbon vehicles, including lard, benzoin lard, olive oil, cottonseed oil and other oils, white petrolatum; emulsifiable or absorbable vehicles, such as hydrophilic petrolatum, hydroxystearyl sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointments; water-soluble ointment vehicles, including polyethylene glycols of different molecular weights; emulsion vehicles, water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see Remington: The Science and Practice of Pharmacy, supra). These vehicles are emollients, but usually require the addition of antioxidants and preservatives.

[0537] Suitable cream bases can be oil-in-water or water-in-oil. Suitable cream vehicles can be water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also known as the "inner" phase, typically comprises petrolatum and a fatty alcohol, such as cetyl alcohol or stearyl alcohol. The aqueous phase typically (but not necessarily) exceeds the oil phase in volume and typically contains a moisturizer. The emulsifier in the cream formulation can be a nonionic, anionic, cationic, or amphoteric surfactant.

[0538] Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules substantially uniformly distributed throughout a liquid carrier. Suitable gelling agents include, but are not limited to, cross-linked acrylic acid polymers such as carbomers, carboxypolyalkylenes and Hydrophilic polymers such as polyethylene oxide, polyethylene oxide-polypropylene oxide copolymers, and polyvinyl alcohol; cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums such as tragacanth and safflower gum; sodium alginate; and gelatin. To prepare a uniform gel, a dispersant such as ethanol or glycerol may be added, or the gelling agent may be dispersed by trituration, mechanical mixing, and / or stirring.

[0539] The pharmaceutical compositions provided herein can be administered rectally, urethrally, vaginally or perivaally in the form of suppositories, pessaries, rods, poultices or hot potions, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays or enemas. These dosage forms can be prepared using conventional methods as described in Remington: The Science and Practice of Pharmacy, supra.

[0540] Rectal, urethral, ​​and vaginal suppositories are solid objects for insertion into body orifices that are solid at room temperature but melt or soften at body temperature to release the active ingredient inside the orifice. Pharmaceutically acceptable carriers used in rectal and vaginal suppositories include bases or vehicles, such as hardeners, which produce a melting point near body temperature when formulated with the pharmaceutical compositions provided herein; and antioxidants as described herein, including bisulfites and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (cocoa butter), glycerol gelatin, polyethylene glycol (polyoxyethylene glycol), spermaceti, paraffins, white and yellow waxes, and suitable mixtures of monoglycerides, diglycerides, and triglycerides of fatty acids, and hydrogels such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid. Combinations of different vehicles can also be used. Rectal and vaginal suppositories can be prepared by compression or molding. Typical weights of rectal and vaginal suppositories are about 2 to about 3 g.

[0541] The pharmaceutical compositions provided herein can be administered ophthalmically in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.

[0542] The pharmaceutical compositions provided herein can be administered intranasally or by inhalation to the respiratory tract. Pharmaceutical compositions can be provided as sprays or solutions (alone or in combination with a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane) for delivery using a pressurized container, pump, sprayer, atomizer (such as one that uses electrohydrodynamics to produce a fine mist), or nebulizer. Pharmaceutical compositions can also be provided as dry powders for insufflation (alone or in combination with an inert carrier such as lactose or phospholipids) and nasal drops. For intranasal use, powders can contain bioadhesives, including polyglucosamine or cyclodextrins.

[0543] Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or an alternative agent suitable for dispersing, solubilizing, or prolonging the release of the active ingredients provided herein; a propellant as a solvent; and / or a surfactant, such as sorbitan trioleate, oleic acid, or oligolactic acid.

[0544] The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 microns or less, or about 10 microns or less. Particles of such sizes can be prepared using comminution methods known to those skilled in the art, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing for forming nanoparticles, high pressure homogenization, or spray drying.

[0545] Capsules, blisters, and cartridges for use in inhalers or insufflators can be formulated with a powder mixture containing: a pharmaceutical composition provided herein; a suitable powder base, such as lactose or starch; and a performance enhancer, such as l-leucine, mannitol, or magnesium stearate. Lactose can be anhydrous or in the form of a monohydrate. Other suitable excipients or carriers include, but are not limited to, polydextrose, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. Pharmaceutical compositions for inhaled / intranasal administration provided herein can further include suitable flavorings, such as menthol and levomenthol; and / or sweeteners, such as saccharin and saccharin sodium.

[0546] The pharmaceutical compositions provided herein for topical administration can be formulated for immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.

[0547] D. Modified Release

[0548] The pharmaceutical compositions provided herein can be formulated as modified release dosage forms. As used herein, the term "modified release" refers to a dosage form in which the rate or location of release of the active ingredient is different from that of an immediate release dosage form when administered by the same route. Modified release dosage forms include, but are not limited to, delayed release, extended release, sustained release, pulsed release, controlled release, accelerated release, and rapid release, targeted release, programmed release, and gastric retention dosage forms. Modified release dosage forms of the pharmaceutical compositions 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 controlled release devices, multiparticulate controlled release devices, ion exchange resins, enteric coatings, multilayer coatings, microparticles, liposomes, and combinations thereof. The release rate of the active ingredient can also be modified by changing the particle size and polymorphism of the active ingredient.

[0549] Examples of modified release include, but are not limited to, those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5 ,639,476; No. 5,354,556; No. 5,639,480; No. 5,733,566; No. 5,739,108; No. 5,891,474; No. 5,922,356; No. 5,958,458; No. 5,972,891; No. 5,980,945; No. 5,993,855; No. 6,045,830; No. 6,087,32 4; No. 6,113,943; No. 6,197,350; No. 6,248,363; No. 6,264,970; No. 6,267,981; No. 6,270,798; No. 6,375,987; No. 6,376,461; No. 6,419,961; No. 6,589,548; No. 6,613,358; No. 6,623,756; No. 6,6 99,500; 6,793,936; 6,827,947; 6,902,742; 6,958,161; 7,255,876; 7,416,738; 7,427,414; 7,485,322; Bussemer et al., Crit. Rev. Ther. Drug Carrier Syst. 2001, 18, 433-458; Modified-Release Drug Delivery, 2nd ed.; Rasborne 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, supra; Conway, Recent Pat. Drug Deliv. Formulations.) 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. Technol. 2008, 13, 413-423; Chrzanowski, AAPS Journal of Pharmaceutical Science and Technology PharmSciTech. 2008, 9, 635-638; Chrzhanovsky, AAPS Pharmaceutical Science and Technology 2008, 9, 639-645; Kalantzi et al., New Drug Delivery Formulations 2009, 3, 49-63; Saigal et al., New Drug Delivery Formulations 2009, 3, 64-70; and Roy et al., J. Control Release 2009, 134, 74-80.

[0550] 1. Matrix controlled release device

[0551] Modified-release dosage forms of the pharmaceutical compositions provided herein can be made using matrix controlled-release devices known to those skilled in the art. See Takada et al., Encyclopedia of Controlled Drug Delivery; Mathiowitz, ed.; Wiley: 1999; Vol. 2.

[0552] In certain embodiments, modified release dosage forms of the pharmaceutical compositions provided herein are formulated using an erodible matrix device that is a water-swellable, erodible, or soluble polymer, including but not limited to synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.

[0553] Materials suitable for forming an erodible matrix include, but are not limited to, chitin, polyglucosamine, polydextrose, and pullulan; agar, gum arabic, gum galaya, and gum arabic. karaya), locust bean gum, tragacanth gum, carrageenan, gum gedi, guar gum, safflower gum and scleroglucans; starches such as dextrin and maltodextrin; hydrophilic colloids such as pectin; phospholipids such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosic materials such as ethylcellulose (EC), methylethylcellulose (MEC), carboxymethylcellulose (CMC), CMEC, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT) and ethyl hydroxyethylcellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid and methacrylic acid ( and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate chloride.

[0554] In certain embodiments, the pharmaceutical compositions provided herein are formulated via a non-erodible matrix device.The active ingredient is dissolved or dispersed in an inert matrix and released following administration primarily by diffusion through the inert matrix. Suitable materials for non-erodible matrix devices include, but are not limited to, insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetate copolymers, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, ethylene / vinyloxyethanol copolymers, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, and polysiloxane carbonate copolymers; hydrophilic polymers such as ethylcellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds such as carnauba wax, microcrystalline wax, and triglycerides.

[0555] In matrix controlled release systems, the desired release kinetics can be controlled, for example, via the type of polymer used, polymer viscosity, particle size of the polymer and / or active ingredient, ratio of active ingredient to polymer, and other excipients or carriers in the composition.

[0556] Modified release dosage forms of the pharmaceutical compositions provided herein can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt granulation followed by compression.

[0557] 2. Osmotic controlled release device

[0558] Modified-release dosage forms of the pharmaceutical compositions provided herein can be manufactured using osmotic controlled-release devices, including but not limited to single-chamber systems, dual-chamber systems, asymmetric membrane technology (AMT), and extrusion core systems (ECS). Typically, such devices have at least two components: (a) a core containing the active ingredient; and (b) a semipermeable membrane having at least one transfer pore that surrounds the core. The semipermeable membrane controls the flow of water from the aqueous environment of use into the core, thereby causing drug release by extrusion through the transfer pore.

[0559] In addition to the active ingredient, the core of the osmotic device optionally includes an osmotic agent that creates a driving force for water transport from the environment of use into the device core. One type of osmotic agent is a water-swellable hydrophilic polymer, also known as an "osmopolymer" and a "hydrogel." Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinyl pyrrolidone (PVP), cross-linked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, copolymers of PVA / PVP with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, tannin, and sodium starch glycolate.

[0560] Another osmotic agent is an osmogen, which is capable of absorbing water to affect an osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric 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 thereof.

[0561] Osmotic agents with different dissolution rates can be used to affect the rate at which the active ingredient is initially delivered from the dosage form. For example, amorphous sugars (such as MANNOGEM TM EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first few hours to quickly produce the desired therapeutic effect, and gradually and continuously release 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 is released at such a rate to replace the amount of active ingredient that is metabolized and excreted.

[0562] The core may also include a wide variety of other excipients and carriers, as described herein, to enhance the efficacy of the dosage form or to aid in stability or processing.

[0563] Materials suitable for forming the semipermeable membrane include various grades of acrylic polymers (acrylics), polyethylene (vinyls), ethers, polyamides, polyesters and cellulose derivatives that are water permeable at physiologically relevant pH and insoluble in water, or that are readily rendered water insoluble by chemical changes such as cross-linking. Examples of suitable polymers suitable for forming the coating include plasticized, non-plasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethylcarbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetic acid, CA ethylcarbonate, CA chloroacetic acid, CA ethyloxalate, CA methylsulfonic acid, CA butylsulfonic acid, CA p-toluenesulfonic acid, acetate agar, amylose triacetate, beta acetate Dextran, beta glucan triacetate, dimethylacetaldehyde, triacetate of locust bean gum, hydroxylated ethylene vinyl acetate, EC, PEG, PPG, PEG / PPG copolymer, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly(methacrylic) acids and esters and copolymers thereof, starch, polydextrose, dextrin, polyglucosamine, collagen, gelatin, polyolefins, polyethers, polysulfones, polyethersulfones, polystyrenes, polyethylene halides, polyethylene esters and ethers, natural and synthetic waxes.

[0564] The semipermeable membrane may also be a hydrophobic microporous membrane in which the pores are substantially filled with a gas and are not wetted by aqueous media but are permeable to water vapor, as disclosed in U.S. Patent No. 5,798, 119. Such hydrophobic but water vapor permeable membranes are typically composed of hydrophobic polymers such as polyolefins, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyethylene halides, polyvinylidene fluoride, polyethylene esters and ethers, natural waxes, and synthetic waxes.

[0565] Transfer pores in the semipermeable membrane can be formed after coating by mechanical or laser drilling. Transfer pores 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 above the core recess. In addition, transfer pores can be formed during the coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Patents 5,612,059 and 5,698,220.

[0566] The total amount of active ingredient released and the rate of release can be substantially regulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery pores.

[0567] The osmotic controlled release dosage form of the pharmaceutical composition may further comprise other conventional excipients or carriers as described herein to aid in the efficacy or processing of the formulation.

[0568] Osmotic 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 of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; and Verma et al., J. Controlled Release 2002, 79, 7-27.

[0569] In certain embodiments, the pharmaceutical compositions provided herein are formulated as AMT controlled-release dosage forms comprising an asymmetric osmotic membrane encapsulating a core comprising the active ingredient and other pharmaceutically acceptable excipients or carriers. See U.S. Patent No. 5,612,059 and International Patent Application Publication No. WO 2002 / 17918. AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and dip-coating methods.

[0570] In certain embodiments, the pharmaceutical compositions provided herein are formulated as ESC controlled-release dosage forms comprising a permeable membrane encapsulating a core comprising the active ingredient, hydroxyethylcellulose, and other pharmaceutically acceptable excipients or carriers.

[0571] 3. Multi-particle controlled release device

[0572] The modified release dosage forms of the pharmaceutical compositions provided herein can be manufactured in the form of multiparticulate controlled release devices comprising a plurality of particles, granules or pellets having a diameter ranging from about 10 μm to about 3 mm, from about 50 μm to about 2.5 mm, or from about 100 μm to about 1 mm. Such multiparticulates can be prepared by methods known to those skilled in the art, including wet and dry granulation, extrusion / spheronization, roller compression, melt congealing, and by spray coating seed cores. See, for example, Multiparticulate Oral Drug Delivery; Ghebre-Sellassie, ed.; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Ghebre-Sellassie, ed.; Marcel Dekker: 1989.

[0573] Other excipients or carriers as described herein may be blended with the pharmaceutical composition to aid processing and formation of multiparticulates. The resulting particles themselves may constitute a multiparticulate device or may be coated with various film-forming materials such as enteric polymers, water-swellable and water-soluble polymers. The multiparticulates may be further processed into capsules or tablets.

[0574] 4. Targeted delivery

[0575] The pharmaceutical compositions provided herein may also be formulated to target specific tissues, receptors, or other areas of the body of the individual being treated, including liposome-, reencapsulated erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, U.S. Patent Nos. 5,709,874; 5,759,542; 5,840,674; 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.

[0576] How to use

[0577] In one embodiment, provided herein are methods 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 compound of Formula I or XXI, or a single enantiomer, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0578] In certain embodiments, the ERBB is a wild-type ERBB. In certain embodiments, the ERBB is an ERBB variant.

[0579] In certain embodiments, ERBB is EGFR. In certain embodiments, ERBB is wild-type EGFR. In certain embodiments, ERBB is an EGFR variant. In certain embodiments, the EGFR variant contains a deletion, insertion, or substitution. In certain embodiments, the EGFR variant contains one or more deletions, insertions, or substitutions at the following amino acid positions: 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, G719C, G719S, G719A, S720P, ΔE746-A750, ΔE746-T751, ΔE746-A750 (ins RP), ΔE746-T751 (ins A / I), ΔE746-T751 (ins VA), ΔE746-S752 (ins A / V), L747S, ΔL747-E749 (A750P), ΔL747-A750 (ins P), ΔL747-T751, ΔL747-T751 (ins P / S), ΔL747-S752, ΔL747-752(E746V), ΔL747-752(P753S), ΔL747-S752(ins Q), ΔL747-P753, ΔL747-P753(ins S), ΔS752-I759, D761Y, ΔD761-E762(ins EAFQ), ΔA763-Y764(ins FQEA), V765A, ΔM766-A767(ins AI), ΔA767-S768(ins TLA), ΔA767-S768(ins SVA), S768I, ΔS768-D770(dup SVD), V769L, ΔV769-D770(ins ASV), ΔD770-N771(ins NPG), ΔD770-N771(ins SVQ), ΔD770-N771(ins SVD), ΔD770-N771(ins G), ΔD770-P772(ins ASV), N771T, ΔP772-H773(ins PR), ΔP772-H773(ins YNP), ΔH773-V774(ins NPH), ΔH773-V774(ins NP), ΔH773-V774(ins H), ΔH773-V774(ins PH), ΔH773-V774(ins GNPH), ΔV774-C775(ins HV), H775Y, P782R, T783A, T784A, T790M, G796A, N826S, A839T, K846R, L858R, L861Q and G863D, with the limitation 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, insertions and / or substitutions, each independently selected from G719C, G719S, G719A, ΔE746-A750, ΔE746-T751, ΔE746-A750 (ins RP), T790M and L858R. In certain embodiments, the EGFR variant contains T790M and / or L858R. In certain embodiments, the EGFR variant comprises one, two, or more deletions, insertions, and / or substitutions, each independently selected from 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). In certain embodiments, the EGFR variant comprises a deletion, insertion, or substitution in exon 19. In certain embodiments, the EGFR variant comprises a deletion, insertion, or substitution in exon 20.

[0580] In certain embodiments, the ERBB is HER2. In certain embodiments, the ERBB is wild-type HER2. In certain embodiments, the ERBB is a HER2 variant. In certain embodiments, the HER2 variant contains a deletion, insertion, or substitution. In certain embodiments, the HER2 variant contains one or more deletions, insertions, or substitutions at the following amino acid positions: 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, T733I, L755S, L755W, ΔL755-T759, I767M, D769H, D769Y, ΔA775-G776 (ins YVMA), G776VC, G776LC, ΔV777-G778 (ins CG), V777L, P780L, ΔP780-Y781 (ins In certain embodiments, the HER2 variant comprises one, two, or more deletions, insertions, and / or substitutions, each independently selected from the group consisting of G309A, L755S, ΔL755-T759, ΔA775-G776 (ins YVMA), V777L, ΔP780-Y781 (ins GSP), V842I, and R896C.

[0581] In certain embodiments, the ERBB is HER3. In certain embodiments, the ERBB is wild-type HER3. In certain embodiments, the ERBB is a HER3 variant. In certain embodiments, the HER3 variant contains a deletion, insertion, or substitution.

[0582] In certain embodiments, the ERBB is HER4. In certain embodiments, the ERBB is wild-type HER4. In certain embodiments, the ERBB is a HER4 variant. In certain embodiments, the HER4 variant contains a deletion, insertion, or substitution.

[0583] In certain embodiments, ERBB is a dimer. In certain embodiments, ERBB is a homodimer. In certain embodiments, ERBB is a heterodimer. In certain embodiments, ERBB is a heterodimer of EGFR, HER2, HER3, HER4, and variants thereof.

[0584] In certain embodiments, the compounds provided herein are selective inhibitors of mutant ERBB. In certain embodiments, the selectivity of the compounds provided herein for mutant ERBB is 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 greater than that for wild-type ERBB.

[0585] In certain embodiments, provided herein is a compound that is a selective inhibitor of mutant EGFR. In certain embodiments, provided herein is a compound that is a selective inhibitor of mutant EGFR. In certain embodiments, provided herein is a compound that is a selective inhibitor of mutant EGFR that is a selective inhibitor of mutant EGFR that is a selective inhibitor of mutant EGFR that is a selective inhibitor of mutant EGFR that is a selective inhibitor of mutant EGFR that is a selective inhibitor of mutant EGFR that is a selective inhibitor of wild-type ...

[0586] In certain embodiments, provided herein are compounds that are selective inhibitors of mutant HER2. In certain embodiments, provided herein are compounds that are selective inhibitors of mutant HER2 that are more selective than wild-type HER2 by about 2 times, about 4 times, about 8 times, about 20 times, about 50 times, about 100 times, about 200 times, about 500 times, or about 1000 times.

[0587] In certain embodiments, the compounds provided herein are selective inhibitors of mutant HER3. In certain embodiments, the compounds provided herein are selective for mutant HER3 over wild-type HER3 by 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.

[0588] In certain embodiments, the compounds provided herein are selective inhibitors of mutant HER4. In certain embodiments, the selectivity of the compounds provided herein for mutant HER4 is 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 greater than that for wild-type HER4.

[0589] In another embodiment, provided herein are methods 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 mixture of two or more diastereoisomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0590] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human primate, livestock (e.g., cattle), sport animal, or pet (e.g., a horse, dog, or cat).

[0591] In certain embodiments, the ERBB-mediated condition, disorder, or disease is a proliferative disease. In certain embodiments, the ERBB-mediated condition, disorder, or disease is cancer. In certain embodiments, the ERBB-mediated condition, disorder, or disease is drug-resistant cancer. In certain embodiments, the ERBB-mediated condition, disorder, or disease is multidrug-resistant cancer. In certain embodiments, the ERBB-mediated condition, disorder, or disease is recurrent multidrug-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 disorder.

[0592] In certain embodiments, the proliferative disease is cancer. In certain embodiments, the cancer is a recurrent cancer. In certain embodiments, the cancer is a drug-resistant cancer. In certain embodiments, the cancer is a recurrent drug-resistant cancer. In certain embodiments, the cancer is a multidrug-resistant cancer. In certain embodiments, the cancer is a recurrent multidrug-resistant cancer.

[0593] In certain embodiments, the cancer is an ERBB inhibitor-resistant cancer. In certain embodiments, the cancer is a reversible ERBB inhibitor-resistant cancer. In certain embodiments, the cancer is an irreversible ERBB inhibitor-resistant cancer. In certain embodiments, the cancer is a recurrent ERBB inhibitor-resistant cancer. In certain embodiments, the cancer is a recurrent reversible ERBB inhibitor-resistant cancer. In certain embodiments, the cancer is a recurrent irreversible ERBB inhibitor-resistant cancer. In certain embodiments, the cancer is resistant to afatinib, canertinib, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, neratinib, pelitinib, varlitinib, or a combination thereof.

[0594] In certain embodiments, the cancer is EGFR inhibitor-resistant cancer. In certain embodiments, the cancer is reversibly EGFR inhibitor-resistant cancer. In certain embodiments, the cancer is irreversibly EGFR inhibitor-resistant cancer. In certain embodiments, the cancer is relapsed EGFR inhibitor-resistant cancer. In certain embodiments, the cancer is relapsed reversibly EGFR inhibitor-resistant cancer. In certain embodiments, the cancer is relapsed irreversibly EGFR inhibitor-resistant cancer.

[0595] In certain embodiments, the cancer is HER2 inhibitor-resistant cancer. In certain embodiments, the cancer is reversibly HER2 inhibitor-resistant cancer. In certain embodiments, the cancer is irreversibly HER2 inhibitor-resistant cancer. In certain embodiments, the cancer is relapsed HER2 inhibitor-resistant cancer. In certain embodiments, the cancer is relapsed reversibly HER2 inhibitor-resistant cancer. In certain embodiments, the cancer is relapsed irreversibly HER2 inhibitor-resistant cancer.

[0596] In certain embodiments, the cancer is HER3 inhibitor-resistant cancer. In certain embodiments, the cancer is reversibly HER3 inhibitor-resistant cancer. In certain embodiments, the cancer is irreversibly HER3 inhibitor-resistant cancer. In certain embodiments, the cancer is relapsed HER3 inhibitor-resistant cancer. In certain embodiments, the cancer is relapsed reversibly HER3 inhibitor-resistant cancer. In certain embodiments, the cancer is relapsed irreversibly HER3 inhibitor-resistant cancer.

[0597] In certain embodiments, the cancer is HER4 inhibitor-resistant cancer. In certain embodiments, the cancer is reversibly HER4 inhibitor-resistant cancer. In certain embodiments, the cancer is irreversibly HER4 inhibitor-resistant cancer. In certain embodiments, the cancer is recurrent HER4 inhibitor-resistant cancer. In certain embodiments, the cancer is recurrent reversibly HER4 inhibitor-resistant cancer. In certain embodiments, the cancer is recurrent irreversibly HER4 inhibitor-resistant cancer.

[0598] In certain embodiments, the proliferative disease is an inflammatory disease. In certain embodiments, the proliferative disease is an immune disorder.

[0599] Conditions, disorders, or diseases that can be treated with the compounds provided herein include, but are not limited to: (1) inflammatory or allergic diseases, including anaphylaxis and allergic disorders, atopic dermatitis, urticaria, drug allergies, insect bite allergies, food allergies (including celiac disease and its analogs), and mastocytosis; (2) inflammatory bowel disease, including Crohn's disease, ulcerative colitis, ileitis, and enteritis; (3) vasculitis and Behcet's syndrome; (4) inflammatory bowel disease, including Crohn's disease, ulcerative colitis, ileitis, and enteritis; (5) vasculitis and Behcet's syndrome; (6) inflammatory bowel disease, including Crohn's disease, ulcerative colitis, ileitis, and enteritis; (7) inflammatory bowel disease, including Crohn's disease, ulcerative colitis, ileitis, and enteritis; (8) inflammatory bowel disease, including Crohn's disease, ulcerative colitis, ileitis, and enteritis; (9) inflammatory bowel disease, including Crohn's disease, ulcerative colitis, ileitis, and enteritis; (10) inflammatory bowel disease, including Crohn's disease, ulcerative colitis, ileitis, and enteritis; (11) inflammatory bowel disease, including Crohn's disease, ulcerative colitis, ileitis, and enteritis; (12) inflammatory bowel disease, including Crohn's disease, ulcerative colitis, ileitis, and enteritis; (13) inflammatory bowel disease, including Crohn's disease, ulcerative colitis, ileitis, and enteritis; (14) inflammatory bowel disease, including Crohn's disease, ulcerative colitis, ileitis, and enteritis; (15) inflammatory bowel disease, including Crohn's disease, ulcerative colitis, ileitis, and enteritis; (16) inflammatory syndrome); (4) psoriasis and inflammatory skin diseases, including dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, viral skin lesions (including those caused by human papillomavirus, HIV or RLV infection), bacterial, fungal and other parasitic skin lesions, and cutaneous lupus erythematosus; (5) asthma and respiratory allergic diseases, including allergic asthma, exercise-induced asthma, allergic rhinitis, otitis media, allergic conjunctivitis, allergic lung disease and chronic obstructive pulmonary disease; (6) autoimmune diseases, including arthritis (including rheumatoid and psoriatic), systemic lupus erythematosus, type I diabetes, myasthenia gravis, multiple sclerosis, Graves' disease and glomerulonephritis; (7) transplant rejection (including allograft rejection and graft-versus-host disease), such as skin transplant 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, coronary artery disease, restenosis, and vascular stenosis; (10) cerebrovascular disorders, including traumatic brain injury, stroke, ischemic reperfusion injury, and aneurysm; (11) breast, skin, prostate, cervix, uterus, ovary, testis, bladder, lung, liver, larynx, oral cavity, colon, and gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain, thyroid gland, and thyroid gland. Cancers of the gland, blood, and lymphatic system; (12) fibrosis, connective tissue diseases, and sarcoidosis; (13) genital and reproductive conditions, including erectile dysfunction; (14) gastrointestinal disorders, including gastritis, ulcers, nausea, pancreatitis, and vomiting; (15) neurological disorders, including Alzheimer's disease; (16) sleep disorders, including insomnia, narcolepsy, sleep apnea, and Pickwick syndrome; (17) pain; (18) kidney disorders; (19) eye disorders, including glaucoma; and (20) infectious diseases, including HIV.

[0600] In certain embodiments, cancers that can be treated with the compounds provided herein include, but are not limited to, (1) leukemias, including, but not limited to, acute leukemias, acute lymphocytic leukemias, acute myelocytic leukemias, such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemic leukemias, and myelodysplastic syndromes or symptoms thereof (e.g., anemia, thrombocytopenia, neutropenia, bilineage cytopenia, or total cytopenia), refractory anemia (RA), RA with ring sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transition (RAEB), -T), leukemia precursors and chronic myelomonocytic leukemia (CMML), (2) chronic leukemias, including (but not limited to) chronic myelocytic (granulocytic) 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 myeloma, including (but not limited to) mild multiple myeloma, non-secretory myeloma, sclerosing myeloma, plasma cell leukemia, solitary plasmacytoma and extramedullary plasmacytoma; (6) Waldenstrom's macroglobulinemia ( (7) monoclonal gammopathy of undetermined significance; (8) benign monoclonal gammopathy; (9) heavy chain disease; (10) skeletal and connective tissue sarcomas, including but not limited to skeletal sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft tissue sarcoma, angiosarcoma (hemangioendothelioma), fibrosarcoma, Kaposi's sarcoma, and sarcoma of the soft tissues. (11) Brain tumors, including but not limited to gliomas, astrocytomas, brain stem gliomas, ependymomas, oligodendrogliomas, nongliomas, acoustic neuromas, craniopharyngiomas, medulloblastomas, meningiomas, pineal cell tumors, pineal cell tumors, and primary brain lymphomas; (12) Breast cancer, including but not limited to adenocarcinomas, lobular (small cell) carcinomas, intraductal carcinomas, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, primary cancers, Paget's disease, and leukemia. disease) and inflammatory breast cancer; (13) adrenal cancer, including but not limited to pheochromocytoma and adrenocortical carcinoma; (14) thyroid cancer, including but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer, and pleomorphic thyroid cancer; (15) pancreatic cancer, including but not limited to insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid tumor or islet cell tumor; (16) pituitary cancer, including but not limited to Cushing's disease disease), prolactin-secreting tumors, acromegaly, and diabetes insipidus; (17) cancers of the eye, including but not limited to ocular melanomas such as iris melanoma, choroidal melanoma, and ciliary body melanoma, and retinoblastoma; (18) cancers of the vagina, including but not limited to squamous cell carcinoma, adenocarcinoma, and melanoma; (19) cancers of the vulva, including but not limited to squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease; (20) cancers of the cervix, including but not limited to squamous cell carcinoma and adenocarcinoma; (21) cancers of the uterus, including but not limited to endometrial carcinoma. (22) ovarian cancer, including but not limited to epithelial ovarian carcinoma, borderline tumor, germ cell tumor, and stromal tumor; (23) esophageal cancer, including but not limited to squamous carcinoma, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; (24) gastric cancer, including but not limited to adenocarcinoma, fungus-like growth (polyp), ulcer, superficial spread, diffuse spread, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26) rectal cancer;(27) Liver cancer, including but not limited to hepatocellular carcinoma and hepatoblastoma; (28) Gallbladder cancer, including but not limited to adenocarcinoma; (29) Cholangiocarcinoma, including but not limited to papillary, nodular, and diffuse; (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; (31) Testicular cancer, including but not limited to germinal tumors, seminoma, pleomorphic, classic (typical), Spermatoma, non-seminomatous spermatomas, embryonal carcinomas, teratomas, and choriocarcinomas (ovarian endodermal sinus tumors); (32) prostate cancer, including but not limited to adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; (33) penile cancer; (34) oral cancer, including but not limited to squamous cell carcinoma; (35) basal cell carcinoma; (36) salivary gland cancer, including but not limited to adenocarcinoma, mucoepidermal carcinoma, and adenoid cystic carcinoma; (37) pharyngeal cancer, including but not limited to squamous cell carcinoma and verrucous; (38) Skin cancer, including but not limited to basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma and acral lentigo melanoma; (39) Kidney cancer, including but not limited to renal cell carcinoma, adenocarcinoma, adrenal tumor, fibrosarcoma and transitional cell carcinoma (renal pelvis and / or uterus); (40) Wilms' tumor; (41) Bladder cancer, including but not limited to transitional cell carcinoma, Squamous cell carcinoma, adenocarcinoma, and carcinosarcoma; and other cancers, including but not limited to myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, and papillary adenocarcinoma (see Fishman et al., 1985, Medicine, 2nd ed., JB Lippincott Co.; Philadelphia and Murphy et al., 1997, Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books USA, Inc., United States of America).

[0601] 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, stomach cancer, or uterine cancer.

[0602] In certain embodiments, the proliferative disease is lung cancer. In certain embodiments, the proliferative disease is drug-resistant lung cancer. In certain embodiments, the proliferative disease is multidrug-resistant lung cancer. In certain embodiments, the proliferative disease is recurrent lung cancer. In certain embodiments, the proliferative disease is recurrent drug-resistant lung cancer. In certain embodiments, the proliferative disease is recurrent multidrug-resistant lung cancer. In certain embodiments, the proliferative disease is non-small cell lung cancer. In certain embodiments, 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 recurrent non-small cell lung cancer. In certain embodiments, the proliferative disease is recurrent drug-resistant non-small cell lung cancer. In certain embodiments, the proliferative disease is recurrent multidrug-resistant non-small cell lung cancer.

[0603] Depending on the disorder, disease or condition being treated and the individual's condition, the compounds or pharmaceutical compositions provided herein can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection or implantation), inhalation, nasal, vaginal, rectal, sublingual or topical (e.g., transdermal or topical) routes of administration and can be formulated, alone or together, in suitable dosage units with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles suitable for each route of administration. Also provided are compounds or pharmaceutical compositions provided herein that are administered in the form of storage formulations in which the active ingredient is released over a predetermined period of time.

[0604] In the treatment, prevention or amelioration of one or more symptoms of the disorders, diseases and conditions described herein, appropriate dosage concentrations are generally in the range of about 0.001 to 100 mg per kilogram of body weight per day (mg / kg / day), about 0.01 to about 75 mg / kg / day, about 0.1 to about 50 mg / kg / day, about 0.5 to about 25 mg / kg / day or about 1 to about 20 mg / kg / day, which can be administered in single or multiple doses. Within this range, the dosage can be in the range of about 0.005 to about 0.05, about 0.05 to about 0.5, about 0.5 to about 5.0, about 1 to about 15, about 1 to about 20 or about 1 to about 50 mg / kg / day.

[0605] For oral administration, the pharmaceutical compositions provided herein can contain about 1.0 to about 1,000 mg of active ingredient. In one embodiment, 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 active ingredient are formulated in tablet form for symptomatic adjustment of the dosage of the patient being treated. The pharmaceutical compositions can be administered in a course of treatment of 1 to 4 times per day, including once, twice, three times, and four times per day.

[0606] However, it is understood that for any particular patient, specific dosage levels and dosing frequency may vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, severity of the specific condition, and the subject undergoing therapy.

[0607] In one embodiment, provided herein are methods of inhibiting cell growth, comprising contacting the cell with a compound provided herein, e.g., a compound of Formula I or XXI, or a single enantiomer, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0608] In another embodiment, provided herein are methods of inhibiting cell growth 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, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0609] In certain embodiments, the cell is a cancer cell. In certain embodiments, the cell contains an ERBB variant.

[0610] In one embodiment, provided herein are methods for modulating the activity of a tyrosine kinase, in one embodiment, an ERBB kinase, comprising contacting an ERBB kinase with a compound disclosed herein, e.g., a compound of Formula I or XXI, or a single enantiomer, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0611] In another embodiment, provided herein are methods 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, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0612] In certain embodiments, ERBB is wild-type ERBB. In certain embodiments, ERBB is an ERBB variant. In certain embodiments, ERBB is EGFR. In certain embodiments, ERBB is wild-type EGFR. In certain embodiments, ERBB is an EGFR variant. In certain embodiments, ERBB is HER2. In certain embodiments, ERBB is wild-type HER2. In certain embodiments, ERBB is a HER2 variant. In certain embodiments, ERBB is HER3. In certain embodiments, ERBB is wild-type HER3. In certain embodiments, ERBB is a HER3 variant. In certain embodiments, ERBB is HER4. In certain embodiments, ERBB is wild-type HER4. In certain embodiments, ERBB is a HER4 variant.

[0613] The compounds provided herein, e.g., compounds 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; may also be combined or used in combination with other agents or therapies that are useful for treating, preventing, or ameliorating one or more symptoms of the condition, disorder, or disease for which the compounds provided herein are useful.

[0614] Suitable additional therapeutic agents may also include, but are not limited to, (1) alpha-adrenergic agents; (2) antiarrhythmic agents; (3) antiatherosclerotic agents, such as ACAT inhibitors; (4) antibiotics, such as anthracyclines, bleomycins, mitomycins, actinomycin D, and plicamycin; (5) anticancer agents and cytotoxic agents, such as alkylating agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethyleneimines, and triazenes; (6) anticoagulants, such as acenocoumarol, argatroban, bivalirudin, lepirudin, fondapari, and dapoxetine; (7) antidiabetic agents such as biguanides (e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulin, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiazolidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), and PPAR-γ agonists;(8) Antifungal agents, such as amorolfine, amphotericin B, anidulafungin, bifonazole, butenafine, butoconazole, caspofungin, ciclopirox, clotrimazole, econazole, fenticonazole, filipin, fluconazole, isoconazole, itraconazole, ketoconazole, nazole), micafungin, miconazole, naftifine, natamycin, nystatin, oxyconazole, ravuconazole, posaconazole, rimocidin, sertaconazole, sulconazole, terbinafine, terconazole, tioconazole, and voriconazole;(9) Anti-inflammatory drugs, for example, nonsteroidal anti-inflammatory drugs, such as aceclofenac, acemetacin, amoxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen, celecoxib, choline magnesium salicylate, diclofenac, diflunisal, etodolac, etoricoxib, toricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid acid), mefenamic acid, meloxicam, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam, tiaprofenic acid, acid), and tolmetin; (10) antimetabolites, such as folic acid antagonists, purine analogs, and pyrimidine analogs; (11) antiplatelet agents, such as GPIIb / IIIa blockers (e.g., abciximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine, and CS-747), cilostazol, dipyridamole, and aspirin; (12) antiproliferative agents, such as methotrexate, FK506 (tacrolimus), and mycophenolate mofetil;(13) Anti-TNF antibodies or soluble TNF receptors, such as etanercept, rapamycin, and leflunimide; (14) aP2 inhibitors; (15) β-adrenergic agents, such as carvedilol and metoprolol; (16) bile acid sequestrants, such as questran; (17) calcium channel blockers, such as amlodipine besylate. besylate); (18) chemotherapeutic agents; (19) cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib; (20) cyclosporine; (21) cytotoxic drugs, such as azathioprine and cyclophosphamide; (22) diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, benzflumethiazide, methylchlorothiazide, trichlorothiazide, polythiazide, benzothiazide, ethacrynic acid, acid), ticrynafen, chlorthalidone, furosemide, 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) farnesyl protein transfer inhibitors; (27) fibrates; (28) growth factor inhibitors, such as PDGF activity modulators; (29) growth hormone secretagogues; (30) HMG CoA reductase inhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (also known as itavastatin, nisvastatin or nisbastatin) and ZD-4522 (also known as rosuvastatin, atavastatin or visastatin); neutral endopeptidase (NEP) inhibitors; (31) hormonal agents, such as glucocorticoids (e.g., cortisone), estrogens / antiestrogens, androgens / antandrogens, progestins and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; (32) immunosuppressants;(33) Mineralocorticoid receptor antagonists, such as spironolactone and eplerenone; (34) Microtubule disruptors, such as ecteinascidins; (35) Microtubule stabilizers, such as pacitaxel, docetaxel, and epothilones AF; (36) MTP inhibitors; (37) Nicotinic acid; (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. (40) platelet-activating factor (PAF) antagonists; (41) platinum coordination complexes, such as cisplatin, satraplatin, and carboplatin; (42) potassium channel openers; (43) pentenyl-protein transfer inhibitors; (44) protein tyrosine kinase inhibitors; (45) renin inhibitors; (46) squalene synthase inhibitors; (47) steroids, such as aldosterone, beclometasone, betamethasone, deoxycorticosterone acetate, and steroids. acetate), fludrocortisone, hydrocortisone (cortisol), prednisolone, prednisone, methylprednisolone, dexamethasone, and triamcinolone; (48) TNF-α inhibitors, such as tenidap; (49) thrombin inhibitors, such as hirudin; (50) thrombolytics, such as anistreplase; ), reteplase, tenecteplase, tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC); (51) thromboxane receptor antagonists, such as ifetroban; (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 compounds.

[0615] In certain embodiments, other therapies that may be used in combination with the compounds provided herein include, but are not limited to, surgery, endocrine therapy, biological response modifiers (e.g., interferons, interleukins, and tumor necrosis factor (TNF)), hyperthermia and hypothermia therapy, and agents to alleviate any side effects (e.g., antiemetics).

[0616] In certain embodiments, additional therapeutic agents that can 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), HDACs (high-dose cytarabine), and methotrexate), purine antagonists and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, cytarbine, and gemcitabine), spindle inhibitors (vinblastine, vincristine, and vinorelbine), podophyllotoxins (etoposide, irinotecan, and topotecan), antibiotics (daunorubicin, daunorubicin), and cytosine.

[0013] Therapeutic approaches include the use of steroids (e.g., steroids), steroids (e.g., steroids), and steroids. These include daunorubicin, doxorubicin, bleomycin, and mitomycin), nitrosoureas (carmustine and lomustine), enzymes (asparaginase), and hormones (tamoxifen, leuprolide, flutamide, and megestrol), imatinib, adriamicin, dexamethasone, and cyclophosphamide. For a more comprehensive discussion of the latest cancer therapies, see http: / / www.nci.nih.gov / , a list of FDA-approved oncology drugs at http: / / www.fda.gov / cder / cancer / druglistframe.htm, and The Merck Manual, Seventeenth Edition, 1999, the entire contents of which are incorporated herein by reference.

[0617] In another embodiment, the methods provided herein comprise administering a compound provided herein, such as a compound of Formula I or XXI, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereoisomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and administering one or more chemotherapeutic agents and / or therapies selected from the group consisting of alkylating agents (e.g., cisplatin, carboplatin); antimetabolites (e.g., methotrexate and 5-FU); antitumor antibiotics (e.g., adriamycin and bleomycin); antitumor vegetable alkaloids (e.g., paclitaxel and etoposide); antitumor hormones (e.g., dexamethasone and tamoxifen); antitumor immunotherapies (e.g., interferon α, β, and γ); radiation therapy; and surgery. In certain embodiments, one or more chemotherapeutic agents and / or therapies are administered to a subject before, during, or after administration of a compound provided herein.

[0618] Such other agents or drugs can be administered simultaneously or sequentially with the compounds provided herein (e.g., compounds of Formula I or XXI), or their enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, or isotopic variants thereof, or their pharmaceutically acceptable salts, solvates, hydrates, or prodrugs, by their usual routes and amounts. When the compounds provided herein are used concurrently with one or more other drugs, pharmaceutical compositions containing such other drugs in addition to the compounds provided herein may be used (but not necessarily). Thus, the pharmaceutical compositions provided herein include compositions containing one or more other active ingredients or therapeutic agents in addition to the compounds provided herein.

[0619] The weight ratio of the compound provided herein to the second active ingredient can vary and will depend on the effective dose of each ingredient. Generally, an effective dose of each ingredient will be used. Thus, for example, when a compound provided herein is combined with an NSAID, the weight ratio of the compound to the NSAID may range from about 1,000:1 to about 1:1,000, or from about 200:1 to about 1:200. Combinations of the compounds provided herein with other active ingredients will generally also be within the aforementioned ranges, but in each case, an effective dose of each active ingredient should be used.

[0620] The compounds provided herein can also be provided in the form of articles of manufacture using packaging materials well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,323,907; 5,052,558; and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for the selected formulation and intended mode of administration and treatment.

[0621] Also provided herein are kits that, when used by a medical practitioner, can simplify the administration of an appropriate amount of an active ingredient to a subject. In certain embodiments, the kits provided herein include containers and dosage forms of a compound provided herein, such as a compound of Formula I or XXI, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereoisomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0622] In certain embodiments, the kit includes a container comprising 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 diastereoisomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and one or more additional therapeutic agents described herein.

[0623] The kits provided herein may further include a device for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, needle-free syringe drip bags, patches, and inhalers. The kits provided herein may also include a condom for administering the active ingredient.

[0624] The kits provided herein may further include a pharmaceutically acceptable vehicle that can be used to administer one or more active ingredients. For example, if the active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit may include a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a sterile, particulate-free solution suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles, including, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0625] The present invention will be further understood from the following non-limiting examples.

[0626] Examples

[0627] As used herein, the notation and conventions used in the methods, schemes, and examples are consistent with those used in contemporary scientific literature (e.g., Journal of the American Chemical Society or Journal of Biological Chemistry), regardless of whether certain abbreviations are specifically defined or not. Specifically, but not limiting, the following abbreviations may be used in the examples and throughout this specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); L (liter); mM (millimole); μM (micromolar); Hz (hertz); MHz (megahertz); mmol (millimole); 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); CDCl3 (deuterated chloroform); DCM (dichloromethane); DMA (N,N-dimethylacetamide); DME (dimethoxyethane); DMF (N,N-dimethylformamide); DMSO (dimethylformamide); DMSO-d6 (deuterated dimethylformamide); EtOAc (ethyl acetate); Et2O (diethyl ether); EtOH (ethanol); MeOH (methanol); PE (petroleum ether); THF (tetrahydrofuran); DIPEA (N,N-diisopropylethylamine); TEA (triethylamine); TFA (trifluoroacetic acid); BOP (benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate); HATU (2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3- tetramethylurea); TBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate); DIPC (1,3-diisopropylcarbodiimide); Ms2O (methanesulfonic anhydride); Me (methyl); Et (ethyl); iPr (isopropyl); tBu (tert-butyl); Boc (tert-butoxycarbonyl); Bn (benzyl); Ph (phenyl); Ms (methanesulfonic acid); and AcO (acetic acid).

[0628] Using KINETEX TM Reversed phase column (5μM XB-C18- HPLC-MS analysis was performed using a Waters HPLC 2790 coupled to a Waters micromass ZQ 4000 (model MAA050) as a mass detector and a Waters 2487 UV as a UV-visible detector. The mobile phases were eluent A (water, 0.05% TFA) and eluent B (CH3OH, 0.05% TFA). HPLC was performed at 1 mL / min using a linear gradient from 10% B to 90% B for 8 minutes, followed by an isocratic gradient at 90% B for 2 minutes, for a total run time of 10 minutes.

[0629] Exemplary implementations are as follows:

[0630] 1. A compound of formula I,

[0631]

[0632] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof;

[0633] R 1 -C(O)CR 1e =CR 1f CR 1g 、 -N 1a C(O)CR 1e =CR 1f CR 1g 、 -S(O)CR 1e =CR 1f CR 1g 、 -S(O2)CR 1e =CR 1f CR 1g 、 -NR 1a S(O)CR 1e =CR 1f CR 1g 、 -NR 1a S(O2)CR 1e =CR 1f CR 1g or

[0634] R 2 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0635] L 1 For bonds, -O-, -S-, -N(R 1A )-or-C(R 1A R 1B )-, where each R 1A and R 1B are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0636] L 2 C 3-10 Cycloalkylene, C 6-14 Arylene, C 7-15 an aralkylene group, a heteroarylene group, or a heterocyclylene group;

[0637] T is a bond, -O-, -S-, -N=, -N(R 4 )-、-C(R 4 )=or-C(R 4 )2-;

[0638] U is a bond, -O-, -S-, -N=, -N(R 5 )-、-C(R 5 )=or-C(R 5 )2-;

[0639] V is a bond, -O-, -S-, -N=, -N(R 6 )-、-C(R 6 )=or-C(R 6 )2-;

[0640] W is a bond, -O-, -S-, -N=, -N(R 7 )-、-C(R 7 )=or-C(R 7 )2-;

[0641] X and Y are each independently C or N;

[0642] Z is NR 2A or CR 2A R 2B , where each R 2A and R 2B are independently hydrogen, halogen, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0643] Each R 4 、R 5 、R 6 and R 7 are independently (a) hydrogen, cyano, halo or nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl; or (c)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;

[0644] Each R 1a 、R 1b 、R 1c and R 1d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic; or R 1a and R 1c Together with the C and N atoms to which they are attached, they form a heterocyclic group; or R 1b and R 1c Together with the nitrogen atom to which it is attached, it forms a heterocyclic group; and

[0645] Each R 1e 、R 1f and R 1g are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0646] The restriction is that no more than one of T, U, V, and W is a bond; and

[0647] The constraint condition is that when L 1 When R is a key, 4 、R 5 、R 6 and R 7 At least one of them is bromine, -OR 7a or -NR 1b R 1c , where R 7a C 4-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0648] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, and in one embodiment one, two, three, or four, substituents Q, wherein each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each further optionally substituted by one or more, in one embodiment by one, two, three or four substituents Q a substituted; and (c)-C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-C(NR a )NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(=NR a )NR b R c 、-OP(O)(OR a )2. -OS(O)R a 、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(=NR d)NR b R c 、-NR a S(O)R d 、-NR a S(O)2R d 、-NR a S(O)NR b R c 、-NR a S(O)2NR b R c 、-SR a 、-S(O)R a 、-S(O)2R a 、-S(O)NR b R c and -S(O)2NR b R c , where each R a 、R b 、R c and R d are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each optionally substituted by one or more, in one embodiment by one, two, three or four substituents Q a or (iii) R b and R c Together with the N atom to which it is attached, it forms a heterocyclic group, which is optionally substituted by one or more, in one embodiment by one, two, three or four substituents Q a replace;

[0649] Each Q a are independently selected from the group consisting of: (a) oxo, cyano, halo, and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; and (c)-C(O)R f 、-C(O)OR f 、-C(O)NR g R h 、-C(NR f )NR g R h 、-ORf 、-OC(O)R f 、-OC(O)OR f 、-OC(O)NR g R h 、-OC(=NR f )NR g R h 、-OP(O)(OR f )2. -OS(O)R f 、-OS(O)2R f 、-OS(O)NR g R h 、-OS(O)2NR g R h 、-NR g R h 、-NR f C(O)R k 、-NR f C(O)OR k 、-NR f C(O)NR g R h 、-NR f C(=NR k )NR g R h 、-NR f S(O)R k 、-NR f S(O)2R k 、-NR f S(O)NR g R h 、-NR f S(O)2NR g R h 、-SR f 、-S(O)R f 、-S(O)2R f 、-S(O)NR g R h and -S(O)2NR g R h ; where each R f 、R g 、R h and R k are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) Rg and R h Together with the nitrogen atom to which it is attached, it forms a heterocyclic group.

[0650] 2. The compound according to embodiment 1, which has the structure of formula I:

[0651]

[0652] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof;

[0653] R 1 is (a) hydrogen, cyano, halide or nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl; or (c)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;

[0654] R 2 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0655] L 2 C 3-10 Cycloalkylene, C 6-14 Arylene, C 7-15 an aralkylene group, a heteroarylene group, or a heterocyclylene group;

[0656] T is a bond, -O-, -S-, -N=, -N(R 4 )-、-C(R 4 )=or-C(R 4 )2-;

[0657] U is a bond, -O-, -S-, -N=, -N(R 5 )-、-C(R 5 )=or-C(R 5 )2-;

[0658] V is a bond, -O-, -S-, -N=, -N(R 6 )-、-C(R 6 )=or-C(R 6 )2-;

[0659] W is a bond, -O-, -S-, -N=, -N(R 7 )-、-C(R 7 )=or-C(R 7 )2-;

[0660] X and Y are each independently C or N;

[0661] Z is NR 2A or CR 2A R 2B , where each R 2A and R 2B are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0662] R 4 、R 5 、R 6 、R 7 and L 1 for:

[0663] (i) Each R 4 、R 5 and R 6 are independently (a) hydrogen, cyano, halo or nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl; or (c)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;

[0664] Each R 7 are independently bromine, -OR 7a or -NR 7b R 7c ;

[0665] R 7a C 4-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0666] R 7b and R 7c are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic; or R 7b and R 7c Together with the nitrogen atom to which they are attached, they form a heterocyclic group; and

[0667] L 1 is a key; or

[0668] (ii) Each R 4 、R 5 、R 6 and R 7 are independently (a) hydrogen, cyano, halo or nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl; or (c)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ; The constraint condition is R 4 、R 5 、R 6 and R 7 At least one of is not hydrogen; and

[0669] L 1 -O-, -S-, -N(R 1A )-or-C(R 1A R 1B )-, where each R 1A and R 1B are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; and

[0670] Each R 1a 、R 1b 、R 1c and R 1d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic; or R 1a and R 1c Together with the C and N atoms to which they are attached, they form a heterocyclic group; or R 1b and R 1c Together with the nitrogen atom to which it is attached, it forms a heterocyclic group;

[0671] The restriction is that no more than one of T, U, V, and W can be a bond;

[0672] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, and in one embodiment one, two, three, or four, substituents Q, wherein each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each further optionally substituted by one or more, in one embodiment by one, two, three or four substituents Q a substituted; and (c)-C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-C(NR a )NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(=NR a )NR b R c 、-OP(O)(OR a )2. -OS(O)R a 、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(=NR d )NR b R c 、-NR a S(O)R d 、-NR a S(O)2R d 、-NR a S(O)NR b R c 、-NR a S(O)2NR b R c 、-SR a 、-S(O)R a 、-S(O)2R a ,-S(O)NR bR c and -S(O)2NR b R c , where each R a 、R b 、R c and R d are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each optionally substituted by one or more, in one embodiment by one, two, three or four substituents Q a or (iii) R b and R c Together with the N atom to which it is attached, it forms a heterocyclic group, which is optionally substituted by one or more, in one embodiment by one, two, three or four substituents Q a replace;

[0673] Each Q a are independently selected from the group consisting of: (a) oxo, cyano, halo, and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; and (c)-C(O)R f 、-C(O)OR f 、-C(O)NR g R h 、-C(NR f )NR g R h 、-OR f 、-OC(O)R f 、-OC(O)OR f 、-OC(O)NR g R h 、-OC(=NR f )NR g R h 、-OP(O)(OR f )2. -OS(O)R f 、-OS(O)2R f 、-OS(O)NR g R h 、-OS(O)2NR g R h 、-NRg R h 、-NR f C(O)R k 、-NR f C(O)OR k 、-NR f C(O)NR g R h 、-NR f C(=NR k )NR g R h 、-NR f S(O)R k 、-NR f S(O)2R k 、-NR f S(O)NR g R h 、-NR f S(O)2NR g R h 、-SR f 、-S(O)R f 、-S(O)2R f 、-S(O)NR g R h and -S(O)2NR g R h ; where each R f 、R g 、R h and R k are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) R g and R h Together with the nitrogen atom to which it is attached, it forms a heterocyclic group.

[0674] 3. The compound according to embodiment 1 or 2, wherein T is -N=.

[0675] 4. The compound according to embodiment 1 or 2, wherein T is -C(R 4 )=.

[0676] 5. The compound according to any one of embodiments 1 to 4, wherein U is -N=.

[0677] 6. The compound according to any one of embodiments 1 to 4, wherein U is -C(R5 )=.

[0678] 7. The compound according to any one of embodiments 1 to 6, wherein V is -N=.

[0679] 8. The compound according to any one of embodiments 1 to 6, wherein V is -C(R 6 )=.

[0680] 9. The compound according to any one of embodiments 1 to 8, wherein W is -N=.

[0681] 10. The compound according to any one of embodiments 1 to 8, wherein W is -C(R 7 )=.

[0682] 11. The compound according to any one of embodiments 1 to 10, wherein X is N.

[0683] 12. The compound according to any one of embodiments 1 to 10, wherein X is C.

[0684] 13. The compound according to any one of embodiments 1 to 12, wherein Y is N.

[0685] 14. The compound according to any one of embodiments 1 to 12, wherein Y is C.

[0686] 15. The compound according to embodiment 1 or 2, which has the structure of formula III:

[0687]

[0688] or a single enantiomer, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0689] 16. The compound according to embodiment 15, which has the structure of Formula IV:

[0690]

[0691] or a single enantiomer, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0692] 17. The compound according to embodiment 1 or 2, which has the structure of Formula V:

[0693]

[0694] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the symbol It indicates that the 6-membered ring contains one N atom in the ring.

[0695] 18. The compound according to embodiment 17, which has the structure of Formula VI:

[0696]

[0697] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the symbol It indicates that the 6-membered ring contains one N atom in the ring.

[0698] 19. The compound according to any one of embodiments 1 to 8 and 10 to 18, wherein R 7 For-OR 7a , where R 7a C 4-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q.

[0699] 20. The compound according to embodiment 19, which has the structure of Formula VIII:

[0700]

[0701] or a single enantiomer, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0702] 21. The compound according to embodiment 20, which has the structure of Formula XIa:

[0703]

[0704] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 2n is C optionally substituted with one or more substituents Q 1-6 Alkyl or -OR 1a .

[0705] 22. The compound according to embodiment 21, wherein R 2n is methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -OH or -OCH3.

[0706] 23. The compound according to any one of embodiments 19 to 22, wherein R 7a C 3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q.

[0707] 24. The compound according to embodiment 23, wherein R 7a is a heterocyclic group, which is optionally substituted with one or more substituents Q.

[0708] 25. The compound according to embodiment 23, wherein R 7a for

[0709]

[0710]

[0711] in:

[0712] p and q are each independently an integer of 0, 1 or 3, provided that the sum of p and q is not less than 1; and each r is independently an integer of 0, 1, 2, 3, 4, 5 or 6.

[0713] 26. The compound according to embodiment 23, wherein R 7a for

[0714]

[0715] 27. The compound according to any one of embodiments 1 to 8 and 10 to 18, wherein R 7 -NR 7b R 7c ,in

[0716] R 7b (i) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (ii) -C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;and

[0717] R 7c is (i) hydrogen; or (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -C(O)R1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;or

[0718] R 7b and R 7c Together with the N atom to which it is attached, it forms a heterocyclic group, which is optionally substituted with one or more substituents Q.

[0719] 28. The compound according to embodiment 27, which has the structure of Formula XII:

[0720]

[0721] or a single enantiomer, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0722] 29. The compound according to embodiment 27 or 28, wherein R 7b C 3-10 Cycloalkyl, C 6-14 Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q.

[0723] 30. The compound according to embodiment 29, wherein R 7b is a heterocyclic group, which is optionally substituted with one or more substituents Q.

[0724] 31. The compound according to embodiment 29, wherein R 7b for

[0725]

[0726]

[0727] in:

[0728] p and q are each independently an integer of 0, 1 or 3, provided that the sum of p and q is not less than 1; and each r is independently an integer of 0, 1, 2, 3, 4, 5 or 6.

[0729] 32. The compound according to any one of embodiments 27 to 31, wherein R 7c For hydrogen.

[0730] 33. A compound according to any one of embodiments 1 to 8 and 10 to 18, wherein R 7 For bromine.

[0731] 34. The compound according to embodiment 1, which has the structure of Formula XVIII:

[0732]

[0733] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 6a (i) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (ii) -C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c .

[0734] 35. The compound according to embodiment 34, which has the structure of Formula XIX:

[0735]

[0736] or a single enantiomer, racemic mixture, mixture of diastereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0737] 36. The compound according to embodiment 34, which has the structure of formula XXa:

[0738]

[0739] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein R 2n is C optionally substituted with one or more substituents Q 1-6 Alkyl or -OR 1a .

[0740] 37. The compound according to embodiment 36, wherein R 2n is methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -OH or -OCH3.

[0741] 38. A compound according to any one of embodiments 34 to 37, wherein R 7 is chlorine, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl or -OR 1a .

[0742] 39. The compound according to embodiment 38, wherein R 7 For chlorine.

[0743] 40. The compound according to any one of embodiments 34 to 39, wherein R 6a for:

[0744]

[0745]

[0746] in:

[0747] p and q are each independently an integer of 0, 1 or 3, provided that the sum of p and q is not less than 1; and each r is independently an integer of 0, 1, 2, 3, 4, 5 or 6.

[0748] 41. A compound according to any one of embodiments 34 to 39, wherein R 6a for:

[0749]

[0750] 42. A compound according to any one of embodiments 1 to 20, 23 to 34 and 38 to 41, wherein L 1 For bonds, -O-, -N(R 1A )-or-C(R 1A R 1B )-.

[0751] 43. The compound according to embodiment 42, wherein L 1 is the key.

[0752] 44. The compound according to embodiment 42, wherein L 1 It is -O-.

[0753] 45. The compound according to embodiment 42, wherein L 1 It is -NH- or -CH2-.

[0754] 46. ​​A compound according to any one of embodiments 1 to 20, 23 to 34 and 38 to 45, wherein L 2 C 3-10 Cycloalkylene, heteroarylene or heterocyclylene, each of which is optionally substituted with one or more substituents Q.

[0755] 47. The compound according to embodiment 46, wherein L 2 is a heteroarylene group or a heterocyclylene group, each of which is optionally substituted with one or more substituents Q.

[0756] 48. The compound according to embodiment 46, wherein L 2 for:

[0757]

[0758] in:

[0759] r is an integer of 0, 1, 2, 3, 4, 5 or 6;

[0760] s is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[0761] Each R L are independently (i) hydrogen; or (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;or

[0762] When there are two or more R L When connected to the same ring, two R L Connected together to form (i) bonds, -O-, -NR N -or-S-; or (ii)C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene or C 2-6 heteroalkenylene, each of which is optionally substituted with one or more substituents Q.

[0763] 49. The compound according to embodiment 46, wherein L 2 for:

[0764]

[0765] in:

[0766] r is an integer of 0, 1, 2, 3, 4, 5 or 6;

[0767] s is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[0768] Each R L are independently (i) hydrogen; or (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1bR 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;or

[0769] When there are two or more R L When connected to the same ring, two R L Connected together to form (i) bonds, -O-, -NR N -or-S-; or (ii)C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene or C 2-6 heteroalkenylene, each of which is optionally substituted with one or more substituents Q.

[0770] 50. The compound according to embodiment 46, wherein L 2 for:

[0771]

[0772] in:

[0773] r is an integer of 0, 1, 2, 3, 4, 5 or 6;

[0774] t is an integer of 0, 1, 2, 3, 4, 5 or 6; and

[0775] Each R L are independently (i) hydrogen; or (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;or

[0776] When there are two or more R L When connected to the same ring, two R L Connected together to form (i) bonds, -O-, -NR N -or-S-; or (ii)C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene or C 2-6 heteroalkenylene, each of which is optionally substituted with one or more substituents Q.

[0777] 51. The compound according to embodiment 46, wherein L 2 for:

[0778]

[0779] in:

[0780] r is an integer of 0, 1, 2, 3, 4, 5 or 6;

[0781] t is an integer of 0, 1, 2, 3, 4, 5 or 6; and

[0782] Each R L are independently (i) hydrogen; or (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;or

[0783] When there are two or more R L When connected to the same ring, two R L Connected together to form (i) bonds, -O-, -NR N -or-S-; or (ii)C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene or C 2-6 heteroalkenylene, each of which is optionally substituted with one or more substituents Q.

[0784] 52. The compound according to any one of embodiments 48 to 51, wherein r is 0.

[0785] 53. The compound according to embodiment 46, wherein L 1 -L 2 for:

[0786]

[0787]

[0788]

[0789] The symbols

[0066] It indicates that the 6-membered ring contains one to three N atoms in the ring, and each sulfur is optionally oxidized to a sulfoxide or sulfone.

[0790] 54. The compound according to embodiment 46, wherein L 1 -L 2 for:

[0791]

[0792]

[0793] 55. The compound according to any one of embodiments 1 to 54, wherein R 1 -C(O)CR 1e =CR 1f CR 1g or

[0794] 56. The compound according to embodiment 55, wherein R 1 Selected from:

[0795]

[0796] 57. The compound according to any one of embodiments 1 to 54, wherein R 1 -N 1a C(O)CR 1e =CR 1f CR 1g or

[0797] 58. The compound according to embodiment 57, wherein R 1 Selected from:

[0798]

[0799] 59. The compound according to any one of embodiments 1 to 20, 23 to 35 and 38 to 58, wherein R 2 C 6-14 Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q.

[0800] 60. The compound according to embodiment 59, wherein R 2 is a 6- to 10-membered monocyclic or bicyclic aromatic group, which is optionally substituted with one or more substituents Q.

[0801] 61. The compound according to embodiment 59, wherein R 2 is a 5- to 10-membered monocyclic or bicyclic heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S, which is optionally substituted with one or more substituents Q.

[0802] 62. The compound according to embodiment 59, wherein R 2 is a 5- to 10-membered monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected from N, O and S, which is optionally substituted with one or more substituents Q.

[0803] 63. The compound according to embodiment 59, wherein R 2is phenyl, pyridyl, pyridazinyl, benzo[c][1,2,5]oxadiazolyl or benzo[c][1,2,5]thiadiazolyl, each of which is optionally substituted with one or more substituents Q.

[0804] 64. A compound according to any one of embodiments 1, 2, 4 to 20, 23 to 35 and 38 to 63, wherein R 4 For hydrogen.

[0805] 65. A compound according to any one of embodiments 1 to 4, 6 to 20, 23 to 35 and 38 to 64, wherein R 5 For hydrogen.

[0806] 66. A compound according to any one of embodiments 1 to 4, 6 to 20, 23 to 35 and 38 to 64, wherein R 5 For-OR 5a , where R 5a C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q.

[0807] 67. A compound according to any one of embodiments 1 to 6, 8 to 20, 23 to 35 and 38 to 66, wherein R 6 For hydrogen.

[0808] 68. A compound according to any one of embodiments 1 to 6, 8 to 20, 23 to 35 and 38 to 66, wherein R 6 For-OR 6a , where R 6a C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q.

[0809] 69. The compound according to any one of embodiments 1 to 20, 23 to 34 and 38 to 68, wherein Z is NH.

[0810] 70. A compound of formula XXI,

[0811]

[0812] or a single enantiomer, racemic mixture, mixture of diastereoisomers or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof;

[0813] R 1 -C(O)CR 1e =CR 1f CR 1g 、 -N 1a C(O)CR 1e =CR 1f CR 1g 、 -S(O)CR 1e =CR 1f CR 1g 、 -S(O2)CR 1e =CR 1f CR 1g 、 -NR 1a S(O)CR 1e =CR 1f CR 1g 、 -NR 1a S(O2)CR 1e =CR 1f CR 1g or

[0814] R 2 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0815] L 1 For bonds, -O-, -S-, -N(R 1A )-or-C(R 1A R 1B )-, where each R 1A and R 1B are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0816] L 2 C3-10 Cycloalkylene, C 6-14 Arylene, C 7-15 an aralkylene group, a heteroarylene group, or a heterocyclylene group;

[0817] Z is NR 2A or CR 2A R 2B , where each R 2A and R 2B are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0818] R 4 and R 6 are each independently (a) hydrogen, cyano, halo or nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl; or (c)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;

[0819] R 5a C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0820] Each R 1a 、R 1b 、R 1c and R 1d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic; or R 1a and R 1c Together with the C and N atoms to which they are attached, they form a heterocyclic group; or R 1b and R 1c Together with the nitrogen atom to which they are attached, they form a heterocyclic group; and

[0821] Each R 1e 、R 1f and R 1g are independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group;

[0822] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, and in one embodiment one, two, three, or four, substituents Q, wherein each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each further optionally substituted by one or more, in one embodiment by one, two, three or four substituents Q a substituted; and (c)-C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-C(NR a )NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(=NR a )NR b R c 、-OP(O)(OR a )2. -OS(O)R a 、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(=NR d )NR b R c 、-NR aS(O)R d 、-NR a S(O)2R d 、-NR a S(O)NR b R c 、-NR a S(O)2NR b R c 、-SR a 、-S(O)R a 、-S(O)2R a 、-S(O)NR b R c and -S(O)2NR b R c , where each R a 、R b 、R c and R d are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each optionally substituted by one or more, in one embodiment by one, two, three or four substituents Q a or (iii) R b and R c Together with the N atom to which it is attached, it forms a heterocyclic group, which is optionally substituted by one or more, in one embodiment by one, two, three or four substituents Q a replace;

[0823] Each Q a are independently selected from the group consisting of: (a) oxo, cyano, halo, and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; and (c)-C(O)R f 、-C(O)OR f 、-C(O)NR g R h 、-C(NR f )NR g R h 、-OR f 、-OC(O)R f 、-OC(O)OR f、-OC(O)NR g R h 、-OC(=NR f )NR g R h 、-OP(O)(OR f )2. -OS(O)R f 、-OS(O)2R f 、-OS(O)NR g R h 、-OS(O)2NR g R h 、-NR g R h 、-NR f C(O)R k 、-NR f C(O)OR k 、-NR f C(O)NR g R h 、-NR f C(=NR k )NR g R h 、-NR f S(O)R k 、-NR f S(O)2R k 、-NR f S(O)NR g R h 、-NR f S(O)2NR g R h 、-SR f 、-S(O)R f 、-S(O)2R f 、-S(O)NR g R h and -S(O)2NR g R h ; where each R f 、R g 、R h and R k are independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) R g and R h Together with the nitrogen atom to which it is attached, it forms a heterocyclic group.

[0824] 71. The compound according to embodiment 70, wherein L 1 For bonds, -O-, -N(R 1A )-or-C(R 1A R 1B )-.

[0825] 72. The compound according to embodiment 71, wherein L 1 is the key.

[0826] 73. The compound according to embodiment 71, wherein L 1 It is -O-.

[0827] 74. The compound according to embodiment 71, wherein L 1 It is -NH- or -CH2-.

[0828] 75. The compound according to any one of embodiments 70 to 74, wherein L 2 C 3-10 Cycloalkylene, heteroarylene or heterocyclylene, each of which is optionally substituted with one or more substituents Q.

[0829] 76. The compound according to embodiment 75, wherein L 2 is a heteroarylene group or a heterocyclylene group, each of which is optionally substituted with one or more substituents Q.

[0830] 77. The compound according to embodiment 75, wherein L 2 for:

[0831]

[0832] in:

[0833] r is an integer of 0, 1, 2, 3, 4, 5 or 6;

[0834] s is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[0835] Each R L are independently (i) hydrogen; or (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;or

[0836] When there are two or more R L When connected to the same ring, two R L Connected together to form (i) bonds, -O-, -NR N -or-S-; or (ii)C 1-6 Alkylene, C 1-6 Heteroalkylene, C2-6 Alkenylene or C 2-6 heteroalkenylene, each of which is optionally substituted with one or more substituents Q.

[0837] 78. The compound according to embodiment 75, wherein L 2 for:

[0838]

[0839] in:

[0840] r is an integer of 0, 1, 2, 3, 4, 5 or 6;

[0841] s is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[0842] Each R L are independently (i) hydrogen; or (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;or

[0843] When there are two or more R L When connected to the same ring, two R L Connected together to form (i) bonds, -O-, -NR N -or-S-; or (ii)C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene or C 2-6 heteroalkenylene, each of which is optionally substituted with one or more substituents Q.

[0844] 79. The compound according to embodiment 75, wherein L 2 for:

[0845]

[0846] in:

[0847] r is an integer of 0, 1, 2, 3, 4, 5 or 6;

[0848] t is an integer of 0, 1, 2, 3, 4, 5 or 6; and

[0849] Each R L are independently (i) hydrogen; or (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c or -S(O)2NR 1b R 1c ;or

[0850] When there are two or more R LWhen connected to the same ring, two R L Connected together to form (i) bonds, -O-, -NR N -or-S-; or (ii)C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene or C 2-6 heteroalkenylene, each of which is optionally substituted with one or more substituents Q.

[0851] 80. The compound according to embodiment 75, wherein L 2 for:

[0852]

[0853] in:

[0854] r is an integer of 0, 1, 2, 3, 4, 5 or 6;

[0855] t is an integer of 0, 1, 2, 3, 4, 5 or 6; and [085...

Claims

1. A compound selected from: or a pharmaceutically acceptable salt thereof.

2. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 3. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 4. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 5. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 6. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, and a medically acceptable excipient.

8. The pharmaceutical composition according to claim 7, wherein the composition is formulated as a single dosage form.

9. The pharmaceutical composition of claim 7, wherein the composition is formulated as an oral, parenteral, nasal, respiratory, pulmonary or intravenous dosage form.

10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is an oral dosage form. The pharmaceutical composition according to claim 10 , wherein the oral dosage form is a tablet or a capsule.

12. The pharmaceutical composition of claim 7, further comprising a second therapeutic agent.

13. Use of a compound according to any one of claims 1 to 6 in the preparation of a medicament for treating, preventing or ameliorating one or more symptoms of a cancer containing an ERBB variant, wherein the cancer is bladder cancer, brain tumor, breast cancer, cancer of the oral cavity and pharynx, colorectal cancer, lung cancer, or pancreatic cancer, prostate cancer, stomach cancer or uterine cancer. The use according to claim 13 , wherein the ERBB variant is an EGFR variant.

15. The use according to claim 14, wherein the EGFR variant contains one or more deletions, insertions or substitutions at the following amino acid positions: 689, 700, 709, 715, 719, 720, 746-759, 761-765, 767-775, 783, 784, 790, 796, 826, 839, 846, 858, 861 and 863.

16. The use according to claim 14, wherein the EGFR variant contains one or more deletions, insertions or substitutions at the following amino acid positions: 719, 746-751, 790 and 858.

17. The use according to claim 14, 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), ΔD761-E762 (ins EAFQ), ΔS768-D770 (dup SVD), ΔV769-D770 (insASV), 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.

18. The use according to claim 14, wherein the EGFR variant contains T790M, L858R or a combination thereof.

19. The use according to claim 13, wherein the ERBB variant is a HER2 variant.

20. The use according to claim 19, wherein the HER2 is overexpressed in cancer.

21. The use of claim 13, wherein the cancer is resistant to EGFR inhibitors.

22. The use of claim 21, wherein the cancer is resistant to afatinib, canertinib, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, neratinib, pelitinib, varlitinib, or a combination thereof.

23. The use according to claim 13, wherein the cancer is lung cancer.

24. The use according to claim 13, wherein the cancer is non-small cell lung cancer.

25. The use according to claim 13, wherein the cancer is relapsed or refractory.

26. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for inhibiting the growth of cancer cells containing ERBB variants.

27. The use according to claim 26, wherein the ERBB variant is an EGFR variant.

28. The use according to claim 27, wherein the EGFR variant contains one or more deletions, insertions or substitutions at the following amino acid positions: 689, 700, 709, 715, 719, 720, 746-759, 761-765, 767-775, 783, 784, 790, 796, 826, 839, 846, 858, 861 and 863.

29. The use according to claim 27, wherein the EGFR variant contains one or more deletions, insertions or substitutions at the following amino acid positions: 719, 746-751, 790 and 858.

30. The use according to claim 27, 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), ΔD761-E762 (ins EAFQ), ΔS768-D770 (dup SVD), ΔV769-D770 (insASV), 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.

31. The use according to claim 27, wherein the EGFR variant contains T790M, L858R or a combination thereof.

32. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for modulating the activity of an ERBB variant.

33. The use according to claim 32, wherein the ERBB variant is an EGFR variant.

34. The use according to claim 33, wherein the EGFR variant contains one or more deletions, insertions or substitutions at the following amino acid positions: 689, 700, 709, 715, 719, 720, 746-759, 761-765, 767-775, 783, 784, 790, 796, 826, 839, 846, 858, 861 and 863.

35. The use according to claim 33, wherein the EGFR variant contains one or more deletions, insertions or substitutions at the following amino acid positions: 719, 746-751, 790 and 858.

36. The use according to claim 33, 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), ΔD761-E762 (ins EAFQ), ΔS768-D770 (dup SVD), ΔV769-D770 (insASV), 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.

37. The use according to claim 33, wherein the EGFR variant contains T790M, L858R or a combination thereof.

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